Paid leave to support parenting-A neglected tool to improve societal well-being and prosperity.

Cohesive families and stimulating and caring environments promoting attachment to caregivers is fundamental for a child's physical and psychosocial growth and development. Parental care, supporting early years development, presupposes the presence and involvement of parents in children's daily life with activities that include breastfeeding, playing, reading and storytelling. However, parents have to balance their child's well-being against employment, career progression and gender equality. Universally accessible and equitably available parental leave addresses this challenge. CONCLUSION: Distinct from compulsory maternity leave, leave at full or nearly full pay for both parents benefits not only families but also societal well-being and prosperity.

The Impact of an Electromagnetic Seed Localization Device Versus Wire Localization on Breast-Conserving Surgery: A Matched-Pair Analysis.

BACKGROUND: For breast-conserving surgery (BCS), several alternatives to wire localization (WL) have been developed. The newest, electromagnetic seed localization (ESL), provides three-dimensional navigation using the electrosurgical tool. This study assessed operative times, specimen volumes, margin positivity, and re-excision rates for ESL and WL. METHODS: Patients who had ESL-guided breast-conserving surgery between August 2020 and August 2021 were reviewed and matched one-to-one with patients who had WL based on surgeon, procedure type, and pathology. Variables were compared between ESL and WL using Wilcoxon rank-sum and Fisher's exact tests. RESULTS: The study matched 97 patients who underwent excisional biopsy (n = 20) or partial mastectomy with (n = 53) or without (n = 24) sentinel lymph node biopsy (SLNB) using ESL. The median operative time for ESL versus WL for lumpectomy was 66 versus 69 min with SLNB (p = 0.76) and 40 versus 34.5 min without SLNB (p = 0.17). The median specimen volume was 36 cm3 using ESL versus 55 cm3 using WL (p = 0.001). For the patients with measurable tumor volume, excess tissue was greater using WL versus ESL (median, 73.2 vs. 52.5 cm3; p = 0.017). The margins were positive for 10 (10 %) of the 97 ESL patients and 18 (19 %) of the 97 WL patients (p = 0.17). In the ESL group, 6 (6 %) of the 97 patients had a subsequent re-excision compared with 13 (13 %) of the 97 WL patients (p = 0.15). CONCLUSIONS: Despite similar operative times, ESL is superior to WL, as evidenced by decreased specimen volume and excess tissue excised. Although the difference was not statistically significant, ESL resulted in fewer positive margins and re-excisions than WL. Further studies are needed to confirm that ESL is the most advantageous of the two methods.

The Environmental Data Initiative: Connecting the past to the future through data reuse.

The Environmental Data Initiative (EDI) is a trustworthy, stable data repository, and data management support organization for the environmental scientist. In a bottom-up community process, EDI was built with the premise that freely and easily available data are necessary to advance the understanding of complex environmental processes and change, to improve transparency of research results, and to democratize ecological research. EDI provides tools and support that allow the environmental researcher to easily integrate data publishing into the research workflow. Almost ten years since going into production, we analyze metadata to provide a general description of EDI's collection of data and its data management philosophy and placement in the repository landscape. We discuss how comprehensive metadata and the repository infrastructure lead to highly findable, accessible, interoperable, and reusable (FAIR) data by evaluating compliance with specific community proposed FAIR criteria. Finally, we review measures and patterns of data (re)use, assuring that EDI is fulfilling its stated premise.

Dupilumab Failure in Treating Dermatomyositis-Associated Pruritus.

Dermatomyositis (DM) is a multisystem inflammatory condition with diverse cutaneous and systemic symptoms. Both muscle and skin involvement are common and can occur simultaneously or sequentially, or individuals can have muscle- or skin-limited disease. Skin involvement in DM can be extensive, and pruritus is one of the most problematic symptoms for the patient. Its pathophysiology is poorly understood, making management challenging for clinicians. A limited number of therapeutic agents target pruritus in DM, adding another challenge for clinicians. Previous case reports suggest dupilumab as a treatment for pruritus in DM. However, our patient experienced no relief. Our patient's failure of dupilumab suggests that its targets, interleukin (IL)-4 and IL-13, do not play a significant role in the pruritus of DM. It is possible that targeting other small molecules in inflammatory pathways could greatly alleviate pruritus for individuals with DM. Further studies need to be conducted to extrapolate the mechanism of pruritus in DM so that individuals with DM can find more significant relief.

