The pathophysiological mechanisms driving disease progression of frontotemporal lobar degeneration (FTLD) and corresponding biomarkers are not fully understood. Here we leveraged aptamer-based proteomics (>4,000 proteins) to identify dysregulated communities of co-expressed cerebrospinal fluid proteins in 116 adults carrying autosomal dominant FTLD mutations (C9orf72, GRN and MAPT) compared with 39 non-carrier controls. Network analysis identified 31 protein co-expression modules. Proteomic signatures of genetic FTLD clinical severity included increased abundance of RNA splicing (particularly in C9orf72 and GRN) and extracellular matrix (particularly in MAPT) modules, as well as decreased abundance of synaptic/neuronal and autophagy modules. The generalizability of genetic FTLD proteomic signatures was tested and confirmed in independent cohorts of (1) sporadic progressive supranuclear palsy-Richardson syndrome and (2) frontotemporal dementia spectrum clinical syndromes. Network-based proteomics hold promise for identifying replicable molecular pathways in adults living with FTLD. 'Hub' proteins driving co-expression of affected modules warrant further attention as candidate biomarkers and therapeutic targets.

The ALLFTD (ARTFL-LEFFTDS Longitudinal Frontotemporal Lobar Degeneration) study is an NIH-funded effort to prepare for clinical trials in sporadic (s-FTLD) and familial (f-FTLD) FTLD syndromes by characterizing cohorts, developing new clinical trial outcome measures, and evaluating disease progression. To understand disease trajectories in the context of potential preventative or disease-modifying therapeutic agents, comprehensive evaluation across multiple time-points is crucial. ALLFTD evaluates participants with FTLD spectrum disorders (bvFTD, svPPA, nfvPPA, FTD-ALS, CBS, PSP), with strong family histories of FTLD, or known FTLD-associated genetic variants within the family. ALLFTD has expanded to include 28 expert sites in North America conducting clinical and neuropsychological evaluations, MR Imaging, blood draws, and CSF collection in willing participants, providing detailed data on participant status and disease progression. Participants are asked to return for annual evaluations. The central data management staff assist sites in retention efforts by providing monthly reports of follow-up visits that are pending, due, or overdue, based on a 15-month period from previous visit. Since enrollment began in January 2020, ALLFTD has conducted 1363 baseline visits, including 339 participants previously enrolled in ALLFTD’s predecessor studies (ARTFL and LEFFTDS). Excluding individuals not anticipated to return due to disease progression (123), participant death (55), or recent enrollment (<15 months; 318), ALLFTD has a retention rate of 83% for a second visit despite early enrollment occurring during COVID restrictions. Retention rates for third and fourth visits are even higher (90% and 97% respectively), suggesting a high degree of engagement in longitudinal participants. Including historic data from ARTFL and LEFFTDS, >1000 participants have multiple visits. Longitudinal assessment of clinical and biomarker profiles in f-FTLD and s-FTLD can inform models of disease onset and progression, allowing analysis of disease trajectories and identification of the most sensitive clinical outcome measures over time. ALLFTD has been successful at recruiting and retaining a large active cohort to obtain detailed clinical and biomarker characterizations; data are available by request.

To assess the interrater reliability of the Multidomain Impairment Rating (MIR) Scale for use in Frontotemporal Lobar Degeneration (FTLD)-related research and clinical trials.

