Patients with atrial fibrillation and diabetes mellitus affected by nonalcoholic fatty liver disease have a greater risk of mortality and worse clinical outcomes.

Background: Nonalcoholic fatty liver disease (NAFLD) is associated with several adverse clinical outcomes. In this study, we assessed the association between NAFLD and several clinical outcome measures in patients with diabetes mellitus (DM) and atrial fibrillation (AF). Methods: We queried the National Inpatient Sample (NIS) between 2016 and 2019 for adult patients who were hospitalized with DM and AF. NAFLD was the independent variable. The primary outcome was inpatient mortality. The secondary outcomes were cardiogenic shock, cardiac arrest, gastrointestinal bleeding (GIB), invasive mechanical ventilation, length of stay, and total hospital charges. A multivariable logistic regression model was used to estimate odds ratios with a 95% confidence interval (CI) and a P value of less than 0.05 was considered significant. Results: There were 6 723 293 hospitalizations with AF and DM and 253 639 (3.7%) had NAFLD. NAFLD and non-NAFLD cohorts had a mean age of 70.4 vs. 73.8 years, respectively. Overall, 55.6% were male and 73.8% were White. NAFLD was found to be significantly associated with in-hospital mortality [adjusted odds ratio (AOR), 4.2; 95% CI, 4.08-4.32], cardiogenic shock (AOR, 4.78; 95% CI, 4.59-4.98), cardiac arrest (AOR, 3.43; 95% CI, 3.27-3.59), GIB (AOR, 1.92; 95% CI, 1.86-1.98), length of stay, and total hospital charges. Conclusion: In patients with AF and DM patients, the presence of NAFLD was associated with significantly worse clinical outcomes and higher resource utilization. Adverse cardiovascular events were common as well as GIB. Screening and prevention strategies modifying the risk and disease severity of NAFLD are needed.

Targeting DBS to the centrolateral thalamic nucleus improves movement in a lesion-based model of acquired cerebellar dystonia in mice.

Dystonia is the third most common movement disorder and an incapacitating co-morbidity in a variety of neurologic conditions. Dystonia can be caused by genetic, degenerative, idiopathic, and acquired etiologies, which are hypothesized to converge on a "dystonia network" consisting of the basal ganglia, thalamus, cerebellum, and cerebral cortex. In acquired dystonia, focal lesions to subcortical areas in the network - the basal ganglia, thalamus, and cerebellum - lead to a dystonia that can be difficult to manage with canonical treatments, including deep brain stimulation (DBS). While studies in animal models have begun to parse the contribution of individual nodes in the dystonia network, how acquired injury to the cerebellar outflow tracts instigates dystonia; and how network modulation interacts with symptom latency remain as unexplored questions. Here, we present an electrolytic lesioning paradigm that bilaterally targets the cerebellar outflow tracts. We found that lesioning these tracts, at the junction of the superior cerebellar peduncles and the medial and intermediate cerebellar nuclei, resulted in acute, severe dystonia. We observed that dystonia is reduced with one hour of DBS of the centrolateral thalamic nucleus, a first order node in the network downstream of the cerebellar nuclei. In contrast, one hour of stimulation at a second order node in the short latency, disynaptic projection from the cerebellar nuclei, the striatum, did not modulate the dystonia in the short-term. Our study introduces a robust paradigm for inducing acute, severe dystonia, and demonstrates that targeted modulation based on network principles powerfully rescues motor behavior. These data inspire the identification of therapeutic targets for difficult to manage acquired dystonia.

Pilot study with randomised control of dual site theta burst transcranial magnetic stimulation (TMS) for methamphetamine use disorder: a protocol for the TARTAN study.

