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1.
Artigo em Inglês | MEDLINE | ID: mdl-32367194

RESUMO

This controlled trial evaluated the effectiveness of a mental health literacy intervention for parents delivered through community sport clubs. In total, 540 parents (321 females, 219 males) of adolescent athletes participated in a brief educational workshop on youth mental health (n = 352) or a community-matched control group (n = 188). Generalised linear mixed models revealed no significant improvements in the intervention group compared to control in the primary mental health literacy outcomes, at 1 month follow-up. However, parents in the intervention group were more likely to seek formal help for themselves, had increased confidence and knowledge to help someone experiencing a mental health disorder, experienced reduced psychological distress, and perceived more support from other parents in their sport club, relative to the control group. Overall, the findings suggest that a brief educational intervention delivered through community sports clubs can positively affect some components of parents' mental health literacy.

2.
Artigo em Inglês | MEDLINE | ID: mdl-32399985

RESUMO

BACKGROUND: The network theory suggests that psychopathology may reflect causal relationships between individual symptoms. Several studies have examined cross-sectional relationships between individual symptoms in youth. However, these studies cannot address the directionality of the temporal relationships hypothesized by the network theory. Therefore, we estimated the longitudinal relationships between individual internalizing, externalizing, and attention symptoms in youth. METHODS: Data from 4,093 youth participants in the Adolescent Brain Cognitive Development (ABCD) study were used. Symptoms were assessed using the Brief Problem Monitor, which was administered at three time points spaced six months apart. Unique longitudinal relationships between symptoms at T1 and T2 were estimated using cross-lagged panel network modeling. Network replicability was assessed by comparing this network to an identically estimated replication network of symptoms at T2 predicting symptoms at T3. RESULTS: After controlling for all other symptoms and demographic covariates, depressed mood, inattention, and worry at T1 were most predictive of other symptoms at T2. In contrast, threats of violence and destructiveness at T2 were most prospectively predicted by other symptoms at T1. The reciprocal associations between depressed mood and worthlessness were among the strongest bivariate relationships in the network. Comparisons between the original network and the replication network (correlation between edge lists = .61; individual edge replicability = 64%-84%) suggested moderate replicability. CONCLUSIONS: Although causal inferences are precluded by the observational design and methodological considerations, these findings demonstrate the directionality of relationships between individual symptoms in youth and highlight depressed mood, inattention, and worry as potential influencers of other symptoms.

3.
Blood Cancer J ; 10(5): 54, 2020 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-32393731

RESUMO

Seventy-six FDA-approved oncology drugs and emerging therapeutics were evaluated in 25 multiple myeloma (MM) and 15 non-Hodgkin's lymphoma cell lines and in 113 primary MM samples. Ex vivo drug sensitivities were mined for associations with clinical phenotype, cytogenetic, genetic mutation, and transcriptional profiles. In primary MM samples, proteasome inhibitors, dinaciclib, selinexor, venetoclax, auranofin, and histone deacetylating agents had the broadest cytotoxicity. Of interest, newly diagnosed patient samples were globally less sensitive especially to bromodomain inhibitors, inhibitors of receptor tyrosine kinases or non-receptor kinases, and DNA synthesis inhibitors. Clustering demonstrated six broad groupings of drug sensitivity linked with genomic biomarkers and clinical outcomes. For example, our findings mimic clinical observations of increased venetoclax responsiveness in t(11;14) patients but also identify an increased sensitivity profile in untreated patients, standard genetic risk, low plasma cell S-Phase, and in the absence of Gain(1q) and t(4;14). In contrast, increased ex vivo responsiveness to selinexor was associated with biomarkers of poor prognosis and later relapse patients. This "direct to drug" screening resource, paired with functional genomics, has the potential to successfully direct appropriate individualized therapeutic approaches in MM and to enrich clinical trials for likely responders.

