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This article examines the relationship between school infrastructure and academic performance in Ecuador. The objective of this research is to identify which types of infrastructure are associated with better student outcomes in elementary schools. The study employs data from the 2019 UNESCO standardized test, ERCE-2019, for Ecuadorian primary schools. The findings indicate a significant positive correlation between various types of school infrastructure and student achievement. Such infrastructure includes art and music installations, on-site nursing facilities, and basic service connections, especially in rural areas. Significant correlations between educational outcomes and large-scale infrastructure investments are either not observed or are inconsistently evidenced. These results challenge the heavy focus on prominent educational infrastructure projects in Ecuador, suggesting an opportunity to reorient educational spending to enhance outcomes cost-effectively. These research findings may apply not only to Ecuador but potentially to the broader Latin American context., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

Background: Brief questionnaires that comprehensively capture key restricted and repetitive behaviours (RRBs) across different informants have potential to support autism diagnostic services. We tested the psychometric properties of the 20-item Repetitive Behaviours Questionnaire-3 (RBQ-3), a questionnaire that includes self-report and informant-report versions enabling use across the lifespan., Method: In Study 1, adults referred to a specialised adult autism diagnostic service (N = 110) completed the RBQ-3 self-report version, and a relative or long-term friend completed the RBQ-3 informant-report version. Clinicians completed the abbreviated version of the Diagnostic Interview for Social and Communication Disorders (DISCO-Abbreviated) with the same adults as part of the diagnostic process. For half of the assessments, clinicians were blind to the RBQ-3 ratings. We tested internal consistency, cross-informant reliability and convergent validity of the RBQ-3. In Study 2, a follow-up online study with autistic (N = 151) and non-autistic (N = 151) adults, we further tested internal consistency of the RBQ-3 self-report version. We also tested group differences and response patterns in this sample., Results: Study 1 showed good to excellent internal consistency for both self- and informant-report versions of the RBQ-3 (total score, α = 0.90, ω = 0.90, subscales, α = 0.76-0.89, ω = 0.77-0.88). Study 1 also showed cross-informant reliability as the RBQ-3 self-report scores significantly correlated with RBQ-3 informant-report scores for the total score (r s = 0.71) and subscales (r s = 0.69-0.72). Convergent validity was found for both self and informant versions of the RBQ-3, which significantly correlated with DISCO-Abbreviated RRB domain scores (r s = 0.45-0.54). Moreover, the RBQ-3 scores showed significantly weaker association with DISCO -Abbreviated scores for the Social Communication domain, demonstrating divergent validity. Importantly, these patterns of validity were found even when clinicians were blind to RBQ-3 items. In Study 2, for both autistic and non-autistic groups, internal consistency was found for the total score (α = 0.82-0.89, ω = 0.81-0.81) and for subscales (α = 0.68-0.85, ω = 0.69-0.85). A group difference was found between groups., Limitations: Due to the characteristics and scope of the specialist autism diagnostic service, further testing is needed to include representative samples of age (including children) and intellectual ability, and those with a non-autistic diagnostic outcome., Conclusions: The RBQ-3 is a questionnaire of RRBs that can be used across the lifespan. The current study tested its psychometric properties with autistic adults without intellectual disability and supported its utility for both clinical diagnostic and research settings., (© 2024. The Author(s).)

Purpose: The aim of the present study was to compare scale and conditional reliability derived from item response theory analyses among the most commonly used, as well as several newly developed, observation, interview, and parent-report autism instruments., Methods: When available, data sets were combined to facilitate large sample evaluation. Scale reliability (internal consistency, average corrected item-total correlations, and model reliability) and conditional reliability estimates were computed for total scores and for measure subscales., Results: Generally good to excellent scale reliability was observed for total scores for all measures, scale reliability was weaker for RRB subscales of the ADOS and ADI-R, reflecting the relatively small number of items for these measures. For diagnostic measures, conditional reliability tended to be very good (> 0.80) in the regions of the latent trait where ASD and non-ASD developmental disability cases would be differentiated. For parent-report scales, conditional reliability of total scores tended to be excellent (> 0.90) across very wide ranges of autism symptom levels, with a few notable exceptions., Conclusions: These findings support the use of all of the clinical observation, interview, and parent-report autism symptom measures examined, but also suggest specific limitations that warrant consideration when choosing measures for specific clinical or research applications., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: During the COVID-19 pandemic, distinct population subsets, including pregnant women, have been differentially affected. While over 90% of COVID-19-infected pregnant women experience a benign course, a subset demonstrates marked clinical exacerbation. Symptomatic pregnant individuals, in particular, present a heightened risk of severe disease in comparison to their non-pregnant counterparts., Objective: The objective of this study is to systematically evaluate the epidemiological characteristics of COVID-19 in pregnant women, assess related maternal mortalities, ascertain the case fatality rate, and delineate associated risk factors., Design: This is a comprehensive population-based ecological study., Methodology: A population-based study was conducted to investigate the epidemiological patterns of COVID-19-associated morbidity and mortality in pregnant women in Ecuador from 27 February 2020 to 14 May 2021., Results: A total of 3274 positive COVID-19 cases were identified among pregnant women, with 22 official fatalities, yielding a case fatality rate of 0.67%. The majority of cases were of Mestizo ethnicity (92.66%); however, the highest case fatality rate was noted among indigenous pregnant women (case fatality rate = 1.25%), those aged between 40 and 44 years (case fatality rate = 2.68%), and those with a history of comorbidities (2.08%). Pregnant women residing at lower altitudes (<2500 m) exhibited a higher incidence rate (0.20/100,000) compared to those at higher altitudes (>2500 m), which stood at 0.17/100,000., Conclusion: The COVID-19 pandemic has profoundly impacted pregnant women in Ecuador during the first 14 months, particularly those with comorbidities, older age, and of indigenous ethnicity. These factors have heightened their vulnerability and susceptibility to severe COVID-19 infection and subsequent mortality. This underscores the urgency for comprehensive protective measures, including prioritization for vaccination. Further studies are needed to inform tailored prevention strategies and therapeutic interventions for these high-risk groups.

