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Inferior sinus venosus defect associated with left hepatic vein drainage to the coronary sinus is an extremely rare condition. We report the case of a 41-year-old man suffering from pulmonary arterial hypertension related to this unusual CHD. Planning of heart-lung transplantation in this case required accurate anatomical description.

The neurophysiology of cells and tissues are monitored electrophysiologically and optically in diverse experiments and species, ranging from flies to humans. Understanding the brain requires integration of data across this diversity, and thus these data must be findable, accessible, interoperable, and reusable (FAIR). This requires a standard language for data and metadata that can coevolve with neuroscience. We describe design and implementation principles for a language for neurophysiology data. Our open-source software (Neurodata Without Borders, NWB) defines and modularizes the interdependent, yet separable, components of a data language. We demonstrate NWB's impact through unified description of neurophysiology data across diverse modalities and species. NWB exists in an ecosystem, which includes data management, analysis, visualization, and archive tools. Thus, the NWB data language enables reproduction, interchange, and reuse of diverse neurophysiology data. More broadly, the design principles of NWB are generally applicable to enhance discovery across biology through data FAIRness., Competing Interests: OR, AT, RL, SG, PB, IS, LN, KS, LF, KB No competing interests declared, BD BD is the Founder and CEO of CatalystNeuro, a software consulting company that works with neurophysiology labs to build state-of-the-art data management workflows. Much of this work involves converting data from lab-specific formats to the NWB standard, and enhancing analysis and visualization tools to read and write NWB data. As such, Dr. Dichter has a personal financial state in the success of the NWB standard, LN LN is a software engineer at MBF Bioscience, a for-profit biotech company that develops microscopy software and hardware, (© 2022, Rübel, Tritt, Ly et al.)

New methods are needed for global lipid profiling due to the complex chemical structures and diverse physicochemical properties of lipids. Herein we introduce a robust data workflow to unambiguously select lipid features from serum ether extracts by multisegment injection-nonaqueous capillary electrophoresis-mass spectrometry (MSI-NACE-MS). An iterative three-stage screening strategy is developed for nontargeted lipid analyses when using multiplexed electrophoretic separations coupled to an Orbitrap mass analyzer under negative ion mode. This approach enables the credentialing of 270 serum lipid features annotated based on their accurate mass and relative migration time, including 128 ionic lipids reliably measured (median CV ≈ 13%) in most serum samples (>75%) from nonalcoholic steatohepatitis (NASH) patients ( n = 85). A mobility map is introduced to classify charged lipid classes over a wide polarity range with selectivity complementary to chromatographic separations, including lysophosphatidic acids, phosphatidylcholines, phosphatidylinositols, phosphatidylethanolamines, and nonesterified fatty acids (NEFAs). Serum lipidome profiles were also used to differentiate high- from low-risk NASH patients using a k -means clustering algorithm, where elevated circulating NEFAs (e.g., palmitic acid) were associated with increased glucose intolerance, more severe liver fibrosis, and greater disease burden. MSI-NACE-MS greatly expands the metabolome coverage of conventional aqueous-based CE-MS protocols and is a promising platform for large-scale lipidomic studies.

Objectives: This study aimed to assess the incidence, associated factors, and outcomes of atrial arrhythmias in adults with atrioventricular septal defect (AVSD)., Background: Data regarding atrial arrhythmias in adults with AVSD are particularly scarce., Methods: Data were analyzed from a multicentric cohort of adult patients with AVSD. Lifetime cumulative incidences of atrial arrhythmias were studied. Multiple logistic regression models were used to identify risk factors., Results: A total of 391 patients (61.6% women) were enrolled with a mean age of 36.3 ± 16.3 years and a mean follow-up of 17.3 ± 14.2 years after initial surgical repair. Overall, 98 patients (25.1%) developed at least 1 episode of atrial arrhythmia at a mean age of 39.2 ± 17.2 years. The mean ages of patients at first episode of intra-atrial re-entrant tachycardia (IART)/ focal atrial tachycardia (FAT) and atrial fibrillation were 33.7 ± 15.3 and 44.3 ± 16.5 years, respectively. The lifetime risks for developing atrial arrhythmia to ages 20, 40, and 60 years were 3.7%, 17.8%, and 55.3%, respectively. IART/FAT was the leading arrhythmia until the age of 45, then atrial fibrillation surpassed IART/FAT. Age (odds ratio [OR]: 1.4; 95% confidence interval [CI]: 1.2-1.6), number of cardiac surgeries (OR: 4.1; 95% CI: 2.5-6.9), left atrial dilatation (OR: 3.1; 95% CI: 1.4-6.8), right atrial dilatation (OR: 4.1; 95% CI: 1.7-10.3), and moderate or severe left atrioventricular valve regurgitation (OR: 3.7; 95% CI: 1.2-11.7) were independently associated with a higher risk of atrial arrhythmias, whereas the type of AVSD and the age at repair were not. The occurrence of atrial arrhythmias was associated with pacemaker implantation (41.8% vs. 8.5%; P < 0.001), heart failure (24.5% vs. 1.0%; P < 0.001), and cerebrovascular accidents (11.2% vs. 3.4%; P = 0.007)., Conclusions: The lifetime risk of atrial arrhythmias in patients with AVSD is considerable with more than half of patients developing ≥1 atrial arrhythmia by the age of 60 and is associated with a significant morbidity. The risk in partial/intermediate AVSD is as high as in complete AVSD and is not impacted by age at repair., Competing Interests: Funding Support and Author Disclosures The authors have received a research grant from the French Institute of Health and Medical Research and the Fédération Française de Cardiologie., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to assess the diagnostic performances of 18 F-fluorodeoxyglucose ( 18 F-FDG) positron emission tomography (PET)/computed tomography (CT) in congenital heart disease (CHD) patients with pulmonary prosthetic valve or conduit endocarditis (PPVE) suspicion., Background: PPVE is a major issue in the growing CHD population. Diagnosis is challenging, and usual imaging tools are not always efficient or validated in this specific population. Particularly, the diagnostic yield of 18 F-FDG PET/CT remains poorly studied in PPVE., Methods: A retrospective multicenter study was conducted in 8 French tertiary centers. Children and adult CHD patients who underwent 18 F-FDG PET/CT in the setting of PPVE suspicion between January 2010 and May 2020 were included. The cases were initially classified as definite, possible, or rejected PPVE regarding the modified Duke criteria and finally by the Endocarditis Team consensus. The result of 18 F-FDG PET/CT had been compared with final diagnosis consensus used as gold-standard in our study., Results: A total of 66 cases of PPVE suspicion involving 59 patients (median age 23 years, 73% men) were included. Sensitivity, specificity, positive predictive value, and negative predictive value of 18 F-FDG PET/CT in PPVE suspicion were respectively: 79.1% (95% CI: 68.4%-91.4%), 72.7% (95% CI: 60.4%-85.0%), 91.9% (95% CI: 79.6%-100.0%), and 47.1% (95% CI: 34.8%-59.4%). 18 F-FDG PET/CT findings would help to correctly reclassify 57% (4 of 7) of possible PPVE to definite PPVE., Conclusions: Using 18 F-FDG PET/CT improves the diagnostic accuracy of the Duke criteria in CHD patients with suspected PPVE. Its high positive predictive value could be helpful in routine to shorten diagnosis and treatment delays and improve clinical outcomes., Competing Interests: Funding Support and Author Disclosures Drs Venet, Jalal, and Thambo were supported by the French Government as part of the “Investments of the future” program managed by the National Research Agency (grant reference ANR-10-IAHU-04). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

