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Fusobacterium nucleatum, a Gram-negative obligate anaerobe, is common to the oral microbiota, but the species is known to infect other sites of the body where it is associated with a range of pathologies. At present, little is known about the mechanisms by which F. nucleatummitigates against oxidative and nitrosative stress. Inspection of the F. nucleatumsubsp. polymorphumATCC 10953 genome reveals that it encodes a flavodiiron protein (FDP; FNP2073) that is known in other organisms to reduce NO to N2O and/or O2to H2O. FNP2073 is dicistronic with a gene encoding a multicomponent enzyme termed BCR for butyryl-CoA reductase. BCR is composed of a butyryl-CoA dehydrogenase domain (BCD), the C-terminal domain of the α-subunit of the electron-transfer flavoprotein (Etfα), and a rubredoxin domain. We show that BCR and the FDP form an α4β4heterotetramic complex and use butyryl-CoA to selectively reduce O2to H2O. The FAD associated with the Etfα domain (α-FAD) forms red anionic semiquinone (FAD•–), whereas the FAD present in the BCD domain (δ-FAD) forms the blue-neutral semiquinone (FADH•), indicating that both cofactors participate in one-electron transfers. This was confirmed in stopped-flow studies where the reduction of oxidized BCR with an excess of butyryl-CoA resulted in rapid (<1.6 ms) interflavin electron transfer evidenced by the formation of the FAD•–. Analysis of bacterial genomes revealed that the dicistron is present in obligate anaerobic gut bacteria considered to be beneficial by virtue of their ability to produce butyrate. Thus, BCR-FDP may help to maintain anaerobiosis in the colon.

The least restrictive environment (LRE) mandate has driven classroom placement decisions for the last five decades. It has been measured as the percentage of time students spend in general education contexts (i.e., Placement A: >80%; Placement B: 40-79%; Placement C: <40%). The mandate and its continuum of placements are predicated on the assumption that students can transition to less restrictive contexts, and that each placement will provide students with the skills needed to succeed in less restrictive contexts and, ultimately, in Placement A. Results from this descriptive analysis of survey responses from a sample of teachers and administrators of 98 elementary students with complex support needs indicate that less time in general education (Placements B and C) results in decreased access to single-grade classes, educator expertise, grade-aligned instructional materials, and general education curriculum. Furthermore, for most of the variables analyzed, the data suggest that Placement B is more closely aligned with Placement C than with Placement A, suggesting that it may function as a restrictive placement. We argue that current LRE implementation is resulting in placement and progress stagnation. To allow students with complex support needs to have inclusive and equitable learning opportunities, LRE must shift away from the concept of percentage of time in general education to requirements of student access to instruction on state-adopted grade-level general education standards within general education contexts and curriculum.

Physiological adaptations during pregnancy alter nutrient and energy metabolism. Creatine may be important for maintaining cellular energy homeostasis throughout pregnancy. However, the impact of pregnancy on endogenous and exogenous creatine availability has never been comprehensively explored.

Early research suggested that compulsive sexual behavior (CSB) and paraphilic interests (PI) are more prevalent in adults with primary tic disorders compared to the general population. However, recent data on this topic remain scarce. We conducted an anonymous online survey capturing data on CSB and PI in adult patients with primary tic disorders. We also explored the role of antipsychotic tic medication and the impact of neuropsychiatric comorbidities like attention-deficit hyperactivity disorder and depression. In total, 62 participants (26 females/36 males) completed the survey. The prevalence of CSB and PI were 12.9% and 19.4%, respectively. There was no association with antipsychotic medication nor with symptoms of depression. However, the presence of attention-deficit hyperactivity disorder was associated with a higher prevalence of both CSB and PI. The current results contrast with earlier reports and show that in adults with primary tic disorders, the prevalence of CSB and PI is not overly prominent.

Physical activity (PA) and weight management are critical components of an effective knee and hip osteoarthritis (OA) management plan, yet most people with OA remain insufficiently active and/or overweight. Clinicians and their care teams play an important role in educating patients with OA about PA and weight management, eliciting patient motivation to engage in these strategies, and referring patients to appropriate self-management interventions. The purpose of this review is to educate clinicians about the current public health and clinical OA guidelines for PA and weight management and highlight a variety of evidence-based self-management interventions available in community and clinical settings and online.

Tic disorders (TDs) can cause considerable functional impairment and are often associated with comorbid conditions, resulting in difficulty managing symptoms. Although several effective evidence-based interventions are available, previous research has found that caregivers of children with TDs often experience substantial burden navigating the health care system to address their child's tics.

