Mitochondrial dysfunction and mitophagy defects in LRRK2-R1441C Parkinson's disease models.

Mutations in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene have been identified as one of the most common genetic causes of Parkinson's disease (PD). The LRRK2 PD-associated mutations LRRK2G2019S and LRRK2R1441C, located in the kinase domain and in the ROC-COR domain, respectively, have been demonstrated to impair mitochondrial function. Here, we sought to further our understanding of mitochondrial health and mitophagy by integrating data from LRRK2R1441C rat primary cortical and human induced pluripotent stem cell-derived dopamine (iPSC-DA) neuronal cultures as models of PD. We found that LRRK2R1441C neurons exhibit decreased mitochondrial membrane potential, impaired mitochondrial function and decreased basal mitophagy levels. Mitochondrial morphology was altered in LRRK2R1441C iPSC-DA but not in cortical neuronal cultures or aged striatal tissue, indicating a cell-type-specific phenotype. Additionally, LRRK2R1441C but not LRRK2G2019S neurons demonstrated decreased levels of the mitophagy marker pS65Ub in response to mitochondrial damage, which could disrupt degradation of damaged mitochondria. This impaired mitophagy activation and mitochondrial function were not corrected by the LRRK2 inhibitor MLi-2 in LRRK2R1441C iPSC-DA neuronal cultures. Furthermore, we demonstrate LRRK2 interaction with MIRO1, a protein necessary to stabilize and to anchor mitochondria for transport, occurs at mitochondria, in a genotype-independent manner. Despite this, we found that degradation of MIRO1 was impaired in LRRK2R1441C cultures upon induced mitochondrial damage, suggesting a divergent mechanism from the LRRK2G2019S mutation.

Safety and efficacy of malaria vaccine candidate R21/Matrix-M in African children: a multicentre, double-blind, randomised, phase 3 trial.

BACKGROUND: Recently, we found that a new malaria vaccine, R21/Matrix-M, had over 75% efficacy against clinical malaria with seasonal administration in a phase 2b trial in Burkina Faso. Here, we report on safety and efficacy of the vaccine in a phase 3 trial enrolling over 4800 children across four countries followed for up to 18 months at seasonal sites and 12 months at standard sites. METHODS: We did a double-blind, randomised, phase 3 trial of the R21/Matrix-M malaria vaccine across five sites in four African countries with differing malaria transmission intensities and seasonality. Children (aged 5-36 months) were enrolled and randomly assigned (2:1) to receive 5 µg R21 plus 50 µg Matrix-M or a control vaccine (licensed rabies vaccine [Abhayrab]). Participants, their families, investigators, laboratory teams, and the local study team were masked to treatment. Vaccines were administered as three doses, 4 weeks apart, with a booster administered 12 months after the third dose. Half of the children were recruited at two sites with seasonal malaria transmission and the remainder at standard sites with perennial malaria transmission using age-based immunisation. The primary objective was protective efficacy of R21/Matrix-M from 14 days after third vaccination to 12 months after completion of the primary series at seasonal and standard sites separately as co-primary endpoints. Vaccine efficacy against multiple malaria episodes and severe malaria, as well as safety and immunogenicity, were also assessed. This trial is registered on ClinicalTrials.gov, NCT04704830, and is ongoing. FINDINGS: From April 26, 2021, to Jan 12, 2022, 5477 children consented to be screened, of whom 1705 were randomly assigned to control vaccine and 3434 to R21/Matrix-M; 4878 participants received the first dose of vaccine. 3103 participants in the R21/Matrix-M group and 1541 participants in the control group were included in the modified per-protocol analysis (2412 [51·9%] male and 2232 [48·1%] female). R21/Matrix-M vaccine was well tolerated, with injection site pain (301 [18·6%] of 1615 participants) and fever (754 [46·7%] of 1615 participants) as the most frequent adverse events. Number of adverse events of special interest and serious adverse events did not significantly differ between the vaccine groups. There were no treatment-related deaths. 12-month vaccine efficacy was 75% (95% CI 71-79; p<0·0001) at the seasonal sites and 68% (61-74; p<0·0001) at the standard sites for time to first clinical malaria episode. Similarly, vaccine efficacy against multiple clinical malaria episodes was 75% (71-78; p<0·0001) at the seasonal sites and 67% (59-73; p<0·0001) at standard sites. A modest reduction in vaccine efficacy was observed over the first 12 months of follow-up, of similar size at seasonal and standard sites. A rate reduction of 868 (95% CI 762-974) cases per 1000 children-years at seasonal sites and 296 (231-362) at standard sites occurred over 12 months. Vaccine-induced antibodies against the conserved central Asn-Ala-Asn-Pro (NANP) repeat sequence of circumsporozoite protein correlated with vaccine efficacy. Higher NANP-specific antibody titres were observed in the 5-17 month age group compared with 18-36 month age group, and the younger age group had the highest 12-month vaccine efficacy on time to first clinical malaria episode at seasonal (79% [95% CI 73-84]; p<0·001) and standard (75% [65-83]; p<0·001) sites. INTERPRETATION: R21/Matrix-M was well tolerated and offered high efficacy against clinical malaria in African children. This low-cost, high-efficacy vaccine is already licensed by several African countries, and recently received a WHO policy recommendation and prequalification, offering large-scale supply to help reduce the great burden of malaria in sub-Saharan Africa. FUNDING: The Serum Institute of India, the Wellcome Trust, the UK National Institute for Health Research Oxford Biomedical Research Centre, and Open Philanthropy.