Population pharmacokinetic study of benzathine penicillin G administration in Indigenous children and young adults with rheumatic heart disease in the Northern Territory, Australia.

BACKGROUND: Benzathine penicillin G (BPG) is the cornerstone of secondary prophylaxis to prevent Streptococcus pyogenes infections, which precede acute rheumatic fever (ARF). The paucity of pharmacokinetic (PK) data from children and adolescents from populations at the highest risk of ARF and rheumatic heart disease (RHD) poses a challenge for determining the optimal dosing and frequency of injections and undermines efforts to develop improved regimens. METHODS: We conducted a 6 month longitudinal PK study of young people receiving BPG for secondary prophylaxis. Throat and skin swabs were collected for microbiological culture along with dried blood spot (DBS) samples for penicillin concentrations. DBSs were assayed using LC-MS/MS. Penicillin concentration datasets were analysed using non-linear mixed-effects modelling and simulations performed using published BMI-for-age and weight-for-age data. RESULTS: Nineteen participants provided 75 throat swabs, 3 skin swabs and 216 penicillin samples. Throat cultures grew group C and G Streptococcus. Despite no participant maintaining penicillin concentration >20 ng/mL between doses, there were no S. pyogenes throat infections and no ARF. The median (range) observed durations >20 ng/mL for the low- and high-BMI groups were 14.5 (11.0-24.25) and 15.0 (7.5-18.25) days, respectively. CONCLUSIONS: Few patients at highest risk of ARF/RHD receiving BPG for secondary prophylaxis maintain penicillin concentrations above the target of 20 ng/mL beyond 2 weeks during each monthly dosing interval. These PK data suggest that some high-risk individuals may get inadequate protection from every 4 week dosing. Future research should explore this gap in knowledge and PK differences between different populations to inform future dosing schedules.

Assessing the landscape of STXBP1-related disorders in 534 individuals.

Disease-causing variants in STXBP1 are among the most common genetic causes of neurodevelopmental disorders. However, the phenotypic spectrum in STXBP1-related disorders is wide and clear correlations between variant type and clinical features have not been observed so far. Here, we harmonized clinical data across 534 individuals with STXBP1-related disorders and analysed 19 973 derived phenotypic terms, including phenotypes of 253 individuals previously unreported in the scientific literature. The overall phenotypic landscape in STXBP1-related disorders is characterized by neurodevelopmental abnormalities in 95% and seizures in 89% of individuals, including focal-onset seizures as the most common seizure type (47%). More than 88% of individuals with STXBP1-related disorders have seizure onset in the first year of life, including neonatal seizure onset in 47%. Individuals with protein-truncating variants and deletions in STXBP1 (n = 261) were almost twice as likely to present with West syndrome and were more phenotypically similar than expected by chance. Five genetic hotspots with recurrent variants were identified in more than 10 individuals, including p.Arg406Cys/His (n = 40), p.Arg292Cys/His/Leu/Pro (n = 30), p.Arg551Cys/Gly/His/Leu (n = 24), p.Pro139Leu (n = 12), and p.Arg190Trp (n = 11). None of the recurrent variants were significantly associated with distinct electroclinical syndromes, single phenotypic features, or showed overall clinical similarity, indicating that the baseline variability in STXBP1-related disorders is too high for discrete phenotypic subgroups to emerge. We then reconstructed the seizure history in 62 individuals with STXBP1-related disorders in detail, retrospectively assigning seizure type and seizure frequency monthly across 4433 time intervals, and retrieved 251 anti-seizure medication prescriptions from the electronic medical records. We demonstrate a dynamic pattern of seizure control and complex interplay with response to specific medications particularly in the first year of life when seizures in STXBP1-related disorders are the most prominent. Adrenocorticotropic hormone and phenobarbital were more likely to initially reduce seizure frequency in infantile spasms and focal seizures compared to other treatment options, while the ketogenic diet was most effective in maintaining seizure freedom. In summary, we demonstrate how the multidimensional spectrum of phenotypic features in STXBP1-related disorders can be assessed using a computational phenotype framework to facilitate the development of future precision-medicine approaches.

Improving the well-being for young people living with rheumatic heart disease: A peer support pilot program through Danila Dilba Health Service.