PurposeTo examine graduating medical student reports of burnout by sex, race and ethnicity, and sexual orientation and explore trends within intersectional demographic groups from 2019-2021 in a national sample.MethodThe authors obtained medical student responses to the 2019-2021 Association of American Medical Colleges (AAMC) Graduation Questionnaires (GQs) linked to data from other AAMC sources. The dataset included year of GQ completion, responses to a modified Oldenburg Burnout Inventory (exhaustion subscale range: 0-24; disengagement subscale range: 0-15), and demographics previously shown to relate to the risk of burnout in medical students, residents, or physicians. Multivariable linear regression analysis was performed to evaluate independent associations between demographics and burnout.ResultsOverall response rate was 80.7%. After controlling for other factors, mean exhaustion scores were higher among Asian (parameter estimate [PE] 0.38, 95% confidence interval [CI] 0.21, 0.54), bisexual (PE 0.97, 95% CI 0.76, 1.17), and gay or lesbian (PE 0.55, 95% CI 0.35, 0.75) students than those who did not identify with each of those respective groups. Mean disengagement scores were lower among female (PE -0.47, 95% CI -0.52, -0.42), Hispanic (PE -0.11, 95% CI -0.22, -0.01), and White (PE -0.10, 95% CI -0.19, 0.00) students and higher among Asian (PE 0.17, 95% CI 0.07, 0.27), Black or African American (PE 0.31, 95% CI 0.18, 0.44), bisexual (PE 0.54, 95% CI 0.41, 0.66), and gay or lesbian (PE 0.23, 95% CI 0.11, 0.35) students than those who did not identify with each of those respective groups. From 2019-2021, mean exhaustion and disengagement scores were relatively stable or improved across nearly all intersectional groups.ConclusionsMale, Asian, Black or African American, and sexual minority students had a higher risk of burnout, while female, Hispanic, White, and heterosexual or straight students had a lower risk of burnout.

BACKGROUND AND OBJECTIVES:TMEM106B has been proposed as a modifier of disease risk in FTLD-TDP, particularly in GRN pathogenic variant carriers. Furthermore, TMEM106B has been investigated as a disease modifier in the context of healthy aging and across multiple neurodegenerative diseases. The objective of this study was to evaluate and compare the effect of TMEM106B on gray matter volume and cognition in each of the common genetic FTD groups and in patients with sporadic FTD. METHODS:Participants were enrolled through the ARTFL/LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study, which includes symptomatic and presymptomatic individuals with a pathogenic variant in C9orf72, GRN, MAPT, VCP, TBK1, TARDBP, symptomatic nonpathogenic variant carriers, and noncarrier family controls. All participants were genotyped for the TMEM106B rs1990622 SNP. Cross-sectionally, linear mixed-effects models were fitted to assess an association between TMEM106B and genetic group interaction with each outcome measure (gray matter volume and UDS3-EF for cognition), adjusting for education, age, sex, and CDR+NACC-FTLD sum of boxes. Subsequently, associations between TMEM106B and each outcome measure were investigated within the genetic group. For longitudinal modeling, linear mixed-effects models with time by TMEM106B predictor interactions were fitted. RESULTS:The minor allele of TMEM106B rs1990622, linked to a decreased risk of FTD, associated with greater gray matter volume in GRN pathogenic variant carriers under the recessive dosage model (N = 82, beta = 3.25, 95% CI [0.37-6.19], p = 0.034). This was most pronounced in the thalamus in the left hemisphere (beta = 0.03, 95% CI [0.01-0.06], p = 0.006), with a retained association when considering presymptomatic GRN pathogenic variant carriers only (N = 42, beta = 0.03, 95% CI [0.01-0.05], p = 0.003). The minor allele of TMEM106B rs1990622 also associated with greater cognitive scores among all C9orf72 pathogenic variant carriers (N = 229, beta = 0.36, 95% CI [0.05-0.066], p = 0.021) and in presymptomatic C9orf72 pathogenic variant carriers (N = 106, beta = 0.33, 95% CI [0.03-0.63], p = 0.036), under the recessive dosage model. DISCUSSION:We identified associations of TMEM106B with gray matter volume and cognition in the presence of GRN and C9orf72 pathogenic variants. The association of TMEM106B with outcomes of interest in presymptomatic GRN and C9orf72 pathogenic variant carriers could additionally reflect TMEM106B's effect on divergent pathophysiologic changes before the appearance of clinical symptoms.