5.
J Sport Exerc Psychol ; : 1-18, 2020 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-32438339

RESUMO

Sport may protect against symptoms of mental disorders that are increasingly prevalent among adolescents. This systematic review explores the relationship between adolescent organized sport participation and self-reported symptoms of anxiety and depression. From 9,955 records screened, 29 unique articles were selected that included 61 effect sizes and 122,056 participants. Effects were clustered into four categories based on the operationalization of sport involvement: absence or presence of involvement, frequency of involvement, volume of involvement, and duration of participation. Results from the random-effects meta-analyses indicated that symptoms of anxiety and depression were significantly lower among sport-involved adolescents than in those not involved in sport, although this effect size was small in magnitude. Meta-regression was used to identify how age and sex explained heterogeneity in effects. Although these results do not signify a causal effect, they do support theorizing that sport participation during adolescence may be a protective environment against anxiety and depressive symptoms.

6.
Development ; 2020 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-32439762

RESUMO

Methylation of histone 3 lysine 4 (H3K4) is a major epigenetic system associated with gene expression. In mammals there are six H3K4 methyltransferases related to yeast Set1 and fly Trithorax, including two orthologs of fly Trithorax-related: MLL3 and MLL4. Exome sequencing has documented high frequencies of MLL3 and MLL4 mutations in many types of human cancer. Despite this emerging importance, the requirements of these paralogs in mammalian development have only been incompletely reported. Here we examined the null phenotypes to establish that MLL3 is first required for lung maturation whereas MLL4 is first required for migration of the anterior visceral endoderm (AVE) that initiates gastrulation. This collective cell migration is preceded by a columnar to squamous transition in visceral endoderm cells that depends on MLL4. Furthermore, Mll4 mutants display incompletely penetrant, sex distorted, embryonic haploinsufficiency and adult heterozygous mutants show aspects of Kabuki syndrome, indicating that MLL4 action, unlike MLL3, is dosage dependent. The highly specific and discordant functions of these paralogs in mouse development argues against their action as general enhancer factors.

7.
J Sci Med Sport ; 2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-32360244

RESUMO

OBJECTIVE: To examine whether meeting the Australian 24-Hour Movement Guidelines was associated with cognitive and psychosocial health in preschoolers. DESIGN: Prospective observational study. METHODS: Cross-sectional (n=247) and 12-month longitudinal (n=185) data from the PATH-ABC study were examined. Physical activity was assessed by accelerometry. Parents reported children's screen time and sleep. Children were categorised at baseline as meeting: i) none/one guideline, ii) two guidelines, or iii) 24-Hour Movement Guidelines. Associations with executive functions and psychosocial health were examined using linear regression, adjusting for covariates and preschool clustering. Longitudinal associations were additionally adjusted for baseline levels of development. RESULTS: High proportions of children met the physical activity (94.3%) and sleep (89.9%) guidelines, 17.8% and 17.4% met screen time and 24-Hour Movement Guidelines, respectively. Cross-sectionally, children meeting both sleep and physical activity guidelines displayed better phonological working memory (p=0.026) and shifting (p= 0.034) scores compared to children who did not. Meeting two (p=0.037) and three (p=0.017) guidelines were associated with better phonological working memory and shifting scores, respectively (vs. meeting 0/1 guideline). Longitudinally, children meeting the physical activity guideline at baseline displayed better shifting performance 12-months later compared to those who did not (p<0.002). No associations with remaining cognitive outcomes, and no associations with psychosocial outcomes were evident. CONCLUSIONS: Null associations suggest that meeting the recommendations may not be adequate for broad cognitive and psychosocial health outcomes in preschoolers. However, supporting preschool children to meet the physical activity and sleep guidelines, may be beneficial for aspects of cognitive health.

9.
J Exp Biol ; 223(Pt 8)2020 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-32312718

RESUMO

During winter at temperate and high latitudes, the low ambient temperatures, limited food supplies and short foraging periods mean small passerines show behavioural, morphological and physiological adaptations to reduce the risk of facing energy shortages. Peripheral tissues vasoconstrict in low ambient temperatures to reduce heat loss and cold injury. Peripheral vasoconstriction has been observed with food restriction in captivity but has yet to be explored in free-ranging animals. We experimentally food restricted both wild and captive great tits (Parus major) during winter months and measured surface temperatures of the bill and eye region using thermal imaging, to investigate whether birds show rapid local heterothermic responses, which may reduce their thermoregulatory costs when facing a perceived imminent food shortage. Our results of a continuously filmed wild population showed that bill temperature was immediately reduced in response to food restriction compared with when food was available ad libitum, an apparent autonomic response. Such immediacy implies a 'pre-emptive' response before the bird experiences any shortfalls in energy reserves. We also demonstrate temporal variation in vasoconstriction of the bill, with bill temperature gradually rising throughout the food restriction after the initial drop. Eye-region temperature in the wild birds remained at similar levels throughout food restriction compared with unrestricted birds, possibly reflecting the need to maintain steady circulation to the central nervous and visual systems. Our findings provide evidence that birds selectively allow the bill to cool when a predictable food supply is suddenly disrupted, probably as a means of minimising depletion of body reserves for a perceived future shortage in energy.