BACKGROUND: Transcranial magnetic stimulation (TMS) (including the theta burst stimulation (TBS) form of TMS used in this study) is a non-invasive means to stimulate nerve cells in superficial areas of the brain. In recent years, there has been a growth in the application of TMS to investigate the modulation of neural networks involved in substance use disorders. This study examines the feasibility of novel TMS protocols for the treatment of methamphetamine (MA) use disorder in an ambulatory drug and alcohol treatment setting. METHODS: Thirty participants meeting the criteria for moderate to severe MA use disorder will be recruited in community drug and alcohol treatment settings and randomised to receive active TMS or sham (control) intervention. The treatment is intermittent TBS (iTBS) applied to the left dorsolateral prefrontal cortex (DLPFC), then continuous TBS (cTBS) to the left orbitofrontal cortex (OFC). Twelve sessions are administered over 4 weeks with opt-in weekly standardized cognitive behaviour therapy (CBT) counselling and a neuroimaging sub-study offered to participants. Primary outcomes are feasibility measures including recruitment, retention and acceptability of the intervention. Secondary outcomes include monitoring of safety and preliminary efficacy data including changes in substance use, cravings (cue reactivity) and cognition (response inhibition). DISCUSSION: This study examines shorter TBS protocols of TMS for MA use disorder in real-world drug and alcohol outpatient settings where withdrawal and abstinence from MA, or other substances, are not eligibility requirements. TMS is a relatively affordable treatment and staff of ambulatory health settings can be trained to administer TMS. It is a potentially scalable and translatable treatment for existing drug and alcohol clinical settings. TMS has the potential to provide a much-needed adjuvant treatment to existing psychosocial interventions for MA use disorder. A limitation of this protocol is that the feasibility of follow-up is only examined at the end of treatment (4 weeks). TRIAL REGISTRATION: Australia New Zealand Clinical Trial Registry ACTRN12622000762752. Registered on May 27, 2022, and retrospectively registered (first participant enrolled) on May 23, 2022, with protocol version 7 on February 24, 2023.

Global survey of hgcA-carrying genomes in marine and freshwater sediments: Insights into mercury methylation processes.

Mercury (Hg) methylation is a microbially mediated process that produces methylmercury (MeHg), a bioaccumulative neurotoxin. A highly conserved gene pair, hgcAB, is required for Hg methylation, which provides a basis for identifying Hg methylators and evaluating their genomic composition. In this study, we conducted a large-scale omics analysis in which 281 metagenomic freshwater and marine sediment samples from 46 geographic locations across the globe were queried. Specific objectives were to examine the prevalence of Hg methylators, to identify horizontal gene transfer (HGT) events involving hgcAB within Hg methylator communities, and to identify associations between hgcAB and microbial biochemical functions/genes. Hg methylators from the phyla Desulfobacterota and Bacteroidota were dominant in both freshwater and marine sediments while Firmicutes and methanogens belonging to Euryarchaeota were identified only in freshwater sediments. Novel Hg methylators were found in the Phycisphaerae and Planctomycetia classes within the phylum Planctomycetota, including potential hgcA-carrying anammox metagenome-assembled genomes (MAGs) from Candidatus Brocadiia. HGT of hgcA and hgcB were identified in both freshwater and marine methylator communities. Spearman's correlation analysis of methylator genomes suggested that in addition to sulfide, thiosulfate, sulfite, and ammonia may be important parameters for Hg methylation processes in sediments. Overall, our results indicated that the biochemical drivers of Hg methylation vary between marine and freshwater sites, lending insight into the influence of environmental perturbances, such as a changing climate, on Hg methylation processes.

Azithromycin resistance in Escherichia coli and Salmonella from food-producing animals and meat in Europe.