BackgroundFrontotemporal lobar degeneration (FTLD) is a leading cause of dementia in individuals aged <65 years. Several challenges to conducting in-person evaluations in FTLD illustrate an urgent need to develop remote, accessible, and low-burden assessment techniques. Studies of unobtrusive monitoring of at-home computer use in older adults with mild cognitive impairment show that declining function is reflected in reduced computer use; however, associations with smartphone use are unknown. ObjectiveThis study aims to characterize daily trajectories in smartphone battery use, a proxy for smartphone use, and examine relationships with clinical indicators of severity in FTLD. MethodsParticipants were 231 adults (mean age 52.5, SD 14.9 years; n=94, 40.7% men; n=223, 96.5% non-Hispanic White) enrolled in the Advancing Research and Treatment of Frontotemporal Lobar Degeneration (ARTFL study) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS study) Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) Mobile App study, including 49 (21.2%) with mild neurobehavioral changes and no functional impairment (ie, prodromal FTLD), 43 (18.6%) with neurobehavioral changes and functional impairment (ie, symptomatic FTLD), and 139 (60.2%) clinically normal adults, of whom 55 (39.6%) harbored heterozygous pathogenic or likely pathogenic variants in an autosomal dominant FTLD gene. Participants completed the Clinical Dementia Rating plus National Alzheimer’s Coordinating Center Frontotemporal Lobar Degeneration Behavior and Language Domains (CDR+NACC FTLD) scale, a neuropsychological battery; the Neuropsychiatric Inventory; and brain magnetic resonance imaging. The ALLFTD Mobile App was installed on participants’ smartphones for remote, passive, and continuous monitoring of smartphone use. Battery percentage was collected every 15 minutes over an average of 28 (SD 4.2; range 14-30) days. To determine whether temporal patterns of battery percentage varied as a function of disease severity, linear mixed effects models examined linear, quadratic, and cubic effects of the time of day and their interactions with each measure of disease severity on battery percentage. Models covaried for age, sex, smartphone type, and estimated smartphone age. ResultsThe CDR+NACC FTLD global score interacted with time on battery percentage such that participants with prodromal or symptomatic FTLD demonstrated less change in battery percentage throughout the day (a proxy for less smartphone use) than clinically normal participants (P<.001 in both cases). Additional models showed that worse performance in all cognitive domains assessed (ie, executive functioning, memory, language, and visuospatial skills), more neuropsychiatric symptoms, and smaller brain volumes also associated with less battery use throughout the day (P<.001 in all cases). ConclusionsThese findings support a proof of concept that passively collected data about smartphone use behaviors associate with clinical impairment in FTLD. This work underscores the need for future studies to develop and validate passive digital markers sensitive to longitudinal clinical decline across neurodegenerative diseases, with potential to enhance real-world monitoring of neurobehavioral change.

Purpose: This study examines sense of belonging (belongingness) in a large population of medical students, residents, and fellows and associations with learner burnout, organizational recruitment retention indicators, and potentially modifiable learning environment factors. Method: All medical students, residents, and fellows at Mayo Clinic sites were surveyed between October and November 2020 with items measuring sense of belonging in 3 contexts (school or program, organization, surrounding community), burnout (2 Maslach Burnout Inventory items), recruitment retention indicators (likelihood of recommending the organization and accepting a job offer), potentially modifiable learning environment factors, and demographics (age, gender, race and ethnicity, LGBTQ+ identification, disability, socioeconomic background). Results: Of 2,257 learners surveyed, 1,261 (56%) responded. The percentage of learners reporting a somewhat or very strong sense of belonging was highest in the school or program (994 of 1,227 [81%]) followed by the organization (957 of 1,222 [78%]) and surrounding community (728 of 1,203 [61%]). In adjusted analyses, learners with very strong organization belongingness had lower odds of burnout (odds ratio [OR], 0.05; 95% CI, 0.02-0.12) and higher odds of being likely to recommend the organization (OR, 505.23; 95% CI, 121.54-2,100.18) and accept a job offer (OR, 38.68; 95% CI, 15.72-95.15; all P < .001). School or program and community belongingness also correlated strongly with these outcomes. In multivariable analyses, social support remained associated with higher odds of belongingness in all 3 contexts; favorable ratings of faculty relationships and leadership representation remained associated with higher odds of belongingness in 2 contexts (school or program and organization); and favorable ratings of diversity, equity, and inclusion learning climate remained associated with belongingness in 1 context (community). Conclusions: Sense of belonging among medical students, residents, and fellows varies across contexts, correlates strongly with burnout and organizational recruitment retention indicators, and is associated with multiple potentially modifiable learning environment factors.

