Search

Trithorax-related H3K4 methyltransferases, KMT2C and KMT2D, are critical epigenetic modifiers. Haploinsufficiency of KMT2C was only recently recognized as a cause of neurodevelopmental disorder (NDD), so the clinical and molecular spectrums of the KMT2C-related NDD (now designated as Kleefstra syndrome 2) are largely unknown. We ascertained 98 individuals with rare KMT2C variants, including 75 with protein-truncating variants (PTVs). Notably, ∼15% of KMT2C PTVs were inherited. Although the most highly expressed KMT2C transcript consists of only the last four exons, pathogenic PTVs were found in almost all the exons of this large gene. KMT2C variant interpretation can be challenging due to segmental duplications and clonal hematopoesis-induced artifacts. Using samples from 27 affected individuals, divided into discovery and validation cohorts, we generated a moderate strength disorder-specific KMT2C DNA methylation (DNAm) signature and demonstrate its utility in classifying non-truncating variants. Based on 81 individuals with pathogenic/likely pathogenic variants, we demonstrate that the KMT2C-related NDD is characterized by developmental delay, intellectual disability, behavioral and psychiatric problems, hypotonia, seizures, short stature, and other comorbidities. The facial module of PhenoScore, applied to photographs of 34 affected individuals, reveals that the KMT2C-related facial gestalt is significantly different from the general NDD population. Finally, using PhenoScore and DNAm signatures, we demonstrate that the KMT2C-related NDD is clinically and epigenetically distinct from Kleefstra and Kabuki syndromes. Overall, we define the clinical features, molecular spectrum, and DNAm signature of the KMT2C-related NDD and demonstrate they are distinct from Kleefstra and Kabuki syndromes highlighting the need to rename this condition., Competing Interests: Declaration of interests R.W. is a consultant (equity) for Alamya Health., (Copyright © 2024 American Society of Human Genetics. All rights reserved.)

The behavioral and neural responses to social exclusion were examined in women randomized to four conditions, varying in levels of attractiveness and friendliness. Informed by evolutionary theory, we predicted that being socially excluded by attractive unfriendly women would be more distressing than being excluded by unattractive women, irrespective of their friendliness level. Our results contradicted most of our predictions but provide important insights into women's responses to interpersonal conflict. Accounting for rejection sensitivity, P300 event-related potential amplitudes were largest when women were excluded by unattractive unfriendly women. This may be due to an expectancy violation or an annoyance with being excluded by women low on social desirability. An examination of anger rumination rates by condition suggests the latter. Only attractive women's attractiveness ratings were lowered in the unfriendly condition, indicating they were specifically punished for their exclusionary behavior. Women were more likely to select attractive women to compete against with one exception-they selected the Black attractive opponent less often than the White attractive opponent when presented as unfriendly. Finally, consistent with studies on retaliation in relation to social exclusion, women tended to rate competitors who rejected them as being more rude, more competitive, less attractive, less nice, and less happy than non-competitors. The ubiquity of social exclusion and its pointed emotional and physiological impact on women demands more research on this topic., (© 2024. The Author(s).)

A new measure to assess friendship jealousy in the context of social media was developed. This one-factor, seven-item measure was psychometrically sound, showing evidence of validity and reliability in three samples of North American adults (Study 1, n  = 491; Study 2, n  = 494; Study 3, n  = 415) and one-, two-, and three-year stability (Study 3). Women reported more social media friendship jealousy than men (Studies 2 and 3) and younger women had the highest levels of social media friendship jealousy (compared with younger men and older men and women; Study 2). Social media friendship jealousy was associated with lower friendship quality (Study 1) and higher social media use and trait jealousy (Study 2). The relation between social media friendship jealousy and internalizing symptoms indicated positive within time associations and longitudinal bidirectional relations (Study 3). Specifically, social media friendship jealousy predicted increases in internalizing problems, and internalizing problems predicted greater social media friendship jealousy accounting for gender and trait levels of social media friendship jealousy and internalizing problems. Anxious and depressed adults may be predisposed to monitor threats to their friendships via social media and experience negative consequences because of this behavior. Although social media interactions can be associated with positive well-being and social connectedness, our results highlight that they can also undermine friendships and mental health due to jealousy., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Love withdrawal is a form of interpersonal manipulation that shares many features with relational aggression; its use by children has not been examined. Guided by social learning theory, we sought to investigate the prevalence of toddlers' use of love withdrawal toward caregivers (parents and teachers) and further investigate how this behavior was associated with relational and physical aggression and parents' use of love withdrawal. These aims were examined using parent and teacher reports in a sample of 198 toddlers (M age  = 33.62 months; SD = 5.00 months; 50.5% girls). We found that most toddlers used love withdrawal directed at parents (79.2%) and teachers (72.1%) when angry and displayed this type of behavior more than relational and physical aggression. Accounting for household income, hours per week in childcare, and child age in months, as well as classroom clustering, we found that relational aggression, and not physical aggression, predicted the use of love withdrawal by toddlers (teacher reports), and that the associations were stronger for love withdrawal and relational aggression than for physical aggression. We also found that parents' use of love withdrawal toward their child was correlated with their reports of their child's use of love withdrawal, but not with their child's use of aggression. These results highlight the importance of considering the use of love withdrawal by children given its association with aggression which is linked to poorer psychosocial functioning., (© 2023 The Authors. Aggressive Behavior published by Wiley Periodicals LLC.)

The COVID-19 pandemic has resulted in many changes that may impact anxiety symptoms (i.e., general anxiety and somatization), particularly for young adults who were at higher risk for anxiety than older adults. We examined anxiety symptoms before (age 19, 20, 21, and 22) and during the pandemic (age 23 and 24) in a cohort of Canadian young adults (n = 396). Latent growth curve models were performed for general anxiety and somatization and the pandemic time points were estimated as structured residuals to quantify the change from participants' expected trajectories. We also examined whether fear of COVID-19 predicted the changes in anxiety symptoms during the pandemic. Results indicated that a history of general anxiety and somatization positively predicted fear of COVID-19 during the pandemic and negatively predicted pandemic change from predicted values for both general anxiety and somatization. Increased COVID-19 fear was related within time to increases in general anxiety at ages 23 and 24 and increases in somatization at age 24. We also found that the proportion of individuals in the subclinical/clinical range of somatization was higher from age 23-24, but not from age 22-23 and there were no differences for general anxiety. Results highlight the need to consider within-person change and development in evaluating anxiety symptom changes and predictors of changes in anxiety symptoms., Competing Interests: Declaration of Competing Interest The authors declare no known conflicts of interest., (Copyright © 2023. Published by Elsevier Ltd.)