In many patients, ostensible idiopathic attention deficit-hyperactivity disorder (ADHD) may actually stem from covert prenatal alcohol exposure (PAE), a treatment-relevant distinction. This study attempted a receiver-operator characteristic (ROC) classification of children with ADHD into those with PAE (ADHD+PAE) and those without (ADHD-PAE) using neurobehavioral instruments alongside magnetic resonance spectroscopy (MRS) and diffusion tensor imaging (DTI) of supraventricular brain white matter. Neurobehavioral, MRS, and DTI endpoints had been suggested by prior findings. Participants included children aged 8-13 years, 23 with ADHD+PAE, 19 with familial ADHD-PAE, and 28 typically developing (TD) controls. With area-under-the-curve (AUC) >0.90, the Conners 3 Parent Rating Scale Inattention (CIn) and Hyperactivity/Impulsivity (CHp) scores and the Behavioral Regulation Index (BRI) of the Behavior Rating Inventory of Executive Function (BRIEF2) excellently distinguished the clinical groups from TD, but not from each other (AUC < 0.70). Combinations of MRS glutamate (Glu) and N-acetyl-compounds (NAA) and DTI mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD), and fractional anisotropy (FA) yielded "good" (AUC > 0.80) discrimination. Neuroimaging combined with CIn and BRI achieved AUC 0.72 and AUC 0.84, respectively. But neuroimaging combined with CHp yielded 14 excellent combinations with AUC ≥ 0.90 (all p < 0.0005), the best being Glu·AD·RD·CHp/(NAA·FA) (AUC 0.92, sensitivity 1.00, specificity 0.82, p < 0.0005). Using Cho in lieu of Glu yielded AUC 0.83. White-matter microstructure and metabolism may assist efforts to discriminate ADHD etiologies and to detect PAE, beyond the ability of commonly used neurobehavioral measures alone., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Sparse data exists on the utility of individual serum non-esterified fatty acids (NEFAs) as clinical and dietary biomarkers and how reporting methods could affect these associations. We investigated the associations of 19 serum NEFAs expressed as µM or mol%, with self-reported dietary intake data, and cardiometabolic health indicators in pregnant women., Methods: In this cross-sectional study, 273 pregnant women in their second trimester each completed a semi-quantitative food-frequency questionnaire and provided fasting serum samples. Comprehensive serum NEFA analysis was performed by multisegment injection-nonaqueous capillary electrophoresis-mass spectrometry. We evaluated the associations of NEFAs using two different reporting methods, with diet quality, specific foods intake, and measures of adiposity and glucose homeostasis., Results: Consistently stronger dietary correlations were observed when expressed as mol%. Serum ω-3 NEFAs were associated with diet quality and fish/fish oil daily servings (DHA mol%, r= 0.37; p = 4.8e-10), and odd-chain NEFAs were associated with full-fat dairy intake (15:0 mol%, r = 0.23; p = 9.0e-5). Glucose intolerance was positively associated with odd chain NEFAs as expressed in µM (r = 0.21; p= 0.001) but inversely associated when expressed as mol% (r = -0.31; p= 2.2e-7). In contrast, monounsaturated NEFAs (µM and mol%) had robust positive associations with pre-pregnancy BMI, second trimester skin-fold thickness, glycated hemoglobin, fasting glucose, and glucose intolerance., Conclusions: This study demonstrates the utility of specific NEFAs and their sub-classes as viable dietary and clinical biomarkers when reported as their relative proportions. More research is needed to investigate inconsistencies between absolute concentrations and relative proportions when reporting fatty acids., (Copyright © 2021. Published by Elsevier Ltd.)

Objectives: Discriminatory attitudes (DA) of dental surgeons towards PLWHIV may hinder their access to oral health care. The objective of this study was to identify the factors associated with the discriminatory attitudes of dentists towards PLHIV in C&#244;te d&#8217;Ivoire., Methods: This was a cross-sectional study conducted on a randomly selected sample of dentists in Abidjan. The data collected were: their socio-professional characteristics, their knowledge of HIV/AIDS, their perceptions and attitudes towards PLWHIV, and whether they had received continuing education or sensitization on HIV/AIDS. Discriminatory attitudes was a binary variable, defined from the combination of four criteria. Numbers and percentages were calculated for all variables. The risk of having DA was estimated by the odds ratio., Results: A total of 120 dentists were surveyed, 43.3% of whom were women and 39.2% from the private sector. They did not know the routes of transmission (29.2%) and the oral pathologies associated with HIV (62.5%). Their perceptions were dominated by the fear of being contaminated during care (69.2%). The frequency of DA was estimated at 69.2%. The main associated factors were: female gender; lack of knowledge of HIV/AIDS-related oral pathologies, lack of the risk of HIV transmission after blood exposure accident, and ignorance of the existence of a law on the protection of PLWHA; and fear of being contaminated., Conclusion: This study reveals that the DA of dental surgeons with regard to PLWHIV in C&#244;te d&#8217;Ivoire are mainly the result of poor knowledge of the disease.

Two hundred patients were refereed for advanced cancer to the oncology department of Luxembourg Hospital in Bamako. All these patients reported intense pain (88 %) which was only treated before admission by OMS level 1 analgesics. It clearly shows that cancer pain is undertreated in Malian peripheral sanitary structures. After evaluation of the pain by analog visual and verbal scales patients, the appropriate analgesic drugs such as morphine (OMS level 3) were given. A control of the pain was obtained in all the patients (100 %) with a dramatic improvement in quality of life. This study emphasizes the need for a pain control program at the Malian state level with a basic education of care givers, hospital-centric networks and access to morphine and opioids at the different levels involved in cancer management., (Copyright © 2021. Published by Elsevier Masson SAS.)

Body dysmorphic disorder (BDD) is characterized by preoccupations with misperceptions of one's physical appearance. Previous neuroimaging studies in BDD have yet to examine dynamic functional connectivity (FC) patterns between brain areas, necessary to capture changes in activity in response to stimuli and task conditions. We used Leading Eigenvector Dynamics Analysis to examine whole-brain dynamic FC from fMRI data during an own-face viewing task in 29 unmedicated adults with BDD with facial concerns and 30 healthy controls. The task involved two parts: (1) unconstrained, naturalistic viewing and (2) holding visual attention in the center of the image, to reduce scanning and fixation on perceived facial flaws. An FC state consisting of bilateral medial orbitofrontal cortex regions occurred significantly less often during the visual attention condition and afterward during the unconstrained face viewing in BDD participants, compared to the first unconstrained face viewing, a pattern that differed from controls. Moreover, the probability of this state during the second unconstrained face viewing was associated with severity of obsessions and compulsions and degree of poor insight in BDD, suggesting its clinical significance. These findings have implications for understanding the pathophysiology of own-face viewing in BDD and how it is affected by modification of viewing patterns, which may have implications for novel perceptual retraining treatment designs., (© 2021. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Background: To date, clinical trials have been underpowered to demonstrate a benefit from ACE inhibitors (ACEis) or angiotensin II receptor blockers (ARBs) in preventing systemic right ventricle (sRV) failure and disease progression in patients with transposition of the great arteries (TGA). This observational study aimed to estimate the effect of ACEi and ARB on heart failure (HF) incidence and mortality in a large population of patients with an sRV., Methods: Data on all patients with an sRV under active follow-up at two tertiary centres between January 2007 and September 2018 were studied. The effect of ACEi and ARB on the incidence of HF and mortality was estimated using a propensity score weighting approach to control confounding., Results: Among the 359 patients with an sRV (32.2 (IQR 26.4-38.3) years, 59.3% male, 66% complete TGA with atrial switch repair and 34% congenitally corrected TGA), 79 (22%) had a moderate to severe sRV dysfunction and 138 (38%) were treated with ACEi or ARB. Fourteen (3.6%) patients died, 8 (2.1%) underwent heart transplantation and 46 (11.8%) had a new HF event over a median follow-up of 7.1 (IQR 4.0-9.4) years. On multivariate Cox analysis with adjustment using propensity score weighting approaches, ACEi or ARBs treatment was not significantly associated with a lower HF incidence or mortality in patients with an sRV., Conclusions: Despite significant neurohormonal activation described in patients with an sRV, there is still no evidence of a beneficial effect of ACEi or ARB on morbidity and mortality in this population., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Noonan syndrome (NS) is a genetic disorder characterized by facial dysmorphism, congenital heart disease, and short stature. In very rare cases, patients with this syndrome have coronary disease. Their management and prognosis are currently unclear. We have described 4 cases of coronary aneurysms/coronary ectasia and 1 case of a single coronary artery in patients with adult Noonan syndrome, followed in a medical and surgical center of adult congenital heart disease. The average age was 49.4years old. The majority of them had both pulmonary stenosis and interauricular communication. None had symptoms of angina, at rest, or with stress. Only one patient who had any structural heart disease, had a thrombotic complication with chronic occlusion of the right coronary and anterior inter ventricular artery, fortuitous finding, with no ischemic signs to functional tests, treated only with anti-vitamin K. Finally, any deaths have also been reported in our series. Coronary artery diseases essentially coronary aneurysm/ectasia remain a rare condition in adult patients with NS. Evolution is unknown and complications such as coronary artery thrombosis do not necessarily require surgical treatment., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Attention-deficit hyperactivity disorder (ADHD) is common in patients with (ADHD+PAE) and without (ADHD-PAE) prenatal alcohol exposure (PAE). Many patients diagnosed with idiopathic ADHD actually have covert PAE, a treatment-relevant distinction. To improve differential diagnosis, we sought to identify brain differences between ADHD+PAE and ADHD-PAE using neurobehavioral, magnetic resonance spectroscopy, and diffusion tensor imaging metrics that had shown promise in past research. Children 8-13 were recruited in three groups: 23 ADHD+PAE, 19 familial ADHD-PAE, and 28 typically developing controls (TD). Neurobehavioral instruments included the Conners 3 Parent Behavior Rating Scale and the Delis-Kaplan Executive Function System (D-KEFS). Two dimensional magnetic resonance spectroscopic imaging was acquired from supraventricular white matter to measure N-acetylaspartate compounds, glutamate, creatine + phosphocreatine (creatine), and choline-compounds (choline). Whole brain diffusion tensor imaging was acquired and used to to calculate fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity from the same superventricular white matter regions that produced magnetic resonance spectroscopy data. The Conners 3 Parent Hyperactivity/Impulsivity Score, glutamate, mean diffusivity, axial diffusivity, and radial diffusivity were all higher in ADHD+PAE than ADHD-PAE. Glutamate was lower in ADHD-PAE than TD. Within ADHD+PAE, inferior performance on the D-KEFS Tower Test correlated with higher neurometabolite levels. These findings suggest white matter differences between the PAE and familial etiologies of ADHD. Abnormalities detected by magnetic resonance spectroscopy and diffusion tensor imaging co-localize in supraventricular white matter and are relevant to executive function symptoms of ADHD., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aims: Infective endocarditis is a severe infection which can occur in adult patients with congenital heart disease. We aimed to determine outcomes and risk factors of death in adult congenital heart disease and to investigate differences with infective endocarditis in non-congenital heart disease., Methods and Results: Between March 2000 and June 2018, 671 consecutive episodes of infective endocarditis in adult patients were retrospectively recorded. Cases were classified according to the modified Duke classification. All adult congenital heart disease cases were managed by infectious disease specialists and adult congenital heart disease cardiologists. During this period, 142 infective endocarditis episodes (21%) occurred in adult congenital heart disease patients with simple (46.5%), moderate (21.1%), or complex (32.4%) congenital heart disease. In-hospital mortality was 12.7%. The strongest predictive factors of in-hospital death in multivariate analysis were complexity of congenital heart disease (odds ratio (OR) 8.02, 95% confidence interval (CI) 1.53-42.07), age (OR 1.05, 95% CI 1.00-1.19) and white blood cell count 12 g/L or greater (OR 8.72, 95% CI 2.42-31.43). Patients with congenital heart disease were significantly younger (median age 36 vs. 67 years, P <0.001), had undergone more redo cardiac surgeries (35.7% vs. 11.3%, P <0.01) and presented with more right-sided infective endocarditis (39.4% vs. 7.9%, P <0.01) than patients without congenital heart disease. Congenital heart disease was associated with two-fold lower in-hospital mortality rates (OR 0.37, 95% CI 0.19-0.74), independently of age, gender, obesity, renal function and side of infective endocarditis., Conclusion: Although mortality associated with infective endocarditis is lower in adult patients with congenital heart disease than patients without congenital heart disease, infective endocarditis mortality is particularly high in patients with complex congenital heart disease. Education and prevention about the risk of infective endocarditis is essential, especially in this group.

