The GenoVA study: Equitable implementation of a pragmatic randomized trial of polygenic-risk scoring in primary care.

Polygenic risk scores (PRSs) hold promise for disease risk assessment and prevention. The Genomic Medicine at Veterans Affairs (GenoVA) Study is addressing three main challenges to the clinical implementation of PRSs in preventive care: defining and determining their clinical utility, implementing them in time-constrained primary care settings, and countering their potential to exacerbate healthcare disparities. The study processes used to test patients, report their PRS results to them and their primary care providers (PCPs), and promote the use of those results in clinical decision-making are modeled on common practices in primary care. The following diseases were chosen for their prevalence and familiarity to PCPs: coronary artery disease; type 2 diabetes; atrial fibrillation; and breast, colorectal, and prostate cancers. A randomized clinical trial (RCT) design and primary outcome of time-to-new-diagnosis of a target disease bring methodological rigor to the question of the clinical utility of PRS implementation. The study's pragmatic RCT design enhances its relevance to how PRS might reasonably be implemented in primary care. Steps the study has taken to promote health equity include the thoughtful handling of genetic ancestry in PRS construction and reporting and enhanced recruitment strategies to address underrepresentation in research participation. To date, enhanced recruitment efforts have been both necessary and successful: participants of underrepresented race and ethnicity groups have been less likely to enroll in the study than expected but ultimately achieved proportional representation through targeted efforts. The GenoVA Study experience to date offers insights for evaluating the clinical utility of equitable PRS implementation in adult primary care.

STING-Dependent Signaling in Microglia or Peripheral Immune Cells Orchestrates the Early Inflammatory Response and Influences Brain Injury Outcome.

While originally identified as an antiviral pathway, recent work has implicated that cyclic GMP-AMP-synthase-Stimulator of Interferon Genes (cGAS-STING) signaling is playing a critical role in the neuroinflammatory response to traumatic brain injury (TBI). STING activation results in a robust inflammatory response characterized by the production of inflammatory cytokines called interferons, as well as hundreds of interferon stimulated genes (ISGs). Global knock-out (KO) mice inhibiting this pathway display neuroprotection with evidence that this pathway is active days after injury; yet, the early neuroinflammatory events stimulated by STING signaling remain understudied. Furthermore, the source of STING signaling during brain injury is unknown. Using a murine controlled cortical impact (CCI) model of TBI, we investigated the peripheral immune and microglial response to injury utilizing male chimeric and conditional STING KO animals, respectively. We demonstrate that peripheral and microglial STING signaling contribute to negative outcomes in cortical lesion volume, cell death, and functional outcomes postinjury. A reduction in overall peripheral immune cell and neutrophil infiltration at the injury site is STING dependent in these models at 24 h. Transcriptomic analysis at 2 h, when STING is active, reveals that microglia drive an early, distinct transcriptional program to elicit proinflammatory genes including interleukin 1-ß (IL-1ß), which is lost in conditional knock-out mice. The upregulation of alternative innate immune pathways also occurs after injury in these animals, which supports a complex relationship between brain-resident and peripheral immune cells to coordinate the proinflammatory response and immune cell influx to damaged tissue after injury.

Loss-of-function variants in JPH1 cause congenital myopathy with prominent facial and ocular involvement.

BACKGROUND: Weakness of facial, ocular and axial muscles is a common clinical presentation in congenital myopathies caused by pathogenic variants in genes encoding triad proteins. Abnormalities in triad structure and function resulting in disturbed excitation-contraction coupling and Ca2+ homeostasis can contribute to disease pathology. METHODS: We analysed exome and genome sequencing data from four unrelated individuals with congenital myopathy characterised by facial, ocular and bulbar involvement. We collected deep phenotypic data from the affected individuals. We analysed the RNA-sequencing (RNA-seq) data of F3-II.1 and performed gene expression outlier analysis in 129 samples. RESULTS: The four probands had a remarkably similar clinical presentation with prominent facial, ocular and bulbar features. Disease onset was in the neonatal period with hypotonia, poor feeding, cleft palate and talipes. Muscle weakness was generalised but prominent in the lower limbs with facial weakness also present. All patients had myopathic facies, bilateral ptosis, ophthalmoplegia and fatigability. Muscle biopsy on light microscopy showed type 1 myofiber predominance and ultrastructural analysis revealed slightly reduced triads, and structurally abnormal sarcoplasmic reticulum.DNA sequencing identified four unique homozygous loss-of-function variants in JPH1, encoding junctophilin-1 in the four families; one stop-gain (c.354C>A;p.Tyr118*) and three frameshift (c.373delG;p.Asp125Thrfs*30, c.1738delC;p.Leu580Trpfs*16 and c.1510delG;p. Glu504Serfs*3) variants. Muscle RNA-seq showed strong downregulation of JPH1 in the F3 proband. CONCLUSIONS: Junctophilin-1 is critical for the formation of skeletal muscle triad junctions by connecting the sarcoplasmic reticulum and T-tubules. Our findings suggest that loss of JPH1 results in a congenital myopathy with prominent facial, bulbar and ocular involvement.

