Complete genome sequence of Parvimonas micra strain JM503A, a genetically tractable dental abscess clinical isolate.

Parvimonas micra is a pathobiont of humans that is often found in abundance at sites of mucosal inflammation as well as within malignant tumors. Here, we report the complete genome sequence of P. micra strain JM503A, which is a genetically tractable clinical isolate derived from a human odontogenic abscess specimen.

Psychosocial experiences of clinicians providing care for children with severe neurological impairment.

AIM: To investigate clinicians' psychosocial experiences navigating interdisciplinary care for children with severe neurological impairment (SNI), for example children with a developmental epileptic encephalopathy; secondarily, to identify preferences for future interventions to support clinicians caring for children with SNI. METHOD: We conducted a qualitative descriptive study with interdisciplinary clinicians by using a purposeful sampling recruitment strategy. Twenty-four participants with expertise caring for children with SNI completed in-depth, semi-structured interviews. We transcribed the interviews, de-identified them, and performed inductive thematic analysis. RESULTS: Thematic analysis elicited interrelated themes. Clinicians experienced immense professional barriers providing patient-centred care across fragmented healthcare contexts. Physical, emotional, and psychological impacts were attributed to inadequate reflective practice training and a paucity of integrated resources to support clinicians over time. Multipronged strategies were prioritized by clinicians, incorporating psychoeducation, interdisciplinary peer mentorship, and psychological resources to build reflective practice skills for clinicians providing complex care in an advancing era of medicine. INTERPRETATION: This study provides novel and in-depth insight into clinicians' experiences navigating care for children with SNI. The results will be used to inform future integrated and multipronged co-developed resources tailored for clinicians, on the basis of their recommendations.

The dynamic impact of location and resection on the glioma CSF proteome.

While serial sampling of glioma tissue is rarely performed prior to recurrence, cerebrospinal fluid (CSF) is an underutilized longitudinal source of candidate glioma biomarkers for understanding therapeutic impacts. However, the impact of key variables to consider in longitudinal CSF samples, including anatomical location and post-surgical changes, remains unknown. To that end, pre- versus post-resection intracranial CSF samples were obtained at early (1-16 days; n=20) or delayed (86-153 days; n=11) timepoints for patients with glioma. Paired lumbar-versus-intracranial glioma CSF samples were also obtained (n=14). Using aptamer-based proteomics, we identify significant differences in the CSF proteome between lumbar, subarachnoid, and ventricular CSF. Our analysis of serial intracranial CSF samples suggests the early potential for disease monitoring and evaluation of pharmacodynamic impact of targeted therapies. Importantly, we found that resection had a significant, evolving longitudinal impact on the CSF proteome. Proteomic data are provided with individual clinical annotations as a resource for the field. One Sentence Summary: Glioma cerebrospinal fluid (CSF) accessed intra-operatively and longitudinally via devices can reveal impacts of treatment and anatomical location.

'High hopes for treatment': Australian stakeholder perspectives of the clinical translation of advanced neurotherapeutics for rare neurological diseases.

INTRODUCTION: Advanced therapies offer unprecedented opportunities for treating rare neurological disorders (RNDs) in children. However, health literacy, perceptions and understanding of novel therapies need elucidation across the RND community. This study explored healthcare professionals' and carers' perspectives of advanced therapies in childhood-onset RNDs. METHODS: In this mixed-methodology cross-sectional study, 20 healthcare professionals (clinicians, genetic counsellors and scientists) and 20 carers completed qualitative semistructured interviews and custom-designed surveys. Carers undertook validated psychosocial questionnaires. Thematic and quantitative data analysis followed. RESULTS: Participants described high positive interest in advanced therapies, but low knowledge of, and access to, reliable information. The substantial 'therapeutic gap' and 'therapeutic odyssey' common to RNDs were recognised in five key themes: (i) unmet need and urgency for access; (ii) seeking information; (iii) access, equity and sustainability; (iv) a multidisciplinary and integrated approach to care and support and (v) difficult decision-making. Participants were motivated to intensify RND clinical trial activity and access to advanced therapies; however, concerns around informed consent, first-in-human trials and clinical trial procedures were evident. There was high-risk tolerance despite substantial uncertainties and knowledge gaps. RNDs with high mortality, increased functional burdens and no alternative therapies were consistently prioritised for the development of advanced therapies. However, little consensus existed on prioritisation to treatment access. CONCLUSIONS: This study highlights the need to increase clinician and health system readiness for the clinical translation of advanced therapeutics for RNDs. Co-development and use of educational and psychosocial resources to support clinical decision-making, set therapeutic expectations and promotion of equitable, effective and safe delivery of advanced therapies are essential. PATIENT OR PUBLIC CONTRIBUTION: Participant insights into the psychosocial burden and information need to enhance the delivery of care in this formative study are informing ongoing partnerships with families, including co-production and dissemination of psychoeducational resources featuring their voices hosted on the Sydney Children's Hospitals Network website SCHN Brain-Aid Resources.