The rates of bullying during the COVID-19 pandemic, a time of unprecedented public health and social restrictions, were compared to earlier times when students attended school in person. Several studies indicated a notable decrease in the prevalence of bullying victimization and perpetration during the pandemic, particularly when online learning was implemented. But studies from countries with fewer social restrictions indicated increases in rates of bullying during the pandemic. Mixed results regarding prevalence rates for some bullying forms (e.g., cyberbullying) were also found. Racialized youth and LGBTQ+ youth reliably reported higher rates of bullying victimization during the pandemic, consistent with pre-pandemic patterns. Reasons for the inconsistencies in findings likely relate to diverse methods, timeframes, and sampling techniques, as well as different experiences with pandemic social restrictions. More longitudinal studies are needed to assess whether bullying involvement did in fact "change" during, compared to before, the pandemic. The findings point to the importance of peer relationships and hint at the potential of increased teacher supervision as a bullying prevention strategy., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest in relation to the content of this review., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

School transitions are common educational experiences for children and adolescents and many of them worry about being bullied during this type of major life-changing point. In a sample of 701 Canadians assessed yearly from grade 5 (age 10) to grade 12 (age 18), we examined heterogeneous patterns of bullying involvement while statistically accounting for the transition into high school. Gender differences were also examined. Results indicated that on average, bullying victimization declined over time with a significant drop noted between grade 8 and grade 9 (the transition into high school), with few differences between girls and boys. Bullying perpetration also declined for most students (no gender differences), with a notable drop found at the transition into high school. However, for a subset of adolescents, the transition into high school was accompanied by an increase in bullying perpetration. These varied experiences highlight the need to model heterogeneity when examining the impact of school transitions on bullying, a neglected focus of inquiry to date. Our results suggest that moving into high school is beneficial for most adolescents involved in bullying, but not for all., (© 2023 The Authors. Aggressive Behavior published by Wiley Periodicals LLC.)

Glioma is a rare brain tumor with a poor prognosis. Familial glioma is a subset of glioma with a strong genetic predisposition that accounts for approximately 5% of glioma cases. We performed whole-genome sequencing on an exploratory cohort of 203 individuals from 189 families with a history of familial glioma and an additional validation cohort of 122 individuals from 115 families. We found significant enrichment of rare deleterious variants of seven genes in both cohorts, and the most significantly enriched gene was HERC2 ( P  = 0.0006). Furthermore, we identified rare noncoding variants in both cohorts that were predicted to affect transcription factor binding sites or cause cryptic splicing. Last, we selected a subset of discovered genes for validation by CRISPR knockdown screening and found that DMBT1, HP1BP3 , and ZCH7B3 have profound impacts on proliferation. This study performs comprehensive surveillance of the genomic landscape of familial glioma.

Introduction: ERF mutation is one of the most recently identified genetic aberrations associated with syndromic craniosynostosis. Data on the pattern of craniosynostosis, surgical management of ERF-related craniosynostosis and outcomes is limited. We report on our single-centre experience in paediatric cohort of patients with syndromic craniosynostosis secondary to ERF mutation., Methods: A retrospective review of all paediatric craniofacial cases was performed over an 8-year period (2014-2022). All patients with genetically confirm ERF-related craniosynostosis were identified, and clinical parameters including, age, sex, pattern of craniosynostosis, associated tonsillar herniation and follow-up period were further analysed from electronic clinical and imaging systems. All patients were selected and discussed in multidisciplinary craniofacial meeting (composed of neurosurgical, maxillofacial, plastics and genetics teams) prior to any surgical intervention., Results: Overall, 10 patients with ERF-related craniosynostosis were identified with a male-to-female ratio of 4:1 with mean age at the time of surgery of 21.6 months with a mean follow-up period of 5.2 years. ERF-confirmed cases led to variable craniosynostosis pattern with multi-sutural synostosis with concurrent sagittal and bilateral lambdoid involvement as the most common pattern (7/10). No patient pre-operatively had evidence of papilloedema on ophthalmological assessment. Eight out of 10 patients had associated low-lying tonsils/hind brain hernia pre-operatively. Eight out of 10 patients required surgery which included 2 fronto-orbital advancement, 3 calvarial remodelling, 2 posterior calvarial remodelling/release and 1 insertion of ventriculoperitoneal shunt., Conclusion: Involvement of sagittal and lambdoid sutures is the most common pattern of craniosynostosis. ERF-related craniosynostosis can have variable pattern of suture fusion, and management of each patient requires unique surgical planning and execution based on clinical needs for the optimal outcomes., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Genome sequencing was first offered clinically in the UK through the 100,000 Genomes Project (100KGP). Analysis was restricted to predefined gene panels associated with the patient's phenotype. However, panels rely on clearly characterised phenotypes and risk missing diagnoses outside of the panel(s) applied. We propose a complementary method to rapidly identify pathogenic variants, including those missed by 100KGP methods., Methods: The Loss-of-function Observed/Expected Upper-bound Fraction (LOEUF) score quantifies gene constraint, with low scores correlated with haploinsufficiency. We applied DeNovoLOEUF, a filtering strategy to sequencing data from 13,949 rare disease trios in the 100KGP, by filtering for rare, de novo, loss-of-function variants in disease genes with a LOEUF score < 0.2. We compared our findings with the corresponding patient's diagnostic reports., Results: 324/332 (98%) of the variants identified using DeNovoLOEUF were diagnostic or partially diagnostic (whereby the variant was responsible for some of the phenotype). We identified 39 diagnoses that were "missed" by 100KGP standard analyses, which are now being returned to patients., Conclusion: We have demonstrated a highly specific and rapid method with a 98% positive predictive value that has good concordance with standard analysis, low false-positive rate, and can identify additional diagnoses. Globally, as more patients are being offered genome sequencing, we anticipate that DeNovoLOEUF will rapidly identify new diagnoses and facilitate iterative analyses when new disease genes are discovered., (© 2022. The Author(s).)