Creatine metabolism likely contributes to energy homeostasis in the human uterus, but whether this organ synthesizes creatine and whether creatine metabolism is adjusted throughout the menstrual cycle and with pregnancy are largely unknown. This study determined endometrial protein expression of creatine-synthesizing enzymes arginine:glycine amidinotransferase (AGAT) and guanidinoacetate methyltransferase (GAMT), creatine kinase (CKBB), and the creatine transporter (SLC6A8) throughout the menstrual cycle in fertile and primary infertile women. It also characterized creatine metabolism at term pregnancy, measuring aspects of creatine metabolism in myometrial and decidual tissue. In endometrial samples, AGAT, GAMT, SLC6A8, and CKBB were expressed in glandular and luminal epithelial cells. Except for SLC6A8, the other proteins were also located in stromal cells. Irrespective of fertility, AGAT, GAMT, and SLC6A8 high-intensity immunohistochemical staining was greatest in the early secretory phase of the menstrual cycle. During the proliferative phase, staining for SLC6A8 protein was greater (P= 0.01) in the primary infertile compared with the fertile group. Both layers of the term pregnant uterus contained creatine, phosphocreatine, guanidinoacetic acid, arginine, glycine, and methionine; detectable gene and protein expression of AGAT, GAMT, CKBB, and ubiquitous mitochondrial CK (uMt-CK); and gene expression of SLC6A8. The proteins AGAT, GAMT, CKBB, and SLC6A8 were uniformly distributed in the myometrium and localized to the decidual glands. In conclusion, endometrial tissue has the capacity to produce creatine and its capacity is highest around the time of fertilization and implantation. Both layers of the term pregnant uterus also contained all the enzymatic machinery and substrates of creatine metabolism.The human uterus has the capacity to produce, transport and metabolise creatine during the menstrual cycle and at term pregnancy, with this capacity is up-regulated during the early secretory phase of the menstrual cycle.Graphical Abstract

AbstractWhen students with extensive support needs (ESN) are included in general education classrooms, they benefit from the expertise of the general education teacher. Despite the central role of the general education teacher in an inclusive classroom, little is known about their perspectives and experiences including students with ESN. The purpose of this study was to investigate general education teachers’ perspectives on inclusive education, how they support students with ESN in their classroom, and experiences that shaped their knowledge of inclusive education. We conducted five focus groups with 16 general education teachers at two elementary schools where all students with disabilities are included in general education classrooms. The general education teachers in this study expressed positive views of inclusive education and advocated for students with ESN to be included in general education classrooms. They supported students with ESN by collaborating with other teachers and providing individualized supports for students. The general education teachers emphasized the role of the school district in shaping the way they provide supports for students with ESN, and they described learning about inclusive education from other teachers. Implications for research and practice are presented and are focused on advancing inclusive education for students with ESN.

ABSTRACTAir pollution and odour annoyance caused by livestock farming often leads to tension and distrust between livestock farmers and non-farming residents in agricultural areas in the Netherlands. In this study, we conducted a citizen science project to measure air quality and odour annoyance in collaboration with farmers, non-farming residents, and the municipality. The aim was to explore whether measuring together through citizen science influenced (1) mutual trust between stakeholders, and (2) their trust in the scientific process and outcomes of this project. We conducted semi-structured interviews with participants before and after participating in the project. Results indicated that measuring together did not improve trust between farmers and their neighbours. However, non-farming residents did express more trust in the municipality and perceived their interests were more fairly taken into account. Moreover, all participants expressed trust in the scientific process and outcomes regarding their ‘own’ measurements; contrasting the distrust they expressed in the ‘official’ governmental data. Control and transparency due to their own involvement, involvement of an independent scientific institute and positive interactions with the scientists’ contributed to this trust. These results highlight the need for further research on the potential impact of citizen science projects on trust in different contexts.

During the COVID-19 pandemic, rapid integration of telehealth into antenatal care occurred to support ongoing maternity care. A programme of this scale had not been previously implemented. We evaluated whether telehealth-integrated antenatal care in an Australian public health system could achieve pregnancy outcomes comparable to those of conventional care to assess its safety and efficacy.