Short-chain fatty acids (SCFAs) and electrolytes are major constituents of human feces involved in maintaining gastrointestinal homeostasis that underlie complex diet, host and microbiome interactions. Reliable quantification of SCFAs and electrolytes is challenging given the heterogeneity of stool specimens from pediatric patients with diarrhea-predominate inflammatory bowel disease (IBD). Herein, we introduce two validated methods for determination of 3 SCFAs and 5 electrolytes consistently quantified from fecal extracts when using capillary electrophoresis with indirect UV detection (CE-iUV), where concentrations are normalized to total dried weight (mmol/kg d.w.). Lyophilization facilitates sample handling and extraction of heterogeneous stool specimens (∼ 15 mg) from a cohort of children with Crohn's disease (CD, n = 12) and ulcerative colitis (UC, n = 10) treated with exclusive enteral nutrition (EEN) or corticosteroid (CS) therapy to induce remission, respectively. Good technical precision (mean CV = 13 %, n = 14) and accuracy (recovery from 84 to 116%) is demonstrated for SCFAs and electrolytes from freeze dried stool extracts using a modified Bligh-Dyer protocol with low micromolar detection limits (∼ 2-15 μM). Fecal butyrate is 2.6-fold higher in CD as compared to UC patients (effect size = 1.51; p = 0.00291), and there is a strong co-linearity between fecal butyrate and acetate (r = 0.835) unlike propionate, which is correlated with fecal calprotectin (r = 0.517), a protein biomarker of intestinal inflammation. Also, a longitudinal study of matching stool samples collected from a sub-set of IBD patients revealed about a 7-fold enrichment in magnesium and calcium following 4 weeks of EEN as compared to baseline (F > 4.1 ; p < 0.05) unlike the CS treatment arm with no changes in other fecal SCFAs and electrolytes, including sodium, potassium, and ammonium. CE-iUV enables rapid fecal SCFA and electrolyte determination as required for new insights into the role of gut dysbiosis in IBD, as well as treatment monitoring of nutritional interventions that stabilize the disease course in affected children., Competing Interests: Declaration of Competing Interest The authors report no declarations of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Critical access hospitals (CAHs) play an important role in providing access to care for many patients in rural communities. Prior studies have shown that these facilities are able to provide timely and quality care for patients who undergo various elective and emergency general surgical procedures. However, little is known about the quality and reimbursement of surgical care for patients undergoing surgery for hip fractures at CAHs compared with non-CAH facilities., Questions/purposes: Are there any differences in 90-day complications, readmissions, mortality, and Medicare payments between patients undergoing surgery for hip fractures at CAHs and those undergoing surgery at non-CAHs?, Methods: The 2005 to 2014 Medicare 100% Standard Analytical Files were queried using ICD-9 procedure codes to identify Medicare-eligible beneficiaries undergoing open reduction and internal fixation (79.15, 79.35, and 78.55), hemiarthroplasty (81.52), and THA (81.51) for isolated closed hip fractures. This database was selected because the claims capture inpatient diagnoses, procedures, charged amounts and paid claims, as well as hospital-level information of the care, of Medicare patients across the nation. Patients with concurrent fixation of an upper extremity, lower extremity, and/or polytrauma were excluded from the study to ensure an isolated cohort of hip fractures was captured. The study cohort was divided into two groups based on where the surgery took place: CAHs and non-CAHs. A 1:1 propensity score match, adjusting for baseline demographics (age, gender, Census Bureau-designated region, and Elixhauser comorbidity index), clinical characteristics (fixation type and time to surgery), and hospital characteristics (whether the hospital was located in a rural ZIP code, the average annual procedure volume of the operating facility, hospital bed size, hospital ownership and teaching status), was used to control for the presence of baseline differences in patients presenting at CAHs and those presenting at non-CAHs. A total of 1,467,482 patients with hip fractures were included, 29,058 of whom underwent surgery in a CAH. After propensity score matching, each cohort (CAH and non-CAH) contained 29,058 patients. Multivariate logistic regression analyses were used to assess for differences in 90-day complications, readmissions, and mortality between the two matched cohorts. As funding policies of CAHs are regulated by Medicare, an evaluation of costs-of-care (by using Medicare payments as a proxy) was conducted. Generalized linear regression modeling was used to assess the 90-day Medicare payments among patients undergoing surgery in a CAH, while controlling for differences in baseline demographics and clinical characteristics., Results: Patients undergoing surgery for hip fractures were less likely to experience many serious complications at a critical access hospital (CAH) than at a non-CAH. In particular, after controlling for patient demographics, hospital-level factors and procedural characteristics, patients treated at a CAH were less likely to experience: myocardial infarction (3% (916 of 29,058) versus 4% (1126 of 29,058); OR 0.80 [95% CI 0.74 to 0.88]; p < 0.001), sepsis (3% (765 of 29,058) versus 4% (1084 of 29,058); OR 0.69 [95% CI 0.63 to 0.78]; p < 0.001), acute renal failure (6% (1605 of 29,058) versus 8% (2353 of 29,058); OR 0.65 [95% CI 0.61 to 0.69]; p < 0.001), and Clostridium difficile infections (1% (367 of 29,058) versus 2% (473 of 29,058); OR 0.77 [95% CI 0.67 to 0.88]; p < 0.001) than undergoing surgery in a non-CAH. CAHs also had lower rates of all-cause 90-day readmissions (18% (5133 of 29,058) versus 20% (5931 of 29,058); OR 0.83 [95% CI 0.79 to 0.86]; p < 0.001) and 90-day mortality (4% (1273 of 29,058) versus 5% (1437 of 29,058); OR 0.88 [95% CI 0.82 to 0.95]; p = 0.001) than non-CAHs. Further, CAHs also had risk-adjusted lower 90-day Medicare payments than non-CAHs (USD 800, standard error 89; p < 0.001)., Conclusion: Patients who received hip fracture surgical care at CAHs had a lower risk of major medical and surgical complications than those who had surgery at non-CAHs, even though Medicare reimbursements were lower as well. Although there may be some degree of patient selection at CAHs, these facilities appear to provide high-value care to rural communities. These findings provide evidence for policymakers evaluating the impact of the CAH program and allocating funding resources, as well as for community members seeking emergent care at local CAH facilities., Level of Evidence: Level III, therapeutic study., Competing Interests: Each author certifies that neither he or she, nor any member of his or her immediate family, has funding or commercial associations (consultancies, stock ownership, equity interest, patent/licensing arrangements, etc.) that might pose a conflict of interest in connection with the submitted article. All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research® editors and board members are on file with the publication and can be viewed on request., (Copyright © 2020 by the Association of Bone and Joint Surgeons.)

