Mono-allelic KCNB2 variants lead to a neurodevelopmental syndrome caused by altered channel inactivation.

Ion channels mediate voltage fluxes or action potentials that are central to the functioning of excitable cells such as neurons. The KCNB family of voltage-gated potassium channels (Kv) consists of two members (KCNB1 and KCNB2) encoded by KCNB1 and KCNB2, respectively. These channels are major contributors to delayed rectifier potassium currents arising from the neuronal soma which modulate overall excitability of neurons. In this study, we identified several mono-allelic pathogenic missense variants in KCNB2, in individuals with a neurodevelopmental syndrome with epilepsy and autism in some individuals. Recurrent dysmorphisms included a broad forehead, synophrys, and digital anomalies. Additionally, we selected three variants where genetic transmission has not been assessed, from two epilepsy studies, for inclusion in our experiments. We characterized channel properties of these variants by expressing them in oocytes of Xenopus laevis and conducting cut-open oocyte voltage clamp electrophysiology. Our datasets indicate no significant change in absolute conductance and conductance-voltage relationships of most disease variants as compared to wild type (WT), when expressed either alone or co-expressed with WT-KCNB2. However, variants c.1141A>G (p.Thr381Ala) and c.641C>T (p.Thr214Met) show complete abrogation of currents when expressed alone with the former exhibiting a left shift in activation midpoint when expressed alone or with WT-KCNB2. The variants we studied, nevertheless, show collective features of increased inactivation shifted to hyperpolarized potentials. We suggest that the effects of the variants on channel inactivation result in hyper-excitability of neurons, which contributes to disease manifestations.

POU3F3-related disorder: Defining the phenotype and expanding the molecular spectrum.

POU3F3 variants cause developmental delay, behavioral problems, hypotonia and dysmorphic features. We investigated the phenotypic and genetic landscape, and genotype-phenotype correlations in individuals with POU3F3-related disorders. We recruited unpublished individuals with POU3F3 variants through international collaborations and obtained updated clinical data on previously published individuals. Trio exome sequencing or single exome sequencing followed by segregation analysis were performed in the novel cohort. Functional effects of missense variants were investigated with 3D protein modeling. We included 28 individuals (5 previously published) from 26 families carrying POU3F3 variants; 23 de novo and one inherited from an affected parent. Median age at study inclusion was 7.4 years. All had developmental delay mainly affecting speech, behavioral difficulties, psychiatric comorbidities and dysmorphisms. Additional features included gastrointestinal comorbidities, hearing loss, ophthalmological anomalies, epilepsy, sleep disturbances and joint hypermobility. Autism, hearing and eye comorbidities, dysmorphisms were more common in individuals with truncating variants, whereas epilepsy was only associated with missense variants. In silico structural modeling predicted that all (likely) pathogenic variants destabilize the DNA-binding region of POU3F3. Our study refined the phenotypic and genetic landscape of POU3F3-related disorders, it reports the functional properties of the identified pathogenic variants, and delineates some genotype-phenotype correlations.

Insurance denials and diagnostic rates in a pediatric genomic research cohort.

PURPOSE: This study aimed to assess the amount and types of clinical genetic testing denied by insurance and the rate of diagnostic and candidate genetic findings identified through research in patients who faced insurance denials. METHODS: Analysis consisted of review of insurance denials in 801 patients enrolled in a pediatric genomic research repository with either no previous genetic testing or previous negative genetic testing result identified through cross-referencing with insurance prior-authorizations in patient medical records. Patients and denials were also categorized by type of insurance coverage. Diagnostic findings and candidate genetic findings in these groups were determined through review of our internal variant database and patient charts. RESULTS: Of the 801 patients analyzed, 147 had insurance prior-authorization denials on record (18.3%). Exome sequencing and microarray were the most frequently denied genetic tests. Private insurance was significantly more likely to deny testing than public insurance (odds ratio = 2.03 [95% CI = 1.38-2.99] P = .0003). Of the 147 patients with insurance denials, 53.7% had at least 1 diagnostic or candidate finding and 10.9% specifically had a clinically diagnostic finding. Fifty percent of patients with clinically diagnostic results had immediate medical management changes (5.4% of all patients experiencing denials). CONCLUSION: Many patients face a major barrier to genetic testing in the form of lack of insurance coverage. A number of these patients have clinically diagnostic findings with medical management implications that would not have been identified without access to research testing. These findings support re-evaluation of insurance carriers' coverage policies.