Psychological wellbeing among parents of a child living with a serious chronic illness: A cross-sectional survey study.

Parents of a child with a chronic illness can experience greater distress than the average population, yet little is understood about differences between illness groups. This cross-sectional survey study aimed to compare parents' psychological distress and perceived wellbeing across five chronic illnesses. Parents from one Australian pediatric hospital completed the Kessler Psychological Distress Scale and seven purpose-designed items about their wellbeing. Data from 106 parents (cancer = 48, cystic fibrosis [CF] = 27, kidney disease = 12, gastrointestinal condition/disorder = 9, developmental and epileptic encephalopathy [DEE] = 10) was analysed using bivariate Pearson's Correlation and linear mixed-effects models. Parents' distress scores differed between groups (F(4,80) = 2.50, p = .049), with the DEE group reporting higher distress than the CF group (mean difference = 6.76, 95% CI [0.11, 13.42]). Distress scores were moderately correlated to parents' perceptions of their child's health and their own wellbeing. Parents' self-reported coping with their child's condition/treatments differed (F(4,81) = 3.24, p = .016), with the DEE group rating their coping as poorer than the CF group (mean difference = -25.32, 95% CI [-46.52, 4.11]). Across all groups, parents reported unmet needs, particularly for psychosocial support and practical/financial assistance. Support interventions may be most effective if tailored to the child's illness, with greater support potentially needed for parents who have a child with DEE and/or severe comorbidities.

FLP: Factor lattice pattern-based automated detection of Parkinson's disease and specific language impairment using recorded speech.

BACKGROUND: Timely detection of neurodevelopmental and neurological conditions is crucial for early intervention. Specific Language Impairment (SLI) in children and Parkinson's disease (PD) manifests in speech disturbances that may be exploited for diagnostic screening using recorded speech signals. We were motivated to develop an accurate yet computationally lightweight model for speech-based detection of SLI and PD, employing novel feature engineering techniques to mimic the adaptable dynamic weight assignment network capability of deep learning architectures. MATERIALS AND METHODS: In this research, we have introduced an advanced feature engineering model incorporating a novel feature extraction function, the Factor Lattice Pattern (FLP), which is a quantum-inspired method and uses a superposition-like mechanism, making it dynamic in nature. The FLP encompasses eight distinct patterns, from which the most appropriate pattern was discerned based on the data structure. Through the implementation of the FLP, we automatically extracted signal-specific textural features. Additionally, we developed a new feature engineering model to assess the efficacy of the FLP. This model is self-organizing, producing nine potential results and subsequently choosing the optimal one. Our speech classification framework consists of (1) feature extraction using the proposed FLP and a statistical feature extractor; (2) feature selection employing iterative neighborhood component analysis and an intersection-based feature selector; (3) classification via support vector machine and k-nearest neighbors; and (4) outcome determination using combinational majority voting to select the most favorable results. RESULTS: To validate the classification capabilities of our proposed feature engineering model, designed to automatically detect PD and SLI, we employed three speech datasets of PD and SLI patients. Our presented FLP-centric model achieved classification accuracy of more than 95% and 99.79% for all PD and SLI datasets, respectively. CONCLUSIONS: Our results indicate that the proposed model is an accurate alternative to deep learning models in classifying neurological conditions using speech signals.