Although the effect of hypoxia on p53 in human papillomavirus (HPV)-positive cancer cells has been studied for decades, the impact of p53 regulation on downstream targets and cellular adaptation processes during different periods under hypoxia remains elusive. Here, we show that, despite continuous repression of HPV16 E6/E7 oncogenes, p53 did not instantly recover but instead showed a biphasic regulation marked by further depletion within 24 h followed by an increase at 72 h. Of note, during E6/E7 oncogene suppression, lysosomal degradation antagonizes p53 reconstitution. Consequently, the transcription of p53 responsive genes associated with senescence (e.g., PML and YPEL3 ) cannot be upregulated. In contrast, downstream genes involved in autophagy (e.g., DRAM1 and BNIP3 ) were activated, allowing the evasion of senescence under hypoxic conditions. Hence, dynamic regulation of p53 along with its downstream network of responsive genes favors cellular adaptation and enhances cell survival, although the expression of the viral E6/E7 -oncogenes as drivers for proliferation remained inhibited under hypoxia.

The objective of this cross-sectional study was to determine the type of care that can be achieved and the epidemiological profile of patients attending the 3 public dental practices in the Haut-Sassandra region, in Côte d'Ivoire. The data collection concerned socio-demographic characteristics, reason for consultation, oral hygiene, dental condition, malocclusions and the availability of equipment for the performance of procedures. The 400 patients observed (51.5% male) were aged 16.0 to 86.0 years (mean=35.5 years; SD=13.1 years). The main reasons for consultation were pain (91.5%) and aesthetics (23.5%). Oral hygiene was insufficient for 36.8% of subjects. Oral conditions were malocclusions (12.8%), caries (98.7%) and edentulous (65.7%) with only 11.8% with prosthesis. The average DMFT index was 9.3. Only extractions and resin attached prostheses were possible in all 3 health facilities. Preventive dentistry (sealent, fluoridation), dentofacial orthopedics and implantology were not available in any dental practice. The most frequently performed acts were extractions (74.5%). The results of this study highlight the need for oral health planning with service equipment and awareness among populations who shouldn't wait until they are in pain to consult., Competing Interests: Conflict of interest: the authors declare no potential conflict of interests., (©Copyright: the Author(s), 2019.)

Background: In Côte d'Ivoire, maternal health service utilization indicators remain low despite improvements in health coverage and the availability of free health care for pregnant women. The objective of the study was to identify the determinants associated with the use of maternal health services in the department of Bloléquin, in western Côte d'Ivoire., Methods: We conducted a cross-sectional study with an analytical focus. The study sample size was 400 women. Study participants were selected through a two-stage cluster survey. The data were collected using a standardized questionnaire whose items concerned socio-demographic data, the different uses of maternal health services, namely childbirth assisted by a health professional, use of family planning, prenatal consultation and postnatal consultation. Logistic regression was used to investigate factors associated with the use of maternal health services. The significance of the statistical tests was set at 5%. The odds ratios and 95% confidence intervals were calculated and interpreted., Results: The results showed that women made less use of family planning services (OR = 0.4), prenatal consultation (OR = 0.2) and assisted childbirth (OR = 0.2) when they provided the funding for care themselves. Women with monthly incomes above $26.8 used family planning services 4 times more than those with lower incomes. Married women used prenatal consultations 3 times more often than unmarried women (CI 95%  = 1.4-7.3). Desiring pregnancy increased the use of post-natal consultations by 3 times (CI 95%  = 1.5-6.1)., Conclusion: Improving the use of maternal health services in western Côte d'Ivoire requires taking into account women's socio-cultural and economic challenges. In initiatives related to the financial empowerment of women, efforts must be made at the level of emotional considerations related to pregnancy.

A ubiquitous problem in aggregating data across different experimental and observational data sources is a lack of software infrastructure that enables flexible and extensible standardization of data and metadata. To address this challenge, we developed HDMF, a hierarchical data modeling framework for modern science data standards. With HDMF, we separate the process of data standardization into three main components: (1) data modeling and specification, (2) data I/O and storage, and (3) data interaction and data APIs. To enable standards to support the complex requirements and varying use cases throughout the data life cycle, HDMF provides object mapping infrastructure to insulate and integrate these various components. This approach supports the flexible development of data standards and extensions, optimized storage backends, and data APIs, while allowing the other components of the data standards ecosystem to remain stable. To meet the demands of modern, large-scale science data, HDMF provides advanced data I/O functionality for iterative data write, lazy data load, and parallel I/O. It also supports optimization of data storage via support for chunking, compression, linking, and modular data storage. We demonstrate the application of HDMF in practice to design NWB 2.0 [13], a modern data standard for collaborative science across the neurophysiology community.

A large body of evidence has linked unhealthy eating patterns with an alarming increase in obesity and chronic disease worldwide. However, existing methods of assessing dietary intake in nutritional epidemiology rely on food frequency questionnaires or dietary records that are prone to bias and selective reporting. Herein, metabolic phenotyping was performed on 42 healthy participants from the Diet and Gene Intervention (DIGEST) pilot study, a parallel two-arm randomized clinical trial that provided complete diets to all participants. Matching single-spot urine and fasting plasma specimens were collected at baseline, and then following two weeks of either a Prudent or Western diet with a weight-maintaining menu plan designed by a dietician. Targeted and nontargeted metabolite profiling was conducted using three complementary analytical platforms, where 80 plasma metabolites and 84 creatinine-normalized urinary metabolites were reliably measured (CV < 30%) in the majority of participants (>75%) after implementing a rigorous data workflow for metabolite authentication with stringent quality control. We classified a panel of metabolites with distinctive trajectories following two weeks of food provisions when using complementary univariate and multivariate statistical models. Unknown metabolites associated with contrasting dietary patterns were identified with high-resolution MS/MS, as well as co-elution after spiking with authentic standards if available. Overall, 3-methylhistidine and proline betaine concentrations increased in both plasma and urine samples after participants were assigned a Prudent diet ( q < 0.05) with a corresponding decrease in the Western diet group. Similarly, creatinine-normalized urinary imidazole propionate, hydroxypipecolic acid, dihydroxybenzoic acid, and enterolactone glucuronide, as well as plasma ketoleucine and ketovaline increased with a Prudent diet ( p < 0.05) after adjustments for age, sex, and BMI. In contrast, plasma myristic acid, linoelaidic acid, linoleic acid, α-linoleic acid, pentadecanoic acid, alanine, proline, carnitine, and deoxycarnitine, as well as urinary acesulfame K increased among participants following a Western diet. Most metabolites were also correlated ( r > ± 0.30, p < 0.05) to changes in the average intake of specific nutrients from self-reported diet records reflecting good adherence to assigned food provisions. Our study revealed robust biomarkers sensitive to short-term changes in habitual diet, which is needed for accurate monitoring of healthy eating patterns in free-living populations, and evidence-based public health policies for chronic disease prevention.

Background: Attention deficit-hyperactivity disorder (ADHD) is common in fetal alcohol spectrum disorders (FASD) but also in patients without prenatal alcohol exposure (PAE). Many patients diagnosed with idiopathic ADHD may actually have ADHD and covert PAE, a treatment-relevant distinction., Methods: We compared proton magnetic resonance spectroscopic imaging (MRSI; N = 44) and diffusion tensor imaging (DTI; N = 46) of the anterior corona radiata (ACR)-a key fiber tract in models of ADHD-at 1.5 T in children with ADHD with PAE (ADHD+PAE), children with ADHD without PAE (ADHD-PAE), children without ADHD with PAE (non-ADHD+PAE), and children with neither ADHD nor PAE (non-ADHD-PAE, i.e., typically developing controls). Levels of choline-compounds (Cho) were the main MRSI endpoint, given interest in dietary choline for FASD; the main DTI endpoint was fractional anisotropy (FA), as ACR FA may reflect ADHD-relevant executive control functions., Results: For ACR Cho, there was an ADHD-by-PAE interaction (p = 0.038) whereby ACR Cho was 26.7% lower in ADHD+PAE than in ADHD-PAE children (p < 0.0005), but there was no significant ACR Cho difference between non-ADHD+PAE and non-ADHD-PAE children. Voxelwise false-discovery rate (FDR)-corrected analysis of DTI revealed significantly (q ≤ 0.0101-0.05) lower FA in ACR for subjects with PAE (ADHD+PAE or non-ADHD+PAE) than for subjects without PAE (ADHD-PAE or non-ADHD-PAE). There was no significant effect of ADHD on FA. Thus, in overlapping samples, effects of PAE on Cho and FA were observed in the same white-matter tract., Conclusions: These findings point to tract focal, white-matter pathology possibly specific for ADHD+PAE subjects. Low Cho may derive from abnormal choline metabolism; low FA suggests suboptimal white-matter integrity in PAE. More advanced MRSI and DTI-and neurocognitive assessments-may better distinguish ADHD+PAE from ADHD-PAE, helping identify covert cases of FASD., (© 2019 Wiley Periodicals, Inc.)