This study explores US medical students' intent to practice in underserved areas, analyzed by demographic characteristics.

This cross-sectional study of US medical students assesses the association of COVID-19 intensity in the clinical learning environment with student burnout and perceptions regarding residency preparedness.

The rural-urban commuting area (RUCA) codes classify communities using measures of population density, urbanization, and daily commuting from U.S. Census Bureau information. The ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study generated RUCA codes for enrolled participants to better understand our cohort demographics. The rural-urban distribution of participants may provide important insights for clinical trial planning. The current RUCA codes are generated from the 2010 decennial census and the 2006-10 American Community Survey data. The codes are numbers (1-10) that describe metropolitan, micropolitan, small town, and rural commuting areas based on the size and direction of the primary (largest) commuting flows. RUCA codes were generated on 784 ALLFTD participants. At their most recent visit, participant median age was 60, 51.1% female, and a median education of 16 years. Participants were classified as clinically normal (39.1%), behavioral variant FTD (25%), nonfluent PPA (6.7%), semantic variant PPA (6.6%), PSP (4.7%), MBCI (4.8%), corticobasal syndrome (5.9%), and the remaining 7% of participants had other dementia-related diagnoses. For participants with sporadic disease, 87.4% live in a metropolitan area, 6.7% a micropolitan area, 3.2% a small-town area, and 3.2% live in a rural area. In familial FTLD, a larger percentage of participants live in micropolitan or small town/rural community (18.8% combined; p = 0.029), driven largely by MAPT family participants (n = 101). 10% of those with a familial MAPT mutation live in a rural area; with an additional 18% in micropolitan (12.9%) or small-town areas (5%). Among those with a familial C9orf72 expansion, 83.3% live in a metropolitan area, 8.9% micropolitan area, 5.6% in a small-town area, and 2.2% in a rural area. Participants with a familial GRN mutation show a similar distribution: 84.7% live in a metropolitan area, 5.6% micropolitan, 6.9% small-town, 2.8% rural. Additional analyses to better understand if FTD families are disproportionately living in rural communities are underway. These analyses will better characterize sporadic and familial FTD demographics to assist with clinical trial design.

The DEMQOL (Dementia Quality of Life) scale is a patient reported questionnaire and proxy form that captures subjective life quality. Participants in ALLFTD and their Study Partners (SP) complete these questionnaires at each study visit. We analyzed the DEMQOL in participants and their SPs when the SP was reported to be a spouse or equivalent. Analyses focused on the final overall quality of life (QoL) rating for the participant (poor, fair, good, or very good). DEMQOL responses from 907 dyads (participant: mean age 58.3±13.4 years, 44% female, and mean education 15.9±2.5 years) were analyzed. Participants rated their overall QoL as very good (45.8%), good (36.5%), fair (14%), and poor (3.5%). SPs rated their participant’s overall QoL as very good (33.6%), good (41%), fair (19.4%), and poor (6%). There was a discordance in ratings between participants and SPs (p<0.0001); in almost 50% of cases, participants rated their QoL better (33.2%) or worse (15.2%) than their SP rated their QoL. When considering disease severity (CDR®+NACC-FTLD global score), participants rated their QoL better than their SP rated their QoL (CDR®+NACC-FTLD = 0: 19.4%, CDR®+NACC-FTLD = 0.5: 42%, and CDR®+NACC-FTLD = 1+: 33.2%), worse than (CDR®+NACC-FTLD = 0: 15.1%, CDR®+NACC-FTLD = 0.5: 13.3%, and CDR®+NACC-FTLD = 1+: 15.2%), or the same (CDR®+NACC-FTLD = 0: 65.6%, CDR®+NACC-FTLD = 0.5: 44.8%, and CDR®+NACC-FTLD = 1+: 51.6%). Among participants and SPs, similarities and differences in QoL ratings are fairly consistent regardless of global CDR®+NACC-FTLD rating. Generally, participants are equally or more optimistic about QoL than their SPs. Longitudinal analyses are forthcoming.