Nasal allergen-neutralizing antibodies correlate closely with tolerated intranasal allergen challenge dose following grass pollen subcutaneous immunotherapy in patients with local allergic rhinitis.

BACKGROUND: Local allergic rhinitis (LAR) is defined by chronic nasal symptoms, absence of atopy, positive nasal allergen challenge (NAC) and a good response to subcutaneous allergen immunotherapy (SCIT). We sought to investigate SCIT capacity to induce local and systemic blocking antibodies in LAR patients. METHODS: A RDBPC study of grass SCIT was performed, with participants receiving either SCIT (Group A; n = 10) or placebo (Group B; n = 14) in the first 6 months. Both groups subsequently received SCIT for 12 months at Year 2. Nasal and serum antibodies (IgG4 , IgA1 and IgA2 ) and their inhibitory capacity were measured at multiple timepoints. RESULTS: The allergen concentration tolerated increased significantly at 6 months (Group A; p = .047) and 24 months (Group B; p = .049) compared with baseline and persisted until the end of the study. Induction of serum sIgA1 to Phl p was seen in Groups A and B, albeit the former being induced earlier (1.71-fold, p = .027). A significant induction in sIgG4 to Phl p 1 and 5 was observed in serum of Group A (p = .047 and p = .0039) and sIgA2 to Phl p in Group B (p = .032 and p = .0098) at 18 and 24 months, respectively. Both local and systemic blocking antibodies can inhibit allergen-IgE complexes binding to CD23 on B cells, and this correlated with level of allergen tolerated intra-nasally in Group A (serum; 𝜌 = -.47, p = .0006, nasal; 𝜌 = -.38, p = .0294). CONCLUSIONS: Grass pollen SCIT induced functional systemic blocking antibodies that correlate with the concentration of allergen tolerated following NAC, highlighting their potential as a biomarker of SCIT in LAR.

Stratification of Fusobacterium nucleatum by local health status in the oral cavity defines its subspecies disease association.

The ubiquitous inflammophilic oral pathobiont Fusobacterium nucleatum (Fn) is widely recognized for its strong association with inflammatory dysbiotic diseases and cancer. Fn is subdivided into four subspecies, which are historically considered functionally interchangeable in the oral cavity. To test this assumption, we analyzed patient-matched dental plaque and odontogenic abscess clinical specimens and examined whether an inflammatory environment selects for/against particular Fn subspecies. Dental plaque harbored a greater diversity of fusobacteria, with Fn. polymorphum dominating, whereas odontogenic abscesses were exceptionally biased for the largely uncharacterized organism Fn. animalis. Comparative genomic analyses revealed significant genotypic distinctions among Fn subspecies that correlate with their preferred ecological niches and support a taxonomic reassignment of each as a distinct Fusobacterium species. Despite originating as a low-abundance organism in dental plaque, Fn. animalis typically outcompetes other oral fusobacteria within the inflammatory abscess environment, which may explain its prevalence in other oral and extraoral diseases.

Expanding the phenotype of Kleefstra syndrome: speech, language and cognition in 103 individuals.

OBJECTIVES: Speech and language impairments are core features of the neurodevelopmental genetic condition Kleefstra syndrome. Communication has not been systematically examined to guide intervention recommendations. We define the speech, language and cognitive phenotypic spectrum in a large cohort of individuals with Kleefstra syndrome. METHOD: 103 individuals with Kleefstra syndrome (40 males, median age 9.5 years, range 1-43 years) with pathogenic variants (52 9q34.3 deletions, 50 intragenic variants, 1 balanced translocation) were included. Speech, language and non-verbal communication were assessed. Cognitive, health and neurodevelopmental data were obtained. RESULTS: The cognitive spectrum ranged from average intelligence (12/79, 15%) to severe intellectual disability (12/79, 15%). Language ability also ranged from average intelligence (10/90, 11%) to severe intellectual disability (53/90, 59%). Speech disorders occurred in 48/49 (98%) verbal individuals and even occurred alongside average language and cognition. Developmental regression occurred in 11/80 (14%) individuals across motor, language and psychosocial domains. Communication aids, such as sign and speech-generating devices, were crucial for 61/103 (59%) individuals including those who were minimally verbal, had a speech disorder or following regression. CONCLUSIONS: The speech, language and cognitive profile of Kleefstra syndrome is broad, ranging from severe impairment to average ability. Genotype and age do not explain the phenotypic variability. Early access to communication aids may improve communication and quality of life.