10.
CNS Spectr ; 25(2): 288-289, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32331018

RESUMO

STUDY OBJECTIVE: Tardive dyskinesia (TD) is a persistent and potentially disabling movement disorder associated with prolonged exposure to antipsychotics and other dopamine receptor blocking agents. Valbenazine is a highly selective vesicular monoamine transporter 2 (VMAT2) inhibitor approved for the treatment of TD in adults. Using data from a long-term study (KINECT 3; NCT02274558), the effects of once-daily valbenazine (40 mg, 80 mg) on TD were assessed using the Abnormal Involuntary Movement Scale (AIMS) in participants who were early responders based on subjective measures, including patient self-report (Patient Global Impression of Change [PGIC]) or clinician judgment (Clinical Impression of Change-Tardive Dyskinesia [CGI-TD]). METHODS: Data from KINECT 3 (6-week double-blind, placebo-controlled [DBPC] period; 42-week double-blind extension) were analyzed post hoc. Long-term outcomes included mean change from baseline to Week 48 in AIMS total score (sum of items 1-7) and AIMS response (≥50% total score improvement from baseline) at Week 48. These AIMS outcomes were assessed in participants who achieved early improvement, defined as a PGIC or CGI-TD score of ≤3 ("minimally improved" or better) at Week 2 (first post-baseline visit of the DBPC period). Participants who initially received placebo were not included in the analyses. RESULTS: In participants who received only valbenazine (40 or 80 mg) during KINECT 3 and had available Week 2 assessment, 50% (72/143) had early PGIC improvement (score ≤3) and 43% (61/142) had early CGI-TD improvement (score ≤3). Baseline characteristics were generally similar between participants who achieved early PGIC or CGI-TD improvement and those who did not. Based on available assessments at Week 48, mean AIMS total score change from baseline in participants with early PGIC improvement was similar to those who did not reach the early PGIC improvement threshold (-4.1 [n=35] vs -3.5 [n=41]). Mean AIMS total score change from baseline in participants with early CGI-TD improvement was similar to those who did not achieve early CGI-TD improvement (-4.2 [n=31] vs -3.5 [n=45]). AIMS response at Week 48 was also similar in those who achieved early PGIC and CGI-TD improvement (40% and 42%, respectively) compared to those who did not achieve early PGIC and CGI-TD improvement (39% and 38%, respectively). CONCLUSIONS: Results from this long-term valbenazine trial indicate that many participants achieved at least minimal patient- and clinician-reported improvement at Week 2. AIMS outcomes at Week 48 demonstrated long-term reductions in TD severity regardless of early response. More research is needed to understand the association between early improvement and long-term treatment effects, but early non-improvement based on subjective measures may not be predictive of long-term treatment failure. PRESENTED: International Congress of Parkinson's Disease and Movement Disorders; September 22-26, 2019; Nice, France. FUNDING ACKNOWLEDGEMENTS: This study was sponsored by Neurocrine Biosciences, Inc.

