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The underlying theme throughout this series of studies authored by the Multicenter anterior cruciate ligament (ACL) Revision Study consortium has been to determine the modifiable predictors or risk factors of long-term outcomes of revision ACL reconstruction. The observational studies described and summarized in the manuscript are both clinically relevant and of great interest in finding out the long-term consequences of the intervention and its relationship to the original injury. The successful completion of these studies has important implications for both therapy and future clinical trials. The identification of modifiable risk factors will play an important role in secondary prevention, while the identification of nonmodifiable risk factors will aid us in counseling our patients and making surgical decisions. Thus, we expect a profound clinical impact on patients' care. More importantly, this project represents an important step forward in bringing evidence to bear in clinical decision making in orthopedic surgery.

STUDY OBJECTIVES: Sleep problems are common, serving as both a predictor and symptom of posttraumatic stress disorder (PTSD), with these bidirectional relationships well established in the literature. While both sleep phenotypes and PTSD are moderately heritable, there has been a paucity of investigation into potential genetic overlap between sleep and PTSD. Here, we estimate genetic correlations between multiple sleep phenotypes (including insomnia symptoms, sleep duration, daytime sleepiness, and chronotype) and PTSD, using results from the largest genome-wide association study (GWAS) to date of PTSD, as well as publicly available GWAS results for sleep phenotypes within UK Biobank data (23 variations, encompassing four main phenotypes). METHODS: Genetic correlations were estimated utilizing linkage disequilibrium score regression (LDSC), an approach that uses GWAS summary statistics to compute genetic correlations across traits, and Mendelian randomization (MR) analyses were conducted to follow up on significant correlations. RESULTS: Significant, moderate genetic correlations were found between insomnia symptoms (rg range 0.36-0.49), oversleeping (rg range 0.32-0.44), undersleeping (rg range 0.48-0.49), and PTSD. In contrast, there were mixed results for continuous sleep duration and daytime sleepiness phenotypes, and chronotype was not correlated with PTSD. MR analyses did not provide evidence for casual effects of sleep phenotypes on PTSD. CONCLUSION: Sleep phenotypes, particularly insomnia symptoms and extremes of sleep duration, have shared genetic etiology with PTSD, but causal relationships were not identified. This highlights the importance of further investigation into the overlapping influences on these phenotypes as sample sizes increase and new methods to investigate directionality and causality become available.

During the immediate period following psychiatric hospitalization, adolescents are at increased risk for suicide attempts and rehospitalization. Because most adolescents return to school during this time, school-related experiences are important considerations during the transition from inpatient hospitalization. This study sought to understand how adolescent perceptions of school may change following hospitalization, and how these changes may predict recovery from a suicide-related crisis. Participants included 155 adolescents (M[subscript]age = 15.2 years; 68.6% female, 65.4% White; 14.7% Hispanic/Latinx; grades 7-12) hospitalized for a suicide-related crisis assessed 3 weeks and 6 months following discharge. Results from Latent Change Score models indicated a worsening of perceptions of teacher relationships (mean change ([delta]) = 1.52), connectedness to learning ([delta] = 1.55), parent involvement ([delta] = 1.82), and academic satisfaction ([delta] = 1.34), as well as higher frequency of perceived bullying victimization ([delta] = 0.71) following hospitalization. Poorer perceptions of teacher relationships and higher frequency of perceived bullying victimization during hospitalization ([beta] = 0.31 and 0.34), as well as worsening changes of teacher relationships and increased frequency of perceived bullying victimization following hospitalization ([beta] = 0.48 and 0.41) were associated with higher levels of suicidal ideation severity 3 weeks following discharge. Poorer and worsening perceptions of teacher relationships were associated with higher levels of suicidal ideation intensity at 3 weeks ([beta] = 0.37 and 0.54). Poorer perceptions of connectedness to learning during hospitalization emerged as a significant predictor of higher levels of suicidal ideation intensity 6 months following hospitalization ([beta] = 0.20). Results reinforce the importance of fostering positive adult relationships and preventing bullying both prior to and immediately following psychiatric hospitalization.