Although the role of high-risk human papillomaviruses (hrHPVs) as etiological agents in cancer development has been intensively studied during the last decades, there is still the necessity of understanding the impact of the HPV E6 and E7 oncogenes on host cells, ultimately leading to malignant transformation. Here, we used newly established immortalized human keratinocytes with a well-defined HPV16 E6E7 expression cassette to get a more complete and less biased overview of global changes induced by HPV16 by employing transcriptome sequencing (RNA-Seq) and stable isotope labeling by amino acids in cell culture (SILAC). This is the first study combining transcriptome and proteome data to characterize the impact of HPV oncogenes in human keratinocytes in comparison with their virus-negative counterparts. To enhance the informative value and accuracy of the RNA-Seq data, four different bioinformatic workflows were used. We identified potential novel upstream regulators (e.g., CNOT7, SPDEF, MITF, and PAX5) controlling distinct clusters of genes within the HPV-host cell network as well as distinct factors (e.g., CPPED1, LCP1, and TAGLN) with essential functions in cancer. Validated results in this study were compared to data sets from The Cancer Genome Atlas (TCGA), demonstrating that several identified factors were also differentially expressed in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) and HPV-positive head and neck squamous cell carcinomas (HNSCs). This highly integrative approach allows the identification of novel HPV-induced cellular changes that are also reflected in cancer patients, providing a promising omics data set for future studies in both basic and translational research. IMPORTANCE Human papillomavirus (HPV)-associated cancers still remain a big health problem, especially in developing countries, despite the availability of prophylactic vaccines. Although HPV oncogenes have been intensively investigated for decades, a study applying recent advances in RNA-Seq and quantitative proteomic approaches to a precancerous model system with well-defined HPV oncogene expression alongside HPV-negative parental cells has been missing until now. Here, combined omics analyses reveal global changes caused by the viral oncogenes in a less biased way and allow the identification of novel factors and key cellular networks potentially promoting malignant transformation. In addition, this system also provides a basis for mechanistic research on novel key factors regulated by HPV oncogenes, especially those that are confirmed in vivo in cervical cancer as well as in head and neck cancer patient samples from TCGA data sets., (Copyright © 2019 Yang et al.)

High-throughput screening methods for fatty acid (FA) determination are urgently needed due to their critical biochemical roles in human health while serving as biomarkers of habitual diet and chronic disease risk assessment. Herein, we introduce multisegment injection-nonaqueous-capillary electrophoresis-mass spectrometry (MSI-NACE-MS) as a multiplexed separation platform for analysis of more than 20 nonesterified FAs in human serum or plasma. Optimization of experimental conditions was required to overcome major technical hurdles in MSI-NACE-MS prior to a rigorous method validation and intermethod comparison with gas chromatography/mass spectrometry (GC/MS). Following a simple methyl- tert-butyl ether extraction, seven serum extracts were analyzed directly by MSI-NACE-MS within a single run (<4 min/sample) under negative ion mode detection that incorporates stringent measures for quality control, including batch correction adjustment. Overall, excellent technical variance (RSD = 10%) and good mutual agreement was demonstrated for 12 nonesterified FAs consistently measured in 50 serum samples analyzed independently by MSI-NACE-MS and GC/MS within the same laboratory (mean bias = 24%, n = 600). Also, total hydrolyzed plasma FAs using MSI-NACE-MS was compared to mean concentrations reported from a NIST standard reference material as an interlaboratory method validation (mean bias = 15%, n = 20). Accurate prediction of ion migration behavior in CE also supports structural elucidation of FAs in conjunction with high resolution MS. For the first time, we demonstrate that MSI-NACE-MS offers a rapid yet robust platform for direct quantification of circulating FAs using volume-restricted blood specimens that expands metabolome coverage to encompass anionic classes of lipids as required for large-scale epidemiological studies.

Aim: The primary aim was to demonstrate adherence to a novel 6-week lifestyle intervention program ("Meals, Mindfulness, & Moving Forward" [M 3 ]) designed to help improve lifestyle practices of youth with a history of at least 1 psychotic episode., Methods: M 3 used a non-equivalent control group design involving clients from a community early intervention program. Seventeen individuals in the active M 3 program and 16 controls were assessed for secondary outcomes at baseline, 6-weeks, and 12-weeks (6 weeks post-intervention) on cardiometabolic and symptomatic outcomes., Results: The program met its primary aim with 88% (15/17) of participants meeting adherence criteria. Compared with the controls, M 3 participants showed significant improvement in positive psychotic symptoms (P = .002)., Conclusion: This pilot study showed that young people involved in a community early intervention program adhered to an activity-based lifestyle program which included mindfulness meditation, yoga and nutrition education, warranting further evaluation with a larger sample size., (© 2018 John Wiley & Sons Australia, Ltd.)

Depression is a commonly occurring symptom in obsessive-compulsive disorder (OCD), and is associated with worse functional impairment, poorer quality of life, and poorer treatment response. Understanding the underlying neurochemical and connectivity-based brain mechanisms of this important symptom domain in OCD is necessary for development of novel, more globally effective treatments. To investigate biopsychological mechanisms of comorbid depression in OCD, we examined effective connectivity and neurochemical signatures in the pregenual anterior cingulate cortex (pACC), a structure known to be involved in both OCD and depression. Resting-state functional magnetic resonance imaging (fMRI) and 1 H magnetic resonance spectroscopy (MRS) data were obtained from participants with OCD (n=49) and healthy individuals of equivalent age and sex (n=25). Granger causality-based effective (directed) connectivity was used to define causal networks involving the right and left pACC. The interplay between fMRI connectivity, 1 H MRS and clinical data was explored by applying moderation and mediation analyses. We found that the causal influence of the right dorsal anterior midcingulate cortex (daMCC) on the right pACC was significantly lower in the OCD group and showed significant correlation with depressive symptom severity in the OCD group. Lower and moderate levels of glutamate (Glu) in the right pACC significantly moderated the interaction between right daMCC-pACC connectivity and depression severity. Our results suggest a biochemical-connectivity-psychological model of pACC dysfunction contributing to depression in OCD, particularly involving intracingulate connectivity and glutamate levels in the pACC. These findings have implications for potential molecular and network targets for treatment of this multi-faceted psychiatric condition.

Cognitive-behavioral therapy (CBT) is effective for pediatric obsessive-compulsive disorder (OCD), but non-response is common. Brain glutamate (Glu) signaling may contribute to OCD pathophysiology and moderate CBT outcomes. We assessed whether Glu measured with magnetic resonance spectroscopy (MRS) was associated with OCD and/or CBT response. Youths aged 7-17 years with DSM-IV OCD and typically developing controls underwent 3 T proton echo-planar spectroscopic imaging (PEPSI) MRS scans of pregenual anterior cingulate cortex (pACC) and ventral posterior cingulate cortex (vPCC)-regions possibly affected by OCD-at baseline. Controls returned for re-scan after 8 weeks. OCD youth-in a randomized rater-blinded trial-were re-scanned after 12-14 weeks of CBT or after 8 weeks of minimal-contact waitlist; waitlist participants underwent a third scan after crossover to 12-14 weeks of CBT. Forty-nine children with OCD (mean age 12.2±2.9 years) and 29 controls (13.2±2.2 years) provided at least one MRS scan. At baseline, Glu did not differ significantly between OCD and controls in pACC or vPCC. Within controls, Glu was stable from scan-to-scan. Within OCD subjects, a treatment-by-scan interaction (p=0.034) was observed, driven by pACC Glu dropping 19.5% from scan-to-scan for patients randomized to CBT, with minor increases (3.8%) for waitlist participants. The combined OCD participants (CBT-only plus waitlist-CBT) also showed a 16.2% (p=0.004) post-CBT decrease in pACC Glu. In the combined OCD group, within vPCC, lower pre-CBT Glu predicted greater post-CBT improvement in symptoms (CY-BOCS; r=0.81, p=0.00025). Glu may be involved in the pathophysiology of OCD and may moderate response to CBT.