Physician Perceptions and Beliefs Regarding End-of-Life Care in a Central California Health System.

Objective: We sought to describe the preparedness, beliefs, and experience regarding end-of-life (EOL) care for in-training and attending physicians. We hoped to clarify how medical training impacts views about EOL, and topics where physicians desire more EOL training. Methods: An online anonymous survey was sent to 766 physicians who worked at Community Medical Centers in Fresno, California from October to December 2016. Descriptive statistics of the population were compiled. Chi-squared and Mann-Whitney U tests comparing differences in personal experience, and preparedness and confidence with palliative care topics by training level were performed. Results: 195 physicians responded to the survey (25%). Respondents were 42% in-training, 55% male, 57% Caucasian, and 38% Christian. Compared to attendings those in-training were younger, more often female, and more likely to have a DO degree. The 2 groups did not differ in ethnicity, specialty, or religion. Attendings were more likely than those in-training (46% vs 14%, P < .001) to have an advance directive, reported a higher level of formal training in discussing prognosis (P = .037), and had higher confidence with palliative care topics like delivering bad news (P = .002), discussing resuscitation status (P = .015), and discussing the new California EOL Option Act (P < .001). Thirty-two percent of respondents believed patients often starve at EOL. Otherwise, knowledge was 90% correct. Conclusions: Physicians in-training are less prepared to discuss EOL topics. Physicians in-training and attendings desire more education in pain management at EOL.

An approach to help differentiate postinfarct scar from borderzone tissue using Ripple Mapping during ventricular tachycardia ablation.

BACKGROUND: Ventricular scar is traditionally highlighted on a bipolar voltage (BiVolt) map in areas of myocardium <0.50 mV. We describe an alternative approach using Ripple Mapping (RM) superimposed onto a BiVolt map to differentiate postinfarct scar from conducting borderzone (BZ) during ventricular tachycardia (VT) ablation. METHODS: Fifteen consecutive patients (left ventricular ejection fraction 30 ± 7%) underwent endocardial left ventricle pentaray mapping (median 5148 points) and ablation targeting areas of late Ripple activation. BiVolt maps were studied offline at initial voltage of 0.50-0.50 mV to binarize the color display (red and purple). RMs were superimposed, and the BiVolt limits were sequentially reduced until only areas devoid of Ripple bars appeared red, defined as RM-scar. The surrounding area supporting conducting Ripple wavefronts in tissue <0.50 mV defined the RM-BZ. RESULTS: RM-scar was significantly smaller than the traditional 0.50 mV cutoff (median 4% vs. 12% shell area, p < .001). 65 ± 16% of tissue <0.50 mV supported Ripple activation within the RM-BZ. The mean BiVolt threshold that differentiated RM-scar from BZ tissue was 0.22 ± 0.07 mV, though this ranged widely (from 0.12 to 0.35 mV). In this study, septal infarcts (7/15) were associated with more rapid VTs (282 vs. 347 ms, p = .001), and had a greater proportion of RM-BZ to RM-scar (median ratio 3.2 vs. 1.2, p = .013) with faster RM-BZ conduction speed (0.72 vs. 0.34 m/s, p = .001). Conversely, scars that supported hemodynamically stable sustained VT (6/15) were slower (367 ± 38 ms), had a smaller proportion of RM-BZ to RM-scar (median ratio 1.2 vs. 3.2, p = .059), and slower RM-BZ conduction speed (0.36 vs. 0.63 m/s, p = .036). RM guided ablation collocated within 66 ± 20% of RM-BZ, most concentrated around the RM-scar perimeter, with significant VT reduction (median 4.0 episodes preablation vs. 0 post, p < .001) at 11 ± 6 months follow-up. CONCLUSION: Postinfarct scars appear significantly smaller than traditional 0.50 mV cut-offs suggest, with voltage thresholds unique to each patient.