Current policy and practice for the identification, management, and treatment of postpartum anxiety in the United Kingdom: a focus group study.

BACKGROUND: Postpartum Anxiety [PPA] is a prevalent problem in society, posing a significant burden to women, infant health, and the National Health Service [NHS]. Despite this, it is poorly detected by current maternal mental health practices. Due to the current lack of appropriate psychometric measures, insufficiency in training of healthcare professionals, fragmentation of maternal mental healthcare policy and practice, and the magnitude of the effects of PPA on women and their infants, PPA is a critical research priority. This research aims to develop a clear understanding from key stakeholders, of the current landscape of maternal mental health and gain consensus of the needs associated with clinically identifying, measuring, and targeting intervention for women with PPA, in the NHS. METHODS: Four focus groups were conducted with a total of 21 participants, via Zoom. Data were analysed using Template Analysis. RESULTS: Analysis rendered four main themes: (1) Defining Postpartum Anxiety; (2) Postpartum Anxiety in Relation to other Mental Health Disorders; (3) Challenges to Measurement and Identification of Maternal Mental Health; and (4) An Ideal Measure of Postpartum Anxiety. CONCLUSIONS: Findings can begin to inform maternal mental healthcare policy as to how to better identify and measure PPA, through the implementation of a postpartum-specific measure within practice, better training and resources for staff, and improved interprofessional communication.

An Integrated Transcriptomics and Genomics Approach Detects an X/Autosome Translocation in a Female with Duchenne Muscular Dystrophy.

Duchenne and Becker muscular dystrophies, caused by pathogenic variants in DMD, are the most common inherited neuromuscular conditions in childhood. These diseases follow an X-linked recessive inheritance pattern, and mainly males are affected. The most prevalent pathogenic variants in the DMD gene are copy number variants (CNVs), and most patients achieve their genetic diagnosis through Multiplex Ligation-dependent Probe Amplification (MLPA) or exome sequencing. Here, we investigated a female patient presenting with muscular dystrophy who remained genetically undiagnosed after MLPA and exome sequencing. RNA sequencing (RNAseq) from the patient's muscle biopsy identified an 85% reduction in DMD expression compared to 116 muscle samples included in the cohort. A de novo balanced translocation between chromosome 17 and the X chromosome (t(X;17)(p21.1;q23.2)) disrupting the DMD and BCAS3 genes was identified through trio whole genome sequencing (WGS). The combined analysis of RNAseq and WGS played a crucial role in the detection and characterisation of the disease-causing variant in this patient, who had been undiagnosed for over two decades. This case illustrates the diagnostic odyssey of female DMD patients with complex structural variants that are not detected by current panel or exome sequencing analysis.

Primary care physician use of patient race and polygenic risk scores in medical decision-making.

