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Purpose: Cystine stones, an autosomal recessive disorder caused by cystinuria, result from pathogenic variants of SLC3A1 and SLC7A9. Previous publications revealed that clinical prevalence is higher than genetically predicted prevalence. Heterozygotes in either gene are not stone formers. However, double heterozygotes (DH), individuals with 2 heterozygous pathogenic variants in both genes, were never evaluated and may explain the gap between clinical and genetic prevalence., Methods: Because of the rarity of the condition, direct clinical observation is impractical. We perform this population study as a surrogate by identifying the observed DH, deriving the theoretical/expected DH, and testing the null hypothesis (NH) that the observed DH frequency is equal or greater than expected. This NH biologically correlate to that DH are asymptomatic and do not have cystine stone., Results: Using the 1000 Genome Database, we identified 0 DH. We derived the theoretical/expected DH with Hardy-Weinberg Equilibrium and Mendel's law of independent assortment as 4.94 × 10-s. Population proportion test revealed z = -0.353, and P = .362, the NH cannot be rejected., Conclusion: Statistical testing does not support that DH are symptomatic, ie, DH of SLC3A1 and SLC7A9 may not present with cystine stone, and other factors responsible for the gap that current genetics knowledge cannot explain., Competing Interests: Conflict of Interest Chen-Han Wilfred Wu: Executive Committee of the Harrington Scholar-Innovator Award Program, Clinical Trials with Moderna. Michelle Baum: Clinical Trials with NovoNordisk, scientific advisory with NovoNordisk, ongoing post-marketing study with Alynylam, scientific advisory with Alnylam. Cantero (previously Orfan)-medical advisory; Chinook-medical advisory., (Copyright © 2024 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Members of the leucine rich repeat (LRR) and PDZ domain (LAP) protein family are essential for animal development and histogenesis. Densin-180, encoded by LRRC7, is the only LAP protein selectively expressed in neurons. Densin-180 is a postsynaptic scaffold at glutamatergic synapses, linking cytoskeletal elements with signalling proteins such as the α-subunit of Ca 2+ /calmodulin-dependent protein kinase II. We have previously observed an association between high impact variants in LRRC7 and Intellectual Disability; also three individual cases with variants in LRRC7 had been described. We identify here 33 individuals (one of them previously described) with a dominant neurodevelopmental disorder due to heterozygous missense or loss-of-function variants in LRRC7. The clinical spectrum involves intellectual disability, autism, ADHD, aggression and, in several cases, hyperphagia-associated obesity. A PDZ domain variant interferes with synaptic targeting of Densin-180 in primary cultured neurons. Using in vitro systems (two hybrid, BioID, coimmunoprecipitation of tagged proteins from 293T cells) we identified new candidate interaction partners for the LRR domain, including protein phosphatase 1 (PP1), and observed that variants in the LRR reduced binding to these proteins. We conclude that LRRC7 encodes a major determinant of intellectual development and behaviour., (© 2024. The Author(s).)

Purpose: The ClinGen Actionability Working Group (AWG) developed an evidence-based framework to generate actionability reports and scores of gene-condition pairs in the context of secondary findings from genome sequencing. Here we describe the expansion of the framework to include actionability assertions., Methods: Initial development of the actionability rubric was based on previously scored adult gene-condition pairs and individual expert evaluation. Rubric refinement was iterative and based on evaluation, feedback, and discussion. The final rubric was pragmatically evaluated via integration into actionability assessments for 27 gene-condition pairs., Results: The resulting rubric has a 4-point scale (limited, moderate, strong, and definitive) and uses the highest-scoring outcome-intervention pair of each gene-condition pair to generate a preliminary assertion. During AWG discussions, predefined criteria and factors guide discussion to produce a consensus assertion for a gene-condition pair, which may differ from the preliminary assertion. The AWG has retrospectively generated assertions for all previously scored gene-condition pairs and are prospectively asserting on gene-condition pairs under assessment, having completed over 170 adult and 188 pediatric gene-condition pairs., Conclusion: The AWG expanded its framework to provide actionability assertions to enhance the clinical value of their resources and increase their utility as decision aids regarding return of secondary findings., Competing Interests: Conflict of Interest A. Buchanan has equity in MeTree and You, Inc. S. Rego is an employee and has options at BillionToOne, Inc. Dr Steiner is an employee with equity of PreventionGenetics, part of Exact Sciences, and reports consulting fees from Leadiant, Mirum, and PTC Therapeutics. All other authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Many interventions improve care and outcomes for people with Alzheimer's Disease and related dementias (ADRD), yet are never disseminated. Pragmatic trials facilitate the adoption and dissemination of best practices, but gaps in pragmatic outcome measurement are a critical obstacle. Our objectives are (1) to describe the development and structure of the IMbedded Pragmatic ADRD Clinical Trials Collaboratory (IMPACT) iLibrary of potential outcome measures for ADRD pragmatic trials, and (2) to assess their pragmatic characteristics., Methods: We identified potential outcome measures from several sources: a database of administrative and clinical outcome measures from ADRD clinical trials registered in ClinicalTrials.gov, published reviews, and IMPACT pilot pragmatic trial outcome measures. The iLibrary reports (a) number of items, (b) completion time, (c) readability for diverse populations, (d) cost or copyright barriers to use, (e) method of administration, (f) assessor training burden, and (g) feasibility of data capture and interpretation in routine care; a summary of pragmatic characteristics of each outcome measure (high, moderate, low); items or descriptions of items; and links to primary citations regarding development or psychometric properties., Results: We included 140 outcome measures in the iLibrary: 66 administrative (100% were pragmatic) and 74 clinical (52% were pragmatic). The most commonly addressed outcome domains from administrative assessments included physical function, quality of care or communication concerns, and psychological symptoms or distress behaviors. The most commonly addressed outcome domains from clinical assessments were psychological symptoms or distress behaviors, physical function, cognitive function, and health-related quality of life., Conclusions: Pragmatic outcome measures are brief, meaningful to diverse populations, easily scored and interpreted by clinicians, and available in electronic format for analysis. The iLibrary can facilitate the selection of measures for a wide range of outcomes relevant to people with ADRD and their care partners., (© 2023 The American Geriatrics Society.)