Objective:Therapeutics targeting frontotemporal dementia (FTD) are entering clinical trials. There are challenges to conducting these studies, including the relative rarity of the disease. Remote assessment tools could increase access to clinical research and pave the way for decentralized clinical trials. We developed the ALLFTD Mobile App, a smartphone application that includes assessments of cognition, speech/language, and motor functioning. The objectives were to determine the feasibility and acceptability of collecting remote smartphone data in a multicenter FTD research study and evaluate the reliability and validity of the smartphone cognitive and motor measures.Participants and Methods:A diagnostically mixed sample of 207 participants with FTD or from familial FTD kindreds (CDR®+NACC-FTLD=0 [n=91]; CDR®+NACC-FTLD=0.5 [n=39]; CDR®+NACC-FTLD>1 [n=39]; unknown [n=38]) were asked to remotely complete a battery of tests on their smartphones three times over two weeks. Measures included five executive functioning (EF) tests, an adaptive memory test, and participant experience surveys. A subset completed smartphone tests of balance at home (n=31) and a finger tapping test (FTT) in the clinic (n=11). We analyzed adherence (percentage of available measures that were completed) and user experience. We evaluated Spearman-Brown split-half reliability (100 iterations) using the first available assessment for each participant. We assessed test-retest reliability across all available assessments by estimating intraclass correlation coefficients (ICC). To investigate construct validity, we fit regression models testing the association of the smartphone measures with gold-standard neuropsychological outcomes (UDS3-EF composite [Staffaroni et al., 2021], CVLT3-Brief Form [CVLT3-BF] Immediate Recall, mechanical FTT), measures of disease severity (CDR®+NACC-FTLD Box Score & Progressive Supranuclear Palsy Rating Scale [PSPRS]), and regional gray matter volumes (cognitive tests only).Results:Participants completed 70% of tasks. Most reported that the instructions were understandable (93%), considered the time commitment acceptable (97%), and were willing to complete additional assessments (98%). Split-half reliability was excellent for the executive functioning (r’s=0.93-0.99) and good for the memory test (r=0.78). Test-retest reliabilities ranged from acceptable to excellent for cognitive tasks (ICC: 0.70-0.96) and were excellent for the balance (ICC=0.97) and good for FTT (ICC=0.89). Smartphone EF measures were strongly associated with the UDS3-EF composite (ß's=0.6-0.8, all pConclusions:These results suggest remote digital data collection of cognitive and motor functioning in FTD research is feasible and acceptable. These findings also support the reliability and validity of unsupervised ALLFTD Mobile App cognitive tests and provide preliminary support for the motor measures, although further study in larger samples is required.

The ARTFL-LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) research consortium is actively enrolling participants across 23 North American centers to characterize sporadic and familial frontotemporal dementia (FTD) and prepare for disease-modifying clinical trials. The ability to identify, otherwise unknown, relatives among these participants is critical to rigorously build family structures for downstream clinical and genetic research studies. Genome-wide SNP genotyping data from ALLFTD participants was used to perform lineage analyses using PLINK. Briefly, QC was performed to remove individuals with low call rate and filter autosomal SNPs for missingness, allele frequency, and deviation from Hardy-Weinberg equilibrium, before pruning SNPs for linkage disequilibrium. Identity-by-descent (IBD) estimates were then calculated for determining relatedness, followed by family-network identification and pedigree reconstruction using PRIMUS. About 46% of ALLFTD participants that were genotyped and passed QC (n = 1,453) had reported a family history, while 50% (n = 721) did not and were considered sporadic. We identified a total of 460 participants that had at least one relative who was second degree or closer (PI_HAT>0.1875) based on IBD sharing, resulting in 150 family networks. This included 9 participants who self-identified as sporadic, demonstrating the utility of direct genetic characterization to determine familiality in FTD. Most of the predicted families were associated with disease causing variants in the 3 major FTD-causing genes: 66 families with known C9orf72 repeat expansion carriers, 35 with MAPT (including 11 families with the variant historically known as p.P301L) and 30 with GRN pathogenic variant carriers, as well as 2 families with carriers of both a C9orf72 expansion and a GRN pathogenic variant. We also identified 5 families with carriers of pathogenic variants in other familial dementia genes (2 TARDBP, 2 VCP and 1 PSEN1), as well as 12 families with yet unknown genetic etiology. This dataset sets up a crucial resource to increase statistical accuracy and power in downstream association studies using the clinical, neuropsychological, neuroimaging and biomarker data currently being generated by the ALLFTD consortium. It will also facilitate genetic studies aimed at novel gene discovery, and identification of haplotypes and genetic modifiers associated with the 3 major FTD causal genes.