Humanitarian research with Syrian refugees can be difficult to conduct in-person, due to COVID-19 containment, security, and logistics issues. We assessed whether the online implementation of a brief, culturally grounded resilience measure would yield reliable responses for use with children and adolescents in the Middle East region. We implemented an online survey screening for socio-economic status, insecurity, prosocial behaviour, and resilience (using the Child Youth Resilience Measure, CYRM) with 119 Syrian refugees (14-18 years old; 74 male, 45 female) living in Jordan. Responses were compared with in-person data, available for a separate cohort of 324 Syrian refugees, previously sampled in Jordan with the same survey instruments. The online CYRM produced reliable and valid responses, as shown by analyses of internal reliability, convergent and divergent validity, and 7-day test-retest consistency. We reflect on logistic, ethical, and methodological challenges of online surveys, and suggest ways to plan and execute online research with hard-to-reach, crisis-affected communities.

The transitional years of early adulthood, with key tasks of identity and intimacy development, engender both opportunities and risks for well-being. We propose that the conceptualization and measurement of early adults' well-being can be improved through (a) an integration of ideas from developmental and psychological science on well-being, (b) the use of short, daily momentary assessments of well-being, and (c) a developmentally-informed examination of the structure of well-being within (and not just across) time. We developed a daily assessment of well-being based on the PERMA model (Seligman, 2011) and used network analysis to gain understanding from this data. Using Ecological Momentary Assessments, we assessed the five PERMA elements in college students' daily life and their network properties. Consistent with the PERMA model, network analysis showed items clustered around theorized elements and formed a unitary network of well-being. Consistent with developmental theory, we found that having positive relationships and positive emotion were most central to early adults' daily well-being.

Childhood maltreatment is highly prevalent and serves as a risk factor for mental and physical disorders. Self-reported childhood maltreatment appears heritable, but the specific genetic influences on this phenotype are largely unknown. The aims of this study were to (1) identify genetic variation associated with self-reported childhood maltreatment, (2) estimate SNP-based heritability (h2snp), (3) assess predictive value of polygenic risk scores (PRS) for childhood maltreatment, and (4) quantify genetic overlap of childhood maltreatment with mental and physical health-related phenotypes, and condition the top hits from our analyses when such overlap is present. Genome-wide association analysis for childhood maltreatment was undertaken, using a discovery sample from the UK Biobank (UKBB) (n = 124,000) and a replication sample from the Psychiatric Genomics Consortium-posttraumatic stress disorder group (PGC-PTSD) (n = 26,290). h2snp for childhood maltreatment and genetic correlations with mental/physical health traits were calculated using linkage disequilibrium score regression. PRS was calculated using PRSice and mtCOJO was used to perform conditional analysis. Two genome-wide significant loci associated with childhood maltreatment (rs142346759, p = 4.35 × 10-8, FOXP1; rs10262462, p = 3.24 × 10-8, FOXP2) were identified in the discovery dataset but were not replicated in PGC-PTSD. h2snp for childhood maltreatment was ~6% and the PRS derived from the UKBB was significantly predictive of childhood maltreatment in PGC-PTSD (r2 = 0.0025; p = 1.8 × 10-15). The most significant genetic correlation of childhood maltreatment was with depressive symptoms (rg = 0.70, p = 4.65 × 10-40), although we show evidence that our top hits may be specific to childhood maltreatment. This is the first large-scale genetic study to identify specific variants associated with self-reported childhood maltreatment. Speculatively, FOXP genes might influence externalizing traits and so be relevant to childhood maltreatment. Alternatively, these variants may be associated with a greater likelihood of reporting maltreatment. A clearer understanding of the genetic relationships of childhood maltreatment, including particular abuse subtypes, with a range of phenotypes, may ultimately be useful in in developing targeted treatment and prevention strategies.

Everyday life presents many experiences that can make people feel connected to another and leave them feeling loved. We conducted two ecological momentary assessment studies (N = 52 and N = 160) to examine people's subjective perceptions of the impact of these experiences by capturing the extent to which they felt loved at several randomly sampled times during their daily life. Individual differences in loving feelings were characterized by baseline levels, within-person variabilities, and slow and fast time scale indicators of change. Results showed that there were considerable individual differences in these characteristics and these individual differences related systematically to both psychological well-being and personality: across two studies, higher felt love baseline levels were related to greater psychological well-being as well as to higher Extraversion personality scores, while people scoring high on Neuroticism showed lower baseline levels.