Failure to meet educational expectations in adolescence can derail an individual's potential, leading to hardship in adulthood. Lower academic achievement is also associated with poorer mental health, and both share common pathways to adult functional outcomes like employment status and economic security. Although linked in adolescence, and predictive of similar outcomes in adulthood, methodological and analytical limitations of the literature do not permit the assessment of the temporal priority between academic achievement and mental health. This omission of directionality hampers intervention and prevention efforts. In this narrative review, we summarize the literature on the temporal ordering between academic achievement and depressive symptoms in adolescence, a particularly vulnerable developmental period. We propose methodological and analytical strategies to guide future research to disentangle the chronological ordering between academic achievement and depressive symptoms-recommendations that can be used to examine other sets of correlated variables over time. Specifically, we highlight methodological issues that require attention such as the need to understand reciprocal and cascading influences over time by attending to repeated measures and timing, measurement consistency, reporter effects, examination of processes and mechanisms, and missing data. Finally, we discuss the need to embrace analytical methods that separate within-person from between-person effects; account for heterogeneity in associations using person-centered approaches; and use the two approaches as complementary, rather than competing, for a more holistic examination of temporality., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: The study aimed to identify novel genes for idiopathic hypogonadotropic hypogonadism (IHH)., Methods: A cohort of 1387 probands with IHH underwent exome sequencing and de novo, familial, and cohort-wide investigations. Functional studies were performed on 2 p190 Rho GTPase-activating proteins (p190 RhoGAP), ARHGAP35 and ARHGAP5, which involved in vivo modeling in larval zebrafish and an in vitro p190A-GAP activity assay., Results: Rare protein-truncating variants (PTVs; n = 5) and missense variants in the RhoGAP domain (n = 7) in ARHGAP35 were identified in IHH cases (rare variant enrichment: PTV [unadjusted P = 3.1E-06] and missense [adjusted P = 4.9E-03] vs controls). Zebrafish modeling using gnrh3:egfp phenotype assessment showed that mutant larvae with deficient arhgap35a, the predominant ARHGAP35 paralog in the zebrafish brain, display decreased GnRH3-GFP+ neuronal area, a readout for IHH. In vitro GAP activity studies showed that 1 rare missense variant [ARHGAP35 p.(Arg1284Trp)] had decreased GAP activity. Rare PTVs (n = 2) also were discovered in ARHGAP5, a paralog of ARHGAP35; however, arhgap5 zebrafish mutants did not display significant GnRH3-GFP+ abnormalities., Conclusion: This study identified ARHGAP35 as a new autosomal dominant genetic driver for IHH and ARHGAP5 as a candidate gene for IHH. These observations suggest a novel role for the p190 RhoGAP proteins in GnRH neuronal development and integrity., Competing Interests: Conflict of Interest The authors declare no conflict of interest., (Copyright © 2022 American College of Medical Genetics and Genomics. All rights reserved.)

Background: Bronchiectasis can result from infectious, genetic, immunological and allergic causes. 60-80% of cases are idiopathic, but a well-recognised genetic cause is the motile ciliopathy, primary ciliary dyskinesia (PCD). Diagnosis of PCD has management implications including addressing comorbidities, implementing genetic and fertility counselling and future access to PCD-specific treatments. Diagnostic testing can be complex; however, PCD genetic testing is moving rapidly from research into clinical diagnostics and would confirm the cause of bronchiectasis., Methods: This observational study used genetic data from severe bronchiectasis patients recruited to the UK 100,000 Genomes Project and patients referred for gene panel testing within a tertiary respiratory hospital. Patients referred for genetic testing due to clinical suspicion of PCD were excluded from both analyses. Data were accessed from the British Thoracic Society audit, to investigate whether motile ciliopathies are underdiagnosed in people with bronchiectasis in the UK., Results: Pathogenic or likely pathogenic variants were identified in motile ciliopathy genes in 17 (12%) out of 142 individuals by whole-genome sequencing. Similarly, in a single centre with access to pathological diagnostic facilities, 5-10% of patients received a PCD diagnosis by gene panel, often linked to normal/inconclusive nasal nitric oxide and cilia functional test results. In 4898 audited patients with bronchiectasis, <2% were tested for PCD and <1% received genetic testing., Conclusions: PCD is underdiagnosed as a cause of bronchiectasis. Increased uptake of genetic testing may help to identify bronchiectasis due to motile ciliopathies and ensure appropriate management., Competing Interests: Conflict of interest: A. Shoemark has received grants from AstraZeneca. G. Wheway is currently employed by Illumina Inc. M.R. Loebinger has received consultancy or speaker fees from Insmed, AstraZeneca, Parion, Grifols and Armata. J.D. Chalmers has received grants or contracts from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Gilead Sciences, Novartis and Insmed; and received consultancy or speaker fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Insmed, Janssen, Novartis and Zambon. J.S. Lucas reports grants from NHS England, NIHR and AIR Charity. H.M. Mitchison is a Trustee of Ciliopathy Alliance. A. De Soyza reports grants from AstraZeneca, GlaxoSmithKline and Pfizer; consulting fees and lecture honoraria from Gilead, GlaxoSmithKline, AstraZeneca, LifeArc and 30T; participation on advisory board at Bayer; receipt of equipment from GlaxoSmithKline. All other authors have nothing to disclose., (Copyright ©The authors 2022. For reproduction rights and permissions contact permissions@ersnet.org.)

Transactional models employing cross-lagged panels have been used for over 40 years to examine the longitudinal relations and directional associations between variables of interest to child and adolescent mental health. Through a narrative synthesis of the literature, we provide an accessible overview of cross-lagged panels with attention to developing a research question, study design and assumptions, dynamic effects (including the random-intercept cross-lagged panel model), and reporting and interpretation of results. Implications and critical appraisal guidelines for readers are discussed throughout. Overall, several key points are highlighted, with particular emphasis on the intended level of inference, model and measure selection, and timing of assessments. Despite limitations in establishing causation, cross-lagged panel models are fundamental to non-experimental epidemiologic research in child mental health and development., Competing Interests: Conflicts of Interest: DB, HB, TV, and EP have no conflicts of interest to declare. SV reports royalties from UpToDate Inc for authorship of materials related to antidepressants and pregnancy. PS receives royalties from Guilford Press and from Simon and Schuster., (Copyright © 2022 Canadian Academy of Child and Adolescent Psychiatry.)