PURPOSE: The use of patient race in medicine is controversial for its potential either to exacerbate or address health disparities. Polygenic risk scores (PRSs) have emerged as a tool for risk stratification models used in preventive medicine. We examined whether PRS results affect primary care physician (PCP) medical decision-making and whether that effect varies by patient race. METHODS: Using an online survey with a randomized experimental design among PCPs in a national database, we ascertained decision-making around atherosclerotic cardiovascular disease prevention and prostate cancer screening for case scenario patients who were clinically identical except for randomized reported race. RESULTS: Across 369 PCPs (email open rate = 10.8%, partial completion rate = 93.7%), recommendations varied with PRS results in expected directions (low-risk results, no available PRS results, and high-risk results). Still, physicians randomized to scenarios with Black patients were more likely to recommend statin therapy than those randomized to scenarios with White patients (odds ratio = 1.74, 95% CI = 1.16-2.59, P = .007) despite otherwise identical clinical profiles and independent of PRS results. Similarly, physicians were more likely to recommend prostate cancer screening for Black patients than for White patients (odds ratio = 1.58, 95% CI = 1.06-2.35, P = .025) despite otherwise identical clinical and genetic profiles. CONCLUSION: Despite advances in precision risk stratification, physicians will likely continue to use patient race implicitly or explicitly in medical decision-making.

Design Strategies for Luminescent Titanocenes: Improving the Photoluminescence and Photostability of Arylethynyltitanocenes.

Complexes that undergo ligand-to-metal charge transfer (LMCT) to d0 metals are of interest as possible photocatalysts. Cp2Ti(C2Ph)2 (where C2Ph = phenylethynyl) was reported to be weakly emissive in room-temperature (RT) fluid solution from its phenylethynyl-to-Ti 3LMCT state but readily photodecomposes. Coordination of CuX between the alkyne ligands to give Cp2Ti(C2Ph)2CuX (X = Cl, Br) has been shown to significantly increase the photostability, but such complexes are not emissive in RT solution. Herein, we investigate whether inhibition of alkyne-Ti-alkyne bond compression might be responsible for the increased photostability of the CuX complexes by investigating the decomposition of a structurally constrained analogue, Cp2Ti(OBET) (OBET = o-bis(ethynyl)tolane). To investigate the mechanism of nonradiative decay from the 3LMCT states in Cp2Ti(C2Ph)2CuX, the photophysical properties were investigated both upon deuteration and upon rigidifying in a poly(methyl methacrylate) film. These investigations suggested that inhibition of structural rearrangement may play a dominant role in increasing emission lifetimes and quantum yields. The bulkier Cp*2Ti(C2Ph)2CuBr was prepared and is emissive at 693 nm in RT THF solution with a photoluminescent quantum yield of 1.3 × 10-3 (τ = 0.18 µs). Time-dependent density functional theory (TDDFT) calculations suggest that emission occurs from a 3LMCT state dominated by Cp*-to-Ti charge transfer.

Feasibility and acceptability of involving bilingual community navigators to improve access to health and social care services in general practice setting of Australia.

BACKGROUND: Patients from culturally and linguistically diverse (CALD) backgrounds often face difficulties in accessing health and social care services. This study explored the feasibility and acceptability of involving community health workers (CHWs) as bilingual community navigators (BCNs) in general practice setting, to help patients from CALD backgrounds access health and social care services in Australia. METHODS: This research was conducted in two general practices in Sydney where most patients are from specific CALD backgrounds (Chinese in one practice and Samoan in other). Three CHWs trained as BCNs were placed in these practices to help patients access health and social care service. A mixed-method design was followed to explore the feasibility and acceptability of this intervention including analysis of a record of services provided by BCNs and post-intervention qualitative interviews with patients, practice staff and BCNs exploring the feasibility and acceptability of the BCNs' role. The record was analyzed using descriptive statistics and interviews were audio-recorded, transcribed, and thematically analyzed. RESULTS: BCNs served a total of 95 patients, providing help with referral to other services (52.6%), information about appointments (46.3%), local resources (12.6%) or available social benefits (23.2%). Most patients received one service from BCNs with the average duration of appointments being half an hour. Overall, BCNs fitted in well within the practices and patients as well as staff of participating practices accepted them well. Their role was facilitated by patients' felt need for and acceptance of BCNs' services, recruitment of BCNs from the patient community, as well as BCNs' training and motivation for their role. Major barriers for patients to access BCNs' services included lack of awareness of the BCNs' roles among some patients and practice staff, unavailability of information about local culture specific services, and inadequate time and health system knowledge by BCNs. Limited funding support and the short timeframe of the project were major limitations of the project. CONCLUSION: BCNs' placement in general practice was feasible and acceptable to patients and staff in these practices. This first step needs to be followed by accredited training, development of the workforce and establishing systems for supervision in order to sustain the program. Future research is needed on the extension of the intrevention to other practices and culture groups.