11.
CNS Spectr ; 25(2): 296-297, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32331030

RESUMO

BACKGROUND: Deutetrabenazine (Austedo) is approved by the FDA for treatment of tardive dyskinesia (TD) in adults. In the 12-week ARM-TD and AIM-TD studies, deutetrabenazine showed clinically significant improvements in Abnormal Involuntary Movement Scale (AIMS) scores compared with placebo, and there were low rates of overall adverse events (AEs) and discontinuations associated with deutetrabenazine. The objective of this study was to evaluate the long-term safety and tolerability of deutetrabenazine in patients with TD at 3 years. METHODS: Patients who completed ARM-TD or AIM-TD were included in this open-label, single-arm extension study, in which all patients restarted/started deutetrabenazine 12 mg/day, titrating up to a maximum total daily dose of 48 mg/day based on dyskinesia control and tolerability. The study comprised a 6-week titration period and a long-term maintenance phase. Safety measures included incidence of AEs, serious AEs (SAEs), and AEs leading to withdrawal, dose reduction, or dose suspension. Exposure-adjusted incidence rates (EAIRs; incidence/patient-years) were used for calculating AE frequencies. This analysis reports results up to Week 158. RESULTS: A total of 343 patients were enrolled (111 received placebo and 232 received deutetrabenazine in the parent studies). At the time of this analysis, 183 patients were still receiving treatment; 259 completed 1 year, 172 completed 2 years, and 41 completed 3 years. There were 623 patient-years of exposure. More than 40% of patients reached the maximum dose. EAIRs of AEs were comparable to or lower than those observed in the ARM-TD and AIM-TD short-term randomized trials of deutetrabenazine vs. placebo. The frequency of SAEs (EAIR 0.10) was similar to that observed with short-term placebo (0.33) and short-term deutetrabenazine (range 0.06-0.33) treatment. AEs leading to withdrawal (0.06), dose reduction (0.10), and dose suspension (0.05) were uncommon. CONCLUSION: These results support the safety outcomes observed in the ARM-TD and AIM-TD parent studies and the safety of deutetrabenazine for long-term use in patients with TD.Funding Acknowledgements: This study was funded by Teva Pharmaceuticals, Petach Tikva, Israel.

12.
CNS Spectr ; 25(2): 284-285, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32331048

RESUMO

BACKGROUND: In the 12-week ARM-TD and AIM-TD studies evaluating deutetrabenazine for the treatment of tardive dyskinesia (TD), the percentage of patients achieving ≥50% response was higher in the deutetrabenazine-treated group than in the placebo group. These studies also showed low rates of overall adverse events (AEs) and discontinuations associated with deutetrabenazine. The current open-label study evaluated the long-term efficacy and safety of deutetrabenazine in patients with TD. METHODS: Patients with TD who completed ARM-TD or AIM-TD could enroll in this open-label, single-arm extension study, titrating up over 6 weeks to a maximum total daily dose of deutetrabenazine 48 mg/day on the basis of dyskinesia control and tolerability. The proportion of Abnormal Involuntary Movement Scale (AIMS; items 1-7) responders was assessed based on response rates for achieving ≥50% improvement from baseline in the open-label extension study. AlMS score was assessed by local site raters for this analysis. RESULTS: 343 patients enrolled in the extension study. At Week 54 (n=249; total daily dose [mean ± standard error]: 38.6±0.66 mg), the mean percentage change from baseline in AIMS score was -40%; 48% of patients achieved a ≥50% response and 59% of those had already achieved a ≥50% response at Week 15. Further, 34% of those who had not achieved a ≥50% response at Week 15 achieved a ≥50% response at Week 54. At Week 106 (n=169; total daily dose: 39.6±0.77 mg), the mean percentage change from baseline in AIMS score was -45%; 55% of patients achieved a ≥50% response, 59% of those patients had already achieved a ≥50% response at Week 15, and 41% of those who had not achieved a ≥50% response at Week 15 but who reached Week 106 achieved a ≥50% response. At Week 132 (n=109; total daily dose: 39.7±0.97 mg), the mean percentage change from baseline in AIMS score was -61%; 55% of patients achieved a ≥50% response, 61% of those patients had already achieved a ≥50% response at Week 15, and 43% of those who had not achieved a ≥50% response at Week 15 but who reached Week 132 achieved a ≥50% response. Completer analysis suggests that long-term efficacy was not due to dose increases over time. Treatment with deutetrabenazine was generally well tolerated. There were 623 patient-years of exposure through Week 158, and exposure-adjusted incidence rates (incidence/patient-years) of adverse events of special interest were 0.01 for akathisia and restlessness, 0.07 for somnolence and sedation, 0.04 for parkinsonism, and 0.05 for depression. CONCLUSIONS: Patients who received long-term treatment with deutetrabenazine achieved response rates that were indicative of clinically meaningful long-term benefit. Results from this open-label trial suggest the possibility of increasing benefit over time with individual dose titration of deutetrabenazine. FUNDING ACKNOWLEDGEMENTS: This study was funded by Teva Pharmaceuticals, Petach Tikva, Israel.