Background: Radiology is a useful tool for diagnosis and intervention in medical practice, and all the components within the teaching-learning process of this subject during undergraduate studies influence successful knowledge application., Objective: This study aimed to describe the level of knowledge in radiology of students in the last two years of medical school and curricular characteristics of their courses in seven Latin American countries., Methods: A multicenter cross-sectional study was carried out on medical students of 7 Latin American countries (Bolivia, Brazil, Colombia, Ecuador, Mexico, Paraguay, and Peru) in their final two years of medical school, using an online questionnaire validated by experts and adapted for each country that assessed knowledge and curricular characteristics in radiology subject. Scores were assigned according to the number of correct answers for the knowledge test. The T-test, and regression analysis with one-way ANOVA were used to search for relationships between the level of knowledge and other variables., Results: A total of 1514 medical students participated in this study. All countries had similar participation ( n  > 200); most participants were women 57.8%. The country with the highest knowledge score was Brazil. Male, sixth year (internship) and from public universities students had higher knowledge score ( n  < 0.05). Participants, who considered radiology more important, and who reported higher compliance with teaching staff with the proposed syllabus, and programmed classes, obtained better scores ( n  < 0.05)., Conclusions: Latin American medical students included in this study have a regular overall level of knowledge of Radiology, apparently influenced by curricular differences such as class and academic program compliance. Efforts to better understand and improve academic training are indispensable., Limitations: The study was subject to selection bias determined by non-probability convenience sampling. The questionnaire assessed only theoretical knowledge and the evaluation system was designed by the investigators.

Introduction: Lymphatic filariasis (LF) is a neglected parasitic disease transmitted by mosquitoes and affecting the lymphatic system. The aim of this study was to analyze the epidemiological and sociodemographic characteristics of patients with LF during the last 11 years of available data in Ecuador., Methods: A 11-year nationwide analysis of hospital admission and in-hospital mortality based on the National Institute of Statistics and Census (INEC) data was conducted in Ecuador from 2011 to 2021. The International Classification of Diseases 10th Revision (ICD-10) code for filariasis (ICD: B74) was used to retrieve information on severe LF as a proxy for incidence among 221 Ecuadorian cities., Results: A total of 26 hospital admissions and 3 deaths due to LF were registered. The highest mortality rate was found in populations over 80 years. Men accounted for 62.5% ( n  = 17) of total number of cases with an average incidence rate of 1.7 cases per/1,000,000, while females accounted for 34.6% ( n  = 9), representing 1 case per/1,000,000 woman. Cities located at lower altitude (459/1,000,000) reported higher incidence rates than those located at higher altitudes (7.4/1,000,000)., Conclusion: This is the first study on LF in Ecuador. Although, Ecuador is not considered endemic for LF, we found evidence of the presence of this disease in recent years. The implementation and improvement of an adequate integrated epidemiological surveillance system will allow early identification of cases and therefore their respective treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Izquierdo-Condoy, Naranjo-Lara, Vásconez-Gonzalez, Fernandez-Naranjo, Placencia-André, Davila, Carrington and Ortiz-Prado.)

Background: Restricted and repetitive patterns of behaviour (RRBs) serve an adaptive role in development. Elevated levels of RRBs beyond the early years, however, are associated with poorer outcome in language, cognition, and wellbeing, and are seen across a range of neurodevelopmental conditions. This study aimed to characterize the association of distinct RRB subtypes at two and six years of age, with internalising and externalising difficulties in a community sample of children., Methods: 485 parents reported on their child's insistence on sameness (IS) and repetitive sensory and motor (RSM) RRBs at two and six years of age using the Repetitive Behaviour Questionnaire (RBQ-2). Emotional and behavioural difficulties were measured using the Strengths and Difficulties Questionnaire (SDQ) at age six., Results: Consistent with previous research, RRBs later in development better predicted emotional and behavioural difficulties at age six than RRBs earlier in development. Moreover, IS RRBs were selectively associated with internalising behaviours and RSM RRBs with externalising behaviours. Importantly, these selective associations depended on when RRBs were measured. Only IS RRBs at age six were significantly associated with internalising behaviour. By contrast, while more RSM RRBs at age six were associated with higher rates of externalising behaviours, higher rates of RSM RRBs at age two were associated with fewer externalising behaviours, adding further support to the previously reported adaptive role of RRBs in early behaviour regulation., Conclusion: Although there is a need for further research to provide a detailed profile of the adaptive periods for IS and RSM RRBs, the present findings support the potential utility of elevated RRBs as a signal for emotional and behavioural difficulties at age six., Competing Interests: The authors have declared that they have no competing or potential conflicts of interest., (© 2023 The Authors. JCPP Advances published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