Solid organ transplant recipients (SOTRs) carry an increased risk of skin cancer development, but limited data exist on the development pattern of cutaneous malignancies in non-White SOTRs. The authors conducted a retrospective chart review of non-White SOTRs at Mayo Clinic who underwent transplantation and subsequently developed skin cancer. This article describes the characteristics and outcomes of non-White patients who developed skin cancer following solid organ transplantation and aims to provide further information that may prove useful in the development of guidelines and interventions to improve patient outcomes. Abstract Objective Solid organ transplant recipients (SOTRs) have an increased risk of skin cancer development, but limited data exist on the development pattern of cutaneous malignancies in non-White SOTRs. The aim of this study was to describe the characteristics and outcomes of non-White patients who developed skin cancer following solid organ transplantation. Methods We conducted a retrospective chart review of non-White SOTRs at the Mayo Clinic who underwent transplantation between November 1987 and April 2020 and subsequently developed skin cancer. Results We identified 32 non-White SOTRs who developed skin cancer in the posttransplant period. Among these, 46.9% were Hispanic/Latinx, 25% were American Indian/Alaskan Native, 21.9% were Asian, and 6.3% were Black/African American. Four patients had a history of nonmelanoma skin cancer pretransplant. In regard to skin cancer type, 21 (65.6%) patients developed squamous cell carcinoma, 15 (46.9%) developed basal cell carcinoma, 5 (15.6%) developed melanoma, and 2 (6.3%) developed sebaceous carcinoma. The median time from transplant to first posttransplant skin cancer was 7.8 years. Conclusions Our study provides further characterization of the development of skin cancer in non-White SOTRs following transplant and identifies a variety of relevant pre- and posttransplant factors. Despite a long follow-up period, the number of patients identified remained low, which is consistent with the literature, indicating a low incidence of skin cancer development in non-White SOTRs. Continued investigation may allow for a more precise identification of risk factors and their degree of significance.

Empathy relies on fronto‐cingular and temporal networks that are selectively vulnerable in behavioral variant frontotemporal dementia (bvFTD). This study modeled when in the disease process empathy changes begin, and how they progress.

The ARTFL-LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study is designed to characterize both sporadic and familial FTLD (f-FTLD) through annual detailed clinical, neuropsychological, biomarker, and neuroimaging assessments to capture disease onset and trajectory in preparation for therapeutic trails in FTLD. Transitions from asymptomatic to mild disease, or from mild to overt, may reveal critical windows for intervention. 169 f-FTLD participants carrying mutations in the main FTLD-associated genes (79 C9orf72; 37 GRN; 53 MAPT) with at least two clinical assessments were included for analysis of phenoconversion from asymptomatic or mild disease. [CDRÒ + NACC FTLD global scores (Miyagawa et al, 2020) were used to define baseline status at first visit: “asymptomatic” = 0 and “mild” = 0.5. Conversion was defined as “partial” (asymptomatic to mild), “definite” (asymptomatic to overt [CDRÒ + NACC FTLD > = 1) and “mild to overt” (0.5 to > = 1). Definite conversion occurred most often in MAPT mutation carriers, with 5/43 asymptomatic carriers transitioning through mild to overt across multiple visits. Definite conversion was also seen in 2/65 C9orf72 expansion carriers and 1/30 GRN mutation carriers. All definite converters were assessed as mild (CDRÒ + NACC FTLD = 0.5) for at least one intermediate visit; definite conversion was observed from 2-4 years from initial assessment. Partial conversions also occurred in all three genetic groups (MAPT: 6; C9orf72: 5; GRN: 5). Further conversion is expected to be observed in these participants in additional follow-up visits. C9orf72 expansion carriers were less likely to progress from a baseline of mild to overt (3/14) than GRN carriers (4/6) or MAPT (7/10). Longitudinal assessment through natural history studies can capture early phenoconversion in carriers of FTLD-associated genetic mutations; corresponding imaging, cognitive, and biomarker profiles captured may provide insights into disease mechanisms and trajectories.