14.
J Neurosurg ; : 1-11, 2020 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-32114534

RESUMO

OBJECTIVE: Deep brain stimulation (DBS) lead placement is increasingly performed with the patient under general anesthesia by surgeons using intraoperative MRI (iMRI) guidance without microelectrode recording (MER) or macrostimulation. The authors assessed the accuracy of lead placement, safety, and motor outcomes in patients with Parkinson disease (PD) undergoing DBS lead placement into the globus pallidus internus (GPi) using iMRI or MER guidance. METHODS: The authors identified all patients with PD who underwent either MER- or iMRI-guided GPi-DBS lead placement at Emory University between July 2007 and August 2016. Lead placement accuracy and adverse events were determined for all patients. Clinical outcomes were assessed using the Unified Parkinson's Disease Rating Scale (UPDRS) part III motor scores for patients completing 12 months of follow-up. The authors also assessed the levodopa-equivalent daily dose (LEDD) and stimulation parameters. RESULTS: Seventy-seven patients were identified (MER, n = 28; iMRI, n = 49), in whom 131 leads were placed. The stereotactic accuracy of the surgical procedure with respect to the planned lead location was 1.94 ± 0.21 mm (mean ± SEM) (95% CI 1.54-2.34) with frame-based MER and 0.84 ± 0.007 mm (95% CI 0.69-0.98) with iMRI. The rate of serious complications was similar, at 6.9% for MER-guided DBS lead placement and 9.4% for iMRI-guided DBS lead placement (RR 0.71 [95% CI 0.13%-3.9%]; p = 0.695). Fifty-seven patients were included in clinical outcome analyses (MER, n = 16; iMRI, n = 41). Both groups had similar characteristics at baseline, although patients undergoing MER-guided DBS had a lower response on their baseline levodopa challenge (44.8% ± 5.4% [95% CI 33.2%-56.4%] vs 61.6% ± 2.1% [95% CI 57.4%-65.8%]; t = 3.558, p = 0.001). Greater improvement was seen following iMRI-guided lead placement (43.2% ± 3.5% [95% CI 36.2%-50.3%]) versus MER-guided lead placement (25.5% ± 6.7% [95% CI 11.1%-39.8%]; F = 5.835, p = 0.019). When UPDRS III motor scores were assessed only in the contralateral hemibody (per-lead analyses), the improvements remained significantly different (37.1% ± 7.2% [95% CI 22.2%-51.9%] and 50.0% ± 3.5% [95% CI 43.1%-56.9%] for MER- and iMRI-guided DBS lead placement, respectively). Both groups exhibited similar reductions in LEDDs (21.2% and 20.9%, respectively; F = 0.221, p = 0.640). The locations of all active contacts and the 2D radial distance from these to consensus coordinates for GPi-DBS lead placement (x, ±20; y, +2; and z, -4) did not differ statistically by type of surgery. CONCLUSIONS: iMRI-guided GPi-DBS lead placement in PD patients was associated with significant improvement in clinical outcomes, comparable to those observed following MER-guided DBS lead placement. Furthermore, iMRI-guided DBS implantation produced a similar safety profile to that of the MER-guided procedure. As such, iMRI guidance is an alternative to MER guidance for patients undergoing GPi-DBS implantation for PD.