Background: The negative effects of COVID-19 infections during pregnancy have been amply described, however, the persistent sequels of this infection have not been explored so far., Objective: The aim of this study was to describe persisting symptoms after COVID-19 infection in pregnant and non-pregnant women in Ecuador., Methods: A cross-sectional analysis based on an online, self-reporting questionnaire was conducted in Ecuador from April to July 2022. Participants were invited by social media, radio, and TV to voluntarily participate in our study. A total of 457 surveys were included in this study. We compared risk factor variables and long-term persisting symptoms of pregnant and non-pregnant women in Ecuador., Results: Overall, 247 (54.1 %) responders claimed to have long-term symptoms after SARS-CoV-2 infection. Most of these symptoms were reported by non-pregnant women (94.0 %). The most common Long-COVID symptoms in pregnant women were fatigue (10.6 %), hair loss (9.6 %), and difficulty concentrating (6.2 %). We found that pregnant women who smoked had a higher risk of suffering fatigue., Conclusions: The most frequent Long-COVID symptoms in pregnant women were fatigue, hair loss, and difficulty concentrating. Apparently, the patterns of presentation of long-term sequelae of SARS-CoV-2 infection in pregnant women do not differ significantly from reports available from studies in the general population., Competing Interests: Competing interests None declared., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: Stroke is the second most common cause of death and disability-adjusted life years (DALYs) globally. However, the incidence and impact of stroke by ethnicity and gender is frequently distinct. This is particularly the case in Ecuador where geographic and economic marginalization are often correlated with ethnic marginalization and the extent to which females lack the same opportunities as their male counterparts. The aim of this paper is to investigate the differential impacts in terms of stroke diagnosis and burden of disease by ethnicity and gender, using hospital discharge records over the years 2015-2020., Methods: This paper calculates stroke incidence, and fatality rates using hospital discharge and death records over the years 2015-2020. The DALY package in R was employed to calculate the Disability Adjusted Life Years lost due to stroke in Ecuador., Results: The results show that while the incidence rate of stroke in males (64.96 per 100,000 persons-year) is higher than that for females on average (57.84 per 100,000 persons-year), males accounted for 52.41% of all stroke cases and 53% of all surviving cases. Thus, hospital data suggests that females had a higher death rate when compared to males. Case fatality rates also differed significantly by ethnicity. The highest fatality rate corresponded to the Montubio ethnic group (87.65%), followed by Afrodescendants (67.21%). The estimated burden of disease of stroke calculated using Ecuadorian hospital records (2015-2020) varied from 1,468 to 2,991 DALY per 1,000 population on average., Discussion: Differences in the burden of disease by ethnic group are likely to reflect differential access to care by region and socio-economic group, both of which are frequently correlated with ethnic composition in Ecuador. Equitable access to health services remains an important challenge in the country. The gender discrepancy in fatality rates suggests that there is a need for targeted educational campaigns to identify stroke signs early, especially in the female population., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Carrington, Romero-Alvarez, Coral-Almeida, Vela, Henríquez-Trujillo and Mascialino.)

Introduction: Job satisfaction has been shown to have important effects at the organizational level. In various corners of the world, physicians are obliged to perform a period of social service, generally at the first level of care in rural or remote areas., Objective: To describe the level of job satisfaction and perceptions of Ecuadorian rural physicians regarding compulsory social service., Methodology: A descriptive, cross-sectional study was conducted based on a self-administered online questionnaire from February to March 2022, in Ecuadorian rural physicians who were performing their compulsory social service. Participants were invited through official outreach groups. A total of 247 surveys were included in this study. We assessed job satisfaction by means of the S20/23 job satisfaction questionnaire and compared these results with sociodemographic variables and job characteristics of the participants. We performed the reliability test (Cronbach's alpha) to find the validity of the S20/23 questionnaire in physicians performing compulsory social service., Results: The majority of participants were women (61.0%), and overall job satisfaction was 4.1/7.0 pts. "indifferent." The only satisfaction factor in which a predominance of dissatisfaction was found related to benefits/remuneration (43.3%). Participants' perceptions of wrong academic guidance during training, insufficient induction, and negative experiences during work were related to higher levels of dissatisfaction ( P  < .05)., Conclusion: The level of job satisfaction of Ecuadorian rural physicians during their compulsory social service was low and graduates indicated a neutral attitude toward job satisfaction in general. Negative perceptions with respect to training and expectation formation prior to and during the mandatory social service generated greater dissatisfaction. The Ministry of Health of Ecuador, as an organizational entity, should implement improvements to increase the job satisfaction of recently graduated physicians, given the implications that this experience may have for their professional future.

Background and Objectives: Drug consumption is a widely developed practice around the world. However, sometimes medicines are acquired with or without prescription, a practice termed self-medication, which can have negative impacts on the health of the population. It has been observed that with the arrival of the coronavirus disease 2019 (COVID-19) pandemic, self-medicated drug consumption figures increased in several countries. To describe the patterns of medication, use and the prevalence of self-medication during the COVID-19 pandemic in inhabitants of the capital province of Pichincha, Ecuador. Materials and Methods: A descriptive, cross-sectional study was conducted based on a self-administered online questionnaire from April to June 2022, among residents of the province of Pichincha, Ecuador. Participants were invited through social networks (WhatsApp and Facebook). A total of 401 surveys were included in this study. Consumption patterns (prescription of and treatment with) of medicines during the pandemic were evaluated, as well as the prevalence of self-medication and variables that characterize the way of acquiring medicines. The Chi-square test was used to look for relationships between consumption patterns, self-medication, and the characteristics of the participants. Results: Most participants were female (53.4%), and 59.4% reported having had COVID-19. A total of 244 (60.9%) consumed medications during the pandemic, mostly for the purpose of treating the infection. About half (48.4%) self-medicated. The most used medications were paracetamol (87.3%) and ibuprofen (47.5%). Drugs consumption as a treatment and informal sources of information (TV, social networks, advice) were associated with the practice of self-medication (p < 0.05). Conclusions: A significant percentage of over-the-counter (OTC) and legal drug use was found to persist after the COVID-19 pandemic. Our findings highlight the effects that alternative forms of information sources other than medical personnel can have on drug consumption and self-medication practices.

The current study aimed to explore the factor structure of a broad range of restricted and repetitive behaviors (RRB) within the autism spectrum. Exploratory structural equation modeling was conducted using individual item-level data from the Diagnostic Interview for Social and Communication Disorders (DISCO). DISCO is a comprehensive semi-structured interview used by clinicians to elicit information from caregivers about the individual's profile of development and behavior. Data from a sample of 226 individuals with a clinical diagnosis of autism spectrum disorder (ASD) (189 males; M age  = 11.82 years, SD age  = 7.87) were analyzed. The six-factor structure provided the most optimal and interpretable fit (comparative fit index = 0.944, Tucker-Lewis index = 0.923, root mean square error of approximation = 0.018). Derived factors were interpreted as repetitive motor behaviors (RMB), unusual sensory and object focused interests (USOI), sensory sensitivity (SS), insistence on sameness (IS), circumscribed interests (CI) and stereotyped language (SL). Age was significantly negatively associated with RMB, USOI and SL but not with SS, IS or CI factor scores. None of the factors were associated with sex. ASD individuals with intellectual disability (ID) had the highest RMB, USOI, SS and SL scores while those without ID had the highest IS and CI scores. Our findings provide preliminary evidence for the utility of the DISCO as a comprehensive measure of several distinct RRB domains in both research and clinical contexts. Importantly, the current investigation highlights crucial areas for measurement development. LAY SUMMARY: The diagnostic Interview for Social and Communication Disorders (DISCO) is a detailed caregiver report clinical interview designed to capture a wide range of key features associated with autism spectrum disorder, including restricted and repetitive behaviors (RRB). This paper provides initial evidence that the DISCO is a promising measure for assessing a wide range of RRB including repetitive motor behaviors, insistence on sameness, circumscribed interests, unusual interests in sensory stimuli, sensory sensitivity and stereotypic language., (© 2022 The Authors. Autism Research published by International Society for Autism Research and Wiley Periodicals LLC.)