Just Seconds of Laughter Reveals Relationship Status: Laughter with Friends Sounds More Authentic and Less Vulnerable than Laughter with Romantic Partners.

The dual pathway model posits that spontaneous and volitional laughter are voiced using distinct production systems, and perceivers rely upon these system-related cues to make accurate judgments about relationship status. Yet, to our knowledge, no empirical work has examined whether raters can differentiate laughter directed at friends and romantic partners and the cues driving this accuracy. In Study 1, raters (N = 50), who listened to 52 segments of laughter, identified conversational partner (friend versus romantic partner) with greater than chance accuracy (M = 0.57) and rated laughs directed at friends to be more pleasant-sounding than laughs directed at romantic partners. Study 2, which involved 58 raters, revealed that prototypical friendship laughter sounded more spontaneous (e.g., natural) and less "vulnerable" (e.g., submissive) than prototypical romantic laughter. Study 3 replicated the findings of the first two studies using a large cross-cultural sample (N = 252). Implications for the importance of laughter as a subtle relational signal of affiliation are discussed.

Latin Dance and Working Memory: The Mediating Effects of Physical Activity Among Middle-Aged and Older Latinos.

Background: Physical activity (PA) is a promising method to improve cognition among middle-aged and older adults. Latinos are at high risk for cognitive decline and engaging in low levels of PA. Culturally relevant PA interventions for middle-aged and older Latinos are critically needed to reduce risk of cognitive decline. We examined changes in cognitive performance among middle-aged and older Latinos participating in the BAILAMOS™ dance program or a health education group and compared the mediating effects of PA between group assignment and change in cognitive domains. Methods: Our 8-month randomized controlled trial tested BAILAMOS™, a 4-month Latin dance program followed by a 4-month maintenance phase. A total of 333 older Latinos aged 55+ were randomized to either BAILAMOS™, or to a health education control group. Neuropsychological tests were administered, scores were converted to z-scores, and specific domains (i.e., executive function, episodic memory, and working memory) were derived. Self-reported PA was assessed, and we reported categories of total PA, total leisure PA, and moderate-to-vigorous PA as minutes/week. A series of ANCOVAs tested changes in cognitive domains at 4 and 8 months. A mediation analysis tested the mediating effects of each PA category between group assignment and a significant change in cognition score. Results: The ANCOVAs found significant improvement in working memory scores among participants in the dance group at month 8 [F (1,328) = 5.79, p = 0.017, d = 0.20], but not in executive functioning [F (2,328) = 0.229, p = 0.80, Cohen's d = 0.07] or episodic memory [F (2,328) = 0.241, p = 0.78, Cohen's d = 0.05]. Follow-up mediation models found that total PA mediated the relationship between group assignment and working memory, in favor of the dance group (ß = 0.027, 95% CI [0.0000, 0.0705]). Similarly, total leisure PA was found to mediate this relationship [ß = 0.035, 95% CI (0.0041, 0.0807)]. Conclusion: A 4-month Latin dance program followed by a 4-month maintenance phase improved working memory among middle-aged and older Latinos. Improvements in working memory were mediated by participation in leisure PA. Our results support the current literature that leisure time PA influences cognition and highlight the importance of culturally relevant PA modalities for Latinos. Clinical Trial Registration: [www.ClinicalTrials.gov], identifier [NCT01988233].

An Exploratory Study of a New Vancomycin Eye Drops Formulation for Extemporaneous Compounding.