15.
JAMA Neurol ; 2020 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-32202612

RESUMO

Importance: One major advantage of developing large, federally funded networks for clinical research in neurology is the ability to have a trial-ready network that can efficiently conduct scientifically rigorous projects to improve the health of people with neurologic disorders. Observations: National Institute of Neurological Disorders and Stroke Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT) was established in 2011 and renewed in 2018 with the goal of being an efficient network to test between 5 and 7 promising new agents in phase II clinical trials. A clinical coordinating center, data coordinating center, and 25 sites were competitively chosen. Common infrastructure was developed to accelerate timelines for clinical trials, including central institutional review board (a first for the National Institute of Neurological Disorders and Stroke), master clinical trial agreements, the use of common data elements, and experienced research sites and coordination centers. During the first 7 years, the network exceeded the goal of conducting 5 to 7 studies, with 9 funded. High interest was evident by receipt of 148 initial applications for potential studies in various neurologic disorders. Across the first 8 studies (the ninth study was funded at end of initial funding period), the central institutional review board approved the initial protocol in a mean (SD) of 59 (21) days, and additional sites were added a mean (SD) of 22 (18) days after submission. The median time from central institutional review board approval to first site activation was 47.5 days (mean, 102.1; range, 1-282) and from first site activation to first participant consent was 27 days (mean, 37.5; range, 0-96). The median time for database readiness was 3.5 months (mean, 4.0; range, 0-8) from funding receipt. In the 4 completed studies, enrollment met or exceeded expectations with 96% overall data accuracy across all sites. Nine peer-reviewed manuscripts were published, and 22 oral presentations or posters and 9 invited presentations were given at regional, national, and international meetings. Conclusions and Relevance: NeuroNEXT initiated 8 studies, successfully enrolled participants at or ahead of schedule, collected high-quality data, published primary results in high-impact journals, and provided mentorship, expert statistical, and trial management support to several new investigators. Partnerships were successfully created between government, academia, industry, foundations, and patient advocacy groups. Clinical trial consortia can efficiently and successfully address a range of important neurologic research and therapeutic questions.

16.
Stem Cell Reports ; 14(4): 703-716, 2020 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-32220329

RESUMO

HIV-associated neurocognitive disorders (HAND) affect over half of HIV-infected individuals, despite antiretroviral therapy (ART). Therapeutically targetable mechanisms underlying HAND remain elusive, partly due to a lack of a representative model. We developed a human-induced pluripotent stem cell (hiPSC)-based model, independently differentiating hiPSCs into neurons, astrocytes, and microglia, and systematically combining to generate a tri-culture with or without HIV infection and ART. Single-cell RNA sequencing analysis on tri-cultures with HIV-infected microglia revealed inflammatory signatures in the microglia and EIF2 signaling in all three cell types. Treatment with the antiretroviral compound efavirenz (EFZ) mostly resolved these signatures. However, EFZ increased RhoGDI and CD40 signaling in the HIV-infected microglia. This activation was associated with a persistent increase in transforming growth factor α production by microglia. This work establishes a tri-culture that recapitulates key features of HIV infection in the CNS and provides a new model to examine the effects of infection, its treatment, and other co-morbid conditions.

17.
J Bacteriol ; 202(11)2020 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-32179626

RESUMO

Clostridioides difficile is one of the leading causes of antibiotic-associated diarrhea. Gut microbiota-derived secondary bile acids and commensal Clostridia that carry the bile acid-inducible (bai) operon are associated with protection from C. difficile infection (CDI), although the mechanism is not known. In this study, we hypothesized that commensal Clostridia are important for providing colonization resistance against C. difficile due to their ability to produce secondary bile acids, as well as potentially competing against C. difficile for similar nutrients. To test this hypothesis, we examined the abilities of four commensal Clostridia carrying the bai operon (Clostridium scindens VPI 12708, C. scindens ATCC 35704, Clostridium hiranonis, and Clostridium hylemonae) to convert cholate (CA) to deoxycholate (DCA) in vitro, and we determined whether the amount of DCA produced was sufficient to inhibit the growth of a clinically relevant C. difficile strain. We also investigated the competitive relationships between these commensals and C. difficile using an in vitro coculture system. We found that inhibition of C. difficile growth by commensal Clostridia supplemented with CA was strain dependent, correlated with the production of ∼2 mM DCA, and increased the expression of bai operon genes. We also found that C. difficile was able to outcompete all four commensal Clostridia in an in vitro coculture system. These studies are instrumental in understanding the relationship between commensal Clostridia and C. difficile in the gut, which is vital for designing targeted bacterial therapeutics. Future studies dissecting the regulation of the bai operon in vitro and in vivo and how this affects CDI will be important.IMPORTANCE Commensal Clostridia carrying the bai operon, such as C. scindens, have been associated with protection against CDI; however, the mechanism for this protection is unknown. Herein, we show four commensal Clostridia that carry the bai operon and affect C. difficile growth in a strain-dependent manner, with and without the addition of cholate. Inhibition of C. difficile by commensals correlated with the efficient conversion of cholate to deoxycholate, a secondary bile acid that inhibits C. difficile germination, growth, and toxin production. Competition studies also revealed that C. difficile was able to outcompete the commensals in an in vitro coculture system. These studies are instrumental in understanding the relationship between commensal Clostridia and C. difficile in the gut, which is vital for designing targeted bacterial therapeutics.