ISSUE ADDRESSED: Aboriginal and Torres Strait Islander peoples in Australia have an inequitable burden of acute rheumatic fever (ARF) and rheumatic heart disease (RHD), concentrated among young people and necessitating ongoing medical care during adolescence. There is an unmet need for improved well-being and support for these young people to complement current biomedical management. METHODS: This pilot program initiative aimed to determine the suitability and appropriate format of an ongoing peer support program to address the needs of young people living with RHD in urban Darwin. RESULTS: Five participants took part in three sessions. Findings demonstrated the peer-support setting was conducive to offering support and enabled participants to share their experiences of living with RHD with facilitators and each other. Satisfaction rates for each session, including both educational components and support activities, were high. CONCLUSIONS: Learnings from the pilot program can inform the following elements of an ongoing peer-support program: characteristics of co-facilitators and external presenters; program format and session outlines; possible session locations; and resourcing. SO WHAT?: Peer support programs for chronic conditions have demonstrated a wide range of benefits including high levels of satisfaction by participants, improved social and emotional well-being and reductions in patient care time required by health professionals. This pilot program demonstrates the same benefits could result for young people living with RHD.

The impact of focused attention on emotional evaluation: An eye-tracking investigation.

Emotional well-being depends on the ability to successfully engage a variety of coping strategies to regulate affective responses. Most studies have investigated the effectiveness of emotion regulation (ER) strategies that are deployed relatively later in the timing of processing that leads to full emotional experiences (i.e. reappraisal and suppression). Strategies engaged in earlier stages of emotion processing, such as those involved in attentional deployment, have also been investigated, but relatively less is known about their mechanisms. Here, we investigate the effectiveness of self-guided focused attention (FA) in reducing the impact of unpleasant pictures on the experienced negative affect. Participants viewed a series of composite images with distinguishable foreground (FG, either negative or neutral) and background (BG, always neutral) areas and were asked to focus on the FG or BG content. Eye-tracking data were recorded while performing the FA task, along with participants' ratings of their experienced emotional response following the presentation of each image. First, proving the effectiveness of self-guided FA in down-regulating negative affect, focusing away from the emotional content of pictures (BG focus) was associated with lower emotional ratings. Second, trial-based eye-tracking data corroborated these results, showing that spending less time gazing within the negative FG predicted reductions in emotional ratings. Third, this reduction was largest among subjects who habitually use suppression to regulate their emotions. Overall, the present findings expand the evidence regarding the FA's effectiveness in controlling the impact of emotional stimuli and inform the development of training interventions emphasizing attentional control to improve emotional well-being. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Modeling seizures in the Human Phenotype Ontology according to contemporary ILAE concepts makes big phenotypic data tractable.

OBJECTIVE: The clinical features of epilepsy determine how it is defined, which in turn guides management. Therefore, consideration of the fundamental clinical entities that comprise an epilepsy is essential in the study of causes, trajectories, and treatment responses. The Human Phenotype Ontology (HPO) is used widely in clinical and research genetics for concise communication and modeling of clinical features, allowing extracted data to be harmonized using logical inference. We sought to redesign the HPO seizure subontology to improve its consistency with current epileptological concepts, supporting the use of large clinical data sets in high-throughput clinical and research genomics. METHODS: We created a new HPO seizure subontology based on the 2017 International League Against Epilepsy (ILAE) Operational Classification of Seizure Types, and integrated concepts of status epilepticus, febrile, reflex, and neonatal seizures at different levels of detail. We compared the HPO seizure subontology prior to, and following, our revision, according to the information that could be inferred about the seizures of 791 individuals from three independent cohorts: 2 previously published and 150 newly recruited individuals. Each cohort's data were provided in a different format and harmonized using the two versions of the HPO. RESULTS: The new seizure subontology increased the number of descriptive concepts for seizures 5-fold. The number of seizure descriptors that could be annotated to the cohort increased by 40% and the total amount of information about individuals' seizures increased by 38%. The most important qualitative difference was the relationship of focal to bilateral tonic-clonic seizure to generalized-onset and focal-onset seizures. SIGNIFICANCE: We have generated a detailed contemporary conceptual map for harmonization of clinical seizure data, implemented in the official 2020-12-07 HPO release and freely available at hpo.jax.org. This will help to overcome the phenotypic bottleneck in genomics, facilitate reuse of valuable data, and ultimately improve diagnostics and precision treatment of the epilepsies.

Phenotypic homogeneity in childhood epilepsies evolves in gene-specific patterns across 3251 patient-years of clinical data.