Purpose: Compounded eye drop solutions of vancomycin hydrochloride have important clinical applications, such as postoperative antimicrobial prophylaxis and bacterial keratitis. There exists a plethora of data to support the use of various liquid vehicles to compound vancomycin hydrochloride eye drops. However, there are a number of limitations for implementation, especially the frequent shortage or discontinuation of the vehicle products. This study was designed to investigate the use of an OTC eye wash product as the evergreen vehicle and to evaluate the physical and chemical stability of the new formulation. Methods: The Advance Eye Relief® eye wash and vancomycin hydrochloride for injection vials were used to prepare 10 and 50 mg/mL vancomycin eye drop solutions. The solutions were packaged in Steri-Droppers® bottles and stored in a freezer for 14 days followed by 28 days in refrigeration. The 14-day period of freezing was included to allow time for sterility testing. At pre-determined stability time points, samples were taken for visual inspection, pH and osmolality measurement, and analysis by a stability-indicating high performance liquid chromatography (HPLC) method. Results: Freshly prepared vancomycin eye drops were clear, colorless, and free of particulates. The pH readings were 7.03 and 6.28 for the 10 and 50 mg/mL solutions, respectively. The osmolality of both solutions were within the range of 300-330 mOsmol/kg and considered isotonic. Initial drug concentrations of all samples were confirmed by HPLC to be within 100%-103% of the label claims. Throughout the stability study period, there were no significant changes in the appearance, pH, or osmolality of any samples. The HPLC results also confirmed that the drug concentrations in all stability samples were within 98%-101% of the initial time zero values and no significant degradation product peaks were observed. Conclusion: A new compounded vancomycin eye drop formulation was developed to mitigate vehicle sourcing issues. This eye drop formulation was easy to prepare, exhibited satisfactory properties for ophthalmic applications, and remained stable chemically and physically when stored for 14 days in freezer followed by 28 days in refrigerator.

Evaluation and Potential Uses of Site Investigation Soil Contamination Data Submitted to Uk Local Government.

There has been considerable brownfield development in the UK since 2000 due to increasing demand for new housing, combined with local opposition to building on greenbelt land. To facilitate this, extensive site investigations have been carried out and the reports submitted to local government as part of the planning process. This research investigates whether this largely untapped resource of site investigation data can be used to improve understanding of potentially toxic elements (PTE) and persistent organic pollutants (POP) at a local scale. The PTE/POP data were extracted from 1707 soil samples across 120 brownfield sites in an urban/suburban region. The samples were analysed to determine the effect of site location, historical use and site age on PTE/POP concentrations. Box plots indicating statistical results together with GIS maps of PTE/POP sample data provided the optimal visualisation of results. The dataset was shown to be a valuable resource, although further exploitation would be enhanced by digitisation of the submitted data. The paper explores potential applications of this data, including background concentrations and anthropogenic enrichment factors for PTE/POP. The results were summarised in a table for the PTE/POP and a preliminary risk assessment process chart to inform developers/regulators on potential PTE/POP levels on brownfield sites on a local scale. This information could focus design and resources for developers for site investigations and risk assessments and improve planning and regulatory guidance. The lack of predictability in PTE/POP results across sites have emphasised the ongoing need for intrusive site investigation on new brownfield developments.

BAILA: A Randomized Controlled Trial of Latin Dancing to Increase Physical Activity in Spanish-Speaking Older Latinos.

BACKGROUND: Latinos are the fastest growing minority group of the older adult population. Although physical activity (PA) has documented health benefits, older Latinos are less likely to engage in leisure time PA than older non-Latino whites. Dance, popular among Latinos, holds promise as a culturally relevant form of PA. PURPOSE: To describe self-reported and device-assessed changes in PA as a result of a randomized controlled trial of BAILAMOS, a 4-month Latin dance program with a 4-month maintenance program, versus a health education control group. METHODS: Adults, aged 55+, Latino/Hispanic, Spanish speaking, with low PA levels at baseline, and risk for disability were randomized to the dance program (n = 167) or health education condition (n = 166). Data were analyzed using multilevel modeling with full information maximum likelihood. RESULTS: A series of multilevel models revealed significant time × group interaction effects for moderate-to-vigorous physical activity (MVPA), dance PA, leisure PA, and total PA. Exploring the interaction revealed the dance group to significantly increase their MVPA, dance PA, leisure PA, and total PA at months 4 and 8. Household PA and activity counts from accelerometry data did not demonstrate significant interaction effects. CONCLUSIONS: The study supports organized Latin dance programs to be efficacious in promoting self-reported PA among older Latinos. Efforts are needed to make dancing programs available and accessible, and to find ways for older Latinos to add more PA to their daily lives. CLINICAL TRIAL INFORMATION: NCT01988233.