CRISPRi: a way to integrate iPSC-derived neuronal models.

The genetic landscape of neurodegenerative diseases encompasses genes affecting multiple cellular pathways which exert effects in an array of neuronal and glial cell-types. Deconvolution of the roles of genes implicated in disease and the effects of disease-associated variants remains a vital step in the understanding of neurodegeneration and the development of therapeutics. Disease modelling using patient induced pluripotent stem cells (iPSCs) has enabled the generation of key cell-types associated with disease whilst maintaining the genomic variants that predispose to neurodegeneration. The use of CRISPR interference (CRISPRi), alongside other CRISPR-perturbations, allows the modelling of the effects of these disease-associated variants or identifying genes which modify disease phenotypes. This review summarises the current applications of CRISPRi in iPSC-derived neuronal models, such as fluorescence-activated cell sorting (FACS)-based screens, and discusses the future opportunities for disease modelling, identification of disease risk modifiers and target/drug discovery in neurodegeneration.

Can 3-dimensional cranial ultrasound be used to successfully reconstruct a 2-dimensional image without compromising on image quality in a neonatal population?

BACKGROUND: Cranial ultrasound is frequently performed in neonatal intensive care units and acquiring 2-dimensional (D) images requires significant training. Three-D ultrasound images can be acquired semi-automatically. OBJECTIVE: This proof-of-concept study aimed to demonstrate that 3-D study image quality compares well with 2-D. If this is successful, 3-D images could be acquired in remote areas and read remotely by experts. MATERIALS AND METHODS: This was a prospective study of 20 neonates, who underwent both routine 2-D and 3-D cranial ultrasounds. Images were reconstructed into standard views extracted from the 3-D volume and evaluated by three radiologists blinded to the acquisition method. The radiologists assessed for the presence of anatomical landmarks and overall image quality. RESULTS: More anatomical structures were identified in the 3-D studies (P<0.01). There was a trend that 3-D ultrasound demonstrated better image quality in the coronal plane, and 2-D in the sagittal plane, only reaching statistical significance for two coronal views and two sagittal views. CONCLUSION: Overall, this study has demonstrated that 3-D cranial ultrasound performs similarly to 2-D and could be implemented into neonatal practice.

A case series evaluation of the Fearless Me! © program for children with intellectual disabilities and anxiety.

OBJECTIVES: Children and adolescents with intellectual disabilities (ID) have high rates of mental health disorders, particularly anxiety disorders. Cognitive behavior therapy (CBT) has largely remained unexamined as a treatment option for this population. Fearless Me! © is an adapted CBT treatment program specifically designed for children and adolescents with ID. METHOD: Eleven children, aged between eight and 17, completed 10 therapy sessions. Measures of anxiety were completed pre and posttreatment and at 3 and 12-month follow-ups by both the children and parents. RESULTS: Six children reported significant reductions in anxiety, with all showing significant reductions in parent-reported child anxiety at either posttreatment assessment, 3-month follow-up, or 12-month follow-up. Results varied across the six children as all parents reported heightened anxiety, but not all children reported high levels of anxiety for themselves. CONCLUSION: Overall, this evaluation provides a sound basis for continued investigation and research into the use of the Fearless Me! © modified CBT program to treat children with ID and anxiety.