The drug overdose epidemic in the US necessitates detailed and timely data to inform public health responses. In this article we describe how an electronic health record (EHR) data-sharing collaboration across health systems in Minnesota that was developed in response to the COVID-19 pandemic was adapted to monitor trends in substance use–related hospital and emergency department (ED) visits. We found large increases in methamphetamine- and opioid-involved hospital and ED visits. Throughout the study period, Native American, Black, and multiple-race people experienced the highest rates of drug-involved hospital and ED visits. Monitoring drug-involved health care use through EHR data has the potential to help public health officials detect trends in near real time before mortality spikes and may also inform early intervention. The use of EHR data also allows for detailed monitoring of the impact of the drug overdose epidemic across racial and ethnic groups.

In response to the COVID-19 pandemic, Victoria’s largest maternity service provider implemented a telehealth-integrated antenatal care (ANC) schedule for high- and low-risk pregnancies. The program has been maintained since March 2020. Given ever-increasing healthcare costs, economic evaluation is crucial to ensure value and guide ongoing use.

Induction of labour is one of the most common obstetric interventions globally. Balloon catheters and vaginal prostaglandins are widely used to ripen the cervix in labour induction. We aimed to compare the effectiveness and safety profiles of these two induction methods.

Since 2010, the rates of induction have risen in Australia (from 25% to 35%) and the United Kingdom (from 20% to 32%). This may be an indication that induction has become more acceptable among women and health providers. In women with unripe cervices, mechanical methods, such as balloon catheters, and pharmacological methods, such as vaginal prostaglandins, are commonly used for cervical ripening to induce labor. Yet, induction poses the risks of cesarean delivery (CD), as well as maternal and neonatal morbidity and mortality. Finding the optimal method to induce labor is important to reduce these risks. The aim of this study was to compare the safety and effectiveness of balloon catheters and vaginal prostaglandins for the induction of labor.This was a meta-analysis using individual patient data from published and unpublished randomized controlled trials that had completed data collection between March 19, 2019, and May 1, 2021. A recent Cochrane review provided additional trials completed before March 19. Eligible trials were those that compared single- or double-balloon catheters with the vaginal prostaglandins, misoprostol, or dinoprostone. The analysis included only women with viable, singleton pregnancies with no exclusion for parity or membrane status. The primary outcomes were CD, a composite of adverse maternal outcomes, and a composite of adverse perinatal outcomes.A total of 12 trials, representing 5460 deliveries, were included in the analysis. Overall, the crude incidence of CD was 27%, the perinatal composite was 13.6%, and the maternal composite was 22.7%. No significant differences in the rate of CD were found between patients who received a balloon catheter and those given vaginal prostaglandin to induce labor (12 trials, 5414 women; adjusted odds ratio [aOR], 1.09; 95% confidence interval [CI], 0.95–1.24). The adverse perinatal composite was lower among those who received balloon catheters (10 trials, 4452 neonates; aOR, 0.80 [95% CI, 0.70–0.92]; I2= 0%). There were no significant differences for the adverse maternal composite measure (10 trials, 4326 women; aOR, 1.02 [95% CI, 0.89–1.18]; I2= 0%). Balloon catheters were associated with fewer instrumental vaginal births than vaginal prostaglandins (10 trials, 4888 women; aOR, 0.82 [95% CI, 0.68–1.00]). In a subgroup analysis, there was a lower chance of the adverse perinatal composite with the use of a single-balloon catheter versus vaginal prostaglandins (9 trials, 2683 neonates; aOR, 0.84 [95% CI, 0.71–0.99]).This study found that labor induction with balloon catheters and vaginal prostaglandins was equally effective and had similar rates of CD and adverse composite maternal outcome. However, induction with a balloon catheter was observed to improve perinatal outcomes.

AbstractSchoolwide Positive Behavioral Interventions and Supports (SWPBIS) is a framework intended to benefit all students in a school. However, recent research suggests that students with significant disabilities may not fully participate in SWPBIS. Given the complex reasons for varied involvement in SWPBIS (e.g., student educational placement), the purpose of this study was to investigate expert perspectives on the extent to which students with significant disabilities should be included in SWPBIS. Overall, experts agreed students with significant disabilities should be included in all tiers of SWPBIS, receive instruction in schoolwide rules and expectations, and have the opportunity to participate in schoolwide reward systems. Experts shared differing perspectives on the ways behavior violations of students with significant disabilities should be documented.