Quality of life in caregivers of a child with a developmental and epileptic encephalopathy.

AIM: To explore the relationship between social care-related quality of life (SCrQoL) for caregivers of a child with a developmental and epileptic encephalopathy (DEE; such as SCN2A and Dravet syndrome) and health literacy, illness perceptions, and caregiver activation. METHOD: As part of a larger pre-post pilot study of an information linker service, caregivers completed a baseline questionnaire which included demographics and measures to assess SCrQoL, health literacy, illness perceptions, and caregiver activation. We used Spearman's Rho to determine relationships between variables. RESULTS: Seventy-two caregivers completed the questionnaire. Total SCrQoL varied widely, ranging from an 'ideal state' to 'high needs state'. Caregivers most frequently reported high needs regarding doing activities they enjoy and looking after themselves. Total SCrQoL was correlated with cognitive (r[70] = -0.414, p < 0.000) and emotional representations of illness (r[70] = -0.503, p < 0.000), but not coherence (r = -0.075, p = 0.529). Total SCrQoL was not correlated with health literacy (r[70] = 0.125, p = 0.295) or caregiver activation (r[70] = 0.181, p = 0.127). INTERPRETATION: Future research should explore whether interventions that help caregivers cognitively reframe the negative experiences of having a child with a DEE, and support them to partake in activities they enjoy, boost their SCrQoL. WHAT THIS PAPER ADDS: Caregiver social care-related quality of life (SCrQoL) varied widely, from 'ideal state' to 'high needs state'. Most common high needs were doing enjoyable activities and self-care. Caregivers with higher SCrQoL may perceive their child's illness as less threatening. SCrQoL does not appear to be related to caregiver activation in this sample.

"We are not a typical family anymore": Exploring the experiences and support needs of fathers of children with Fragile X syndrome in Australia.

A diagnosis of the X-linked condition Fragile X syndrome (FXS) in a child commonly reveals the mother's carrier status. Previous research focused on the genetic counseling process for the child and maternal family, despite calls for more research on the support needs of fathers. This study explored experiences and support needs of fathers at least 1 year after their child's FXS diagnosis to understand barriers and enablers and optimize health outcomes for the family. In-depth interviews were conducted with 11 fathers recruited through the Australian Genetics of Learning Disability Service and the Fragile X Association. Deidentified transcripts were analyzed using thematic analysis guided by an inductive approach. Four themes emerged: (1) making life easier through understanding-yesterday and today, (2) the path to a new normal-today and tomorrow, (3) seeking information and support, and (4) what men want. Fathers reported diagnostic odysseys, postdiagnostic grief, and challenges adjusting. They highlighted difficulties in understanding their child's unique behaviors and needs, responding to their partner's psychological support needs, planning for their child's future, and navigating complex health and disability systems. Participants suggested health professionals facilitate father-to-father support and psychological counseling. These findings highlight the unmet needs of fathers and suggest that a strengths-based approach is critically important given the recognized mental health impact.

Mechanisms and Predictive Biomarkers of Allergen Immunotherapy in the Clinic.