Insufficient PrEParation: an assessment of primary care prescribing habits and use of pre-exposure prophylaxis in patients at risk of HIV acquisition at a single medical centre.

OBJECTIVES: To assess HIV pre-exposure prophylaxis (PrEP) prescribing habits by primary care providers and the number of patients at risk of HIV acquisition at a single medical centre in the Northwestern USA from 1 July 2018 to 31 June 2020. METHODS: An electronic cross-sectional survey was administered in April and May 2021 to providers in family medicine, internal medicine, adolescent and young adult health, student health and women's health clinics affiliated with the medical centre with questions pertaining to PrEP prescribing practices. Electronic medical record abstraction was used to quantify the number of eligible patients who sought care in primary care departments and the adherence to PrEP initiation guidelines from 1 July 2018 to 31 June 2020. RESULTS: 74% (61/82) of providers reported familiarity with national clinical practice guidelines for the prevention of HIV infection. 50% (41/82) of respondents were located in family medicine clinics. 57% (47/82) of providers counseled less than one-quarter of those who they identified as at risk of HIV infection. The major barriers to prescribing PrEP were insufficient time and lack of familiarity with guidelines. Of the 4330 eligible patients for PrEP, 8% (337/4330) received at least one PrEP prescription during the study period. For patients newly prescribed PrEP, only 23% (39/170) had appropriate counseling and labs at initiation. The top three qualifying indications for PrEP were identifying as transgender (36%, n=1562), high-risk sexual behaviour (32%, n=1405) and injection drug use (30%, n=1289). CONCLUSIONS: This study highlights intervention points in the HIV prevention cascade warranting attention in order to achieve the 2025 Ending the HIV Epidemic in the U.S. target for PrEP coverage. These include increasing provider adherence to prescribing guidelines and reducing the logistical barriers to prescribing.

Impact of naturalistic smartphone positioning on acoustic measures of voicea).

Smartphone technology has been used for at-home health monitoring, but there are few available applications (apps) for tracking acoustic measures of voice for those with chronic voice problems. Current apps limit the user by restricting the range of smartphone positions to those that are unnatural and non-interactive. Therefore, we aimed to understand how more natural smartphone positions impacted the accuracy of acoustic measures in comparison to clinically acquired and derived measures. Fifty-six adults (11 vocally healthy, 45 voice disordered, aged 18-80 years) completed voice recordings while holding their smartphones in four different positions (e.g., as if reading from the phone, up to the ear, etc.) while a head-mounted high-quality microphone attached to a handheld acoustic recorder simultaneously captured voice recordings. Comparisons revealed that mean fundamental frequency (Hz), maximum phonation time (s), and cepstral peak prominence (CPP; dB) were not impacted by phone position; however, CPP was significantly lower on smartphone recordings than handheld recordings. Spectral measures (low-to-high spectral ratio, harmonics-to-noise ratio) were impacted by the phone position and the recording device. These results indicate that more natural phone positions can be used to capture specific voice measures, but not all are directly comparable to clinically derived values.

Childhood Experiences and Perspectives of Individuals With Orofacial Clefts: A Qualitative Systematic Review.

OBJECTIVE: Children and adolescents with orofacial clefts may experience ongoing psychosocial impacts due to the continuous nature of cleft treatments, facial and dental differences, and speech and hearing difficulties. The aim of this qualitative systematic review was to better understand the experiences of children and adolescents with orofacial clefts. DESIGN: A systematic search strategy using PubMed, Embase, Emcare, Scopus, and Web of Science databases was performed to identify relevant qualitative studies evaluating the lived experience of children and adolescents with orofacial clefts from inception through to June 2021. Eligible studies were critically appraised using the Joanna Briggs methodology and a meta-aggregative approach. RESULTS: The search identified 2466 studies, with 13 found to meet the inclusion criteria. Extraction of 155 findings resulted in 27 categories, which were meta-aggregated into 7 overarching synthesized findings. These 7 core findings included aspects of child experience and findings that enhanced or impeded child experience at the individual, family, and community levels. CONCLUSIONS: Factors that impeded child experience at the individual, family, and community levels were more pronounced than factors that enhanced their experience among children and adolescents with orofacial clefts. Further initiatives are needed to provide support to individuals, families, and school communities to enhance children's experience of orofacial cleft during the formative childhood and adolescent years.

Mothers with borderline personality disorders' experiences of mother-infant dialectical behavior therapy.