Genomic answers for children: Dynamic analyses of >1000 pediatric rare disease genomes.

PURPOSE: This study aimed to provide comprehensive diagnostic and candidate analyses in a pediatric rare disease cohort through the Genomic Answers for Kids program. METHODS: Extensive analyses of 960 families with suspected genetic disorders included short-read exome sequencing and short-read genome sequencing (srGS); PacBio HiFi long-read genome sequencing (HiFi-GS); variant calling for single nucleotide variants (SNV), structural variant (SV), and repeat variants; and machine-learning variant prioritization. Structured phenotypes, prioritized variants, and pedigrees were stored in PhenoTips database, with data sharing through controlled access the database of Genotypes and Phenotypes. RESULTS: Diagnostic rates ranged from 11% in patients with prior negative genetic testing to 34.5% in naive patients. Incorporating SVs from genome sequencing added up to 13% of new diagnoses in previously unsolved cases. HiFi-GS yielded increased discovery rate with >4-fold more rare coding SVs compared with srGS. Variants and genes of unknown significance remain the most common finding (58% of nondiagnostic cases). CONCLUSION: Computational prioritization is efficient for diagnostic SNVs. Thorough identification of non-SNVs remains challenging and is partly mitigated using HiFi-GS sequencing. Importantly, community research is supported by sharing real-time data to accelerate gene validation and by providing HiFi variant (SNV/SV) resources from >1000 human alleles to facilitate implementation of new sequencing platforms for rare disease diagnoses.

Effects of the WRITE Symptoms Interventions on Symptoms and Quality of Life Among Patients With Recurrent Ovarian Cancers: An NRG Oncology/GOG Study (GOG-0259).

PURPOSE: GOG-259 was a 3-arm randomized controlled trial of two web-based symptom management interventions for patients with recurrent ovarian cancer. Primary aims were to compare the efficacy of the nurse-guided (Nurse-WRITE) and self-directed (SD-WRITE) interventions to Enhanced Usual Care (EUC) in improving symptoms (burden and controllability) and quality of life (QOL). METHODS: Patients with recurrent or persistent ovarian, fallopian, or primary peritoneal cancer with 3+ symptoms were eligible for the study. Participants completed baseline (BL) surveys (symptom burden and controllability and QOL) before random assignment. WRITE interventions lasted 8 weeks to develop symptom management plans for three target symptoms. All women received EUC: monthly online symptom assessment with provider reports; online resources; and every 2-week e-mails. Outcomes were evaluated at 8 and 12 weeks after BL. Repeated-measures modeling with linear contrasts evaluated group by time effects on symptom burden, controllability, and QOL, controlling for key covariates. RESULTS: Participants (N = 497) reported mean age of 59.3 ± 9.2 years. At BL, 84% were receiving chemotherapy and reported a mean of 14.2 ± 4.9 concurrent symptoms, most commonly fatigue, constipation, and peripheral neuropathy. Symptom burden and QOL improved significantly over time (P < .001) for all three groups. A group by time interaction (P < .001) for symptom controllability was noted whereby both WRITE intervention groups had similar improvements from BL to 8 and 12 weeks, whereas EUC did not improve over time. CONCLUSION: Both WRITE Intervention groups showed significantly greater improvements in symptom controllability from BL to 8 and BL to 12 weeks compared with EUC. There were no significant differences between Nurse-WRITE and SD-WRITE. SD-WRITE has potential as a scalable intervention for a future implementation study.

COVID-19 Cases and Deaths in Skilled Nursing Facilities in Cook County, Illinois.