OBJECTIVES: To characterize the genetic basis of azithromycin resistance in Escherichia coli and Salmonella collected within the EU harmonized antimicrobial resistance (AMR) surveillance programme in 2014-18 and the Danish AMR surveillance programme in 2016-19. METHODS: WGS data of 1007 E. coli [165 azithromycin resistant (MIC > 16 mg/L)] and 269 Salmonella [29 azithromycin resistant (MIC > 16 mg/L)] were screened for acquired macrolide resistance genes and mutations in rplDV, 23S rRNA and acrB genes using ResFinder v4.0, AMRFinder Plus and custom scripts. Genotype-phenotype concordance was determined for all isolates. Transferability of mef(C)-mph(G)-carrying plasmids was assessed by conjugation experiments. RESULTS: mph(A), mph(B), mef(B), erm(B) and mef(C)-mph(G) were detected in E. coli and Salmonella, whereas erm(C), erm(42), ere(A) and mph(E)-msr(E) were detected in E. coli only. The presence of macrolide resistance genes, alone or in combination, was concordant with the azithromycin-resistant phenotype in 69% of isolates. Distinct mph(A) operon structures were observed in azithromycin-susceptible (n = 50) and -resistant (n = 136) isolates. mef(C)-mph(G) were detected in porcine and bovine E. coli and in porcine Salmonella enterica serovar Derby and Salmonella enterica 1,4, [5],12:i:-, flanked downstream by ISCR2 or TnAs1 and associated with IncIγ and IncFII plasmids. CONCLUSIONS: Diverse azithromycin resistance genes were detected in E. coli and Salmonella from food-producing animals and meat in Europe. Azithromycin resistance genes mef(C)-mph(G) and erm(42) appear to be emerging primarily in porcine E. coli isolates. The identification of distinct mph(A) operon structures in susceptible and resistant isolates increases the predictive power of WGS-based methods for in silico detection of azithromycin resistance in Enterobacterales.

Clinical case report of intractable paroxysmal sympathetic hyperactivity in TANGO2 deficiency disorder.

TANGO2 deficiency disorder (TDD) is a neurodegenerative disease characterized by a broad and variable spectrum of clinical manifestations, even among individuals sharing the same pathogenic variants. Here, we report a severely affected individual with TDD presenting with intractable paroxysmal sympathetic hyperactivity (PSH). While progressive brain atrophy has been observed in TDD, PSH has not been reported. Despite comprehensive workup for an acute trigger, no definite cause was identified, and pharmacological interventions were ineffective to treat PSH. Ultimately care was redirected to comfort measures. This article expands the clinical phenotype of patients with TDD, highlights the possibility of PSH in these patients, and the need for continued research for better treatments of TDD.

Purkinje cell dysfunction causes disrupted sleep in ataxic mice.

Purkinje cell dysfunction disrupts movement and causes disorders such as ataxia. Recent evidence suggests that Purkinje cell dysfunction may also alter sleep regulation. Here, we used an ataxic mouse model generated by silencing Purkinje cell neurotransmission (L7Cre;Vgatfx/fx) to better understand how cerebellar dysfunction impacts sleep physiology. We focused our analysis on sleep architecture and electrocorticography (ECoG) patterns based on their relevance to extracting physiological measurements during sleep. We found that circadian activity is unaltered in the mutant mice, although their sleep parameters and ECoG patterns are modified. The L7Cre;Vgatfx/fx mutant mice have decreased wakefulness and rapid eye movement (REM) sleep, while non-rapid eye movement (NREM) sleep is increased. The mutants have an extended latency to REM sleep, which is also observed in human ataxia patients. Spectral analysis of ECoG signals revealed alterations in the power distribution across different frequency bands defining sleep. Therefore, Purkinje cell dysfunction may influence wakefulness and equilibrium of distinct sleep stages in ataxia. Our findings posit a connection between cerebellar dysfunction and disrupted sleep and underscore the importance of examining cerebellar circuit function in sleep disorders.

Microglial- neuronal crosstalk in chronic viral infection through mTOR, SPP1/OPN and inflammasome pathway signaling.

HIV-infection of microglia and macrophages (MMs) induces neuronal injury and chronic release of inflammatory stimuli through direct and indirect molecular pathways. A large percentage of people with HIV-associated neurologic and psychiatric co-morbidities have high levels of circulating inflammatory molecules. Microglia, given their susceptibility to HIV infection and long-lived nature, are reservoirs for persistent infection. MMs and neurons possess the molecular machinery to detect pathogen nucleic acids and proteins to activate innate immune signals. Full activation of inflammasome assembly and expression of IL-1ß requires a priming event and a second signal. Many studies have demonstrated that HIV infection alone can activate inflammasome activity. Interestingly, secreted phosphoprotein-1 (SPP1/OPN) expression is highly upregulated in the CNS of people infected with HIV and neurologic dysfunction. Interestingly, all evidence thus far suggests a protective function of SPP1 signaling through mammalian target of rapamycin (mTORC1/2) pathway function to counter HIV-neuronal injury. Moreover, HIV-infected mice knocked down for SPP1 show by neuroimaging, increased neuroinflammation compared to controls. This suggests that SPP1 uses unique regulatory mechanisms to control the level of inflammatory signaling. In this mini review, we discuss the known and yet-to-be discovered biological links between SPP1-mediated stimulation of mTOR and inflammasome activity. Additional new mechanistic insights from studies in relevant experimental models will provide a greater understanding of crosstalk between microglia and neurons in the regulation of CNS homeostasis.