Capillary electrophoresis-mass spectrometry (CE-MS) represents a high efficiency microscale separation platform for untargeted profiling of polar/ionic metabolites that is ideal for volume-restricted biological specimens with minimal sample workup. Despite these advantages, the long-term stability of CE-MS remains a major obstacle hampering its widespread application in metabolomics notably for routine analysis of anionic metabolites under negative ion mode conditions. Herein, we report for the first time that commonly used ammonia containing buffers compatible with electrospray ionization (ESI)-MS can compromise the integrity of fused-silica capillaries via aminolysis of their outer polyimide coating. Unlike organic solvent swelling effects, this chemical process occurs under aqueous conditions that is dependent on ammonia concentration, buffer pH, and exposure time resulting in a higher incidence of capillary fractures and current errors during extended operation. Prevention of polyimide aminolysis is achieved by using weakly alkaline ammonia containing buffers (pH < 9) in order to preserve the tensile strength of the polyimide coated fused-silica capillary. Alternatively, less nucleophilic primary/secondary amines can be used as electrolytes without polyimide degradation, whereas chemically resistant polytetrafluoroethylene coating materials offer higher pH tolerance in ammonia. In this work, multisegment injection (MSI)-CE-MS was used as multiplexed separation platform for high throughput profiling of anionic metabolites when using optimized buffer conditions to prevent polyimide degradation. A diverse range of acidic metabolites in human urine were reliably measured by MSI-CE-MS via serial injection of seven urine samples within a single run, including organic acids, food-specific markers, microbial-derived compounds and over-the-counter drugs as their sulfate and glucuronide conjugates. This approach offers excellent throughput (<5 min/sample) and acceptable intermediate precision (average CV ≈ 16%) with high separation efficiency as reflected analysis of 30 anionic metabolites following 238 repeated sample injections of human urine over 3 days while using a single nonisotope internal standard for data normalization. Careful optimization and rigorous validation of CE-MS protocols are crucial for developing a rapid, low cost, and robust screening platform for metabolomics that is amenable to large-scale clinical and epidemiological studies.

Focal brain metabolic effects detected by proton magnetic resonance spectroscopy (MRS) in obsessive-compulsive disorder (OCD) represent prospective indices of clinical status and guides to treatment design. Sampling bilateral pregenual anterior cingulate cortex (pACC), anterior middle cingulate cortex (aMCC), and thalamus in 40 adult patients and 16 healthy controls, we examined relationships of the neurometabolites glutamate+glutamine (Glx), creatine+phosphocreatine (Cr), and choline-compounds (Cho) with OCD diagnosis and multiple symptom types. The latter included OC core symptoms (Yale-Brown Obsessive-Compulsive Scale - YBOCS), depressive symptoms (Montgomery-Åsberg Depression Rating Scale - MADRS), and general functioning (Global Assessment Scale - GAS). pACC Glx was 9.7% higher in patients than controls. Within patients, Cr and Cho correlated negatively with YBOCS and MADRS, while Cr correlated positively with the GAS. In aMCC, Cr and Cho correlated negatively with MADRS, while Cr in thalamus correlated positively with GAS. These findings present moderate support for glutamatergic and cingulocentric perspectives on OCD. Based on our prior metabolic model of OCD, we offer one possible interpretation of these group and correlational effects as consequences of a corticothalamic state of elevated glutamatergic receptor activity alongside below-normal glutamatergic transporter activity., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Galectin-7 (Gal-7) is negatively regulated in cervical cancer, and appears to be a link between the apoptotic response triggered by cancer and the anti-tumoral activity of the immune system. Our understanding of how cervical cancer cells and their molecular networks adapt in response to the expression of Gal-7 remains limited., Methods: Meta-analysis of Gal-7 expression was conducted in three cervical cancer cohort studies and TCGA. In silico prediction and bisulfite sequencing were performed to inquire epigenetic alterations. To study the effect of Gal-7 on cervical cancer, we ectopically re-expressed it in the HeLa and SiHa cervical cancer cell lines, and analyzed their transcriptome and SILAC-based proteome. We also examined the tumor and microenvironment host cell transcriptomes after xenotransplantation into immunocompromised mice. Differences between samples were assessed with the Kruskall-Wallis, Dunn's Multiple Comparison and T tests. Kaplan-Meier and log-rank tests were used to determine overall survival., Results: Gal-7 was constantly downregulated in our meta-analysis (p < 0.0001). Tumors with combined high Gal-7 and low galectin-1 expression (p = 0.0001) presented significantly better prognoses (p = 0.005). In silico and bisulfite sequencing assays showed de novo methylation in the Gal-7 promoter and first intron. Cells re-expressing Gal-7 showed a high apoptosis ratio (p < 0.05) and their xenografts displayed strong growth retardation (p < 0.001). Multiple gene modules and transcriptional regulators were modulated in response to Gal-7 reconstitution, both in cervical cancer cells and their microenvironments (FDR < 0.05 %). Most of these genes and modules were associated with tissue morphogenesis, metabolism, transport, chemokine activity, and immune response. These functional modules could exert the same effects in vitro and in vivo, even despite different compositions between HeLa and SiHa samples., Conclusions: Gal-7 re-expression affects the regulation of molecular networks in cervical cancer that are involved in diverse cancer hallmarks, such as metabolism, growth control, invasion and evasion of apoptosis. The effect of Gal-7 extends to the microenvironment, where networks involved in its configuration and in immune surveillance are particularly affected.

A simple and popular psychophysical model-usually described as overlapping Gaussian tuning curves arranged along an ordered internal scale-is capable of accurately describing both human and nonhuman behavioral performance and neural coding in magnitude estimation, production, and reproduction tasks for most psychological dimensions (e.g., time, space, number, or brightness). This model traditionally includes two parameters that determine how a physical stimulus is transformed into a psychological magnitude: (1) an exponent that describes the compression or expansion of the physical signal into the relevant psychological scale (β), and (2) an estimate of the amount of inherent variability (often called internal noise) in the Gaussian activations along the psychological scale (σ). To date, linear slopes on log-log plots have traditionally been used to estimate β, and a completely separate method of averaging coefficients of variance has been used to estimate σ. We provide a respectful, yet critical, review of these traditional methods, and offer a tutorial on a maximum-likelihood estimation (MLE) and a Bayesian estimation method for estimating both β and σ [PsiMLE(β,σ)], coupled with free software that researchers can use to implement it without a background in MLE or Bayesian statistics (R-PsiMLE). We demonstrate the validity, reliability, efficiency, and flexibility of this method through a series of simulations and behavioral experiments, and find the new method to be superior to the traditional methods in all respects.

Key Points: At the parallel fibre-Purkinje cell glutamatergic synapse, little or no Ca(2+) entry takes place through postsynaptic neurotransmitter receptors, although postsynaptic calcium increases are clearly involved in the synaptic plasticity. Postsynaptic voltage-gated Ca(2+) channels therefore constitute the sole rapid postsynaptic Ca(2+) signalling mechanism, making it essential to understand how they contribute to the synaptic signalling. Using a selective T-type calcium channel antagonist, we describe a T-type component of the EPSC that is activated by the AMPA receptor-mediated depolarization of the spine and thus will contribute to the local calcium dynamics. This component can amount up to 20% of the EPSC, and this fraction is maintained even at the high frequencies sometimes encountered in sensory processing. Modelling based on our biophysical characterization of T-type calcium channels in Purkinje cells suggests that the brief spine EPSCs cause the activated T-type channels to deactivate rather than inactivate, enabling repetitive activation., Abstract: In the cerebellum, sensory information is conveyed to Purkinje cells (PC) via the granule cell/parallel fibre (PF) pathway. Plasticity at the PF-PC synapse is considered to be a mechanism of information storage in motor learning. The induction of synaptic plasticity in the cerebellum and elsewhere usually involves intracellular Ca(2+) signals. Unusually, postsynaptic Ca(2+) signalling in PF-PC spines does not involve ionotropic glutamatergic receptors because postsynaptic NMDA receptors are absent and the AMPA receptors are Ca(2+) -impermeable; postsynaptic voltage-gated Ca(2+) channels therefore constitute the sole rapid Ca(2+) signalling mechanism. Low-threshold activated T-type calcium channels are present at the synapse, although their contribution to PF-PC synaptic responses is unknown. Taking advantage of 3,5-dichloro-N-[1-(2,2-dimethyl-tetrahydro-pyran-4-ylmethyl)-4-fluoro-piperidin-4-ylmethyl]-benzamide, a selective T-type channel antagonist, we show in the mouse that inhibition of these channels reduces PF-PC excitatory postsynaptic currents and excitatory postsynaptic potentials by 15-20%. This contribution was preserved during sparse input and repetitive activity. We characterized the biophysical properties of native T-type channels in young animals and modelled their activation during simulated dendritic excitatory postsynaptic potential waveforms. The comparison of modelled and observed synaptic responses suggests that T-type channels only activate in spines that are strongly depolarized by their synaptic input, a process requiring a high spine neck resistance. This brief and local activation ensures that T-type channels rapidly deactivate, thereby limiting inactivation during repetitive synaptic activity. T-type channels are therefore ideally situated to provide synaptic Ca(2+) entry at PF-PC spines., (© 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.)