Given the rarity of genetic frontotemporal dementia (FTD), researchers across the world have come together to form the FTD Prevention Initiative (FPI) in an effort to improve prevention trials design. As this initiative begins to bring together large-scale data from worldwide cohort series, including ALLFTD in North America and GENFI in Europe and Canada, it is critical for FPI to quantify the level of relatedness between all participants. Here we provide the most recent update to these ongoing analyses. Genome-wide SNP genotyping data from 1,684 ALLFTD and 568 GENFI participants was used to perform lineage analyses using PLINK. Briefly, QC was performed similarly in all datasets to remove individuals with low call rate and filter autosomal SNPs for missingness, frequency, and deviation from Hardy-Weinberg equilibrium. Genetic ancestry was inferred by projecting genotyped samples into the principal components of the 1000 Genomes reference panel, using R package bigsnpr. Overlapping ALLFTD and GENFI genotyping data was then used, in a two-stage approach, to calculate pairwise identity-by-descent (IBD) estimates and KING coefficients, followed by family-network identification and pedigree reconstruction using PRIMUS. First, we calculated IBD estimates among all participants by restricting pairs to those with estimates>0.1875 (up to second-degree relatives). Overall, we identified a total of 292 second-degree family networks, including 168 ALLFTD and 120 GENFI families, mostly associated with pathogenic variants in the 3 major FTD-causing genes. We also identified 4 family networks with participants enrolled in both the ALLFTD and GENFI series, as well as several multi-site families within the ALLFTD consortium. This first, overall approach allowed us to predict close relationships even between individuals with different ancestral backgrounds, including at least 4 confirmed admixed families. More distant relationships were also detected within ALLFTD and GENFI by performing ancestry-based analysis among participants with estimated European ancestry, using the KING-robust algorithm. These lineage analyses allowed us to identify, otherwise unknown, close (and distant) relatives from different study sites, as well as within the ALLFTD and GENFI series. This dataset will be a crucial resource to increase statistical accuracy and power in upcoming collaborative FPI studies.

The ALLFTD Consortium aims to characterize preclinical and prodromal stage of familial Frontotemporal Lobar Degeneration (f-FTLD) to prepare for clinical trials in FTLD. We prospectively followed 320 asymptomatic participants of the ALLFTD Consortium who are family members of f-FTLD with a mutation in MAPT (n = 106), GRN (n = 74), or C9orf72 (n = 140), and describe the ratings on the eight domains of CDR® plus NACC FTLD (FTLD-CDR) in those who phenoconverted to Mild Behavioral and/or Cognitive Impairment (MBCI). MBCI was diagnosed by the proposed research criteria for MBCI-FTD (Barker MS, et al. Brain 2022). Participants who were diagnosed as MBCI but returned to asymptomatic at the following visit were excluded from the FTLD-CDR assessment. ANOVA was used to compare continuous variables, and chi-square test was used to compare categorical variables across the groups. Thirty-six participants (15 MAPT , 9 GRN , 12 C9orf72 ) developed MBCI during follow-up visits, 13 participants (5 MAPT , 3 GRN , 5 C9orf72 ) were diagnosed as MBCI but were characterized as asymptomatic at the following visit, and 271 participants stayed asymptomatic. Percentage of male in MBCI participants was 50% ( MAPT 60%, GRN 33%, C9orf72 50%, p = 0.45). Age at phenoconversion to MBCI was 53.6±13.0 years old, the youngest in MAPT and the oldest in GRN participants ( MAPT 44.3±8.3, GRN 63.1±11.3, C9orf72 56.4±10.8, p<0.001). Abnormal rating on each of the eight CDR® plus NACC FTLD domains at the initial visit of MBCI phenoconversion were observed in: “Memory” 36% ( MAPT 33%, GRN 33%, C9orf72 44%, p = 0.95); “Orientation” 8% ( MAPT 7%, GRN 8%, C9orf72 11%, p = 0.93); “Judgment/Problem Solving” 44% ( MAPT 47%, GRN 50%, C9orf72 33%, p = 0.73); “Community Affairs” 22% ( MAPT 27%, GRN 17%, C9orf72 22%, p = 0.82); “Home/Hobbies” 25% ( MAPT 40%, GRN 8%, C9orf72 22%, p = 0.16); “Personal Care” 0%; “Behavior/Comportment/Personality” 44% ( MAPT 60%, GRN 42%, C9orf72 22%, p = 0.19); “Language” 31% ( MAPT 13%, GRN 50%, C9orf72 33%, p = 0.12). The three most common FTLD-CDR domains initially disturbed in the prodromal stage of fFTLD were “Behavior/Comportment/Personality”, “Judgment/Problem Solving”, and “Memory”, while “Orientation” was intact in the majority of the individuals. Memory impairment without disorientation was seen in one-third of the prodromal fFTLD participants.