Purpose: Exome and genome sequencing have drastically accelerated novel disease gene discoveries. However, discovery is still hindered by myriad variants of uncertain significance found in genes of undetermined biological function. This necessitates intensive functional experiments on genes of equal predicted causality, leading to a major bottleneck., Methods: We apply the loss-of-function observed/expected upper-bound fraction metric of intolerance to gene inactivation to curate a list of predicted haploinsufficient disease genes. Using data from the 100,000 Genomes Project, we adopt a gene-to-patient approach that matches de novo loss-of-function variants in constrained genes to patients with rare disease. Through large-scale aggregation of data, we reduce excess analytical noise currently hindering novel discoveries., Results: Results from 13,949 trios revealed 643 rare, de novo predicted loss-of-function events filtered from 1044 loss-of-function observed/expected upper-bound fraction-constrained genes. A total of 168 variants occurred within 126 genes without a known disease-gene relationship. Of these, 27 genes had >1 kindred affected, and for 18 of these genes, multiple kindreds had overlapping phenotypes. Two years after initial analysis, 11 of 18 (61%) of these genes have been independently published as novel disease gene discoveries., Conclusion: Using large cohorts and adopting gene-based approaches can rapidly and objectively accelerate dominantly inherited novel gene discovery by targeting the most appropriate genes for functional validation., Competing Interests: Conflict of Interest All authors declare no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Primary ciliopathies represent a group of inherited disorders due to defects in the primary cilium, the 'cell's antenna'. The 100,000 Genomes Project was launched in 2012 by Genomics England (GEL), recruiting National Health Service (NHS) patients with eligible rare diseases and cancer. Sequence data were linked to Human Phenotype Ontology (HPO) terms entered by recruiting clinicians., Methods: Eighty-three prescreened probands were recruited to the 100,000 Genomes Project suspected to have congenital malformations caused by ciliopathies in the following disease categories: Bardet-Biedl syndrome (n=45), Joubert syndrome (n=14) and 'Rare Multisystem Ciliopathy Disorders' (n=24). We implemented a bespoke variant filtering and analysis strategy to improve molecular diagnostic rates for these participants., Results: We determined a research molecular diagnosis for n=43/83 (51.8%) probands. This is 19.3% higher than previously reported by GEL (n=27/83 (32.5%)). A high proportion of diagnoses are due to variants in non-ciliopathy disease genes (n=19/43, 44.2%) which may reflect difficulties in clinical recognition of ciliopathies. n=11/83 probands (13.3%) had at least one causative variant outside the tiers 1 and 2 variant prioritisation categories (GEL's automated triaging procedure), which would not be reviewed in standard 100,000 Genomes Project diagnostic strategies. These include four structural variants and three predicted to cause non-canonical splicing defects. Two unrelated participants have biallelic likely pathogenic variants in LRRC45 , a putative novel ciliopathy disease gene., Conclusion: These data illustrate the power of linking large-scale genome sequence to phenotype information. They demonstrate the value of research collaborations in order to maximise interpretation of genomic data., Competing Interests: Competing interests: Disclosure: HB, RPJB and AS are employed by Genomics England, UK. GW is employed by Illumina. The other authors declare no conflict of interest., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Many have examined the desirability and mate competition tactics of adults higher on psychopathy using cross-sectional data, but few have studied the longitudinal associations between the lower-order factors of psychopathy (e.g., primary and secondary psychopathy) with indices of mating behavior in adolescents. More work is also needed to unravel how psychopathic youth outcompete rivals for mates. Delinquency has long been associated with dating and sexual behavior in adolescents, which may help to explain the competitive success of youth higher in psychopathic traits in vying for mates. We used cross-lagged panel modeling with three waves of data from a randomly drawn sample of 514 Canadian adolescents who provided annual self-reports of primary and secondary psychopathy, delinquency, and dating involvement from Grades 10 to 12 (15-18 years of age). Constructs were temporally stable. Secondary psychopathy and delinquency had positive within-time correlations with current dating status in Grade 10. A cross-lagged pathway from delinquency to dating involvement was supported from Grade 10 to 11, which replicated from Grade 11 to 12. However, this effect was specific to boys and not girls. An indirect effect also emerged whereby secondary psychopathy in Grade 10 increased the likelihood of being in a dating relationship in Grade 12 via heightened delinquency in Grade 11.

Purpose: Genome sequencing (GS) for diagnosis of rare genetic disease is being introduced into the clinic, but the complexity of the data poses challenges for developing pipelines with high diagnostic sensitivity. We evaluated the performance of the Genomics England 100,000 Genomes Project (100kGP) panel-based pipelines, using craniosynostosis as a test disease., Methods: GS data from 114 probands with craniosynostosis and their relatives (314 samples), negative on routine genetic testing, were scrutinized by a specialized research team, and diagnoses compared with those made by 100kGP., Results: Sixteen likely pathogenic/pathogenic variants were identified by 100kGP. Eighteen additional likely pathogenic/pathogenic variants were identified by the research team, indicating that for craniosynostosis, 100kGP panels had a diagnostic sensitivity of only 47%. Measures that could have augmented diagnoses were improved calling of existing panel genes (+18% sensitivity), review of updated panels (+12%), comprehensive analysis of de novo small variants (+29%), and copy-number/structural variants (+9%). Recent NHS England recommendations that partially incorporate these measures should achieve 85% overall sensitivity (+38%)., Conclusion: GS identified likely pathogenic/pathogenic variants in 29.8% of previously undiagnosed patients with craniosynostosis. This demonstrates the value of research analysis and the importance of continually improving algorithms to maximize the potential of clinical GS., (© 2021. The Author(s).)

We examined the impact of COVID-19 on bullying prevalence rates in a sample of 6578 Canadian students in Grades 4 to 12. To account for school changes associated with the pandemic, students were randomized at the school level into two conditions: (1) the pre-COVID-19 condition, assessing bullying prevalence rates retrospectively before the pandemic, and (2) the current condition, assessing rates during the pandemic. Results indicated that students reported far higher rates of bullying involvement before the pandemic than during the pandemic across all forms of bullying (general, physical, verbal, and social), except for cyber bullying, where differences in rates were less pronounced. Despite anti-Asian rhetoric during the pandemic, no difference was found between East Asian Canadian and White students on bullying victimization. Finally, our validity checks largely confirmed previous published patterns in both conditions: (1) girls were more likely to report being bullied than boys, (2) boys were more likely to report bullying others than girls, (3) elementary school students reported higher bullying involvement than secondary school students, and (4) gender diverse and LGTBQ + students reported being bullied at higher rates than students who identified as gender binary or heterosexual. These results highlight that the pandemic may have mitigated bullying rates, prompting the need to consider retaining some of the educational reforms used to reduce the spread of the virus that could foster caring interpersonal relationships at school such as reduced class sizes, increased supervision, and blended learning., (© 2021 Wiley Periodicals LLC.)

Background: Decision-makers need quantifiable data on costs and outcomes to determine the optimal mix of antenatal models of care to offer. This study aimed to examine the cost utility of a publicly funded Midwifery Group Practice (MGP) caseload model of care compared to other models of care and demonstrate the feasibility of conducting such an analysis to inform service decision-making., Objective: To provide a methodological framework to determine the value of public midwifery in different settings., Methods: Incremental costs and incremental utility (health gains measured in quality-adjusted life years (QALYs)) of public MGP caseload were compared to other models of care currently offered at a large tertiary hospital in Australia. Patient Reported Outcomes Measurement Information System Global Short Form scores were converted into utility values by mapping to the EuroQol 5 dimensions and then converting to QALYs. Costs were assessed from a health system funder's point of view., Results: There were 85 women in the public MGP caseload care group and 72 received other models of care. Unadjusted total mean cost for mothers' and babies' health service use from study entry to 12 months post-partum was $27 618 for MGP caseload care and $33 608 for other models of care. After adjusting for clinical and demographic differences between groups, total costs were 22% higher (cost ratio: 1.218, P = 0.04) for other models of maternity care. When considering costs to all funders, public MGP caseload care cost $5208 less than other models of care. There was no significant difference in QALY between the two groups (difference: 0.010, 95% CI: -0.038, 0.018)., Conclusion: Public MGP caseload care costs 22% less than other models of care, after accounting for differences in baseline characteristics between groups. There were no significant differences in QALYs. Public MGP caseload care produced comparable health outcomes, with some indication that outcomes may be better for lower cost per woman., (© The Author(s) 2021. Published by Oxford University Press on behalf of International Society for Quality in Health Care. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