Delivering Serious News in Pediatric Cardiology-A Pilot Program.

Pediatric cardiology fellows receive limited training on delivering serious news. This is a teachable skill through simulation-based communication. While studies have shown the use of communication courses in pediatrics, there have been none in pediatric cardiology. Pediatric cardiologists recognize the importance of good communication and desire further development of these skills. Based on an internal needs assessment, three cases were developed; fetal hypoplastic left heart syndrome, teenager with new hypertrophic cardiomyopathy, and young-adult with Fontan failure. A 4-h simulation course using evidence-based methods to teach delivering serious news was designed, consisting of a didactic session, case demonstration and small group case-based encounters with simulated patients. Trainees completed standardized pre/post-course surveys to assess perception of skill and preparedness. Paired survey responses were compared. Six pediatric cardiology fellows participated. Only 33% had received formal training in delivering serious news and 17% in techniques of responding to patient's emotions. The proportion of participants who felt good about their ability to deliver serious news and deal with a family's emotions increased from 0 to 83%. The proportion of participants who felt prepared to provide serious news about a patient's illness increased from 17 to 67%. Given the small number of participants, results were not statistically significant. All participants felt that the course was valuable in improving communication skills. A formal communication course increased perception of skill and preparedness among trainees. We provide an evidence-based framework and clinical cases for delivering serious news in pediatric cardiology, which is generalizable to other training programs.

Th17/1 and ex-Th17 cells are detected in patients with polyarticular juvenile arthritis and increase following treatment.

BACKGROUND: A better understanding of the pathogenesis of polyarticular juvenile idiopathic arthritis (polyJIA) is needed to aide in the development of data-driven approaches to guide selection between therapeutic options. One inflammatory pathway of interest is JAK-STAT signaling. STAT3 is a transcription factor critical to the differentiation of inflammatory T helper 17 cells (Th17s). Previous studies have demonstrated increased STAT3 activation in adult patients with rheumatoid arthritis, but less is known about STAT3 activation in polyJIA. We hypothesized that Th17 cells and STAT3 activation would be increased in treatment-naïve polyJIA patients compared to pediatric controls. METHODS: Blood from 17 patients with polyJIA was collected at initial diagnosis and again if remission was achieved (post-treatment). Pediatric healthy controls were also collected. Peripheral blood mononuclear cells were isolated and CD4 + T cell subsets and STAT activation (phosphorylation) were evaluated using flow cytometry. Data were analyzed using Mann-Whitney U and Wilcoxon matched-pairs signed rank tests. RESULTS: Treatment-naïve polyJIA patients had increased Th17 cells (CD3 + CD4 + interleukin(IL)-17 +) compared to controls (0.15% v 0.44%, p < 0.05), but Tregs (CD3 + CD4 + CD25 + FOXP3 +) from patients did not differ from controls. Changes in STAT3 phosphorylation in CD4 + T cells following ex vivo stimulation were not significantly different in patients compared to controls. We identified dual IL-17 + and interferon (IFN)γ + expressing CD4 + T cells in patients, but not controls. Further, both Th17/1 s (CCR6 + CD161 + IFNγ + IL-17 +) and ex-Th17s (CCR6 + CD161 + IFNγ + IL-17neg) were increased in patients' post-treatment (Th17/1: 0.3% v 0.07%, p < 0.05 and ex-Th17s: 2.3% v 1.4%, p < 0.05). The patients with the highest IL-17 expressing cells post-treatment remained therapy-bound. CONCLUSIONS: Patients with polyJIA have increased baseline Th17 cells, potentially reflecting higher tonic STAT3 activation in vivo. These quantifiable immune markers may identify patients that would benefit upfront from pathway-focused biologic therapies. Our data also suggest that inflammatory CD4 + T cell subsets not detected in controls but increased in post-treatment samples should be further evaluated as a tool to stratify patients in remission on medication. Future work will explore these proposed diagnostic and prognostic biomarkers.