Study Design: Randomized control trial.Introduction: Thumb carpometacarpal (CMC) osteoarthritis (OA) is a common cause of hand pain and disability. Standard conservative therapy (SCT) for thumb CMC OA includes an orthosis and instruction in joint protection, adaptive equipment, and pain relieving modalities. The dynamic stability home exercise (HE) program is complementary conservative therapy designed to strengthen the stabilizing muscles of the thumb CMC.Purpose of the Study: To investigate whether the addition of HE to SCT (SCT + HE) was more effective at reducing pain and disability in thumb CMC OA compared to SCT alone.Methods: The study compared 2 groups: SCT and SCT + HE. The SCT group received SCT with in-home pain management instructions, joint protection strategies with adaptive equipment, and a hand-based thumb-spica orthosis. The SCT + HE group received HE program instructions for adductor stretching and opponens and first dorsal interosseous strengthening in addition to SCT. Our primary outcome measure was the numerical rating scale (NRS) with secondary outcome measures of QuickDASH (shortened Disabilities of the Arm, Shoulder and Hand questionnaire), range of motion, grip strength, and pinch strength. Outcome measurements were assessed at first visit, 6 weeks, and 6 months.Results: There was no statistical difference between the 2 groups for NRS and QuickDASH at 6 weeks ( P = . 28 and P = . 36, respectively) or 6 months ( P = . 52 and P = . 97, respectively). However, there was a statistically significant decrease in NRS and QuickDASH scores at 6 weeks and 6 months within both groups.Conclusions: Both SCT and SCT + HE are effective at reducing pain and disability in OA of the thumb CMC joint. Neither therapy program was superior to the other at improving NRS or QuickDASH scores at 6 -week or 6-month follow-up.(c) 2021 Elsevier Inc. All rights reserved.

Introduction Surgical site infections (SSI) continue to be a risk associated with surgery. The Centers for Disease Control (CDC) uses surgical wound class (SWC) to predict SSI postoperatively. Prior studies have shown that the current wound class definitions are unreliable for surgical subspecialties. Therefore, an alternative surgical wound classification (ASWC) was created to more accurately reflect risk of SSI following orthopedic procedures. The purpose of this study was to compare the two systems. Methods Seventy patients who developed 90-day SSI following total joint arthroplasty (TJA) were matched 1:1 to patients without postoperative SSI. The SWC was recorded from operative reports. Wounds were then retrospectively reclassified according to the ASWC based on preoperative history from the medical record. The degree of agreement and degree of association with occurrence of SSI was compared between the two systems. Results The proportion of agreement between the systems was poor (41.4%). The current SWC was associated with risk of SSI in both unadjusted (p=0.045) and multivariable analysis (p=0.050). Comparatively, the ASWC demonstrated a stronger association with SSI in both unadjusted (p=0.001) and multivariable analysis (p=0.001). Conclusion The results of this study suggest that the ASWC is more predictive for SSI following TJA than the current SWC definitions for total joint arthroplasty.