Five years after the publication of DSM-5 in 2013, three widely used diagnostic instruments have published algorithms designed to represent its (sub-)criteria for Autism Spectrum Disorder (ASD) in children and adolescents. This study aimed to: (1) establish the content validity of these three DSM-5-adapted algorithms, and (2) identify problems with the operationalization of DSM-5 diagnostic criteria in measurable and observable behaviors. Algorithm items of the Autism Diagnostic Observation Schedule-Second Edition (ADOS-2), Developmental, Dimensional and Diagnostic Interview (3di) and Diagnostic Interview for Social and Communication Disorders-11th edition (DISCO-11) were mapped onto DSM-5 sub-criteria. The development and decision-making rules integrated in their algorithms were then compared with DSM-5. Results demonstrated significant variability in the number and nature of sub-criteria covered by the ADOS-2, 3di and DISCO-11. In addition to differences in the development of algorithms and cut-off scores, instruments also differed in the extent to which they follow DSM-5 decision-making rules for diagnostic classification. We conclude that such differences in interpretation of DSM-5 criteria provide a challenge for symptom operationalization which will be most effectively overcome by consensus, testing and reformulation.

Background: Recognising the signs of autism spectrum disorder (ASD) can be a challenge for frontline professionals. The use of brief parent-completed questionnaires for recording the signs of ASD in school-aged children may be an important and efficient contributor to professional insight. However, to date, such questionnaires have not been designed to be used in coordination with current standardised Diagnostic and Statistical Manual of Mental Disorders (DSM-5) diagnostic tools. Furthermore, the measurement characteristics of such questionnaires have been unexplored across countries that differ in levels of national autism service provision and cultural interpretation of the signs of ASD., Methods: A new 14-item questionnaire (Signposting Questionnaire for Autism (SQ-A)) was developed using published DSM-5 items from a clinical interview, the Diagnostic Interview for Social Communication Disorders (DISCO). Measurement comparison was tested with the Short Autism Spectrum Quotient-Child (AQ-10) and the Strengths and Difficulties Questionnaire (SDQ). Parents of 4-11-year-old children in the UK (N = 200) and Latvia (N = 104) completed all three questionnaires. Information on clinical diagnosis provided by parents led to classification into three groups: ASD diagnosis, other conditions and no conditions. In the UK, a subsample of teachers also provided cross-informant reliability., Results: In both countries, there was evidence of acceptable to good internal consistency for the SQ-A, with significantly higher scores for the ASD group and evidence of convergent and discriminant validity. There was also good parent-teacher reliability for the three measures. Notably, the questionnaires designed specifically to measure autism (SQ-A, AQ-10) performed more similarly to one another compared to the broader SDQ, with differences found for the ASD group. The overall pattern of responding to the three questionnaires was highly similar between countries., Conclusions: These results indicate the potential of the 14-item SQ-A to guide frontline professionals in the recognition of the signs of autism in children, facilitating the provision of appropriate support.

The rate of diagnosis of autism in adults has increased over recent years; however, the profile of behaviours in these individuals is less understood than the profile seen in those diagnosed in childhood. Better understanding of this profile will be essential to identify and remove potential barriers to diagnosis. Using an abbreviated form of the Diagnostic Interview for Social and Communication Disorders, comparisons were drawn between the profile of a sample of able adults diagnosed in adulthood and the profile of a sample of able children. Results revealed both similarities and differences. A relative strength in non-verbal communication highlighted a potential barrier to diagnosis according to DSM-5 criteria for the adult sample, which may also have prevented them from being diagnosed as children.

Kir7.1 is an inwardly rectifying potassium channel with important roles in the regulation of the membrane potential in retinal pigment epithelium, uterine smooth muscle, and hypothalamic neurons. Regulation of G protein-coupled inwardly rectifying potassium (GIRK) channels by G protein-coupled receptors (GPCRs) via the G protein βγ subunits has been well characterized. However, how Kir channels are regulated is incompletely understood. We report here that Kir7.1 is also regulated by GPCRs, but through a different mechanism. Using Western blotting analysis, we observed that multiple GPCRs tested caused a striking reduction in the complex glycosylation of Kir7.1. Further, GPCR-mediated reduction of Kir7.1 glycosylation in HEK293T cells did not alter its expression at the cell surface but decreased channel activity. Of note, mutagenesis of the sole Kir7.1 glycosylation site reduced conductance and open probability, as indicated by single-channel recording. Additionally, we report that the L241P mutation of Kir7.1 associated with Lebers congenital amaurosis (LCA), an inherited retinal degenerative disease, has significantly reduced complex glycosylation. Collectively, these results suggest that Kir7.1 channel glycosylation is essential for function, and this activity within cells is suppressed by most GPCRs. The melanocortin-4 receptor (MC4R), a GPCR previously reported to induce ligand-regulated activity of this channel, is the only GPCR tested that does not have this effect on Kir7.1., (© 2018 Carrington et al.)