While genetic studies of epilepsies can be performed in thousands of individuals, phenotyping remains a manual, non-scalable task. A particular challenge is capturing the evolution of complex phenotypes with age. Here, we present a novel approach, applying phenotypic similarity analysis to a total of 3251 patient-years of longitudinal electronic medical record data from a previously reported cohort of 658 individuals with genetic epilepsies. After mapping clinical data to the Human Phenotype Ontology, we determined the phenotypic similarity of individuals sharing each genetic etiology within each 3-month age interval from birth up to a maximum age of 25 years. 140 of 600 (23%) of all 27 genes and 3-month age intervals with sufficient data for calculation of phenotypic similarity were significantly higher than expect by chance. 11 of 27 genetic etiologies had significant overall phenotypic similarity trajectories. These do not simply reflect strong statistical associations with single phenotypic features but appear to emerge from complex clinical constellations of features that may not be strongly associated individually. As an attempt to reconstruct the cognitive framework of syndrome recognition in clinical practice, longitudinal phenotypic similarity analysis extends the traditional phenotyping approach by utilizing data from electronic medical records at a scale that is far beyond the capabilities of manual phenotyping. Delineation of how the phenotypic homogeneity of genetic epilepsies varies with age could improve the phenotypic classification of these disorders, the accuracy of prognostic counseling, and by providing historical control data, the design and interpretation of precision clinical trials in rare diseases.

Computational analysis of 10,860 phenotypic annotations in individuals with SCN2A-related disorders.

PURPOSE: Pathogenic variants in SCN2A cause a wide range of neurodevelopmental phenotypes. Reports of genotype-phenotype correlations are often anecdotal, and the available phenotypic data have not been systematically analyzed. METHODS: We extracted phenotypic information from primary descriptions of SCN2A-related disorders in the literature between 2001 and 2019, which we coded in Human Phenotype Ontology (HPO) terms. With higher-level phenotype terms inferred by the HPO structure, we assessed the frequencies of clinical features and investigated the association of these features with variant classes and locations within the NaV1.2 protein. RESULTS: We identified 413 unrelated individuals and derived a total of 10,860 HPO terms with 562 unique terms. Protein-truncating variants were associated with autism and behavioral abnormalities. Missense variants were associated with neonatal onset, epileptic spasms, and seizures, regardless of type. Phenotypic similarity was identified in 8/62 recurrent SCN2A variants. Three independent principal components accounted for 33% of the phenotypic variance, allowing for separation of gain-of-function versus loss-of-function variants with good performance. CONCLUSION: Our work shows that translating clinical features into a computable format using a standardized language allows for quantitative phenotype analysis, mapping the phenotypic landscape of SCN2A-related disorders in unprecedented detail and revealing genotype-phenotype correlations along a multidimensional spectrum.

Natriuretic Equation to Predict Loop Diuretic Response in Patients With Heart Failure.

BACKGROUND: Most acute decompensated heart failure admissions are driven by congestion. However, residual congestion is common and often driven by the lack of reliable tools to titrate diuretic therapy. The authors previously developed a natriuretic response prediction equation (NRPE), which predicts sodium output using a spot urine sample collected 2 h after loop diuretic administration. OBJECTIVES: The purpose of this study was to validate the NRPE and describe proof-of-concept that the NRPE can be used to guide diuretic therapy. METHODS: Two cohorts were assembled: 1) the Diagnosing and Targeting Mechanisms of Diuretic Resistance (MDR) cohort was used to validate the NRPE to predict 6-h sodium output after a loop diuretic, which was defined as poor (<50 mmol), suboptimal (<100 mmol), or excellent (>150 mmol); and 2) the Yale Diuretic Pathway (YDP) cohort, which used the NRPE to guide loop diuretic titration via a nurse-driven automated protocol. RESULTS: Evaluating 638 loop diuretic administrations, the NRPE showed excellent discrimination with areas under the curve ≥0.90 to predict poor, suboptimal, and excellent natriuretic response, and outperformed clinically obtained net fluid loss (p < 0.05 for all cutpoints). In the YDP cohort (n = 161) using the NRPE to direct therapy mean daily urine output (1.8 ± 0.9 l vs. 3.0 ± 0.8 l), net fluid output (-1.1 ± 0.9 l vs. -2.1 ± 0.9 l), and weight loss (-0.3 ± 0.3 kg vs. -2.5 ± 0.3 kg) improved substantially following initiation of the YDP (p < 0.001 for all pre-post comparisons). CONCLUSIONS: Natriuretic response can be rapidly and accurately predicted by the NRPE, and this information can be used to guide diuretic therapy during acute decompensated heart failure. Additional study of diuresis guided by the NRPE is warranted.