Innovating the Model for Student Pharmacists to Increase Access to Hepatitis C Testing (Project IMPACT).

BACKGROUND: Previous initiatives have described the feasibility of conducting point-of-care testing (POCT) for hepatitis C virus (HCV) within community pharmacies. Limited research has been conducted to evaluate the role of student pharmacists and technicians in providing these services. OBJECTIVE: Describe the implementation of a student pharmacist-run HCV POCT initiative within an independent community pharmacy and evaluate the linkage to care process. PRACTICE DESCRIPTION: One specialty and 3 community pharmacies managed by one independent pharmacy chain. PRACTICE INNOVATION: Pharmacy students screened participants for HCV and referred those with a reactive result or reporting untreated HCV to a partnering medical facility for confirmatory testing. Individuals with confirmed HCV had the option to receive their prescriptions, along with monthly telephonic monitoring services from the independent pharmacy's specialty pharmacy. EVALUATION METHODS: Researchers evaluated the number of participants who screened reactive or reported current HCV infection, successful referrals to medical care, and prescriptions dispensed by the specialty pharmacy for HCV treatment. RESULTS: From September 2020 to September 2022, 236 individuals were screened for HCV at the pharmacy, of whom 11 screened reactive (4.7%) and 4 participants reported untreated HCV infection. In total, 15 participants were referred to care and 4 of these participants (26.7%) were successfully linked. One participant received prescriptions and telephonic monitoring for HCV treatment from the specialty pharmacy as a direct result of Project IMPACT (Innovating the Model for Student Pharmacists to Increase Access to Hepatitis C Testing). PRACTICE IMPLICATIONS AND CONCLUSIONS: Project IMPACT demonstrated that community pharmacies can increase access to HCV screenings by using student pharmacists and technicians. Potential strategies to improve the linkage to care process include enhancing the quality of patient education and implementing telehealth services.

Cardiac and pulmonary findings in dysferlinopathy: A 3-year, longitudinal study.

INTRODUCTION/AIMS: There is debate about whether and to what extent either respiratory or cardiac dysfunction occurs in patients with dysferlinopathy. This study aimed to establish definitively whether dysfunction in either system is part of the dysferlinopathy phenotype. METHODS: As part of the Jain Foundation's International Clinical Outcome Study (COS) for dysferlinopathy, objective measures of respiratory and cardiac function were collected twice, with a 3-y interval between tests, in 188 genetically confirmed patients aged 11-86 y (53% female). Measures included forced vital capacity (FVC), electrocardiogram (ECG), and echocardiogram (echo). RESULTS: Mean FVC was 90% predicted at baseline, decreasing to 88% at year 3. FVC was less than 80% predicted in 44 patients (24%) at baseline and 48 patients (30%) by year 3, including ambulant participants. ECGs showed P-wave abnormalities indicative of delayed trans-atrial conduction in 58% of patients at baseline, representing a risk for developing atrial flutter or fibrillation. The prevalence of impaired left ventricular function or hypertrophy was comparable to that in the general population. DISCUSSION: These results demonstrate clinically significant respiratory impairment and abnormal atrial conduction in some patients with dysferlinopathy. Therefore, we recommend that annual or biannual follow-up should include FVC measurement, enquiry about arrhythmia symptoms and peripheral pulse palpation to assess cardiac rhythm. However, periodic specialist cardiac review is probably not warranted unless prompted by symptoms or abnormal pulse findings.

Learning from a codesign exercise aimed at developing a navigation intervention in the general practice setting.