BACKGROUND: Borderline personality disorder (BPD) is increasingly diagnosed in perinatal and infant settings, and research suggests that as well as an escalation of BPD symptoms in this period, these symptoms may also be detrimental to infant development. Providing tailored treatments during the postnatal period may help women and prevent an intergenerational cycle of emotional and interpersonal symptoms in infants. Mother-infant dialectical behavior therapy (MI-DBT) has produced promising, yet inconsistent, improvements on quantitative scales of maternal mental health and the mother-infant relationship. The qualitative evaluation may provide complementary information. AIMS: This study aimed to explore the subjective experiences of women who had completed MI-DBT. MATERIAL AND METHODS: Thematic analysis of semistructured interviews conducted on 13 women undertaking MI-DBT before, post, and 12 months after MI-DBT were analyzed for themes. RESULTS: Five major themes were identified. Overall, the women expressed that their emotional literacy and regulation improved after MI-DBT, subsequently addressing key risks and challenges such as uncertainty around their child's cues, and low self-esteem, and potentially improving the women's mentalization capability. DISCUSSION AND CONCLUSIONS: This study consolidates previous research on maternal BPD, and provides qualitative evidence of the benefits of MI-DBT for mothers as both individuals and as parents with likely flow-on effects for infants. Lived experience input for future adaptations was a valuable gain.

Tackling differential attainment in specialist GP training in England and Scotland.

In this article NHS England and NHS Education for Scotland describe practical ways we are tackling differences in the attainment of people training as general practitioners (GPs).Trainees from minority ethnic groups and international medical graduates are less likely than others to qualify as GPs. It is difficult to change systemic inequalities, but over the past five years we have made practical changes to GP speciality training. Educators recognise there is an issue and are trying to tackle it.For example, people who had not successfully qualified had an opportunity to return to GP training. When we provided individualised targeted support, the proportion who completed training significantly increased (76%).This was a catalyst for reviewing unconscious bias in GP training. We implemented a national programme to tackle differential attainment and system-level bias. Educators now work with all GP trainees to identify their individual needs. Supervisors are trained to recognise bias and provide targeted support. There is mental health support and regular reviews to see whether trainees are ready to sit exams. Trainee representatives are championing the learner voice in national committees. Exams are being altered to reduce unconscious bias. We are monitoring attainment over time.The key message is that differential attainment should not be in the 'too hard basket'. The narrative is changing from 'can't do' to 'must do', supported by appropriate leadership, promotion and resourcing. There is much more to do, but we are making changes, evaluating and applying our learning. We have moved from talking to taking action.

Support After Suicide: A Thematic Analysis of Siblings' Experience.

Suicide is a worldwide phenomenon resulting in the deaths of more than 700,000 people each year. For every suicide, there are those left behind. The research on sibling's experiences of grief and the support they require after the loss of their sibling is limited. This study explored the experiences of grief and the support siblings bereaved through suicide experienced. Support groups passed on study information to individuals they felt were suitable for participation. Ten adult siblings were interviewed for the study. Thematic analysis was used to find three themes, shared understanding, holding space for grief, and relationships. The findings indicate that siblings desire support from other siblings bereaved through suicide, as well as social support free from stigma that is willing to listen. The relationship between the suicided sibling and the living sibling had effects on the grief experience, as well as parentification, and effects from organisational interaction.

Efficacy of a low-dose candidate malaria vaccine, R21 in adjuvant Matrix-M, with seasonal administration to children in Burkina Faso: a randomised controlled trial.