Background: FSHD is caused by specific genetic mutations resulting in activation of the Double Homeobox 4 gene (DUX4). DUX4 targets hundreds of downstream genes eventually leading to muscle atrophy, oxidative stress, abnormal myogenesis, and muscle inflammation. We hypothesized that DUX4-induced aberrant expression of genes triggers a sustained autoimmune response against skeletal muscle cells.Objective: This study aimed at the identification of autoantibodies directed against muscle antigens in FSHD. Moreover, a possible relationship between serum antibody reactivity and DUX4 expression was also investigated.Methods: FSHD sera (N?=?138, 48±16 years, 48% male) and healthy control sera (N?=?20, 47±14 years, 50% male) were analyzed by immunoblotting for antibodies against several skeletal muscle protein extracts: healthy muscle, FSHD muscle, healthy and FSHD myotubes, and inducible DUX4 expressing myoblasts. In addition, DUX4 expressing myoblasts were analyzed by immunofluorescence with FSHD and healthy control sera.Results: The results showed that the reactivity of FSHD sera did not significantly differ from that of healthy controls, with all the tested muscle antigen extracts. Besides, the immunofluorescent staining of DUX4-expressing myoblasts was not different when incubated with either FSHD or healthy control sera.Conclusion: Since the methodology used did not lead to the identification of disease-specific autoantibodies in the FSHD cohort, we suggest that autoantibody-mediated pathology may not be an important disease mechanism in FSHD. Nevertheless, it is crucial to further unravel if and which role the immune system plays in FSHD pathogenesis. Other innate as well as adaptive immune players could be involved in the complex DUX4 cascade of events and could become appealing druggable targets.

Little evidence is available on the use of telehealth for antenatal care. In response to the COVID-19 pandemic, we developed and implemented a new antenatal care schedule integrating telehealth across all models of pregnancy care. To inform this clinical initiative, we aimed to assess the effectiveness and safety of telehealth in antenatal care.

Prenatal exposure to alcohol leads to a greater incidence of many cardiovascular‐related diseases, presumably via a mechanism that may involve increased oxidative stress. An agonist of peroxisome proliferator‐activated receptor gamma (PPARγ; rosiglitazone) has been shown to suppress alcohol‐induced neuroinflammation and oxidative stress. The goal of this study was to determine whether acute and chronic treatment with rosiglitazone could restore or prevent impaired nitric oxide synthase (NOS)‐dependent responses of cerebral arterioles in male and female adult (14–16 weeks old) rats exposed to alcohol in utero. We fed Sprague‐Dawley dams a liquid diet with or without 3% ethanol for the duration of their pregnancy (21–23 days). In the first series of studies, we examined the reactivity of cerebral arterioles to eNOS‐ (ADP), nNOS‐dependent (NMDA), and NOS‐independent agonists in male and female adult rats before and during acute (1 hour) topical application of rosiglitazone (1 µM). In a second series of studies, we examined the influence of chronic treatment with rosiglitazone (3 mg/kg/day in drinking water for 2–3 weeks) on the responses of cerebral arterioles in male and female adult rats exposed to alcohol in utero. We found that in uteroexposure to alcohol similarly reduced responses of cerebral arterioles to ADP and NMDA, but not to nitroglycerin in male and female adult rats. In addition, acute treatment of the male and female adult rats with rosiglitazone similarly restored this impairment in cerebral vascular function to that observed in controls. We also found that chronic treatment with rosiglitazone prevented impaired vascular function in male and female adult rats that were exposed to alcohol in utero. PPARγ activation may be an effective and relevant treatment to reverse or prevent cerebral vascular abnormalities associated with prenatal exposure to alcohol. Prenatal exposure to alcohol impairs critical vasodilator pathways of cerebral arterioles via an increase in oxidative stress. We found that acute and chronic treatment with an agonist of PPARg (rosiglitazone) prevented impaired vasodilation. Our findings have broad implications regarding mechanisms by which prenatal exposure to alcohol impairs neurovascular coupling, which may be an important contributing factor in the pathogenesis of symptoms associated with fetal alcohol spectrum disorders (FASD) in adults, i.e., cognitive decline, behavioral disorders, dementia, seizures and perhaps stroke.

Affecting over 32 million US adults, osteoarthritis (OA) is a complex and serious disease that warrants particular clinical attention given its extensive patient and economic burden, combined with its connection to other chronic conditions and the fact that there is currently no cure. The most effective management and prevention strategies for OA require a partnership between providers and patients, pairing clinical care with patient self-management activities such as physical activity, weight loss, education, and injury prevention.