Phase 1 randomized pharmacokinetic and safety study of a 90-day tenofovir vaginal ring in the United States.

INTRODUCTION: Tenofovir-based oral pre-exposure prophylaxis is currently approved for HIV prevention; however, adherence in women has been low. A vaginal gel containing tenofovir (TFV) demonstrated partial protection to HIV but protection was not confirmed in additional studies. Vaginal rings offer user-controlled long-acting HIV prevention that could overcome adherence and protection challenges. TFV may also help prevent herpes simplex virus type 2 acquisition when delivered intravaginally. We evaluated the pharmacokinetics, safety, adherence and acceptability of a 90-day TFV ring. METHODS: Between January and June 2019, Microbicide Trials Network (MTN)-038 enrolled 49 HIV-negative participants into a phase 1, randomized (2:1) trial comparing a 90-day ring containing 1.4 grams (g) TFV to a placebo ring. TFV concentrations were quantified in plasma, cervicovaginal fluid (CVF), rectal fluid and cervical tissue, and TFV-diphosphate (TFV-DP) in cervical tissue. Used rings were analysed for residual TFV. Safety was assessed by adverse events (AEs); acceptability and adherence by self-report. RESULTS: Mean age was 29.5; 46 identified as cisgender-female and three gender non-conforming. There were no differences in the proportion of participants with grade ≥2 genitourinary AEs in the TFV versus placebo arms (p = 0.41); no grade ≥3 AEs were reported. Geometric mean TFV concentrations increased through day 34 in CVF/rectal fluid and day 59 in plasma, but declined across compartments by day 91. Geometric mean TFV-DP tissue concentrations exceeded the 1000 fmol/mg target through day 56, but fell to 456 fmol/mg at day 91. Among 32 rings returned at the end of the study, 13 had no or low (<0.1 g) residual TFV. Residual TFV did not differ by socio-demographics, sexual activity, Nugent Score or vaginal microbiota. Most participants reported being fully adherent to ring use: 85% and 81% in the TFV and placebo arms, respectively (p = 1.00). A majority of participants reported liking the ring (median 8 on a 10-point Likert scale) and reported a high likelihood of using the ring in the future, if effective (median 9). CONCLUSIONS: The 90-day TFV ring was well-tolerated, acceptable and exceeded target cervical tissue concentrations through day 56, but declined thereafter. Additional studies are needed to characterize the higher release from TFV rings in some participants and the optimal duration of use.

When is vancomycin prophylaxis necessary? Risk factors for MRSA surgical site infection.

Background: The 2022 SHEA/IDSA/APIC guidance for surgical site infection (SSI) prevention recommends reserving vancomycin prophylaxis to patients who are methicillin-resistant Staphylococcus aureus (MRSA) colonized. Unfortunately, vancomycin prophylaxis remains common due to the overestimation of MRSA risk and the desire to cover MRSA in patients with certain healthcare-associated characteristics. To optimize vancomycin prophylaxis, we sought to identify risk factors for MRSA SSI. Methods: This was a single-center, case-control study of patients with a postoperative SSI after undergoing a National Healthcare Safety Network operative procedure over eight years. MRSA SSI cases were compared to non-MRSA SSI controls. Forty-two demographic, medical, and surgical characteristics were evaluated. Results: Of the 441 patients included, 23 developed MRSA SSIs (rate = 5.2 per 100 SSIs). In the multivariable model, we identified two independent risk factors for MRSA SSI: a history of MRSA colonization or infection (OR, 9.0 [95% CI, 1.9-29.6]) and hip or knee replacement surgery (OR, 3.8 [95% CI, 1.3-9.9]). Hemodialysis, previous hospitalization, and prolonged hospitalization prior to the procedure had no measurable association with odds of MRSA SSI. Conclusions: Patients with prior MRSA colonization or infection had 9-10 times greater odds of MRSA SSI and patients undergoing hip and knee replacement had 3-4 times greater odds of MRSA SSI. Healthcare-associated characteristics, such as previous hospitalization or hemodialysis, were not associated with MRSA SSI. Our findings support national recommendations to reserve vancomycin prophylaxis for patients who are MRSA colonized, as well as those undergoing hip and knee replacement, in the absence of routine MRSA colonization surveillance.