A community sample of 192 parents reported on their children's restricted and repetitive behaviors (RRBs) at mean ages 15 months (N = 138), 26 months (N = 191), and 77 months (N = 125) using the Repetitive Behavior Questionnaire-2 (RBQ-2). Consistent with previous factor analytic research, 2 factors were found at each age: 1 comprising repetitive sensory and motor behaviors (RSM), and the other comprising insistence on sameness behaviors including rigidity, routines, and restricted interests (IS). Regression analyses indicated that RSM and IS subtypes develop independently. RSM at 77 months was predicted only by RSM behaviors at 26 months and not by IS behaviors at either 15 or 26 months nor by RSM behaviors at 15 months. IS at 77 months was predicted by IS behaviors at both 15 and 26 months, but not by RSM behaviors at either 15 or 26 months. Our findings provide evidence that there is stability of 2 independent subtypes of RRBs, RSM and IS, across early childhood and that these subtypes develop independently of each other. (PsycINFO Database Record, ((c) 2017 APA, all rights reserved).)

Two manganese(I) carbonyl complexes derived from 2-(pyridyl)benzothiazole (pbt) and 1,10-phenanthroline (phen) release carbon monoxide (CO) under low-power broad-band visible-light illumination. CO photorelease from [Mn(CO) 3 (pbt)(PTA)]CF 3 SO 3 (1, where PTA = 1,3,5-triaza-7-phosphaadamantane) is accompanied by an emergence of a strong fluorescence around 400 nm from almost nonfluorescent preirradiated 1. However, [Mn(CO) 3 (phen)(PTA)]CF 3 SO 3 (2) showed no such phenomenon upon prolonged illumination under similar experimental conditions. The two analogous rhenium(I) complexes, namely, [Re(CO) 3 (pbt)(PTA)]CF 3 SO 3 (3) and [Re(CO) 3 (phen)(PTA)]CF 3 SO 3 (4), have also been synthesized and characterized to compare their photo properties with the manganese congeners. Complexes 3 and 4 exhibit moderate CO release upon irradiation with low-power UV light. All four complexes are highly soluble in anaerobic/aerobic aqueous media and are also considerably more stable when kept under dark conditions. The inherently luminescent rhenium complex 3 was utilized to demonstrate cellular internalization of these types of compounds by MDA-MB-231 (human breast cancer) cells, while the two biocompatible manganese(I) complexes (1 and 2) have been applied to assess the cell viability of these malignant cells upon CO delivery.

The discovery of salutary effects of low doses of carbon monoxide (CO) has spurred interest in designing exogenous molecules that can deliver CO to biological targets under controlled conditions. Herein we report a water-soluble photosensitive manganese carbonyl complex [MnBr(CO)3(pyTAm)] (2) (pyTAm = 2-(pyridyl)imino-triazaadamantane) that can be triggered to release CO upon exposure to visible light. Inclusion of a triazaadamantyl pharmacophore into the coligand of 2 improves its stability and solubility in water. Change in the coligand from 2-(pyridyl)imino-triazaadamantane to 2-(pyridyl)iminoadamantane (pyAm) or 2-(quinonyl)imino-triazaadamantane (qyTAm) dramatically alters these desired properties of the photoCORM. In addition to structures and CO-releasing properties of the three analogous complexes 1-3 from these three α-diimine ligands, theoretical calculations have been performed to determine the origin of Mn-CO bond labilization upon illumination. Rapid delivery of CO to myoglobin under physiological conditions attests the potential of 2 as a biocompatible photoCORM.

A Re(I) carbonyl complex derived from 2-(2-pyridyl)-benzothiazole (pbt), [Re(H2O)(CO)3(pbt)](CF3SO3) (1), rapidly releases CO under low-power UV illumination. CO photorelease from 1 is accompanied by a change in luminescence from orange to deep blue. These two distinct luminescence signals have been successfully employed to track (a) the entry of the pro-drug 1 into cancer cells and (b) the end of the CO (drug) delivery step within the target.

The melanocortin peptides derived from pro-opiomelanocortin (POMC) were originally understood in terms of the biological actions of α-melanocyte-stimulating hormone (α-MSH) on pigmentation and adrenocorticotrophic hormone on adrenocortical glucocorticoid production. However, the discovery of POMC mRNA and melanocortin peptides in the CNS generated activities directed at understanding the direct biological actions of melanocortins in the brain. Ultimately, discovery of unique melanocortin receptors expressed in the CNS, the melanocortin-3 (MC3R) and melanocortin-4 (MC4R) receptors, led to the development of pharmacological tools and genetic models leading to the demonstration that the central melanocortin system plays a critical role in the regulation of energy homeostasis. Indeed, mutations in MC4R are now known to be the most common cause of early onset syndromic obesity, accounting for 2-5% of all cases. This review discusses the history of these discoveries, as well as the latest work attempting to understand the molecular and cellular basis of regulation of feeding and energy homeostasis by the predominant melanocortin peptide in the CNS, α-MSH., Competing Interests: Declaration of interest The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review., (© 2016 Society for Endocrinology.)

Background: Government policy and national practice guidelines have created an increasing need for autism services to adopt an evidence-based practice approach. However, a gap continues to exist between research evidence and its application. This study investigated the difference between autism researchers and practitioners in their methods of acquiring knowledge., Methods: In a questionnaire study, 261 practitioners and 422 researchers reported on the methods they use and perceive to be beneficial for increasing research access and knowledge. They also reported on their level of engagement with members of the other professional community., Results: Researchers and practitioners reported different methods used to access information. Each group, however, had similar overall priorities regarding access to research information. While researchers endorsed the use of academic journals significantly more often than practitioners, both groups included academic journals in their top three choices. The groups differed in the levels of engagement they reported; researchers indicated they were more engaged with practitioners than vice versa., Conclusions: Comparison of researcher and practitioner preferences led to several recommendations to improve knowledge sharing and translation, including enhancing access to original research publications, facilitating informal networking opportunities and the development of proposals for the inclusion of practitioners throughout the research process., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Two manganese(i) carbonyl complexes derived from α,α'-diimine ligands with extended conjugated framework namely [MnBr(CO)3(BIAN)] () and [MnBr(CO)3(MIAN)] (), have been synthesized and structurally characterized. Unlike the previously reported photoactive CO-releasing molecules (photoCORMs), these two complexes exhibit unusually high sensitivity toward low power (0.3-10 mW) visible light (λ ≥ 520 nm) even in the solid state and rapidly release carbon monoxide (CO) upon illumination. The role of the ligand frames in such activity has been examined with the help of theoretical calculations. Application of these photoCORMs in delivering high fluxes of CO to biological targets is anticipated.