Allergen immunotherapy (AIT) remains to be the only disease-modifying treatment for IgE-mediated allergic diseases such as allergic rhinitis. It can provide long-term clinical benefits when given for 3 years or longer. Mechanisms of immune tolerance induction by AIT are underscored by the modulation of several compartments within the immune system. These include repair of disruption in epithelial barrier integrity, modulation of the innate immune compartment that includes regulatory dendritic cells and innate lymphoid cells, and adaptive immune compartments such as induction of regulatory T and B cells. Altogether, these are also associated with the dampening of allergen-specific TH2 and T follicular helper cell responses and subsequent generation of blocking antibodies. Although AIT is effective in modifying the immune response, there is a lack of validated and clinically relevant biomarkers that can be used to monitor desensitization, efficacy, and the likelihood of response, all of which can contribute to accelerating personalized medication and increasing patient care. Candidate biomarkers comprise humoral, cellular, metabolic, and in vivo biomarkers; however, these are primarily studied in small trials and require further validation. In this review, we evaluate the current candidates of biomarkers of AIT and how we can implement changes in future studies to help us identify clinically relevant biomarkers of safety, compliance, and efficacy.

Equitable and accessible informed healthcare consent process for people with intellectual disability: a systematic literature review.

OBJECTIVE: To identify factors acting as barriers or enablers to the process of healthcare consent for people with intellectual disability and to understand how to make this process equitable and accessible. DATA SOURCES: Databases: Embase, MEDLINE, PsychINFO, PubMed, SCOPUS, Web of Science and CINAHL. Additional articles were obtained from an ancestral search and hand-searching three journals. ELIGIBILITY CRITERIA: Peer-reviewed original research about the consent process for healthcare interventions, published after 1990, involving adult participants with intellectual disability. SYNTHESIS OF RESULTS: Inductive thematic analysis was used to identify factors affecting informed consent. The findings were reviewed by co-researchers with intellectual disability to ensure they reflected lived experiences, and an easy read summary was created. RESULTS: Twenty-three studies were included (1999 to 2020), with a mix of qualitative (n=14), quantitative (n=6) and mixed-methods (n=3) studies. Participant numbers ranged from 9 to 604 people (median 21) and included people with intellectual disability, health professionals, carers and support people, and others working with people with intellectual disability. Six themes were identified: (1) health professionals' attitudes and lack of education, (2) inadequate accessible health information, (3) involvement of support people, (4) systemic constraints, (5) person-centred informed consent and (6) effective communication between health professionals and patients. Themes were barriers (themes 1, 2 and 4), enablers (themes 5 and 6) or both (theme 3). CONCLUSIONS: Multiple reasons contribute to poor consent practices for people with intellectual disability in current health systems. Recommendations include addressing health professionals' attitudes and lack of education in informed consent with clinician training, the co-production of accessible information resources and further inclusive research into informed consent for people with intellectual disability. PROSPERO REGISTRATION: CRD42021290548.

The prevalence of Fusobacterium nucleatum subspecies in the oral cavity stratifies by local health status.

The ubiquitous inflammophilic pathobiont Fusobacterium nucleatum is widely recognized for its strong association with a variety of human dysbiotic diseases such as periodontitis and oral/extraoral abscesses, as well as multiple types of cancer. F. nucleatum is currently subdivided into four subspecies: F. nucleatum subspecies nucleatum (Fn. nucleatum), animalis (Fn. animalis), polymorphum (Fn. polymorphum), and vincentii/fusiforme (Fn. vincentii). Although these subspecies have been historically considered as functionally interchangeable in the oral cavity, direct clinical evidence is largely lacking for this assertion. Consequently, we assembled a collection of oral clinical specimens to determine whether F. nucleatum subspecies prevalence in the oral cavity stratifies by local oral health status. Patient-matched clinical specimens of both disease-free dental plaque and odontogenic abscess were analyzed with newly developed culture-dependent and culture-independent approaches using 44 and 60 oral biofilm/tooth abscess paired specimens, respectively. Most oral cavities were found to simultaneously harbor multiple F. nucleatum subspecies, with a greater diversity present within dental plaque compared to abscesses. In dental plaque, Fn. polymorphum is clearly the dominant organism, but this changes dramatically within odontogenic abscesses where Fn. animalis is heavily favored over all other fusobacteria. Surprisingly, the most commonly studied F. nucleatum subspecies, Fn. nucleatum, is only a minor constituent in the oral cavity. To gain further insights into the genetic basis for these phenotypes, we subsequently performed pangenome, phylogenetic, and functional enrichment analyses of oral fusobacterial genomes using the Anvi'o platform, which revealed significant genotypic distinctions among F. nucleatum subspecies. Accordingly, our results strongly support a taxonomic reassignment of each F. nucleatum subspecies into distinct Fusobacterium species. Of these, Fn. animalis should be considered as the most clinically relevant at sites of active inflammation, despite being among the least characterized oral fusobacteria.