Sex Differences in Response-Contingent Cannabis Vapor Administration During Adolescence Mediate Enduring Effects on Behavioral Flexibility and Prefrontal Microglia Activation in Rats.

Introduction: Cannabis is the most used illicit drug in the United States. With many states passing legislation to permit its recreational use, there is concern that cannabis use among adolescents could increase dramatically in the coming years. Historically, it has been difficult to model real-world cannabis use to investigate the causal relationship between cannabis use in adolescence and behavioral and neurobiological effects in adulthood. Materials and Methods: We used a response-contingent vapor administration model to investigate long-term effects of cannabis use during adolescence on the medial prefrontal cortex (mPFC) and mPFC-dependent behaviors in male and female rats. Results: Adolescent (35- to 55-day-old) female rats had significantly higher rates of responding for vaporized Δ9-tetrahydrocannabinol (THC)-dominant cannabis extract (CANTHC) compared with adolescent males. In adulthood (70-110 days old), female, but not male, CANTHC rats also took more trials to reach criterion and made more regressive errors in an automated attentional set-shifting task compared with vehicle rats, thereby indicating sex differences in behavioral flexibility impairments. Notably, sex-treatment interactions were not observed when rats of each sex were exposed to a noncontingent CANTHC vapor dosing regimen that approximated CANTHC vapor deliveries earned by females. No differences were observed in effort-based decision making in either sex. In the mPFC, female (but not male) CANTHC rats displayed more reactive microglia with no changes in myelin basic protein expression or dendritic spine density. Conclusion: Altogether, these data reveal important sex differences in rates of responding for CANTHC vapor in adolescence that may confer enduring alterations to mPFC structure and function and suggest that there may be subtle differences in the effects of response-contingent versus noncontingent cannabis exposure that should be systematically examined in future studies.

Policy implementation strategies to address rural disparities in access to care for stroke patients.

Context: Stroke systems of care (SSOC) promote access to stroke prevention, treatment, and rehabilitation and ensure patients receive evidence-based treatment. Stroke patients living in rural areas have disproportionately less access to emergency medical services (EMS). In the United States, rural counties have a 30% higher stroke mortality rate compared to urban counties. Many states have SSOC laws supported by evidence; however, there are knowledge gaps in how states implement these state laws to strengthen SSOC. Objective: This study identifies strategies and potential challenges to implementing state policy interventions that require or encourage evidence-supported pre-hospital interventions for stroke pre-notification, triage and transport, and inter-facility transfer of patients to the most appropriate stroke facility. Design: Researchers interviewed representatives engaged in implementing SSOC across six states. Informants (n = 34) included state public health agency staff and other public health and clinical practitioners. Outcomes: This study examined implementation of pre-hospital SSOCs policies in terms of (1) development roles, processes, facilitators, and barriers; (2) implementation partners, challenges, and solutions; (3) EMS system structure, protocols, communication, and supervision; and (4) program improvement, outcomes, and sustainability. Results: Challenges included unequal resource allocation and EMS and hospital services coverage, particularly in rural settings, lack of stroke registry usage, insufficient technologies, inconsistent use of standardized tools and protocols, collaboration gaps across SSOC, and lack of EMS stroke training. Strategies included addressing scarce resources, services, and facilities; disseminating, training on, and implementing standardized statewide SSOC protocols and tools; and utilizing SSOC quality and performance improvement systems and approaches. Conclusions: This paper identifies several strategies that can be incorporated to enhance the implementation of evidence-based stroke policies to improve access to timely stroke care for all patient populations, particularly those experiencing disparities in rural communities.