18.
J Biomech ; 104: 109741, 2020 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-32178849

RESUMO

Infant positioning in daily life, particularly in relation to active neck and back muscles, may affect spinal development, psychosocial progression, and motor milestone achievement. Yet the impact of infant body position on muscle activity is unknown. The objective of this study was to evaluate neck and back muscle activity of healthy infants in common positions and baby devices. Healthy full-term infants (n = 22, 2-6 months) participated in this experimental study. Daily sleep and positioning were reported by caregivers. Cervical paraspinal and erector spinae muscle activity was measured using surface electromyography (EMG) in five positions: lying prone, lying supine, held in-arms, held in a baby carrier, and buckled into a car seat. Mean filtered EMG signal and time that muscles were active were calculated. Paired t-tests were used to compare positions to the prone condition. Caregivers reported that infants spent 12% of daily awake time prone, 43% in supine-lying baby gear, and 44% held in-arms or upright in a baby carrier. Infants exhibited highest erector spinae activity when prone, and lowest cervical paraspinal muscle activity in the car seat. No differences were found between in-arms carrying and babywearing. This first evaluation of the muscle activity of healthy infants supports the importance of prone time in infants' early spinal development because it promotes neck and back muscle activity. Carrying babies in-arms or in baby carriers may also be beneficial to neck muscle development, while prolonged time spent in car seats or containment devices may be detrimental to spinal development.

19.
J Nerv Ment Dis ; 208(5): 397-402, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32053566

RESUMO

Aberrant threat reactivity has been implicated in the pathophysiology of posttraumatic stress disorder (PTSD); however, the literature on this association is mixed. One factor that may contribute to this inconsistent association is differences in severity of posttraumatic stress symptoms (PTSSs) across studies, but no studies have tested this hypothesis. The relation between PTSD and threat reactivity may also differ between unpredictable threats (U-threats) and predictable threats (P-threats), given burgeoning evidence to support a particular role for aberrant responding to U-threat in PTSD. The present study examined how PTSS severity relates to startle potentiation to U-threat and P-threat in a trauma-exposed community sample (N = 258). There was a negative linear, but not quadratic, relation between PTSS severity and startle potentiation to U-threat, but not P-threat. Blunted defensive responding to U-threat may therefore contribute to higher levels of PTSSs and may represent a novel treatment target for higher levels of PTSSs.

20.
Environ Sci Technol ; 54(5): 2892-2901, 2020 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-32088956

RESUMO

Aquatic ecosystems worldwide face growing threats from elevated levels of contaminants from human activities. Toxic levels of selenium (Se) shown to cause deformities in birds, fish, and mammals can transfer from parents to progeny during embryonic development or accumulate through Se-enriched diets. For migratory species that move across landscapes, tracking exposure to elevated Se is vital to mitigating vulnerabilities. Yet, traditional toxicological investigations resolve only recent Se exposure. Here, we use a novel combination of X-ray fluorescence microscopy and depositional chronology in a biomineral to reveal for the first time provenance, life stage, and duration of toxic Se exposure over the lifetime of an organism. Spinal deformities observed in wild Sacramento Splittail (Pogonichthys macrolepidotus), an imperiled migratory minnow, were attributed to elevated Se acquired through maternal transfer and juvenile feeding on contaminated prey. This novel approach paves the way for diagnosing sources, pathways, and potential for a cumulative exposure of Se relevant for conservation.


Assuntos
Cyprinidae , Selênio , Poluentes Químicos da Água , Animais , Dieta , Ecossistema , Fígado
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