We examined the temporal precedence between perceived peer rejection, rejection sensitivity, depression, and aggression in a sample of 544 adolescents (55.7% girls; M age = 14.96 years at the first measured time point) assessed yearly from Grade 9 to Grade 12. Using developmental cascade modelling to analyze the data, our study supported the symptoms-driven and social process models, in that perceived rejection was preceded by either depression or aggression at different times across adolescence. Similarly, rejection sensitivity was also preceded by depression and/or aggression. Although depression initiated the cascade leading to rejection sensitivity, our model also supported a bidirectional relation across late adolescence as rejection sensitivity also predicted future depression. Overall, our findings provide support that internalizing and externalizing problems lead to interpersonal difficulties with peers, such as perceived rejection and demonstrate the unique role of rejection sensitivity with regard to depression and aggression independent from perceived peer rejection.

Bullying events have frequently been the focus of coverage by news media, including news stories about teens whose death from suicide was attributed to cyberbullying. Previous work has shown that news media coverage is influential to readers in areas such as suicide, infectious disease outbreaks, and tobacco use. News media may be an untapped resource to promote bullying prevention messages, though current news media approaches to describing bullying and cyberbullying remain unexplored. The purpose of this study was to evaluate the current state of news media coverage of bullying and cyberbullying. A sample of newspaper articles covering bullying or cyberbullying across regional and national US newspapers from 6 recent years was identified. A content analysis using natural language processing was conducted with the Linguistic Inquiry and Word Count (LIWC) software program for key variables including affective, social, and cognitive processes. Evaluation included the percentage of words that represented Fear-based reporting such as alarmist words (e.g., epidemic, tragic), as well as words that represent Public Health-oriented messages such as prevention. A total of 463 newspaper articles met inclusion criteria, including 140 cyberbullying articles and 323 bullying articles. Findings indicated that cyberbullying articles scored higher on affective processes such as measures of anxiety (Mdn = 0.34) compared to bullying articles (Mdn = 0.22). A greater number of cyberbullying articles were Fear-based (41.4%) than were bullying articles (19.5%). An equivalent number of cyberbullying articles (50.0%) and bullying articles (49.8%) were Public Health-oriented. Findings may be used to collaborate with journalists toward optimizing prevention-oriented reporting.

The individual and societal burden of psychopathy warrants an investigation into identifying its early precursors and developmental course. Accordingly, we examined the longitudinal pathways between primary and secondary psychopathic traits, anxiety, and borderline personality disorder (BPD) features across adolescence. Participants included 572 Canadian adolescents (253 girls; aged 13.96 [SD = 0.37] in Grade 8; 70.6% Caucasian) who were assessed annually on five occasions (Grades 8-12) using the Antisocial Process Screening Device (psychopathic traits), the Behavior Assessment System for Children-2 (symptoms of anxiety), and the Borderline Personality Features Scale for Children (features of BPD). Autoregressive latent trajectory models with structured residuals provided stringent tests of within-person cross-lagged associations, while controlling for sex, race/ethnicity, household income, and parental education. Results indicated that primary psychopathic traits were preceded by and predicted anxiety such that individuals who increased in primary psychopathic traits subsequently declined in anxiety, and vice versa. Results also indicated that BPD features were associated with secondary psychopathic traits and anxiety. Specifically, increases in BPD features were linked with increases in secondary psychopathic traits and anxiety. Our results suggest that even after accounting for between-person associations and other known correlates, the development of psychopathic traits is embedded within the development of emotional characteristics and personality features. This highlights areas for intervention in adolescence, particularly around the core, shared trait of impulsivity and anger. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

We investigated the longitudinal associations between self-reported aggression, self-perceived social status, and dating in adolescence using an intrasexual competition theoretical framework. Participants consisted of 536 students in Grade 9 (age 15), recruited from a community sample, who were assessed on a yearly basis until they were in Grade 11 (age 17). Adolescents self-reported their use of direct and indirect aggression, social status, and number of dating partners. A cross-lagged panel model that controlled for within-time covariance and across-time stability while examining cross-lagged pathways was used to analyze the data. The findings revealed that direct aggression did not predict dating behavior and was negatively associated with self-perceived social status in Grade 10. Self-perceived social status in Grade 9 was positively associated with greater use of indirect aggression in Grade 10. Regarding dating, in Grade 9, self-perceived social status positively predicted more dating partners the following year, while in Grade 10, it was higher levels of indirect aggression that predicted greater dating activity the following year. Overall, there were no significant sex differences in the model. The study supports the utility of evolutionary psychological theory in explaining peer aggression, and suggests that although social status can increase dating opportunities, as adolescents mature, indirect aggression becomes the most successful and strategic means of competing intrasexually and gaining mating advantages., (© 2018 Wiley Periodicals, Inc.)

Background: Reporting the outcomes for women and newborns accessing private midwives with visiting rights in Australia is important, especially since this data cannot currently be disaggregated from routinely collected perinatal data., Aim: 1) Evaluate the outcomes of women and newborns cared for by midwives with visiting access at one Queensland facility and 2) explore private midwives views about the structures and processes contributing to clinical outcomes., Methods: Mixed methods. An audit of the 'all risk' 529 women receiving private midwifery care. Data were compared with national core maternity variables using Chi square statistics. Telephone interviews were conducted with six private midwives and data analysed using thematic analysis., Findings: Compared to national data, women with a private midwife were significantly more likely to be having a first baby (49.5% vs 43.6% p=0.007), to commence labour spontaneously (84.7% vs 52.7%, p<0.001), experience a spontaneous vaginal birth (79% vs 54%, p<0.001) and not require pharmacological pain relief (52.9% vs 23.1%, p<0.001). The caesarean section rate was significantly lower than the national rate (13% vs 32.8%, p<0.001). In addition fewer babies required admission to the Newborn Care Unit (5.1% vs 16%, p<0.001). Midwives were proud of their achievements. Continuity of care was considered fundamental to achieving quality outcomes. Midwives valued the governance processes embedded around the model., Conclusions: Private midwives with access to the public system is safe. Ensuring national data collection accurately captures outcomes relative to model of care in both the public and private sector should be prioritised., (Copyright © 2017 Australian College of Midwives. Published by Elsevier Ltd. All rights reserved.)