Impact of State Stroke Systems of Care Laws on Stroke Outcomes.

Since 2003, 38 US states and Washington, DC have adopted legislation and/or regulations to strengthen stroke systems of care (SSOCs). This study estimated the impact of SSOC laws on stroke outcomes. We used a coded legal dataset of 50 states and DC SSOC laws (years 2003-2018), national stroke accreditation information (years 1997-2018), data from the Healthcare Cost and Utilization Project (years 2012-2018), and National Vital Statistics System (years 1979-2019). We applied a natural experimental design paired with longitudinal modeling to estimate the impact of having one or more SSOC policies in effect on outcomes. On average, states with one or more SSOC policies in effect achieved better access to primary stroke centers (PSCs) than expected without SSOC policies (ranging from 2.7 to 8.0 percentage points (PP) higher), lower inpatient hospital costs (USD 610-1724 less per hospital stay), lower age-adjusted stroke mortality (1.0-1.6 fewer annual deaths per 100,000), a higher proportion of stroke patients with brain imaging results within 45 min of emergency department arrival (3.6-5.0 PP higher), and, in some states, lower in-hospital stroke mortality (5 fewer deaths per 1000). Findings were mixed for some outcomes and there was limited evidence of model fit for others. No effect was observed in racial and/or rural disparities in stroke mortality.

Tobacco treatment incorporating contingency management, nicotine replacement therapy, and behavioral counseling for pregnant women who use substances: a feasibility trial.

Introduction: Most pregnant women with substance use problems smoke, and few will quit during their pregnancy. Tobacco treatment is often overlooked, with the focus usually placed on other substance use. Additionally, few targeted effective treatments for this group exist. To address this, the feasibility of an intensive tobacco treatment incorporating contingency management (CM) that featured non-face-to-face delivery was examined. Methods: A single-arm pre-post design feasibility trial was conducted in three antenatal services that support women who use substances in metropolitan Australia. Participants were over the age of 15, had <33-week gestation, and smoked tobacco daily. They received financial incentives for daily carbon monoxide-verified smoking abstinence or reduction through an internet-based CM programme, nicotine replacement therapy (NRT) posted to women and partners or household members who smoked and telephone-delivered behavioral counseling from study enrolment to birth. Results: Of the 101 referrals, 46 women (46%) consented. The mean (SD) age was 31(±6) years, and the gestation period was 22(±6) weeks. Nineteen (41%) of those enrolled were retained for 12-week postpartum. Of 46 women, 32 (70%) utilized CM; 32 (70%) used NRT for ≥2 weeks; 23 (50%) attended ≥1 counseling session; and 15 (22%) received NRT for partners/household members. Fifteen (33%) were verified abstinent from tobacco at delivery after a median (IQR) period of abstinence of 65(36-128) days. All non-smokers at birth utilized NRT and financial incentives, and 9/15 (60%) utilized counseling. Four (9%) were abstinent at 12-week postpartum. Median cigarettes smoked/day reduced from baseline to delivery (10(6-20) to 1(0-6) p =< 0.001). Women who quit smoking had more education (72% vs. 33% p =< 0.02), completed more CO samples (median (IQR) 101(59-157) vs. 2(0-20) p =< 0.001), and received more incentives (median (IQR) $909($225-$1980) vs. $34($3-$64) p =< 0.001). Intervention acceptability was rated favorably by participants (9 items rated 0-10 with scores >5 considered favorable). Discussion: This study demonstrated the feasibility and acceptability of a consumer-informed, non-face-to-face intensive tobacco treatment, highlighting the potential of remotely delivered technology-based CM to reduce the health impact of tobacco smoking in high-priority populations. The intervention demonstrates scale-up potential. Future studies should extend treatment into the postpartum period, utilizing new technologies to enhance CM delivery and improve counseling provision and partner support. Clinical trial registration: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=374196, ACTRN1261800056224.

Metaorganismal choline metabolism shapes olfactory perception.