A designed photoactive CO releasing molecule (photoCORM), namely, fac-[MnBr(CO)3(pbt)] (1, pbt = 2-(2-pyridyl)benzothiazole), promotes CO-induced death of MDA-MB-231 human breast cancer cells upon illumination with broadband visible light. The CO release from this photoCORM can be tracked by rise in fluorescence within the cellular matrix due to deligation of the pbt ligand. The results of this study suggest the potential of 1 in eradication of cancer cells through CO delivery.

The recent surprising discovery of the beneficial effects of carbon monoxide (CO) in mammalian physiology has drawn attention toward site-specific delivery of CO to biological targets. To avoid difficulties in handling of this noxious gas in hospital settings, researchers have focused their attention on metal carbonyl complexes as CO-releasing molecules (CORMs). Because further control of such CO delivery through light-triggering can be achieved with photoactive metal carbonyl complexes (photoCORMs), we and other groups have attempted to isolate such complexes in the past few years. Typical metal carbonyl complexes release CO when exposed to UV light, a fact that often deters their use in biological systems. From the very beginning, our effort therefore was directed toward identifying design principles that could lead to photoCORMs that release CO upon illumination with low-power (5-15 mW/cm(2)) visible and near-IR light. In our work, we have utilized Mn(I), Re(I), and Ru(II) centers (all d(6) ground state configuration) to ensure overall stability of the carbonyl complexes. We also hypothesized that transfer of electron density from the electron-rich metal centers to π* MOs of the ligand frame via strong metal-to-ligand charge transfer (MLCT) transitions in the visible/near-IR region would weaken metal-CO back-bonding and promote rapid CO photorelease. This expectation has been realized in a series of carbonyl complexes derived from a variety of designed ligands and smart choice of ligand/coligand combinations. Several principles have emerged from our systematic approach to the design of principal ligands and the choice of auxiliary ligands (in addition to the number of CO) in synthesizing these photoCORMs. In each case, density functional theory (DFT) and time-dependent DFT (TDDFT) study afforded insight into the dependence of the CO photorelease from a particular photoCORM on the wavelength of light. Results of these theoretical studies indicate that extended conjugation in the principal ligand frames as well as the nature of the donor groups lower the energy of the lowest unoccupied MOs (LUMOs) while auxiliary ligands like PPh3 and Br(-) modulate the energy of the occupied orbitals depending on their strong σ- or π-donating abilities. As a consequence, the ligand/coligand combination dictates the energy of the MLCT bands of the resulting carbonyl complexes. The rate of CO photorelease can be altered further by proper disposition of the coligands in the coordination sphere to initiate trans-effect or alter the extent of π back-bonding in the metal-CO bonds. Addition of more CO ligands blue shift the MLCT bands, while intersystem crossing impedes labilization of metal-CO bonds in several Re(I) and Ru(II) carbonyl complexes. We anticipate that our design principles will provide help in the future design of photoCORMs that could eventually find use in clinical studies.

The therapeutic potential of photoactive CO-releasing molecules (photoCORMs) have called for close examination of the roles of the ligand(s) and the central metal atoms on the overall photochemical labilization of the metal-CO bonds. Along this line, we have synthesized four metal complexes, namely, [MnBr(azpy)(CO)3 ] (1), [Mn(azpy)(CO)3 (PPh3 )]ClO4 (2), [ReBr(azpy)(CO)3 ] (3), and [Re(azpy)(CO)3 (PPh3 )]ClO4 (4), derived from 2-phenylazopyridine. These complexes were characterized by spectroscopic and crystallographic studies. Although both 1 and 3 exhibit strong metal-to-ligand charge-transfer bands in the 500-600 nm region, only 1 photoreleases CO upon illumination with visible light. Results of theoretical studies were used to gain insight into this surprising difference. Strong spin-orbit coupling (prominent in heavy metals) appears to promote intersystem crossing to a triplet state in 3, a step that discourages CO release upon illumination with visible light. Slow release of CO from 2 and 4 also indicates that strong σ-donating ligands, such as Br(-) , accelerate the rate of CO photorelease relative to π-acid ligands, such as PPh3 ., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Two Mn(I) carbonyl complexes namely [MnBr(azpy)(CO)3] and [Mn(azpy)(CO)3(PPh3)](ClO4) (azpy = 2-phenylazopyridine) have been synthesized and characterized. Both complexes exhibit rapid CO release upon exposure to low power visible light. [MnBr(azpy)(CO)3] shows significant phototoxicity toward two malignant cell lines HeLa and MDA-MB-231.

Background: Introduction of proposed criteria for DSM-5 Autism Spectrum Disorder (ASD) has raised concerns that some individuals currently meeting diagnostic criteria for Pervasive Developmental Disorder (PDD; DSM-IV-TR/ICD-10) will not qualify for a diagnosis under the proposed changes. To date, reports of sensitivity and specificity of the new criteria have been inconsistent across studies. No study has yet considered how changes at the 'sub domain' level might affect overall sensitivity and specificity, and few have included individuals of different ages and ability levels., Methods: A set of DSM-5 ASD algorithms were developed using items from the Diagnostic Interview for Social and Communication Disorders (DISCO). The number of items required for each DSM-5 subdomain was defined either according to criteria specified by DSM-5 (Initial Algorithm), a statistical approach (Youden J Algorithm), or to minimise the number of false positives while maximising sensitivity (Modified Algorithm). The algorithms were designed, tested and compared in two independent samples (Sample 1, N = 82; Sample 2, N = 115), while sensitivity was assessed across age and ability levels in an additional dataset of individuals with an ICD-10 PDD diagnosis (Sample 3, N = 190)., Results: Sensitivity was highest in the Initial Algorithm, which had the poorest specificity. Although Youden J had excellent specificity, sensitivity was significantly lower than in the Modified Algorithm, which had both good sensitivity and specificity. Relaxing the domain A rules improved sensitivity of the Youden J Algorithm, but it remained less sensitive than the Modified Algorithm. Moreover, this was the only algorithm with variable sensitivity across age. All versions of the algorithm performed well across ability level., Conclusions: This study demonstrates that good levels of both sensitivity and specificity can be achieved for a diagnostic algorithm adhering to the DSM-5 criteria that is suitable across age and ability level., (© 2013 The Authors. Journal of Child Psychology and Psychiatry © 2013 Association for Child and Adolescent Mental Health.)