Developmental and epileptic encephalopathy (DEE) is a group of conditions characterized by the co-occurrence of epilepsy and intellectual disability (ID), typically with developmental plateauing or regression associated with frequent epileptiform activity. The cause of DEE remains unknown in the majority of cases. We performed whole-genome sequencing (WGS) in 197 individuals with unexplained DEE and pharmaco-resistant seizures and in their unaffected parents. We focused our attention on de novo mutations (DNMs) and identified candidate genes containing such variants. We sought to identify additional subjects with DNMs in these genes by performing targeted sequencing in another series of individuals with DEE and by mining various sequencing datasets. We also performed meta-analyses to document enrichment of DNMs in candidate genes by leveraging our WGS dataset with those of several DEE and ID series. By combining these strategies, we were able to provide a causal link between DEE and the following genes: NTRK2, GABRB2, CLTC, DHDDS, NUS1, RAB11A, GABBR2, and SNAP25. Overall, we established a molecular diagnosis in 63/197 (32%) individuals in our WGS series. The main cause of DEE in these individuals was de novo point mutations (53/63 solved cases), followed by inherited mutations (6/63 solved cases) and de novo CNVs (4/63 solved cases). De novo missense variants explained a larger proportion of individuals in our series than in other series that were primarily ascertained because of ID. Moreover, these DNMs were more frequently recurrent than those identified in ID series. These observations indicate that the genetic landscape of DEE might be different from that of ID without epilepsy., (Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Background: Fumarate hydratase (FH) deficiency is a rare autosomal recessive disorder which results in a major defect in cellular metabolism. It presents in infancy with progressive encephalopathy, hypotonia, seizures and failure to thrive and is often fatal in childhood. It is caused by mutations in the FH gene (1q42.1) that result in deficiency of the citric acid cycle enzyme fumarate hydratase, resulting in accumulation of fumaric acid. Heterozygous germline mutations in the FH gene predispose to an aggressive autosomal dominant inherited early-onset kidney cancer syndrome: hereditary leiomyomatosis and renal cell cancer (HLRCC)., Case Presentation: Cascade FH mutation screening enabled the early diagnosis of a renal tumour in an asymptomatic parent of a child with fumarate hydratase deficiency, resulting in timely and possibly life-saving treatment., Conclusion: While the theoretical risk of kidney cancer in parents of children with recessive fumarate hydratase deficiency is well recognized, to our knowledge this is the first report of a kidney tumour being detected in a parent by screening performed for this indication. This underscores the importance of offering lifelong kidney surveillance to such parents and other heterozygous relatives of children born with fumarate hydratase deficiency.

Achondroplasia is the most common form of short limb dwarfism in humans. The shortening of the limb lengths in achondroplasia is widely described as "rhizomelic." While this appearance may be convincing clinically, the description is not necessarily true or helpful radiologically. The aims of this study, were therefore, to determine whether rhizomelic shortening is a true feature of achondroplasia at diagnosis in infancy. Humeral, radial, femoral, and tibial diaphyseal lengths were recorded by two independent observers from 22 skeletal surveys of infants with achondroplasia and compared with 150 normal age-matched control subjects. Upper and lower limb bone length ratios (radial/humeral and tibial/femoral lengths, respectively) in both groups were compared using an unpaired t-test. Mean upper limb length ratios were statistically higher within the achondroplasia group at 0.87 ± 0.04 (n = 22, mean age 70 ± 94 days) compared to normal controls at 0.79 ± 0.02 (n = 150, mean age 113 days ± 88 days; P < 0.0001). Lower limb length ratios were not significantly different between groups (0.84 ± 0.04 vs. 0.83 ± 0.02, P = 0.46). There was good inter-observer agreement of limb length measurements, with an average measurement difference of 0.1 ± 1.4 mm. In conclusion, infants with achondroplasia demonstrate statistically significant rhizomelic shortening within the upper limbs, but not lower limbs at diagnosis, compared to normal controls. The term "rhizomelic shortening" in relation to achondroplasia should be reserved when describing upper limb proportions. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Background: We sought to investigate the diagnostic yield and mutation spectrum in previously reported genes for early-onset epilepsy and disorders of severe developmental delay., Methods: In 400 patients with these disorders with no known underlying aetiology and no major structural brain anomaly, we analysed 46 genes using a combination of targeted sequencing on an Illumina MiSeq platform and targeted, exon-level microarray copy number analysis., Results: We identified causative mutations in 71/400 patients (18%). The diagnostic rate was highest among those with seizure onset within the first two months of life (39%), although overall it was similar in those with and without seizures. The most frequently mutated gene was SCN2A (11 patients, 3%). Other recurrently mutated genes included CDKL5, KCNQ2, SCN8A (six patients each), FOXG1, MECP2, SCN1A, STXBP1 (five patients each), KCNT1, PCDH19, TCF4 (three patients each) and ATP1A3, PRRT2 and SLC9A6 (two patients each). Mutations in EHMT1, GABRB3, LGI1, MBD5, PIGA, UBE3A and ZEB2 were each found in single patients. We found mutations in a number of genes in patients where either the electroclinical features or dysmorphic phenotypes were atypical for the identified gene. In only 11 cases (15%) had the clinician sufficient certainty to specify the mutated gene as the likely cause before testing., Conclusions: Our data demonstrate the considerable utility of a gene panel approach in the diagnosis of patients with early-onset epilepsy and severe developmental delay disorders., They provide further insights into the phenotypic spectrum and genotype-phenotype correlations for a number of the causative genes and emphasise the value of exon-level copy number testing in their analysis., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