OBJECTIVES: In this study, we aimed to describe and evaluate the codesign of an intervention in general practice setting to help address navigation problems faced by the patients from the culturally and linguistically diverse (CALD) community in Australia. METHODS: An experience-based codesign (EBCD) methodology was adopted using the Double Diamond design process. Two codesign workshops were conducted online with 13 participants including patients, their caregivers, health service providers, researchers, and other stakeholders. Workshops were audio-recorded, transcribed, and thematically analyzed. RESULTS: The codesign participants identified several navigation problems among CALD patients such as inadequate health literacy, cultural and language barriers, and difficulties with navigating health and social services. They believed that bilingual community navigators (BCNs; lay health workers from the same language or cultural background) could help them address these problems. However, this depended on BCNs being trained and supervised, with a clear role definition and manageable workloads, and not used as an interpreter. In undertaking the codesign process, we found that pre-workshop consultations were useful to ensure engagement, especially for consumers who participated more actively in group activities with service providers after these and their own separate small group discussions during the workshop. CONCLUSION: Overall, participants identified that BCNs could offer help in addressing the problems faced by the CALD patients in accessing care in general practice setting. The codesign process provided new insights into the navigation problems faced by CALD patients in accessing care and collaboratively developed a strategy for further testing and evaluation.

The role of generalizability in moral and political psychology.

The aim of the social and behavioral sciences is to understand human behavior across a wide array of contexts. Our theories often make sweeping claims about human nature, assuming that our ancestors or offspring will be prone to the same biases and preferences. Yet we gloss over the fact that our research is often based in a single temporal context with a limited set of stimuli. Political and moral psychology are domains in which the context and stimuli are likely to matter a great deal (Van Bavel, Mende-Siedlecki, Brady, & Reinero, 2016). In response to Yarkoni (see BBS issue), we delve into topics related to political and moral psychology that likely depend on features of the research. These topics include understanding differences between liberals and conservatives, when people are willing to sacrifice someone to save others, the behavior of political leaders, and the dynamics of intergroup conflict.

Influence of an industrial discharge on long-term dynamics of abiotic and biotic resources in Lavaca Bay, Texas, USA.

The current study seeks to identify possible anthropogenic and/or natural environmental stressors that may account for the long-term decline of ecosystem health in Lavaca Bay, Texas, USA. The Formosa Plastics Corporation instituted monitoring of an industrial discharge into the bay with 16 fixed point stations and quarterly sampling from 1993 to 2020. Comprehensive measurements included organic and inorganic solutes in surface water, porewater and sediment, sediment content, plankton, nekton, and infaunal benthos. All parameter trends changed over time due to climate, freshwater inflow events, and/or seasonal changes. Biological community structure and sediment changed with distance from the discharge site. Dominance characterized community structure because three to four taxa comprised > 70% of individuals for nekton (trawl and gill net), phytoplankton, zooplankton, and ichthyoplankton samples. Sediment became sandier over time (48 to 75%) and away from the discharge. Surface water and porewater at reference (R) stations and stations near the discharge site had similar hydrographical and biological trends over time, indicating no long-term impact due to the discharge. However, 99.9% of 424,671 measurements of organic contaminants were non-detectable because the methods were insensitive to ambient concentrations. Thus, it is still not known if contaminants play a role in the long-term decline of ecosystem health in Lavaca Bay. Furthermore, only four R stations were sampled and were all 3810 m from the discharge site, so it is possible that trends in R stations do not represent the natural background. Future studies should include more R stations and lower detection limits for contaminants.

Preregistered Replication of "Feeling Superior Is a Bipartisan Issue: Extremity (Not Direction) of Political Views Predicts Perceived Belief Superiority".

There is currently a debate in political psychology about whether dogmatism and belief superiority are symmetric or asymmetric across the ideological spectrum. Toner, Leary, Asher, and Jongman-Sereno (2013) found that dogmatism was higher among conservatives than liberals, but both conservatives and liberals with extreme attitudes reported higher perceived superiority of beliefs. In the current study, we conducted a preregistered direct and conceptual replication of this previous research using a large nationally representative sample. Consistent with Toner et al.'s findings, our results showed that conservatives had higher dogmatism scores than liberals, whereas both conservative and liberal extreme attitudes were associated with higher belief superiority compared with more moderate attitudes. As in their study, we also found that whether conservative or liberal attitudes were associated with higher belief superiority was topic dependent. Contrasting Toner et al.'s findings, our results also showed that ideologically extreme individuals had higher dogmatism. We discuss implications of these results for theoretical debates in political psychology.

Community Health Workers as Healthcare Navigators in Primary Care Chronic Disease Management: a Systematic Review.