What Family Circumstances, During COVID-19, Impact on Parental Mental Health in an Inner City Community in London?

The introduction of lockdown due to a public health emergency in March 2020 marked the beginning of substantial changes to daily life for all families with young children. Here we report the experience of families from London Borough of Tower Hamlets with high rates of poverty and ethnic and linguistic diversity. This inner city community, like communities worldwide, has experienced a reduction or closure in access to education, support services, and in some cases, a change in or loss of income, job, and food security. Using quantitative survey items (N = 992), we examined what differences in family circumstances, for mothers and fathers of young children aged 0-5 living in Tower Hamlets, during March 2020 to November 2020, were associated with their mental health status. We measure parental mental health using symptoms of depression (self-report: Patient Health Questionnaire depression scale: PHQ-8), symptoms of anxiety levels (self-report: General Anxiety Disorder: GAD-7), and perceptions of direct loneliness. We find parental mental health difficulties are associated with low material assets (financial security, food security, and children having access to outside space), familial assets (parents time for themselves and parent status: lone vs. cohabiting), and community assets (receiving support from friends and family outside the household). South Asian parents and fathers across ethnicities were significantly more likely to experience mental health difficulties, once all other predictors were accounted for. These contributing factors should be considered for future pandemics, where restrictions on people's lives are put in place, and speak to the importance of reducing financial insecurity and food insecurity as a means of improving the mental health of parents.

Correction: A longitudinal footprint of genetic epilepsies using automated electronic medical record interpretation.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

A longitudinal footprint of genetic epilepsies using automated electronic medical record interpretation.

PURPOSE: Childhood epilepsies have a strong genetic contribution, but the disease trajectory for many genetic etiologies remains unknown. Electronic medical record (EMR) data potentially allow for the analysis of longitudinal clinical information but this has not yet been explored. METHODS: We analyzed provider-entered neurological diagnoses made at 62,104 patient encounters from 658 individuals with known or presumed genetic epilepsies. To harmonize clinical terminology, we mapped clinical descriptors to Human Phenotype Ontology (HPO) terms and inferred higher-level phenotypic concepts. We then binned the resulting 286,085 HPO terms to 100 3-month time intervals and assessed gene-phenotype associations at each interval. RESULTS: We analyzed a median follow-up of 6.9 years per patient and a cumulative 3251 patient years. Correcting for multiple testing, we identified significant associations between "Status epilepticus" with SCN1A at 1.0 years, "Severe intellectual disability" with PURA at 9.75 years, and "Infantile spasms" and "Epileptic spasms" with STXBP1 at 0.5 years. The identified associations reflect known clinical features of these conditions, and manual chart review excluded provider bias. CONCLUSION: Some aspects of the longitudinal disease histories can be reconstructed through EMR data and reveal significant gene-phenotype associations, even within closely related conditions. Gene-specific EMR footprints may enable outcome studies and clinical decision support.

Potentially Problematic Opioid Prescriptions Among Individuals With Private Insurance and Medicaid.

OBJECTIVE: Opioid analgesics can be safe and effective when used properly. Reducing prescriptions that increase adverse outcomes is a focus for addressing the opioid crisis. In this study, the rate of potentially problematic opioid prescriptions was examined over 11 years in a large sample of U.S. patients. METHODS: Claims from the IBM MarketScan commercial database (about 45 million) and multistate Medicaid database (about 7 million) from 2005 to 2015 were used to calculate rates of the following potentially problematic prescription practices: prescriptions for high-dose opioids for 90 days or more, prescriptions from multiple providers, prescriptions of long-acting or extended-release opioids for acute pain, overlap between prescriptions for opioids, and overlap between prescriptions for opioids and benzodiazepines. RESULTS: Among patients with an opioid prescription, about 8% of those with private insurance and about 14% of those with Medicaid coverage had at least two incidents of potentially problematic prescriptions per year. Over the study period, rates increased for some practices (opioid-benzodiazepine overlap) and decreased for others (prescriptions from multiple providers). Receipt of potentially problematic prescriptions was higher among older patients, female patients with private insurance, and whites and male patients covered by Medicaid. CONCLUSIONS: A significant percentage of patients who are prescribed opioids experience problematic prescription practices. Targeted policy and clinical interventions that reduce potentially problematic prescription could be a focus for addressing the U.S. opioid crisis.