One monocarbonyl and one dicarbonyl complex of ruthenium(II), namely, [Ru(Cl)(CO)(qmtpm)(PPh3)]BF4 (2) and [Ru(Cl)(CO)2(qmtpm)]ClO4 (3), derived from the tridentate ligand 2-quinoline-N-(2'-methylthiophenyl)methyleneimine (qmtpm) have been synthesized and structurally characterized. The qmtpm ligand binds in a meridional fashion in these carbonyl complexes, and in 3, the two carbon monoxide (CO) ligands are cis to each other. Solutions of 2 in ethanol, chloroform, or acetonitrile rapidly release CO upon illumination with low-power (3-15 mW) light in the 300-450 nm range. Loss of CO from 2 brings about a dramatic color change from yellow to magenta because of the formation of [Ru(Cl)(MeCN)(qmtpm)(PPh3)]BF4 (4). In acetonitrile, photorelease of CO from 3 under 360 nm light occurs in two steps, and the violet photoproduct [Ru(Cl)(MeCN)2(qmtpm)](+) upon reaction with Ag(+) and PPh3 affords red [Ru(MeCN)2(qmtpm)(PPh3)](ClO4)2 (5). The structure of 5 has also been determined by X-ray crystallography. Reduced myoglobin assay confirms that 2 and 3 act as photoactive CO-releasing molecules (photoCORMs) that deliver 1 and 2 equiv of CO, respectively. The results of density functional theory (DFT) and time-dependent DFT studies confirm that electronic transitions from molecular orbitals with predominantly Ru-CO character to ligand-based π* orbitals facilitate CO release from these two photoCORMs. Complexes 2-5 have provided an additional opportunity to analyze the roles of the ancillary ligands, namely, PPh3, Cl(-), and MeCN, in shifting the positions of the metal-to-ligand charge-transfer bands and the associated sensitivity of the two photoCORMs to different wavelengths of light. Collectively, the results provide helpful hints toward the future design of photoCORMs that release CO upon exposure to visible light.

This letter describes the further exploration of two series of M(1) allosteric agonists, TBPB and VU0357017, previously reported from our lab. Within the TPBP scaffold, either electronic or steric perturbations to the central piperidine ring led to a loss of selective M(1) allosteric agonism and afforded pan-mAChR antagonism, which was demonstrated to be mediated via the orthosteric site. Additional SAR around a related M(1) allosteric agonist family (VU0357017) identified similar, subtle 'molecular switches' that modulated modes of pharmacology from allosteric agonism to pan-mAChR orthosteric antagonism. Therefore, all of these ligands are best classified as bi-topic ligands that possess high affinity binding at an allosteric site to engender selective M(1) activation, but all bind, at higher concentrations, to the orthosteric ACh site, leading to non-selective orthosteric site binding and mAChR antagonism., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The unusual role of CO as a signaling molecule in several physiological pathways has spurred research in the area of synthesizing new CO-releasing molecules (CORMs) as exogenous CO donors. Auxiliary control on CO delivery can be achieved if CO can be released under the control of light. To synthesize such photoactive CORMs (photoCORMs) with the aid of smart design, a series of manganese carbonyls have been synthesized with ligands that contain extended conjugation and electron-rich donors on their frames. Five such photoCORMs, namely, [Mn(pimq)(CO)(3)(MeCN)]ClO(4) (1, where pimq = (2-phenyliminomethyl)quinoline), [Mn(qmtpm)(CO)(3)(MeCN)]ClO(4) (2, where qmtpm = 2-quinoline-N-(2'-methylthiophenyl) methyleneimine), [Mn(qmtpm)(CO)(3)Br] (3) [Mn(pmtpm)(CO)(3)(MeCN)]ClO(4) (4, where pmtpm = 2-pyridyl-N-(2'-methylthiophenyl)methyleneimine), and [Mn(pmtpm)(CO)(3)Br] (5), have been synthesized and structurally characterized. These designed carbonyls readily release CO upon exposure to light (400-550 nm). The apparent CO release rates and quantum yield values at 509 nm (φ(509)) of the photoCORMs increase steadily with rise in conjugation in the ligand frame and inclusion of a -SMe group. Addition of Br(-) as an ancillary ligand also improves the CO-donating capacity. Results of density functional theory (DFT) and time dependent DFT (TDDFT) studies indicate that low energy metal-to-ligand charge transfer (MLCT) transitions from Mn-CO bonding into ligand-π orbitals lead to reduction of M-CO(π*) back-bonding and loss of CO from these photoCORMs. Inclusion of -SMe and Br(-) in the coordination sphere attenuates the energies of the HOMO and LUMO levels and causes further enhancement of CO photorelease. Collectively, the results of this work demonstrate that new photoCORMs with excellent sensitivity to visible light can be synthesized on the basis of smart design principles.

Herein we report the discovery and SAR of a novel metabotropic glutamate receptor 3 (mGlu(3)) NAM probe (ML289) with 15-fold selectivity versus mGlu(2). The mGlu(3) NAM was discovered via a 'molecular switch' from a closely related, potent mGlu(5) positive allosteric modulator (PAM), VU0092273. This NAM (VU0463597, ML289) displays an IC(50) value of 0.66 μM and is inactive against mGlu(5)., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Several small molecule species formally known primarily as toxic gases have, over the past 20 years, been shown to be endogenously generated signaling molecules. The biological signaling associated with the small molecules NO, CO, H₂S (and the nonendogenously generated O₂), and their derived species have become a topic of extreme interest. It has become increasingly clear that these small molecule signaling agents form an integrated signaling web that affects/regulates numerous physiological processes. The chemical interactions between these species and each other or biological targets is an important factor in their roles as signaling agents. Thus, a fundamental understanding of the chemistry of these molecules is essential to understanding their biological/physiological utility. This review focuses on this chemistry and attempts to establish the chemical basis for their signaling functions.