CaV3.1 T-type channels are abundant at the cerebellar synapse between parallel fibers and Purkinje cells where they contribute to synaptic depolarization. So far, no specific physiological function has been attributed to these channels neither as charge carriers nor more specifically as Ca(2+) carriers. Here we analyze their incidence on synaptic plasticity, motor behavior, and cerebellar motor learning, comparing WT animals and mice where T-type channel function has been abolished either by gene deletion or by acute pharmacological blockade. At the cellular level, we show that CaV3.1 channels are required for long-term potentiation at parallel fiber-Purkinje cell synapses. Moreover, basal simple spike discharge of the Purkinje cell in KO mice is modified. Acute or chronic T-type current blockade results in impaired motor performance in particular when a good body balance is required. Because motor behavior integrates reflexes and past memories of learned behavior, this suggests impaired learning. Indeed, subjecting the KO mice to a vestibulo-ocular reflex phase reversal test reveals impaired cerebellum-dependent motor learning. These data identify a role of low-voltage activated calcium channels in synaptic plasticity and establish a role for CaV3.1 channels in cerebellar learning.

Purpose: Neurobehavioral comorbidities are common in pediatric epilepsy with enduring adverse effects on functioning, but their neuroanatomic underpinning is unclear. Striatal and thalamic abnormalities have been associated with childhood-onset epilepsies, suggesting that epilepsy-related changes in the subcortical circuit might be associated with the comorbidities of children with epilepsy. We aimed to compare subcortical volumes and their relationship with age in children with complex partial seizures (CPS), childhood absence epilepsy (CAE), and healthy controls (HC). We examined the shared versus unique structural-functional relationships of these volumes with behavior problems, intelligence, language, peer interaction, and epilepsy variables in these two epilepsy syndromes., Methods: We investigated volumetric differences of caudate, putamen, pallidum, and thalamus in children with CPS (N = 21), CAE (N = 20), and HC (N = 27). Study subjects underwent structural magnetic resonance imaging (MRI), intelligence, and language testing. Parent-completed Child Behavior Checklists provided behavior problem and peer interaction scores. We examined the association of age, intelligence quotient (IQ), language, behavioral problems, and epilepsy variables with subcortical volumes that were significantly different between the children with epilepsy and HC., Key Findings: Both children with CPS and CAE exhibited significantly smaller left thalamic volume compared to HC. In terms of developmental trajectory, greater thalamic volume was significantly correlated with increasing age in children with CPS and CAE but not in HC. With regard to the comorbidities, reduced left thalamic volumes were related to more social problems in children with CPS and CAE. Smaller left thalamic volumes in children with CPS were also associated with poor attention, lower IQ and language scores, and impaired peer interaction., Significance: Our study is the first to directly compare and detect shared thalamic structural abnormalities in children with CPS and CAE. These findings highlight the vulnerability of the thalamus and provide important new insights on its possible role in the neurobehavioral comorbidities of childhood-onset epilepsy., (Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.)

Objective: Previous voxel-based and regions-of-interest (ROI)-based diffusion tensor imaging (DTI) studies have found above-normal mean diffusivity (MD) and below-normal fractional anisotropy (FA) in subjects with attention-deficit/hyperactivity disorder (ADHD). However, findings remain mixed, and few studies have examined the contribution of ADHD familial liability to white matter microstructure., Method: We used refined DTI tractography methods to examine MD, FA, axial diffusivity (AD), and radial diffusivity (RD) of the anterior thalamic radiation, cingulum, corticospinal tract, inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, forceps major, forceps minor, superior longitudinal fasciculus, and uncinate fasciculus in children and adolescents with ADHD (n = 56), unaffected siblings of ADHD probands (n = 31), and healthy controls (n = 17)., Results: Subjects with ADHD showed significantly higher MD than controls in the anterior thalamic radiation, forceps minor, and superior longitudinal fasciculus. Unaffected siblings of subjects with ADHD displayed similar differences in MD as subjects with ADHD. Although none of the tested tracts showed a significant effect of FA, the tracts with elevated MD likewise displayed elevated AD both in subjects with ADHD and in unaffected siblings. Differences in RD between subjects with ADHD, unaffected siblings, and controls were not as widespread as differences in MD and AD., Conclusion: Our findings suggest that disruptions in white matter microstructure occur in several large white matter pathways in association with ADHD and indicate a familial liability for the disorder. Furthermore, MD may reflect these abnormalities more sensitively than FA., (Copyright © 2013 American Academy of Child & Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Neuroimaging studies in multiple modalities have implicated the left or right dorsolateral prefrontal cortex (here, middle frontal gyrus) in attentional functions, in ADHD, and in dopamine agonist treatment of ADHD. The far lateral location of this cortex in the brain, however, has made it difficult to study with magnetic resonance spectroscopy (MRS). We used the smaller voxel sizes of the magnetic resonance spectroscopic imaging (MRSI) variant of MRS, acquired at a steep coronal-oblique angle to sample bilateral middle frontal gyrus in 13 children and adolescents with ADHD and 13 age- and sex-matched healthy controls. Within a subsample of the ADHD patients, aspects of attention were also assessed with the Trail Making Task. In right middle frontal gyrus only, mean levels of N-acetyl-aspartate + N-acetyl-aspartyl-glutamate (tNAA), creatine + phosphocreatine (Cr), choline-compounds (Cho), and myo-inositol (mI) were significantly lower in the ADHD than in the control sample. In the ADHD patients, lower right middle frontal Cr was associated with worse performance on Trails A and B (focused attention, concentration, set-shifting), while the opposite relationship held true for the control group on Trails B. These findings add to evidence implicating right middle frontal cortex in ADHD. Lower levels of these multiple species may reflect osmotic adjustment to elevated prefrontal cortical perfusion in ADHD and/or a previously hypothesized defect in astrocytic production of lactate in ADHD resulting in decelerated energetic metabolism (Cr), membrane synthesis (Cho, mI), and acetyl-CoA substrate for NAA synthesis. Lower Cr levels may indicate attentional or executive impairments., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Infections with high-risk human papillomaviruses (HPVs) are causally involved in the development of anogenital cancer. HPVs apparently evade the innate immune response of their host cells by dysregulating immunomodulatory factors such as cytokines and chemokines, thereby creating a microenvironment that favors malignancy. One central key player in the immune surveillance interactome is interleukin-1 beta (IL-1β) which not only mediates inflammation, but also links innate and adaptive immunity. Because of its pleiotropic physiological effects, IL-1β production is tightly controlled on transcriptional, post-translational and secretory levels. Here, we describe a novel mechanism how the high-risk HPV16 E6 oncoprotein abrogates IL-1β processing and secretion in a NALP3 inflammasome-independent manner. We analyzed IL-1β regulation in immortalized keratinocytes that harbor the HPV16 E6 and/or E7 oncogenes as well as HPV-positive cervical tumor cells. While in primary and in E7-immortalized human keratinocytes the secretion of IL-1β was highly inducible upon inflammasome activation, E6-positive cells did not respond. Western blot analyses revealed a strong reduction of basal intracellular levels of pro-IL-1β that was independent of dysregulation of the NALP3 inflammasome, autophagy or lysosomal activity. Instead, we demonstrate that pro-IL-1β is degraded in a proteasome-dependent manner in E6-positive cells which is mediated via the ubiquitin ligase E6-AP and p53. Conversely, in E6- and E6/E7-immortalized cells pro-IL-1β levels were restored by siRNA knock-down of E6-AP and simultaneous recovery of functional p53. In the context of HPV-induced carcinogenesis, these data suggest a novel post-translational mechanism of pro-IL-1β regulation which ultimately inhibits the secretion of IL-1β in virus-infected keratinocytes. The clinical relevance of our results was further confirmed in HPV-positive tissue samples, where a gradual decrease of IL-1β towards cervical cancer could be discerned. Hence, attenuation of IL-1β by the HPV16 E6 oncoprotein in immortalized cells is apparently a crucial step in viral immune evasion and initiation of malignancy.

It has been difficult to determine how cognitive systems change over the grand time scale of an entire life, as few cognitive systems are well enough understood; observable in infants, adolescents, and adults; and simple enough to measure to empower comparisons across vastly different ages. Here we address this challenge with data from more than 10,000 participants ranging from 11 to 85 years of age and investigate the precision of basic numerical intuitions and their relation to students' performance in school mathematics across the lifespan. We all share a foundational number sense that has been observed in adults, infants, and nonhuman animals, and that, in humans, is generated by neurons in the intraparietal sulcus. Individual differences in the precision of this evolutionarily ancient number sense may impact school mathematics performance in children; however, we know little of its role beyond childhood. Here we find that population trends suggest that the precision of one's number sense improves throughout the school-age years, peaking quite late at ∼30 y. Despite this gradual developmental improvement, we find very large individual differences in number sense precision among people of the same age, and these differences relate to school mathematical performance throughout adolescence and the adult years. The large individual differences and prolonged development of number sense, paired with its consistent and specific link to mathematics ability across the age span, hold promise for the impact of educational interventions that target the number sense.