OBJECTIVE: The COVID-19 pandemic has had a devastating impact on older adults residing in skilled nursing facilities. This study examined the pathways through which community and facility factors may have affected COVID-19 cases and deaths in skilled nursing facilities. METHODS: We used structural equation modeling to examine the number of COVID-19 cases and deaths in skilled nursing facilities in Cook County, Illinois, from January 1 through September 30, 2020. We used data from the Centers for Medicare & Medicaid Services, the Illinois Department of Public Health, and the Cook County Medical Examiner's Office to determine the number of resident COVID-19 cases and deaths, number of staff cases, facility-level characteristics, and community-level factors. RESULTS: Poorer facility quality ratings and higher numbers of staff COVID-19 cases were associated with increased numbers of resident COVID-19 cases and deaths. For-profit ownership was associated with larger facilities and higher resident-to-staff ratios, which increased the number of staff COVID-19 cases. Furthermore, skilled nursing facilities with a greater percentage of White residents were in areas with lower levels of social vulnerability and were less likely to be for-profit and, thus, were associated with higher quality. CONCLUSIONS: For-profit ownership was associated with lower facility quality ratings and increases in the number of staff COVID-19 cases, leading to increased resident COVID-19 cases and deaths. Establishing enforceable regulations to ensure quality standards in for-profit skilled nursing facilities is critical to prevent future outbreaks and reduce health disparities in facilities serving racial and ethnic minority populations.

TAB2 variants cause cardiovascular heart disease, connective tissue disorder, and developmental delay.

Congenital heart defects (CHD) are the most commonly occurring birth defect and can occur in isolation or with additional clinical features comprising a genetic syndrome. Autosomal dominant variants in TAB2 are recognized by the American Heart Association as causing nonsyndromic CHD, however, emerging data point to additional, extra-cardiac features associated with TAB2 variants. We identified 15 newly reported individuals with pathogenic TAB2 variants and reviewed an additional 24 subjects with TAB2 variants in the literature. Analysis showed 64% (25/39) of individuals with disease resulting from TAB2 single nucleotide variants (SNV) had syndromic CHD or adult-onset cardiomyopathy with one or more extra-cardiac features. The most commonly co-occurring features with CHD or cardiomyopathy were facial dysmorphism, skeletal and connective tissue defects and most subjects with TAB2 variants present as a connective tissue disorder. Notably, 53% (8/15) of our cohort displayed developmental delay and we suspect this may be a previously unappreciated feature of TAB2 disease. We describe the largest cohort of subjects with TAB2 SNV and show that in addition to heart disease, features across multiple systems are present in most TAB2 cases. In light of our findings, we recommend that TAB2 be included on the list of genes that cause syndromic CHD, adult-onset cardiomyopathy, and connective tissue disorder.

22q11.2 duplications: Expanding the clinical presentation.

22q11.2 duplication syndrome has a frequency of ~1/700 in the intellectual disability population. Despite this frequency, there is limited information on the variable clinical presentation. Although the phenotype and incidence of congenital anomalies are well described for 22q11.2 deletion syndrome, they are not as well understood for individuals with 22q11.2 duplication syndrome. This study is a single-center, retrospective review of patients diagnosed with 22q11.2 duplication syndrome designed to categorize the variable phenotype seen in these individuals. The data suggest that the incidence of congenital anomalies may be higher than previously reported for this syndrome. Affected individuals are at increased risk for a variety of problems including gastrointestinal complications, endocrine dysfunction, ophthalmologic abnormalities, palatal anomalies, congenital heart disease, musculoskeletal differences, and neurologic abnormalities. Individuals with 22q11.2 duplication syndrome would benefit from care coordinated by a multidisciplinary team and managed according to the 22q11.2 deletion syndrome guidelines.

Vocal modulation in human mating and competition.