The relative impact of school transition versus development on peer victimization and bullying perpetration were examined in a natural experiment involving 698 students where half transitioned into middle school from Grade 5 to Grade 6 and the other half remained in their elementary school over the same period. Results indicated that, on average, peer victimization decreased over the transition period while bullying perpetration remained stable for the whole sample. Multilevel modeling was used to investigate the effects of school transition and sex on changes in victimization and perpetration. Results indicated that the effect of transition status on changes in peer victimization was moderated by sex. Middle school transition status predicted decreases in peer victimization for girls, but not for boys, who transitioned. However, school transition status and participants' sex (and their interaction) did not predict changes in perpetration over time. Our findings indicate that changes in student involvement with peer victimization are better understood as a contextual rather than a typical developmental process, whereas bullying perpetration may be better understood as developmental., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Introduction: Patau syndrome, trisomy 13, is the third commonest autosomal trisomy. It is associated with a 25-50% prevalence of epilepsy, but detailed electroclinical descriptions are rare. The occurrence of early-onset photosensitivity has recently been reported in single patients., Materials/patients: We collected electroclinical data on 8 infants (age range from 2 months to 3 years and 9 months, median: 17 months) with Patau syndrome referred for an EEG in our Clinical Neurophysiology Department between 1991 and 2011., Methods: All EEGs, case-notes, cytogenetic diagnosis and neuroimaging when available were reviewed; data on the occurrence of seizures, epileptiform discharges, photoparoxysmal response and their characteristics in terms of positive frequencies, latencies, grade and duration were noted and analysed., Results: Two patients had been previously diagnosed with epilepsy (one with tonic spasms and one with multiple seizure types). We found 3 patients with photosensitive myoclonic epilepsy (37.5%), and one with non-photosensitive myoclonic epilepsy. We also recorded non-epileptic myoclonic jerks in one patient known to suffer from epileptic spasms. Among photosensitive patients we found self-limited, Waltz's grade 2-4, spike-wave/polyspike-wave discharges in low, medium and high frequency ranges in two patients and in the high frequency range in the third patient, with latencies and duration from less than 1s to a maximum of 9s., Conclusions: In our cohort of Patau syndrome patients, we found a high prevalence of spasms and photic-induced myoclonic jerks. Photosensitivity shows an unusual early age of onset., (Copyright © 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Objective: This study examined midwives' perceptions of organisational structures and processes of care when working in a caseload model (Midwifery Group Practice MGP) for socially disadvantaged and vulnerable childbearing women., Design: This study used Donabedian's theoretical framework for evaluating the quality of health care provision. Of the 17 eligible midwives, 15 participated in focus group discussions and two others provided written comments. Thematic analysis was guided by three headings; clinical outcomes, processes of care and organisational structure., Findings: Midwives believed they provided an excellent service to socially disadvantaged and vulnerable childbearing women. Midwives gained satisfaction from working in partnership with women, working across their full scope of practice, and making a difference to the women. However the midwives perceived the MGP was situated within an organisation that was hostile to the caseload model of care. Midwives felt frustrated and distressed by a lack of organisational support for the model and a culture of blame dominated by medicine. A lack of material resources and no identified office space created feelings akin to 'homelessness'. Together these challenges threatened the cohesiveness of the MGP and undermined midwives' ability to advocate for women and keep birth normal., Key Conclusions: If access to caseload midwifery care for women with diverse backgrounds and circumstances is to be enhanced, then mechanisms need to be implemented to ensure organisational structures and processes are developed to sustain midwives in the provision of 'best practice' maternity care., Implications for Practice: Women accessing midwifery caseload care have excellent maternal and newborn outcomes. However there remains limited understanding of the impact of organisational structures and processes of care on clinical outcomes., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Importance: Atopic dermatitis (AD) is thought to be a double-hit phenomenon with an unknown environmental component and a genetic abnormality likely centered on the filaggrin gene. Biologically, the presence of Staphylococcus aureus in AD was reported more than 2 decades ago, but the relationship to AD has been elusive., Objective: To explore the bacteria that produce the biofilms in the lesions of AD and the response of the innate immune system to these biofilm occlusions of the sweat ducts by specifically evaluating Toll-like receptor 2., Design, Setting, and Participants: University hospital dermatologic clinic study involving the environmental component related to the characterization, correlation, and impact of staphylococci and their biofilms in AD. We processed routine skin swabs from lesional and nonlesional skin from 40 patients with AD and performed scrapings and biopsies. We also obtained 20 samples from controls (10 inflamed skin samples and 10 normal skin samples)., Exposures: Gram staining, bright-field microscopy, hematoxylin and eosin, periodic acid-Schiff, Congo red, and light microscopy., Main Outcomes and Measures: Association of staphylococcal biofilms with AD pathogenesis., Results: All AD-affected samples contained multidrug-resistant staphylococci, with S aureus (42.0%) and Staphylococcus epidermidis (20.0%) as the predominant species. All isolates were positive for extracellular polysaccharide and biofilm (85.0% strong biofilm producers and 15.0% moderately to weakly positive). Polymerase chain reaction revealed the biofilm-mediating icaD (93.0%) and aap (12.5%) genes in the isolates (some contained both). We also examined tissues for microbial identification, extracellular biomass formation, biofilm formation, and staphylococcal biofilm in skin tissues. Occlusion of sweat ducts with periodic acid-Schiff-positive and Congo red-positive material was noted on microscopic tissue examination. Toll-like receptor 2 was shown to be activated in AD lesional skin (immediately proximal to the sweat ducts), which likely led to the initiation of proteinase-activated receptor 2-mediated pruritus and MyD88-mediated spongiosis., Conclusions and Relevance: Biofilm formation by AD-associated staphylococci almost certainly plays a major role in the occlusion of sweat ducts and leads to inflammation and pruritus. We believe the environmental hit in AD relates to staphylococci and their biofilms, which occlude sweat ducts.

Background: Supplemental educational reading material is of no value to patients if it is not read and comprehended., Objective: Using standardized research tools, online patient education materials were comparatively assessed for readability and length in words to identify the strengths and weaknesses of widely utilized sources., Methods: Three sources of patient-education material on the internet (WebMD.com, Wikipedia.org, and MedicineOnline.com) were compared with materials produced by the American Academy of Dermatology for readability utilizing Flesch-Kincaid Grade Level and Flesch Reading Ease Scale. Automated word counts were used to determine the length of each educational piece., Results: The information presented in American Academy of Dermatology electronic pamphlets on the internet is significantly harder to comprehend than MedicineOnline.com, but easier than Wikipedia.org. The latter site proved significantly harder to comprehend than all other sources. The American Academy of Dermatology electronic pamphlets and MedicineOnline.com materials were the most concise, averaging 1,200 words or less, although this was not a statistically significant difference in length compared to other online patient-education resources. No single source of online patient-education material demonstrates optimal features with regard to each of these parameters., Limitations: Only 15 topic areas in the four most commonly accessed sources of patient information were analyzed in this study., Conclusion: No single source of commonly used internet patient-education material demonstrates optimal features with regard to readability, length, and presence of photographic illustrations. These educational materials should target a length of 1,200 words, be illustrated with clinical images, and readability should correspond with the national average reading level.

Many drugs exist in the crystalline solid state due to reasons of stability and ease of handling during the various stages of drug development. Crystalline solids can exist in the form of polymorphs, solvates or hydrates. Phase transitions such as polymorph interconversion, desolvation of solvate, formation of hydrate and conversion of crystalline to amorphous form may occur during various pharmaceutical processes, which may alter the dissolution rate and transport characteristics of the drug. Hence it is desirable to choose the most suitable and stable form of the drug in the initial stages of drug development. The current focus of research in the solid-state area is to understand the origins of polymorphism at the molecular level, and to predict and prepare the most stable polymorph of a drug. The recent advances in computational tools allow the prediction of possible polymorphs of the drug from its molecular structure. Sensitive analytical methods are being developed to understand the nature of polymorphism and to characterize the various crystalline forms of a drug in its dosage form. The aim of this review is to emphasize the recent advances made in the area of prediction and characterization of polymorphs and solvates, to address the current challenges faced by pharmaceutical scientists and to anticipate future developments.