Objective: Determine the relationship between cognitive function and postoperative outcomes., Methods: This IRB-approved retrospective cohort study included all patients treated between August 2015 and March 2020 undergoing major surgery for aerodigestive cancer or cutaneous/thyroid cancer that required free-flap reconstruction at Henry Ford Hospital. Routine administration of the Montreal Cognitive Assessment (MoCA) was completed as part of preoperative psychosocial evaluation. Outcomes included postoperative diagnosis of delirium, discharge disposition, return to the emergency department within 30 days of surgery, and readmission within 30 days of surgery. Univariate and multivariate logistic regression were used to determine the associations between preoperative MoCA score and each outcome measure., Results: One hundred thirty-five patients with HNC were included in the study (mean [SD] age, 60.7 [±10.8] years; 70.4% [n = 95] male; 83.0% [n = 112] White, 16.3% [n = 22] Black). The average preoperative MoCA score was 23.4 (SD ± 4.5). Based on the MoCA score, 35% (n = 47) scored ≥26 (i.e., normal cognitive status), 55.6% (n = 75) scored between 18 and 25 (i.e., mild impairment), 8.1% (n = 11) scored between 10 and 17 (i.e., moderate impairment), and 1.5% (n = 2) scored <10 (i.e., severe impairment). After adjusting for other variables, a lower MoCA score was associated with discharge disposition to a location other than home and prolonged length of hospital stay., Conclusions: Preoperative cognitive function in patients undergoing major head and neck surgery for head and neck cancer was associated with discharge destination and length of stay., Level of Evidence: 3 Laryngoscope, 133:2999-3005, 2023., (© 2023 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: Cystine stone is a Mendelian genetic disease caused by SLC3A1 or SLC7A9. In this study, we aimed to estimate the genetic prevalence of cystine stones and compare it with the clinical prevalence to better understand the disease etiology., Methods: We analyzed genetic variants in the general population using the 1000 Genomes project and the Human Gene Mutation Database to extract all SLC3A1 and SLC7A9 pathogenic variants. All variants procured from both databases were intersected. Pathogenic allele frequency, carrier rate, and affected rate were calculated and estimated based on Hardy-Weinberg equilibrium., Results: We found that 9 unique SLC3A1 pathogenic variants were carried by 26 people and 5 unique SLC7A9 pathogenic variants were carried by 12 people, all of whom were heterozygote carriers. No homozygote, compoun d heterozygote, or double heterozygote was identified in the 1000 Genome database. Based on the Hardy-Weinberg equilibrium, the calculated genetic prevalence of cystine stone disease is 1 in 30,585., Conclusion: The clinical prevalence of cystine stone has been previously reported as 1 in 7,000, a notably higher figure than the genetic prevalence of 1 in 30,585 calculated in this study. This suggests that the etiology of cystine stone is more complex than what our current genetic knowledge can explain. Possible factors that may contribute to this difference include novel causal genes, undiscovered pathogenic variants, alternative inheritance models, founder effects, epigenetic modifications, environmental factors, or other modifying factors. Further investigation is needed to fully understand the etiology of cystine stone., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Alzheimer's disease-related dementias (ADRD) are a leading cause of disability and death. In late-stage ADRD most people prioritize comfort, but care to achieve comfort is rare. Comfort Matters combines palliative and geriatric care practices for nursing home dementia care, but in-person training reaches few sites. To facilitate dissemination, we developed Comfort First, a web-based training toolkit with video demonstration of Comfort Matters practices., Methods: We developed and pilot-tested Comfort First (NIA Intervention Stage 1). Stakeholder advisors representing nursing home residents, caregiver, and clinical perspectives guided development. Professional videographers filmed Comfort Matters staff to illustrate comfort-focused dementia care skills. Video training modules, supported by an implementation manual, address Understanding the Person with Dementia, Promoting Quality of Life and Comfort, Working as a Team, Responding When People with Dementia are Distressed, Addressing Pain, and Making Comfort First a Reality. We then delivered Comfort First to 3 nursing homes. Implementation and outcome evaluation assessed the number and clinically diverse roles of trained staff and post-test knowledge., Results: Nursing home staff roles (n = 146) were diverse: certified nursing assistants (40%), nurses (19%), administrators (11%), activities staff (6%), therapy staff (5%) and other roles. Individual participants' knowledge scores ranged from 50-100%; however average post-test knowledge scores were high, ranging from 90% (Addressing Pain) to 99% (Promoting Quality of Life and Comfort, Making Comfort First a Reality)., Conclusions: The Comfort First web-based training toolkit combines best practices in palliative care and geriatric care for ADRD, using video demonstrations to support broader dissemination of these skills. Initial evaluation demonstrates acceptability and knowledge uptake for staff in diverse clinical roles; future research should include evaluation of practice change. Consistent with the intent of its public funding, Comfort First will be widely disseminated at a minimal cost., (© 2023 The American Geriatrics Society.)