The human voice is dynamic, and people modulate their voices across different social interactions. This article presents a review of the literature examining natural vocal modulation in social contexts relevant to human mating and intrasexual competition. Altering acoustic parameters during speech, particularly pitch, in response to mating and competitive contexts can influence social perception and indicate certain qualities of the speaker. For instance, a lowered voice pitch is often used to exert dominance, display status and compete with rivals. Changes in voice can also serve as a salient medium for signalling a person's attraction to another, and there is evidence to support the notion that attraction and/or romantic interest can be distinguished through vocal tones alone. Individuals can purposely change their vocal behaviour in attempt to sound more attractive and to facilitate courtship success. Several findings also point to the effectiveness of vocal change as a mechanism for communicating relationship status. As future studies continue to explore vocal modulation in the arena of human mating, we will gain a better understanding of how and why vocal modulation varies across social contexts and its impact on receiver psychology. This article is part of the theme issue 'Voice modulation: from origin and mechanism to social impact (Part I)'.

Patient-Reported Outcomes in a Nationally Representative Sample of Older Internet Users: Cross-sectional Survey.

BACKGROUND: The rapid diffusion of the internet has decreased consumer reliance on health care providers for health information and facilitated the patients' ability to be an agent in control of their own health. However, empirical evidence is limited regarding the effects of health-related internet use among older adults, which is complicated by the proliferation of online health and medical sources of questionable scientific accuracy. OBJECTIVE: We explore the effects of health-related internet use, education, and eHealth literacy on medical encounters and patient-reported outcomes. Patient-reported outcomes are categorized into two dimensions: (1) self-reported health problem and (2) affective distress (feeling worried and anxious) due to information obtained. We were particularly interested in whether education and eHealth literacy moderate the association between perceived strain in medical encounters and patient-reported outcomes. METHODS: Our study sample consisted of online panel members who have used the internet as a resource for health information, randomly drawn from one of the largest probability-based online research panels. This paper specifically reports results obtained from older panel members (age≥60 years: n=194). First, we examined descriptive statistics and bivariate associations (Pearson correlations and independent samples t tests). We used hierarchical ordinary least squares regression analyses by running separate regressions for each patient-reported outcome. In model 1, we entered the main effects. In model 2, technology and medical encounter variables were included. Model 3 added the statistical interaction terms. RESULTS: Age (ß=-.17; P=.02), gender (ß=-.22; P=.01), and medical satisfaction (ß=-.28; P=.01) were significant predictors of self-reported health problems. Affective distress was positively predicted by gender (ß=.13; P=.05) and satisfaction with medical encounters (ß=.34; P<.001) but negatively predicted by education (ß=-.18; P=.03) and eHealth literacy (ß=-.32; P=.01). The association between experiencing a health problem in relation to health-related internet use and perception of strained medical encounters was greater among respondents with lower levels of education (ß=-.55; P=.04). There was also a significant interaction between education and eHealth literacy in predicting the level of affective distress (ß=-.60; P=.05), which indicated that higher levels of education predicted lower averages of feeling anxiety and worry despite lower eHealth literacy. Older women reported higher averages of affective distress (ß=.13; P=.05), while older men reported higher averages of experiencing a self-reported health problem (ß=-.22; P=.01). CONCLUSIONS: This study provides evidence for the effect of health-related internet use on patient-reported outcomes with implications for medical encounters. The results could be used to guide educational and eHealth literacy interventions for older individuals.

Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders.