Recent research in autism spectrum disorder (ASD) has aroused interest in anterior cingulate cortex and in the neurometabolite glutamate. We report two studies of pregenual anterior cingulate cortex (pACC) in pediatric ASD. First, we acquired in vivo single-voxel proton magnetic resonance spectroscopy ((1)H MRS) in 8 children with ASD and 10 typically developing controls who were well matched for age, but with fewer males and higher IQ. In the ASD group in midline pACC, we found mean 17.7% elevation of glutamate + glutamine (Glx) (p<0.05) and 21.2% (p<0.001) decrement in creatine + phosphocreatine (Cr). We then performed a larger (26 subjects with ASD, 16 controls) follow-up study in samples now matched for age, gender, and IQ using proton magnetic resonance spectroscopic imaging ((1)H MRSI). Higher spatial resolution enabled bilateral pACC acquisition. Significant effects were restricted to right pACC where Glx (9.5%, p<0.05), Cr (6.7%, p<0.05), and N-acetyl-aspartate + N-acetyl-aspartyl-glutamate (10.2%, p<0.01) in the ASD sample were elevated above control. These two independent studies suggest hyperglutamatergia and other neurometabolic abnormalities in pACC in ASD, with possible right-lateralization. The hyperglutamatergic state may reflect an imbalance of excitation over inhibition in the brain as proposed in recent neurodevelopmental models of ASD.

Background: Trichomonas vaginalis is a sexually transmitted infection, which is largely underestimated because of ineffective screening protocols and lack of public health attention., Methods: Two studies were conducted to assess the frequency of missed diagnosis of T. vaginalis when using current routine practices for T. vaginalis screening in high-risk female populations. The first study compares the rate of positivity detected using wet preparation microscopy to the number of cases found using polymerase chain reaction (PCR) using residual samples from women attending a public health sexually transmitted disease clinic. The second study compares universal to targeted screening of symptomatic women using PCR on vaginal samples from women screened for sexually transmitted disease at a correctional facility., Results: In the first study, a 5-fold increased incidence of T. vaginalis infection was detected when PCR was performed instead of wet mount microscopy in a sample of 222 women screened at a sexually transmitted disease clinic. The second study detected a 5-fold increase in cases among a sample of 471 incarcerated women when universal screening was implemented., Conclusions: Improving detection of T. vaginalis is critical, given that when left untreated, T. vaginalis increases susceptibility to coinfections including human immunodeficiency virus. Changing screening protocols to use improved diagnostic tools and applying universal screening resulted in increased case finding for T. vaginalis among high-risk women. The prevalence of T. vaginalis coupled with its negative impact on health necessitate greater public health attention is needed in order to reduce incidence rates, improve diagnosis, and to better understand this important, yet underestimated, pathogen.

Traditional medicine of which is a part traditional odontology occupies an important place within the African societies. It often constitutes the first appeal (80 % of the population) because of the high cost of the care, the incapacity of the human and material resources but also the faiths of the populations. This reality makes valuation of the traditional odontology a necessity. This study comes within this framework. It's a contribution for a better knowledge of practices and plants used in traditional odontology in Ivory Coast. So, after a presentation of some traditional knowledge's and their fields of application, the authors review studies made on the efficiency of plants in the prevention of tooth decay and the treatment of some oral diseases. The objective of these researches is to elaborate effective and financially affordable traditional improved drugs.

We have investigated interferon-kappa (IFN-kappa) regulation in the context of human papillomavirus (HPV)-induced carcinogenesis using primary human foreskin keratinocytes (HFK), immortalized HFKs encoding individual oncoproteins of HPV16 (E6, E7, and E6/E7), and cervical carcinoma cells. Here, IFN-kappa was suppressed in the presence of E6, whereas its expression was not affected in HFKs or E7-immortalized HFKs. Transcription could be reactivated after DNA demethylation but was decreased again upon drug removal. Partial reactivation could also be accomplished when E6 was knocked down, suggesting a contribution of E6 in IFN-kappa de novo methylation. We identified a single CpG island near the transcriptional start site as being involved in selective IFN-kappa expression. To prove the functional relevance of IFN-kappa in building up an antiviral response, IFN-kappa was ectopically expressed in cervical carcinoma cells where protection against vesicular stomatitis virus-mediated cytolysis could be achieved. Reconstitution of IFN-kappa was accompanied by an increase of p53, MxA, and IFN-regulatory factors, which was reversed by knocking down either IFN-kappa or p53 by small interfering RNA. This suggests the existence of a positive feedback loop between IFN-kappa, p53, and components of IFN signaling pathway to maintain an antiviral state. Our in vitro findings were further corroborated in biopsy samples of cervical cancer patients, in which IFN-kappa was also downregulated when compared with normal donor tissue. This is the first report showing an epigenetic silencing of type I IFN after HPV16 oncogene expression and revealing a novel strategy on how high-risk HPVs can abolish the innate immune response in their genuine host cells.

Abnormal amygdala volumes in pediatric mood-anxiety disorders and attention deficit hyperactivity disorder (ADHD), as well as high rates of these diagnoses in childhood absence epilepsy (CAE), prompted this study of amygdala volume in CAE. Twenty-six children with CAE and 23 normal children, aged 6.6-15.8 years, underwent MRI at 1.5 T. The tissue imaged with MRI was segmented, and amygdala volumes were obtained by manual tracings. There were no significant amygdala volume differences between the CAE and normal groups. Within the CAE group, however, the children with ADHD had significantly smaller amygdala volumes than the subjects with CAE with no psychopathology and those with mood/anxiety diagnoses. There was also a significant relationship between higher seizure frequency and greater amygdala asymmetry in the epilepsy group. Given ongoing development of the amygdala during late childhood and adolescence, despite the lack of significant group differences in amygdala volumes, the association of amygdala volume abnormalities with ADHD and seizure frequency implies a possible impact of the disorder on amygdala development and CAE-associated comorbidities, such as ADHD.

The limited choice and poor performance of red-emitting calcium (Ca(2+)) indicators have hampered microfluorometric measurements of the intracellular free Ca(2+) concentration in cells expressing yellow- or green-fluorescent protein constructs. A long-wavelength Ca(2+) indicator would also permit a better discrimination against cellular autofluorescence than the commonly used fluorescein-based probes. Here, we report an improved synthesis and characterization of Calcium Ruby, a red-emitting probe consisting of an extended rhodamine chromophore (578/602 nm peak excitation/emission) conjugated to BAPTA and having an additional NH(2) linker arm. The low-affinity variant (K(D,Ca) approximately 30 microM) with a chloride in meta position that was specifically designed for the detection of large and rapid Ca(2+) transients. While Calcium Ruby is a mitochondrial Ca(2+)probe, its conjugation, via the NH(2) tail, to a 10,000 MW dextran abolishes the sub-cellular compartmentalization and generates a cytosolic Ca(2+) probe with an affinity matched to microdomain Ca(2+) signals. As an example, we show depolarization-evoked Ca(2+) signals triggering the exocytosis of individual chromaffin granules. Calcium Ruby should be of use in a wide range of applications involving dual- or triple labeling schemes or targeted sub-cellular Ca(2+) measurements.

The aim of this study is the assessment of anaemia importance in patients consulting the dentist. 168 patients, all kind, of the dental office of the National Institute of Public Health of Abidjan, from 3 years ago, whom haematological statute is unknown are selected. Each person, after filling out a survey paper, is submitted to dental and haematological investigations. As result, 33% of our patients have anaemia. 95% of them are women. Pupils represent 48% of the anaemic.

Abidjan, the economical capital of Ivory Coast has a CAO of 2.7 with index O practically nil. The professional density is one surgeon for 12.000 inhabitants. Abidjan population, despite the requirements in increasing care has not recourse to the dental surgeons for their assumption of responsibility. The general objective of our study is to describe the therapeutic itinerary in odonto-stomatology of the Abidjan population. We have realised a questionnaire survey beside of population sample. The results show that 25 per cent of our population gives up care despite the presence of pain or embarrassment. Our study has allowed highlighting all the other recourses to the care. Indeed, the people who give up the care have much other recourse which has be identified in order of importance: the modern and traditional self-medication. Let us note in our study, that the choice of dental surgeon knows a constant evolution from the first to the third recourse. The lack of financial means constitutes however the first obstacle at the accessibility to the oral care in Ivory Coast.

The exaggerated consumption of sugars under its various associate shapes to an insufficiency of mouth and tooth hygiene could drag some tooth decays. These tooth decays, when they demonstrate, leads to a destruction of the temporary teeth, with for corollaries of the aesthetic and functional problems. The therapeutic are not always apparent especially when there is coexistence of coronary destruction to juxtapose to the gum without reaching pulp with some precocious a toothlessing. The authors, across some cases clinics treated to the breast of service of Paediatric Dentistry shows different types of therapeutic possibilities in function of the shapes clinics. He was about conservative treatments or of extraction, of prothesis restorations to the aide of the Crown order form, of infantile removable prosthesis and of composite prosthesis.