Hydrogen sulfide is an endogenously generated molecule with many reported physiological functions. Although several biological targets have been proposed, the biochemical mechanisms by which it elicits activity are not established. Thus, in an effort to begin to delineate the fundamental biological chemistry of H(2)S, we have examined the reaction of H(2)S with oxidized thiols and thiol proteins in order to determine whether persulfide formation occurs, is stable and how this may affect protein function. We have found that persulfides are easily generated, relatively stable and can alter enzyme activity. Moreover, we have begun to develop methodology for in situ generation of persulfides to facilitate further study of this potentially important species., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Due to recent discoveries of important and novel biological activity, nitroxyl (HNO) has become a molecule of significant interest. Although it has been used in the past as a treatment for alcoholism, it is currently being touted as a treatment for heart failure. It is becoming increasingly clear that many of the biological actions of HNO can be attributed to its ability to react with specific thiol- and, possibly, heme-proteins. Herein is discussed the chemistry of HNO with likely biological targets. A particular focus is given to targets associated with the pharmacological utility of HNO as a cardiovascular agent and for the treatment of alcoholism.

There have been many functional imaging studies of the brain basis of theory of mind (ToM) skills, but the findings are heterogeneous and implicate anatomical regions as far apart as orbitofrontal cortex and the inferior parietal lobe. The functional imaging studies are reviewed to determine whether the diverse findings are due to methodological factors. The studies are considered according to the paradigm employed (e.g., stories vs. cartoons and explicit vs. implicit ToM instructions), the mental state(s) investigated, and the language demands of the tasks. Methodological variability does not seem to account for the variation in findings, although this conclusion may partly reflect the relatively small number of studies. Alternatively, several distinct brain regions may be activated during ToM reasoning, forming an integrated functional "network." The imaging findings suggest that there are several "core" regions in the network-including parts of the prefrontal cortex and superior temporal sulcus-while several more "peripheral" regions may contribute to ToM reasoning in a manner contingent on relatively minor aspects of the ToM task., ((c) 2008 Wiley-Liss, Inc.)

The analogue of glutathione disulphide (GSSG) in which the disulphide bridge of GSSG is replaced by -CH2-S- was synthesised from L-cystathionine using t-butoxycarbonyl and t-butyl ester protection with triethylsilane-promoted deprotection. This analogue (GCSG) was found to be a linear, competitive inhibitor of yeast glutathione reductase (Ki value 981 microM at pH 7.0), a very poor substrate and not to act as an irreversible inhibitor of glutathione reductase. The weak binding of GCSG to glutathione reductase permitted the use of transferred nuclear Overhauser effect spectroscopy (TRNOESY) to investigate the bound conformation of GCSG in its complex with glutathione reductase. The solution structure of free GCSG was investigated by NMR spectroscopy using a range of NMR techniques. The TRNOESY experiment allowed a range of conformations to be determined for the central bridge region (containing the -CH2-S- replacement) of GCSG bound to yeast glutathione reductase. Using the nuclear Overhauser effect constraints thus derived, in combination with molecular graphics and energy minimisation based on the known crystal coordinates of glutathione disulphide (GSSG) bound to human erythrocyte glutathione reductase, allowed an explanation of the lack of substrate activity of GCSG, its inactivity as a suicide inactivator and its relatively weak binding in terms of the enforced mislocation of the -CH2-S- bridge with respect to the catalytic residues (relative to GSSG). Thus, the simple replacement of -S- by -CH2-, common in medicinal chemistry, can lead to poor receptor binding if the replacement occurs in a central, rather than peripheral, part of the ligand under modification.

Syntheses are described for and structure:activity studies undertaken of the anti-tumour activity of (2-crotonyloxymethyl-(4R,5R,6R)-4,5,6-trihydroxycyclohex-2-+ ++enone) (1) and its analogues 1-crotonyloxymethyl-(3R,4S,5R)-3,4,5-trihydroxycyclohex-1-en e (3), 1-crotonyloxymethyl-(3R,4S,5S)-3,4,5-trihydroxycyclohexene (4) and 2-crotonyloxymethyl-2-cyclohexenone (5), which differ from 1 in the presence/absence of the cyclic keto group and/or the stereochemistry at one of the -OH bearing carbon atoms. None of the above compounds, including 1, directly inhibited glyoxalase I, isolated for the first time to homogeneity from rat Yoshida sarcomas and for which a purification protocol was developed. The apparent inhibition of glyoxalase I by 1 and 5 (but not detected for 4 or 3) could be explained by reaction of 1 and 5 with the glutathione present in the assay buffer and the consequent depletion of substrate. 1 and 5 were found to react readily with glutathione whereas 4 and 3 did not react. In vitro chemosensitivity studies against a panel of tumour cell lines of both mouse and human origin showed that in parallel with their thiol reactivity, 1 and 5 exhibited significant in vitro cytotoxicity whereas 4 and 3 did not. Concentrations of drug required to cause 50% cell kill (ID50 values) were in the range 0.5-19 microM (0.1-2.8 micrograms/ml) for 5, and 3-44 microM (0.7-10 micrograms/ml) for 1. The structural features causing the differences in antitumour effects were localized on this basis to the alpha,beta-unsaturated ketone linkage as opposed to the stereochemistry of the (trihydroxy) alcoholic sites.

1. Yeast glyoxalase I was inactivated by N-acetylimidazole and tetranitromethane, the latter process following pK app 7.31 and irreversibly producing a protein with a spectrum typical of 3-nitrotyrosine. 2. For yeast glyoxalase I, amino-acid analysis and protection studies with S-(p-bromobenzyl)glutathione, a competitive inhibitor, indicated two classes of tetranitromethane-reactive tyrosine residues, fast- and slow-reacting, with the latter class containing the crucial tyrosine(s). 3. Human erythrocyte glyoxalase I was inactivated by tetranitromethane in fast and slow processes, protection studies in this case indicating the important tyrosine(s) as fast-reacting.