FSHD is caused by specific genetic mutations resulting in activation of the Double Homeobox 4 gene (DUX4). DUX4 targets hundreds of downstream genes eventually leading to muscle atrophy, oxidative stress, abnormal myogenesis, and muscle inflammation. We hypothesized that DUX4-induced aberrant expression of genes triggers a sustained autoimmune response against skeletal muscle cells. This study aimed at the identification of autoantibodies directed against muscle antigens in FSHD. Moreover, a possible relationship between serum antibody reactivity and DUX4 expression was also investigated. FSHD sera (N = 138, 48±16 years, 48%male) and healthy control sera (N = 20, 47±14 years, 50%male) were analyzed by immunoblotting for antibodies against several skeletal muscle protein extracts: healthy muscle, FSHD muscle, healthy and FSHD myotubes, and inducible DUX4 expressing myoblasts. In addition, DUX4 expressing myoblasts were analyzed by immunofluorescence with FSHD and healthy control sera. The results showed that the reactivity of FSHD sera did not significantly differ from that of healthy controls, with all the tested muscle antigen extracts. Besides, the immunofluorescent staining of DUX4-expressing myoblasts was not different when incubated with either FSHD or healthy control sera. Since the methodology used did not lead to the identification of disease-specific autoantibodies in the FSHD cohort, we suggest that autoantibody-mediated pathology may not be an important disease mechanism in FSHD. Nevertheless, it is crucial to further unravel if and which role the immune system plays in FSHD pathogenesis. Other innate as well as adaptive immune players could be involved in the complex DUX4 cascade of events and could become appealing druggable targets.

(Abstracted from Lancet2021;398:41–52)In response to the COVID-19 pandemic, health care systems around the world had to quickly adapt to protect patients and staff from exposure. In Australia, a government initiative was launched to temporarily change public health funding to support the use of telehealth.

Lanthionine synthase from the oral bacterium Fusobacterium nucleatumis a fold type II pyridoxal-5′-phosphate (PLP)-dependent enzyme that catalyzes the β-replacement of l-cysteine by a second molecule of l-cysteine to form H2S and l-lanthionine. The meso-isomer of the latter product is incorporated into the F. nucleatumpeptidoglycan layer. Herein, we investigated the catalytic role of S224, which engages in hydrogen-bond contact with the terminal carboxylate of l-lanthionine in the closed conformation of the enzyme. Unexpectedly, the S224A variant elicited a 7-fold increase in the turnover rate for H2S and lanthionine formation and a 70-fold faster rate constant for the formation of the α-aminoacrylate intermediate compared to the wild-type enzyme. Presteady state kinetic analysis further showed that the reaction between S224A and l-cysteine leads to the formation of the more reactive ketoenamine tautomer of the α-aminoacrylate. The α-aminoacrylate with the protonated Schiff base is not an observable intermediate in the analogous reaction with the wild type, which may account for its attenuated kinetic properties. However, the S224A substitution is detrimental to other aspects of the catalytic cycle; it facilitates the α,β-elimination of l-lanthionine, and it weakens the enzyme’s catalytic preference for the formation of l-lanthionine over that of l-cystathionine.

Gilles de la Tourette syndrome (TS) is a complex neurodevelopmental disorder characterized by the presence of motor and vocal tics as well as psychiatric comorbidities such as attention-deficit/hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), depression, and anxiety. The underlying cause of the disease is still unknown, but several lines of evidence suggest a paramount role of the dopaminergic system. Based on the clinical observation that cannabis-based medicine including cannabis and delta-9-tetrahydrocannabinol (THC, dronabinol) may improve TS, alternatively, an involvement of the endocannabinoid system (ECS) has been suggested. In this study we measured cerebrospinal fluid (CSF) levels of the two most important endocannabinoids “N”-arachidonoylethanolamine (AEA, anandamide) and 2-arachidonoylglycerol (2-AG), the endocannabinoid-like molecule palmitoyl ethanolamide (PEA), and the lipid arachidonic acid (AA) in a sample of adult patients with TS (n= 20) compared with controls (n= 19) using liquid-liquid lipid extraction and simultaneous quantification by liquid chromatography multiple reaction monitoring (LC/MRM). CSF levels of AEA (p= 0.0018), 2-AG (p= 0.0003), PEA (p= 0.02), and AA (p< 0.0001) were significantly increased in TS compared with controls. Levels of 2-AG correlated with the severity of comorbid ADHD (p< 0.01). This is the first study, demonstrating alterations in the ECS suggesting an involvement of this system in the pathophysiology of TS. It can be speculated that elevated endocannabinoid levels either represent secondary changes in order to compensate for alterations in other neurotransmitter systems such as the dopaminergic system, are simply an epiphenomenon or, alternatively, represent the primary cause of TS.