BACKGROUND: With the increasing number of genomic sequencing studies, hundreds of genes have been implicated in neurodevelopmental disorders (NDDs). The rate of gene discovery far outpaces our understanding of genotype-phenotype correlations, with clinical characterization remaining a bottleneck for understanding NDDs. Most disease-associated Mendelian genes are members of gene families, and we hypothesize that those with related molecular function share clinical presentations. METHODS: We tested our hypothesis by considering gene families that have multiple members with an enrichment of de novo variants among NDDs, as determined by previous meta-analyses. One of these gene families is the heterogeneous nuclear ribonucleoproteins (hnRNPs), which has 33 members, five of which have been recently identified as NDD genes (HNRNPK, HNRNPU, HNRNPH1, HNRNPH2, and HNRNPR) and two of which have significant enrichment in our previous meta-analysis of probands with NDDs (HNRNPU and SYNCRIP). Utilizing protein homology, mutation analyses, gene expression analyses, and phenotypic characterization, we provide evidence for variation in 12 HNRNP genes as candidates for NDDs. Seven are potentially novel while the remaining genes in the family likely do not significantly contribute to NDD risk. RESULTS: We report 119 new NDD cases (64 de novo variants) through sequencing and international collaborations and combined with published clinical case reports. We consider 235 cases with gene-disruptive single-nucleotide variants or indels and 15 cases with small copy number variants. Three hnRNP-encoding genes reach nominal or exome-wide significance for de novo variant enrichment, while nine are candidates for pathogenic mutations. Comparison of HNRNP gene expression shows a pattern consistent with a role in cerebral cortical development with enriched expression among radial glial progenitors. Clinical assessment of probands (n = 188-221) expands the phenotypes associated with HNRNP rare variants, and phenotypes associated with variation in the HNRNP genes distinguishes them as a subgroup of NDDs. CONCLUSIONS: Overall, our novel approach of exploiting gene families in NDDs identifies new HNRNP-related disorders, expands the phenotypes of known HNRNP-related disorders, strongly implicates disruption of the hnRNPs as a whole in NDDs, and supports that NDD subtypes likely have shared molecular pathogenesis. To date, this is the first study to identify novel genetic disorders based on the presence of disorders in related genes. We also perform the first phenotypic analyses focusing on related genes. Finally, we show that radial glial expression of these genes is likely critical during neurodevelopment. This is important for diagnostics, as well as developing strategies to best study these genes for the development of therapeutics.

Association of diet quality and physical function among overweight and obese primarily African American older adults with lower extremity osteoarthritis.

BACKGROUND: Strategies to reduce osteoarthritis (OA) symptoms and increase physical function in persons with lower extremity (LE) OA is a public health priority. OBJECTIVE: To examine associations between diet quality and measures of physical function among overweight and obese older adults with self-reported LE OA. METHODS: 413 overweight and obese primarily African American adults ≥60 years old with LE OA were assessed. Diet quality was quantified using the Healthy Eating Index-2010 (HEI-2010) and Alternative Healthy Eating Index-2010 (AHEI-2010). The six-minute walk, 30-second chair-stands, and timed up-and-go tests were used to assess physical function. Unadjusted and multivariable linear regressions were performed to assess associations between the diet quality and measures of physical function. RESULTS: The mean age of the subjects was 67.8 (SD 5.9) years and mean BMI was 34.8 (SD 5.5) kg/m2. Adjusting for total calories, AHEI-2010 total score was associated with superior performance on the six-minute walk test. However, the association was attenuated when also controlling for age, gender, BMI, waist circumference, self-reported pain, and physical activity. HEI-2010 was not associated with the physical function measures. CONCLUSION: AHEI-2010 total score was positively associated with walking speed among older overweight and obese primarily AA older adults with LE OA. However, the association weakened when adjusting for subject covariates. The relationship between diet quality and physical function among health disparate populations should be further investigated in larger cohorts and using rigorous experimental study design.

Nager syndrome in patient lacking acrofacial dysostosis: Expanding the phenotypic spectrum of SF3B4-related disease.

Nager syndrome epitomizes the acrofacial dysostoses, which are characterized by craniofacial and limb defects. The craniofacial defects include midfacial retrusion, downslanting palpebral fissures, prominent nasal bridge, and micrognathia. Limb malformations typically include hypoplasia or aplasia of radial elements including the thumb. Nager syndrome is caused by haploinsufficiency of SF3B4, encoding a spliceosomal protein called SAP49. Here, we report a patient with a loss of function variant in SF3B4 without acrofacial dysostosis or limb defects, whose reason for referral was developmental and growth delay. This patient is evidence of a broader phenotypic spectrum associated with SF3B4 variants than previously appreciated.