5-Nitrobarbituric acid (dilituric acid) was extensively used with great success as a chemical microscopic reagent for the qualitative identification of primary phenylalkylamines. This methodology was based on the characterization of observed crystal morphologies, since a unique crystal habit could be associated with each adduct product. To understand the scientific foundations which permitted chemical microscopy to function as a useful analytical technique, the products formed between dilituric acid and a series of primary phenylalkylamines were characterized using polarizing optical microscopy, powder X-ray diffraction, thermal analysis, and solid-state nuclear magnetic resonance. It was deduced that the origins of the different crystal morphologies associated with each of the crystalline adducts arose from the ability of the systems to form differing structural types and/or hydrates upon crystallization. The degree of hydration in the crystalline phenylalkylamine adducts appeared to increase as additional carbon atoms were added between the aromatic ring and the terminal amine group of the aliphatic sidechain.

Many pharmaceutical compounds contain one or more centers of dissymmetry, thus presenting a unique series of regulatory and compendial requirements. Although most often characterized using chiral chromatography, these molecules can be effectively studied using the various techniques of chiroptical spectroscopy. Techniques which have been found to be very useful for such work include polarimetry, optical rotatory dispersion, circular dichroism, and circularly polarized luminescence. The principles underlying each effect will be briefly outlined, and the application of each illustrated through the inclusion of appropriate examples.

5-Nitrobarbituric acid (dilituric acid) has been used as a chemical microscopic reagent for the qualitative identification of alkali metal (Group IA) and alkaline earth (Group IIA) cations. This methodology was based on the characterization of observed crystal morphologies, since a unique crystal habit could be associated with each adduct product. To understand the scientific foundations which permitted chemical microscopy to function as a useful analytical technique, the products formed between dilituric acid and the Group IA and IIA cations were characterized using polarizing optical microscopy, powder X-ray diffraction, thermal analysis and solid-state nuclear magnetic resonance. It was found that the origins of the different crystal morphologies associated with each of the adduct arose from the ability of the systems to form various hydrate species, which could also contain structural variations due to cation/diliturate packing patterns.

The short-term stability of Revex, nalmefene hydrochloride injection, was determined in a number of diluents commonly employed for intravenous use. An HPLC method was used to follow the potency of the diluted solutions, and was fully validated for its intended concentration range prior to its use. Dilutions of Revex were prepared separately in 0.9% sodium chloride injection, 0.45% sodium chloride injection, 5% dextrose injection, 5% dextrose and 0.45% sodium chloride injection, lactated Ringer's injection, 5% dextrose and lactated Ringer's injection and 5% sodium hydrogencarbonate injection. Each admixture was stored at 4 degrees C, room temperature (21 degrees C) and 40 degrees C, with samples being tested after storage at each temperature for 0, 24, 48 and 72 h. Defining stability as the retention of at least 95% of the initial drug concentration at the end of the storage period, it was concluded that the diluted solutions of Revex were uniformly stable for up to 72 h in all of the injectable solutions maintained at either 4, 21 or 40 degrees C.

Mirfentanil hydrochloride, a novel CNS analgesic with a short duration of action, was successfully encapsulated in liposomes having a variety of compositions. The lipid composition of the formulation was varied to optimize the stabilization of liposomes and the encapsulation of solutes. Retention of mirfentanil hydrochloride was evaluated by storing loaded liposomes at several temperatures, and also after the physical stressing of formulations. High efficiency of drug encapsulation was observed in liposomes prepared using dipalmitoyl-L-alpha-phosphatidylcholine (DPPC) and the ternary mixture of dimyristoyl-L-alpha-phosphatidylcholine, cholesterol, and dicetyl phosphate (DMPC/CHOL/DCP), both with and without the further incorporation of monosialoganglioside (GM1). Only 35% of encapsulated drug was lost when the formulations containing GM1 were incubated with human plasma over a 24 hour period, suggesting that liposomal formulations containing GM1 could be used to control drug release in vivo.

The stability of Revex, nalmefene hydrochloride injection, has been studied at several temperatures for periods up to 36 months. The data were obtained using a HPLC method for the potency determination, and for the level of the sole degradation product (2,2'-bisnalmefene). These methods were found to be characterized by excellent precision, linearity, and accuracy over the analyte concentration ranges established. The stability data were found to be interpretable using first-order kinetics, and essentially comparable rate constants were calculated for both the potency loss and the formation of 2,2'-bisnalmefene. Applying the Arrhenius equation to these data, a rate constant of 0.00441 month-1 was deduced for the reactions taking place at 25 degrees C. This low value is consistent with the excellent stability exhibited by the product, and amply justifies its shelf life.

A rapid, sensitive ICP-MS method was developed to determine palladium in fosinopril sodium. The assay could not be carried out in a purely aqueous solvent owing to the instability of the palladium species in this media. It was found that the most appropriate vehicle for solubilization of this material was a solution of 25% (v/v) 2-butoxyethanol and water. A minimum quantifiable limit of 0.1 microns g-1 for Pd in the sample (corresponding to 1 ng Pd mL-1 in the analyte solution) was obtained.

It has been shown previously that the disodium salt of a new HMG-CoA reductase inhibitor (SQ-33600) is capable of existing as a number of hydrate species [1]. Three crystalline solid hydrates and one liquid crystalline phase have been identified, each having a definite stability over a defined range of humidity. These forms have been found to exhibit varying fluorescence properties in their respective solid states, with differences in bandshapes and intensities being noted for each. These spectral variations have been correlated with the known pseudopolymorphism of the compound.

The historical, clinical, neurological and neuropsychological features of 13 subjects with independently diagnosed dementia associated with alcoholism (AlcD) were compared to 13 subjects with probable Alzheimer's disease (AD), matched for age and severity of dementia. Neurological abnormalities were present in all the subjects with AlcD even though the diagnosis of Wernicke-Korsakoff was recorded in only one of these subjects. Only one subject with probable AD demonstrated any neurological abnormality. There was no difference between the AD and AlcD subjects in either the total scores of the Mini-Mental State Examination (MMSE) or in any of the subscores. The presence of neurological signs does appear to be a useful method to assist in the diagnosis of AlcD.

The two polymorphic modifications of fosinopril sodium have been characterized as to their differences in melting behaviour, powder X-ray diffraction patterns, Fourier transform infrared spectra (FTIR), and solid-state 31P- and 13C-NMR spectra. The polymorphs were found to be enantiotropically related based upon melting point, heat of fusion, and solution mediated transformation data. Analysis of the solid-state FTIR and 13C-NMR data indicated that the environment of the acetal side chain of fosinopril sodium differed in two polymorphs, and that there might be cis-trans isomerization about the C6-N peptide bond. These conformational differences are postulated as the origin of the observed polymorphism.