BACKGROUND: Stalled progress in controlling Plasmodium falciparum malaria highlights the need for an effective and deployable vaccine. RTS,S/AS01, the most effective malaria vaccine candidate to date, demonstrated 56% efficacy over 12 months in African children. We therefore assessed a new candidate vaccine for safety and efficacy. METHODS: In this double-blind, randomised, controlled, phase 2b trial, the low-dose circumsporozoite protein-based vaccine R21, with two different doses of adjuvant Matrix-M (MM), was given to children aged 5-17 months in Nanoro, Burkina Faso-a highly seasonal malaria transmission setting. Three vaccinations were administered at 4-week intervals before the malaria season, with a fourth dose 1 year later. All vaccines were administered intramuscularly into the thigh. Group 1 received 5 µg R21 plus 25 µg MM, group 2 received 5 µg R21 plus 50 µg MM, and group 3, the control group, received rabies vaccinations. Children were randomly assigned (1:1:1) to groups 1-3. An independent statistician generated a random allocation list, using block randomisation with variable block sizes, which was used to assign participants. Participants, their families, and the local study team were all masked to group allocation. Only the pharmacists preparing the vaccine were unmasked to group allocation. Vaccine safety, immunogenicity, and efficacy were evaluated over 1 year. The primary objective assessed protective efficacy of R21 plus MM (R21/MM) from 14 days after the third vaccination to 6 months. Primary analyses of vaccine efficacy were based on a modified intention-to-treat population, which included all participants who received three vaccinations, allowing for inclusion of participants who received the wrong vaccine at any timepoint. This trial is registered with ClinicalTrials.gov, NCT03896724. FINDINGS: From May 7 to June 13, 2019, 498 children aged 5-17 months were screened, and 48 were excluded. 450 children were enrolled and received at least one vaccination. 150 children were allocated to group 1, 150 children were allocated to group 2, and 150 children were allocated to group 3. The final vaccination of the primary series was administered on Aug 7, 2019. R21/MM had a favourable safety profile and was well tolerated. The majority of adverse events were mild, with the most common event being fever. None of the seven serious adverse events were attributed to the vaccine. At the 6-month primary efficacy analysis, 43 (29%) of 146 participants in group 1, 38 (26%) of 146 participants in group 2, and 105 (71%) of 147 participants in group 3 developed clinical malaria. Vaccine efficacy was 74% (95% CI 63-82) in group 1 and 77% (67-84) in group 2 at 6 months. At 1 year, vaccine efficacy remained high, at 77% (67-84) in group 1. Participants vaccinated with R21/MM showed high titres of malaria-specific anti-Asn-Ala-Asn-Pro (NANP) antibodies 28 days after the third vaccination, which were almost doubled with the higher adjuvant dose. Titres waned but were boosted to levels similar to peak titres after the primary series of vaccinations after a fourth dose administered 1 year later. INTERPRETATION: R21/MM appears safe and very immunogenic in African children, and shows promising high-level efficacy. FUNDING: The European & Developing Countries Clinical Trials Partnership, Wellcome Trust, and National Institute for Health Research Oxford Biomedical Research Centre.

Relaxation and related therapies for people with multiple sclerosis (MS): A systematic review.

OBJECTIVE: To establish the effectiveness of relaxation and related therapies in treating Multiple Sclerosis related symptoms and sequelae. DATA SOURCES: PsycINFO, PubMed, Embase, CINAHL, ProQuest Dissertations and Theses Global databases were searched. METHODS: We included studies from database inception until 31 December 2021 involving adult participants diagnosed with multiple sclerosis or disseminated sclerosis, which featured quantitative data regarding the impact of relaxation interventions on multiple sclerosis-related symptoms and sequelae. Studies which examined multi-modal therapies - relaxation delivered in combination with non-relaxation interventions - were excluded. Risk of bias was assessed using the Revised Risk of Bias tool for randomised trials - ROB2, Risk of Bias in Non-Randomised Studies of Interventions ROBINS-I), and within and between-group effects were calculated (Hedges' g). RESULTS: Twenty-eight studies met inclusion criteria. Twenty-three of these were randomised controlled trials, with 1246 total participants. This review reports on this data, with non-randomised study data reported in supplemental material. Post -intervention relaxation was associated with medium to large effect-size improvement for depression, anxiety, stress and fatigue. The effects of relaxation were superior to wait-list or no treatment control conditions; however, comparisons with established psychological or physical therapies were mixed. Individual studies reported sustained effects (≤ 6 months) with relaxation for stress, pain and quality of life. Most studies were rated as having a high/serious risk of bias. CONCLUSION: There is emerging evidence that relaxation therapies can improve outcomes for persons with multiple sclerosis. Given the high risk of bias found for included studies, stronger conclusions cannot be drawn.

Hindering resilience in the transition to parenthood: a thematic analysis of parents' perspectives.