BACKGROUND: This review was carried out to synthesize the evidence of the effectiveness of community health worker (CHW) navigation in primary care chronic disease management. METHODS: We searched the English language literature between January 1990 and March 2020 in Medline, Embase, Emcare, PubMed, Psych Info, CINAHL, Scopus, and Medline Epub ahead of print. Data extraction, quality rating, and assessment of the reporting of interventions were performed by two reviewers independently and the findings were synthesized narratively. RESULTS: Twenty-nine articles met the inclusion criteria. All but two were carried out in the USA and half were randomized controlled trials. Six of the 29 studies were of strong methodological quality while 12 were moderate and 11 weak. Overall, CHW navigation interventions were effective in increasing adherence to cancer screening and improving use of primary care for chronic disease management. There was insufficient evidence that they improved clinical outcomes or risk factors and reduced use of secondary or tertiary care or that they were cost-effective. However, criteria for recruitment, duration, and mode of training and supervision arrangements varied greatly between studies. DISCUSSION: CHW navigation interventions improved aspects of chronic disease management. However, there is insufficient evidence of the impact on patient experience, clinical outcomes, or cost-effectiveness of the interventions. Future research should focus on standardizing organizational components of the CHW navigation interventions and evaluating their cost-effectiveness. PROTOCOL REGISTRATION: The review protocol was published in PROSPERO (CRD42020153921).

Older working adults in the HEAF study are more likely to report loneliness after two years of follow-up if they have negative perceptions of their work quality.

BACKGROUND: Loneliness is an important public health issue associated with mortality and morbidity. Often researched amongst older people, less is known about risk factors for loneliness among adults aged 50-64 years who are in work. We investigated (a) if exit from the workforce increases the odds of loneliness; (b) whether adverse psychosocial work factors are associated with increased odds of loneliness over 2 years of follow-up; and (c) whether the association is stronger among subjects still working compared with those who have exited the workforce. METHODS: Data came from the Health and Employment After Fifty (HEAF) study, a large population cohort who provided questionnaire information about work and health at baseline and 2 annual follow-ups. Logistic regression was used to explore the association between psychosocial risk factors and loneliness at follow-up 2, with adjustment for loneliness at baseline, sex, age, self-rated health, living alone, and mental health diagnosis. RESULTS: Of the initial 8134 participants, 4521 were working at baseline and provided data for this analysis. Of those, 507 (11.2%) were defined as lonely at 2 years' follow-up. Exiting the workforce was not significantly associated with loneliness (OR = 1.1, 95%CI: 0.7-1.7). However, negative psychosocial work factors predicted loneliness at follow-up. After mutual adjustment, lack of choice at work (OR: 1.5, 95%CI: 1.1-1.9), often lying awake worrying about work (OR: 1.4, 95%CI: 1.0-1.9) and perceived not coping with physical demands of the job (OR: 1.3, 95%CI: 1.0-1.7) were independent predictors, with associations robust to adjustment for demographic factors and health. Associations were only slightly altered when we restricted the sample to those who remained in work until the end of follow-up. CONCLUSIONS: Loneliness amongst middle-aged working adults is not predicted by permanent work exit but is predicted by individuals' perceptions about their work. Provision of good-quality work, matched to the capacity of the older worker, could prevent loneliness.

Access to appropriate health care for non-English speaking migrant families with a newborn/young child: a systematic scoping literature review.

BACKGROUND: Recently arrived culturally and linguistically diverse migrant mothers in Western Industrialised Nations are less likely to access health care and are more likely to report negative healthcare experiences than more established migrant or non-migrant populations. This is particularly an issue in Australia where nearly half of all Australians were born overseas or have at least one parent born overseas. METHODS: A systematic scoping review was conducted to identify a) the main enablers and barriers to accessing appropriate health care for migrant families with a new baby/young child who speak a language other than English, and b) the effectiveness of interventions that have been tested to improve access to appropriate health care for this group. Three academic databases (CINAHL, Medline and ProQuest) were searched, with additional publications identified through expert knowledge and networks. Data was extracted and analysed according to the Access framework, which conceptualises access to health care as being generated by the interaction of dimensions of accessibility of services (supply side) and abilities of potential users (demand side). RESULTS: A total of 1964 records were screened for eligibility, with nine of these included in the review. Seven studies only described barriers and enablers to health care access, one study reported on an evaluation of an intervention and one study described the barriers and enablers and the evaluation of an intervention. This review identified that the most significant barriers occurred on the supply side, within the 'appropriateness' domain. Overall, the most frequently cited barrier was a lack of cultural sensitivity/understanding of different cultural practices (five studies). The most significant enablers also occurred on the supply side, but within the 'acceptability' domain. The most frequently cited enabler was cultural sensitivity and understanding. CONCLUSIONS: There is a dearth of evaluated interventions in the peer reviewed literature to improve appropriate access to postnatal care for migrant families who speak a language other than English. The literature focuses on identifying barriers and enablers to access to healthcare for this population group. Interventions which aim to address barriers within the 'appropriateness' dimension may have the greatest impact on access.