Subtle modifications to oxytocin produce ligands that retain potency and improved selectivity across species.

Oxytocin and vasopressin mediate various physiological functions that are important for osmoregulation, reproduction, cardiovascular function, social behavior, memory, and learning through four G protein-coupled receptors that are also implicated in high-profile disorders. Targeting these receptors is challenging because of the difficulty in obtaining ligands that retain selectivity across rodents and humans for translational studies. We identified a selective and more stable oxytocin receptor (OTR) agonist by subtly modifying the pharmacophore framework of human oxytocin and vasopressin. [Se-Se]-oxytocin-OH displayed similar potency to oxytocin but improved selectivity for OTR, an effect that was retained in mice. Centrally infused [Se-Se]-oxytocin-OH potently reversed social fear in mice, confirming that this action was mediated by OTR and not by V1a or V1b vasopressin receptors. In addition, [Se-Se]-oxytocin-OH produced a more regular contraction pattern than did oxytocin in a preclinical labor induction and augmentation model using myometrial strips from cesarean sections. [Se-Se]-oxytocin-OH had no activity in human cardiomyocytes, indicating a potentially improved safety profile and therapeutic window compared to those of clinically used oxytocin. In conclusion, [Se-Se]-oxytocin-OH is a novel probe for validating OTR as a therapeutic target in various biological systems and is a promising new lead for therapeutic development. Our medicinal chemistry approach may also be applicable to other peptidergic signaling systems with similar selectivity issues.

Clustering of Neuropsychiatric Disease in First-Degree and Second-Degree Relatives of Patients With Amyotrophic Lateral Sclerosis.

Importance: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative condition primarily involving the motor system. There is increasing epidemiologic evidence of an association between ALS and a wider spectrum of neurodegenerative and neuropsychiatric disorders among family members, including schizophrenia and psychotic illness and suicidal behavior. Objective: To examine the frequency and range of neuropsychiatric conditions that occur within individual first-degree and second-degree relatives of patients with ALS. Design, Setting, and Participants: In this population-based, case-control family aggregation study, all 202 patients included in the Irish ALS Register between January 1, 2012, and January 31, 2014, with definite, probable, or possible ALS as defined by El Escorial criteria were invited to participate. A total of 75 patients were unable or refused to participate and were excluded; the remaining 127 patients with incident ALS were genotyped for the C9orf72 repeat expansion and 132 age- and sex-matched controls were included in the study. Main Outcome and Measures: The prevalence of defined neuropsychiatric disease in first-degree and second-degree relatives of patients with ALS and matched controls was determined. Results: Mean (SD) age at diagnosis of the 127 patients in the study (58 women and 69 men) was 64.2 (10.7) years. Data from 2116 relatives of patients with ALS were reported, including 924 first-degree relatives, 1128 second-degree relatives, and 64 third-degree relatives. Data from controls were reported from 829 first-degree and 1310 second-degree relatives. A total of 77 patients with ALS (61.4%) and 51 control participants (38.6%) reported at least 1 first-degree or second-degree relative with a history of schizophrenia, psychosis, suicide, depression, alcoholism, or autism (relative risk [RR], 1.50; 95% CI, 1.08-2.17; P = .02). Cluster analysis suggested the following 2 subgroups based on the number of family members with a neuropsychiatric condition: expected (0-2) and high (≥3). Within the high subgroup, ALS kindreds presented a significantly higher rate of psychiatric illness than did controls (28 of 39 [71.8%]; mean [SD] number of siblings, 4.29 [1.41]; P = .001). A strong family history of schizophrenia (RR, 3.40; 95% CI, 1.27-9.30; P = .02), suicide (RR, 3.30; 95% CI, 1.07-10.05; P = .04), autism (RR, 10.10; 95% CI, 1.30-78.80; P = .03), and alcoholism (RR, 1.48; 95% CI, 1.01-2.17; P = .045) was reported in ALS kindreds. A total of 5 of 29 probands (17.2%) with a strong family history of neuropsychiatric conditions (≥3 first-degree or second-degree relatives) carried the C9orf72 repeat expansion. Conclusions and Relevance: Neuropsychiatric symptoms in addition to schizophrenia, including obsessive-compulsive disorder, autism, and alcoholism, occur more frequently in ALS kindreds than in controls. The presence of the C9orf72 repeat expansion does not fully account for this finding, suggesting the presence of additional pleiotropic genes associated with both ALS and neuropsychiatric disease in the Irish population.