Objective: Investigate parents' recollections of resilience hindering experiences in the first year of parenthood.Background: The transition to parenthood is a significant period of change in the lifespan. Understanding the factors which undermine resilience during this process will help illuminate resilience theory and provision of perinatal support.Methods: We conducted a thematic analysis of in-depth interviews with 10 parents (including four fathers) and examined factors hindering resilience as a global theme within a broader thematic network.Results: We identified two organising themes; context which related to external experiences and relationships and appraisals which related to parents' internal attributions and experiences. We refined these organising themes into 24 specific resilience hindering factors including ambivalence about parenthood, fear of judgement, compromised self-care and relationship change. We also collated parents' suggested changes to structural supports such as providing a comprehensive overview of services available to new parents, having credible resources online, engaging fathers directly in perinatal care and a greater focus on postnatal support such as prioritising continuity of care and making longer hospital stays available.Conclusion: Our work illuminates parents' own thoughts about factors hindering resilience in the transition to parenthood and provides direct recommendations from consumers about improvements to provision of support throughout this critical period.

Do fellowships for newly qualified GPs improve retention? Evaluation of London's SPIN New to Practice Fellowships.

BACKGROUND: We explored whether having a variety of work roles and extra support during the first 2 years after qualifying would retain general practitioners (GPs) in London. Newly qualified GPs were offered a Fellowship comprising permanent salaried positions, part-time (portfolio) roles outside general practice and peer support for 1-2 years. METHODS: We surveyed newly qualified GPs taking part in the Fellowship near the beginning of their Fellowship (91) and again after 8-10 months (93). We interviewed 34 newly qualified GPs taking part in the Fellowship and 20 who were not. We surveyed and interviewed representatives from employing practices (171), organisations hosting portfolio roles (20), those facilitating the Fellowship (10) and other stakeholders (43). FINDINGS: Over a 2.5-year period, employers recruited and retained 425 newly qualified GPs to salaried posts using the Fellowship. Eighty-eight per cent of the newly qualified GPs taking part said they intended to stay working in local practices. They said that undertaking a portfolio role helped them feel valued, had more variety and integration with the wider professional community. Those with two or more portfolio sessions per week were the most positive. CONCLUSIONS: Portfolio roles and peer support may increase newly qualified GPs intention to stay working in salaried posts, however it is too early to say whether these intentions will translate into behaviour. WHAT THIS EVALUATION ADDS TO CURRENT KNOWLEDGE: Portfolio roles and monthly peer support helped newly qualified GPs feel supported and valued, which may influence their intention to stay working in general practice locally.

Can a training hub deliver undergraduate medical education with patient educators?

BACKGROUND: Medical schools may find it difficult to coordinate GP practices to support undergraduate medical education in primary care. In England, every Integrated Care System area now has a funded training hub to plan and upskill the primary care and community health workforce. We evaluated whether a training hub could help deliver undergraduate medical education, co-facilitated by patient educators. No published research has evaluated this model before. METHODS: We used before and after surveys (617 students), interviews (28) and focus groups (20 people) with undergraduate medical students, patient educators and training hub and medical school team members. FINDINGS: It was feasible for a training hub to develop and co-deliver a workshop with patient educators. 61% of Year 4 undergraduate students (first clinical year) took part, a high attendance rate during the COVID-19 pandemic. 80% of students said they learnt a lot about managing conditions in primary care and the community as a result. They particularly valued engaging with patient educators and seeing interprofessional working between GPs and pharmacists, which were cornerstones of the training hub approach. The hub was able to recruit and retain patient educators more effectively than the medical school alone. Patient educators said they felt valued and developed new skills. CONCLUSIONS: Working with training hubs may be part of the solution to issues medical schools face when organising undergraduate education about primary care. This small evaluation suggests that this model could be tested further.

Zebrafish dscaml1 Deficiency Impairs Retinal Patterning and Oculomotor Function.