Healthy urban planning: an institutional policy analysis of strategic planning in Sydney, Australia.

Rapid urbanization requires health promotion practitioners to understand and engage with strategic city planning. This policy analysis research investigated how and why health was taken up into strategic land use planning in Sydney, Australia, between 2013 and 2018. This qualitative study develops two case studies of consecutive instances of strategic planning in Sydney. Data collection was done via in-depth stakeholder interviews (n = 11) and documentary analysis. Data collection and analysis revolved around core categories underpinning policy institutions (actors, structures, ideas, governance and power) to develop an explanatory narrative of the progress of 'health' in policy discourse over the study period. The two strategic planning efforts shifted in policy discourse. In the earlier plan, 'healthy built environments' was positioned as a strategic direction, but without a mandate for action the emphasis was lost in an economic growth agenda. The second effort shifted that agenda to ecological sustainability, a core aspect of which was 'Liveability', having greater potential for health promotion. However, 'health' remained underdeveloped as a core driver for city planning remaining without an institutional mandate. Instead, infrastructure coordination was the defining strategic city problem and this paradigm defaulted to emphasizing 'health precincts' rather than positioning health as core for the city. This research demonstrates the utility in institutional analysis to understanding positioning health promotion in city planning. Despite potential shifts in policy discourse and a more sophisticated approach to planning holistically, the challenge remains of embedding health within the institutional mandates driving city planning.

The social function of rationalization: An identity perspective.

In this commentary, we offer an additional function of rationalization. Namely, in certain social contexts, the proximal and ultimate function of beliefs and desires is social inclusion. In such contexts, rationalization often facilitates distortion of rather than approximation to truth. Understanding the role of social identity is not only timely and important, but also critical to fully understand the function(s) of rationalization.

Congenital Titinopathy: Comprehensive characterization and pathogenic insights.

OBJECTIVE: Comprehensive clinical characterization of congenital titinopathy to facilitate diagnosis and management of this important emerging disorder. METHODS: Using massively parallel sequencing we identified 30 patients from 27 families with 2 pathogenic nonsense, frameshift and/or splice site TTN mutations in trans. We then undertook a detailed analysis of the clinical, histopathological and imaging features of these patients. RESULTS: All patients had prenatal or early onset hypotonia and/or congenital contractures. None had ophthalmoplegia. Scoliosis and respiratory insufficiency typically developed early and progressed rapidly, whereas limb weakness was often slowly progressive, and usually did not prevent independent walking. Cardiac involvement was present in 46% of patients. Relatives of 2 patients had dilated cardiomyopathy. Creatine kinase levels were normal to moderately elevated. Increased fiber size variation, internalized nuclei and cores were common histopathological abnormalities. Cap-like regions, whorled or ring fibers, and mitochondrial accumulations were also observed. Muscle magnetic resonance imaging showed gluteal, hamstring and calf muscle involvement. Western blot analysis showed a near-normal sized titin protein in all samples. The presence of 2 mutations predicted to impact both N2BA and N2B cardiac isoforms appeared to be associated with greatest risk of cardiac involvement. One-third of patients had 1 mutation predicted to impact exons present in fetal skeletal muscle, but not included within the mature skeletal muscle isoform transcript. This strongly suggests developmental isoforms are involved in the pathogenesis of this congenital/early onset disorder. INTERPRETATION: This detailed clinical reference dataset will greatly facilitate diagnostic confirmation and management of patients, and has provided important insights into disease pathogenesis. Ann Neurol 2018;83:1105-1124.