International Undiagnosed Diseases Programs (UDPs): components and outcomes.

Over the last 15 years, Undiagnosed Diseases Programs have emerged to address the significant number of individuals with suspected but undiagnosed rare genetic diseases, integrating research and clinical care to optimize diagnostic outcomes. This narrative review summarizes the published literature surrounding Undiagnosed Diseases Programs worldwide, including thirteen studies that evaluate outcomes and two commentary papers. Commonalities in the diagnostic and research process of Undiagnosed Diseases Programs are explored through an appraisal of available literature. This exploration allowed for an assessment of the strengths and limitations of each of the six common steps, namely enrollment, comprehensive clinical phenotyping, research diagnostics, data sharing and matchmaking, results, and follow-up. Current literature highlights the potential utility of Undiagnosed Diseases Programs in research diagnostics. Since participants have often had extensive previous genetic studies, research pipelines allow for diagnostic approaches beyond exome or whole genome sequencing, through reanalysis using research-grade bioinformatics tools and multi-omics technologies. The overall diagnostic yield is presented by study, since different selection criteria at enrollment and reporting processes make comparisons challenging and not particularly informative. Nonetheless, diagnostic yield in an undiagnosed cohort reflects the potential of an Undiagnosed Diseases Program. Further comparisons and exploration of the outcomes of Undiagnosed Diseases Programs worldwide will allow for the development and improvement of the diagnostic and research process and in turn improve the value and utility of an Undiagnosed Diseases Program.

Corrigendum: Zilucoplan, a macrocyclic peptide inhibitor of human complement component 5, uses a dual mode of action to prevent terminal complement pathway activation.

[This corrects the article DOI: 10.3389/fimmu.2023.1213920.].

"Somewhere to turn to with my questions": A pre-post pilot of an information linker service for caregivers who have a child with a Developmental and Epileptic Encephalopathy.

BACKGROUND: Caregivers of a child with a Developmental and Epileptic Encephalopathy (DEE) often report challenges accessing relevant and understandable information regarding their child's condition. We developed GenE Compass, an information linker service where caregivers are invited to submit questions and receive high-quality, personalised reports. We conducted a pilot evaluation to determine the feasibility and acceptability of GenE Compass. METHODS: We invited eligible caregivers to complete a baseline questionnaire (Q1) prior to receiving three months access to submit an unlimited number of questions to GenE Compass. We then invited caregivers to complete a follow-up questionnaire (Q2) and optional interview. Caregivers also had the opportunity to share report-specific feedback at the time of receiving each report. RESULTS: Seventy-two caregivers completed Q1, of which 41 submitted at least one question (range = 1-7). We received a total of 76 questions. The median turnaround time was 12 working days for our information linker (range = 1-28). Thirty-seven caregivers completed Q2, of whom 32 submitted at least one question (87 %). Overall, caregivers were highly satisfied with GenE Compass and their reports, and indicated that they would use it in the future if they had another question. Caregivers' qualitative data from Q1 and interviews highlighted the ongoing need for an information linker service like GenE Compass due to a lack of understandable information and limited resources, and the benefit in reducing burden of constant information searching. CONCLUSION: Our study shows that GenE Compass is feasible with the appropriate allocation of resources and highly acceptable to caregivers who have a child with a DEE.

Fatal Allergic Reaction to Gadolinium Contrast.

Gadolinium-based contrast agents (GBCA) have been used to enhance the sensitivity and specificity of disease diagnoses. They have excellent safety profiles. However, rare adverse events may happen. We present a case of severe fatal allergic reaction to GBCA in a 35-year-old patient.