Microbes living in the intestine can regulate key signaling processes in the central nervous system that directly impact brain health. This gut-brain signaling axis is partially mediated by microbe-host-dependent immune regulation, gut-innervating neuronal communication, and endocrine-like small molecule metabolites that originate from bacteria to ultimately cross the blood-brain barrier. Given the mounting evidence of gut-brain crosstalk, a new therapeutic approach of "psychobiotics" has emerged, whereby strategies designed to primarily modify the gut microbiome have been shown to improve mental health or slow neurodegenerative diseases. Diet is one of the most powerful determinants of gut microbiome community structure, and dietary habits are associated with brain health and disease. Recently, the metaorganismal (i.e., diet-microbe-host) trimethylamine N-oxide (TMAO) pathway has been linked to the development of several brain diseases including Alzheimer's, Parkinson's, and ischemic stroke. However, it is poorly understood how metaorganismal TMAO production influences brain function under normal physiological conditions. To address this, here we have reduced TMAO levels by inhibiting gut microbe-driven choline conversion to trimethylamine (TMA), and then performed comprehensive behavioral phenotyping in mice. Unexpectedly, we find that TMAO is particularly enriched in the murine olfactory bulb, and when TMAO production is blunted at the level of bacterial choline TMA lyase (CutC/D), olfactory perception is altered. Taken together, our studies demonstrate a previously underappreciated role for the TMAO pathway in olfactory-related behaviors.

Purkinje cell dysfunction causes disrupted sleep in ataxic mice.

Purkinje cell dysfunction causes movement disorders such as ataxia, however, recent evidence suggests that Purkinje cell dysfunction may also alter sleep regulation. Here, we used an ataxia mouse model generated by silencing Purkinje cell neurotransmission ( L7 Cre ;Vgat fx/fx ) to better understand how cerebellar dysfunction impacts sleep physiology. We focused our analysis on sleep architecture and electrocorticography (ECoG) patterns based on their relevance to extracting physiological measurements during sleep. We found that circadian activity is unaltered in the mutant mice, although their sleep parameters and ECoG patterns are modified. The L7 Cre ;Vgat fx/fx mutant mice have decreased wakefulness and rapid eye movement (REM) sleep, while non-rapid eye movement (NREM) sleep is increased. The mutant mice have an extended latency to REM sleep, which is also observed in human ataxia patients. Spectral analysis of ECoG signals revealed alterations in the power distribution across different frequency bands defining sleep. Therefore, Purkinje cell dysfunction may influence wakefulness and equilibrium of distinct sleep stages in ataxia. Our findings posit a connection between cerebellar dysfunction and disrupted sleep and underscore the importance of examining cerebellar circuit function in sleep disorders. Summary Statement: Utilizing a precise genetic mouse model of ataxia, we provide insights into the cerebellum's role in sleep regulation, highlighting its potential as a therapeutic target for motor disorders-related sleep disruptions.

Electromyography as a Method for Distinguishing Dystonia in Mice.

Electromyography (EMG) methods allow quantitative analyses of motor function. The techniques include intramuscular recordings that are performed in vivo. However, recording muscle activity in freely moving mice, particularly in models of motor disease, often creates challenges that prevent the acquisition of clean signals. Recording preparations must be stable enough for the experimenter to collect an adequate number of signals for statistical analyses. Instability results in a low signal-to-noise ratio that prohibits proper isolation of EMG signals from the target muscle during the behavior of interest. Such insufficient isolation prevents the analysis of full electrical potential waveforms. In this case, resolving the shape of a waveform to differentiate individual spikes and bursts of muscle activity can be difficult. A common source of instability is an inadequate surgery. Poor surgical techniques cause blood loss, tissue damage, poor healing, encumbered movement, and unstable implantation of the electrodes. Here, we describe an optimized surgical procedure that ensures electrode stability for in vivo muscle recordings. We implement our technique to obtain recordings from agonist and antagonist muscle pairs in the hindlimbs of freely moving adult mice. We validate the stability of our method by holding EMG recordings during dystonic behavior. Our approach is ideal for studying normal and abnormal motor function in actively behaving mice and valuable for recording intramuscular activity when considerable motion is expected.