Down syndrome cell adhesion molecules (dscam and dscaml1) are essential regulators of neural circuit assembly, but their roles in vertebrate neural circuit function are still mostly unexplored. We investigated the functional consequences of dscaml1 deficiency in the larval zebrafish (sexually undifferentiated) oculomotor system, where behavior, circuit function, and neuronal activity can be precisely quantified. Genetic perturbation of dscaml1 resulted in deficits in retinal patterning and light adaptation, consistent with its known roles in mammals. Oculomotor analyses revealed specific deficits related to the dscaml1 mutation, including severe fatigue during gaze stabilization, reduced saccade amplitude and velocity in the light, greater disconjugacy, and impaired fixation. Two-photon calcium imaging of abducens neurons in control and dscaml1 mutant animals confirmed deficits in saccade-command signals (indicative of an impairment in the saccadic premotor pathway), whereas abducens activation by the pretectum-vestibular pathway was not affected. Together, we show that loss of dscaml1 resulted in impairments in specific oculomotor circuits, providing a new animal model to investigate the development of oculomotor premotor pathways and their associated human ocular disorders.SIGNIFICANCE STATEMENTDscaml1 is a neural developmental gene with unknown behavioral significance. Using the zebrafish model, this study shows that dscaml1 mutants have a host of oculomotor (eye movement) deficits. Notably, the oculomotor phenotypes in dscaml1 mutants are reminiscent of human ocular motor apraxia, a neurodevelopmental disorder characterized by reduced saccade amplitude and gaze stabilization deficits. Population-level recording of neuronal activity further revealed potential subcircuit-specific requirements for dscaml1 during oculomotor behavior. These findings underscore the importance of dscaml1 in the development of visuomotor function and characterize a new model to investigate potential circuit deficits underlying human oculomotor disorders.

Effectiveness of dialectical behavior therapy skills training group for adults with borderline personality disorder.

OBJECTIVE: This study evaluated the effectiveness of the Dialectical Behavior Therapy Skills Training Group (DBT-ST) component of DBT. METHOD: Participants (N = 114) attended an 18-20-week DBT-ST. The study utilized a quasi-experimental design with a within-persons control group for a measure of borderline personality disorder (BPD) symptoms (at referral), and emergency department (ED) presentations, and psychiatric bed-days (both assessed for 6 months pre- and post-intervention). Primary outcomes were the number of BPD symptoms, psychological distress, depression, rate of ED presentations, and psychiatric inpatient bed-days. RESULTS: After completing DBT-ST, participants had reduced BPD symptoms, psychological distress, and depression (p < 0.001). The waitlist control group showed no improvement in BPD symptoms (p = 0.085). The rate of ED presentations was reduced (p = 0.001). There was no reduction in psychiatric inpatient bed-days (p = 0.160), likely due to insufficient power. CONCLUSIONS: DBT-ST participation in addition to treatment-as-usual is an effective treatment for people with BPD.

Enhancing resilience in the transition to parenthood: a thematic analysis of parents' perspectives.

Objective: Investigate parents' recollections of resilience enhancing experiences in the first year of parenthood.Background: Resilience is a concept of emerging interest in transition to parenthood research. Little is known about parents' descriptions and experiences of resilience in the first year of parenthood and existing research is based on data about mothers only.Methods: We conducted a thematic analysis of in-depth interviews with 10 parents (including four fathers) and created a thematic network of factors which participants described as enhancing their resilience in the first year of parenthood.Results: The thematic network comprised a number of subthemes (such as personal skills and support structures), and 39 specific resilience enhancing factors. These included personal skills such as acceptance, compassion, assertiveness and help-seeking; sources of support with the most preferred source for parents their partner, followed by mothers, peers, and midwifery; and important engagement characteristics displayed by support providers including attunement to the parent's needs and good communication skills.Conclusion: Our work contributes to an important gap in the literature and identifies factors for future research to explore and develop.

Review: Inflammation and anxiety-based disorders in children and adolescents - a systematic review and meta-analysis.

BACKGROUND: Anxiety-based disorders are common and are often chronic with an onset during childhood or adolescence. An emerging literature has examined the role of inflammation in these disorders by measuring blood concentrations of inflammatory markers such as cytokines, C-reactive protein (CRP) and immune markers such as white blood cell counts. However, existing results are inconsistent, with available meta-analyses only including adult populations. We believe this is the first systematic review and meta-analysis to investigate these inconsistencies among the population of children and adolescents. METHODS: A systematic search of five electronic databases was conducted to identify studies which compared inflammatory markers between individuals with an anxiety-based disorder and healthy controls. Study quality was assessed, and pooled effect sizes (Hedges' g) were calculated using random-effects meta-analyses. RESULTS: Nine independent studies were identified. The combined meta-analysis of 16 cytokines and CRP was approaching significance; however, no significant between-group difference was observed for meta-analyses of individual inflammatory or immune markers. Heterogeneity was high, and quality assessments identified important limitations; primarily, small sample sizes and a lack of control over confounding variables. CONCLUSIONS: Although no significant effects were observed, the small number of included studies and limitations in study or reporting quality render these findings provisional. Research in this area has the potential for important clinical implications in relation to therapeutic interventions. Important recommendations for further research are put forth.