Genome-wide association studies (GWASs) have focused primarily on populations of European descent, but it is essential that diverse populations become better represented. Increasing diversity among study participants will advance our understanding of genetic architecture in all populations and ensure that genetic research is broadly applicable. To facilitate and promote research in multi-ancestry and admixed cohorts, we outline key methodological considerations and highlight opportunities, challenges, solutions, and areas in need of development. Despite the perception that analyzing genetic data from diverse populations is difficult, it is scientifically and ethically imperative, and there is an expanding analytical toolbox to do it well.

Lissencephaly is a severe brain malformation in which failure of neuronal migration results in agyria or pachygyria and in which the brain surface appears unusually smooth. It is often associated with microcephaly, profound intellectual disability, epilepsy, and impaired motor abilities. Twenty-two genes are associated with lissencephaly, accounting for approximately 80% of disease. Here we report on 12 individuals with a unique form of lissencephaly; these individuals come from eight unrelated families and have bi-allelic mutations in APC2, encoding adenomatous polyposis coli protein 2. Brain imaging studies demonstrate extensive posterior predominant lissencephaly, similar to PAFAH1B1-associated lissencephaly, as well as co-occurrence of subcortical heterotopia posterior to the caudate nuclei, "ribbon-like" heterotopia in the posterior frontal region, and dysplastic in-folding of the mesial occipital cortex. The established role of APC2 in integrating the actin and microtubule cytoskeletons to mediate cellular morphological changes suggests shared function with other lissencephaly-encoded cytoskeletal proteins such as α-N-catenin (CTNNA2) and platelet-activating factor acetylhydrolase 1b regulatory subunit 1 (PAFAH1B1, also known as LIS1). Our findings identify APC2 as a radiographically distinguishable recessive form of lissencephaly.

BackgroundAlcoholism is a multifactorial disorder influenced by multiple gene loci, each with small effect. Studies suggest shared genetic influences across DSM-IV alcohol dependence symptoms, but shared effects across DSM-5 alcohol use disorder remains unknown. We aimed to test the assumption of genetic homogeneity across the 11 criteria of DSM-5 alcohol use disorder (AUD).MethodsData from 2596 alcohol using individuals of European ancestry from the Study of Addiction: Genetics and Environment were used to examine the genomewide SNP-heritability (h2SNP) and SNP-covariance (rGSNP) between 11 DSM-5 AUD symptoms. Phenotypic relationships between symptoms were examined to confirm an underlying liability of AUD and the SNP-heritability of the observed latent trait and the co-heritabilityamong AUD symptoms was assessed using Genomic-Relatedness-Matrix-Restricted-Maximum-Likelihood. Genetic covariance among symptoms was examined using factor analysis.ResultsPhenotypic relationships confirmed a unidimensional underlying liability to AUD. Factor and parallel analyses of the observed genetic variance/covariance provided evidence of genetic homogeneity. Additive genetic effects on DSM-5 AUD symptoms varied from 0.10 to 0.37 and largely overlapped (rG-SNP across symptoms ranged from 0.49 - 0.92). The additive genetic effect on the DSM-5 AUD factor was 0.36, 0.14 for DSM-5 AUD diagnosis, and was 0.22 for DSM-5 AUD severity.ConclusionsCommon genetic variants influence DSM-5 AUD symptoms. Despite evidence for a common AUD factor, the evidence of only partially overlapping genetic effects across AUD symptoms further substantiates the need to simultaneously model common and symptom-specific genetic effects in molecular genetic studies in order to best characterize the genetic liability.

BackgroundRevision anterior cruciate ligament (ACL) reconstruction has been documented to have worse outcomes than primary ACL reconstruction. The reasons remain varied and not completely understood.MethodsPatients undergoing revision ACL reconstruction were prospectively enrolled. Data collected included baseline demographics, surgical technique and pathological condition, prescribed rehabilitation instructions, and a series of validated patient-reported outcome instruments. Patients were followed for 2 years and asked to complete a set of outcome instruments identical to those completed at baseline. Subsequent surgical procedures on the ipsilateral knee were recorded. Regression analysis was used to control for age, sex, activity level, baseline outcome scores, and the above-mentioned rehabilitation-related variables in order to assess the factors affecting clinical outcomes 2 years after revision ACL reconstruction.ResultsA total of 843 patients met the inclusion criteria and were successfully enrolled, and 82% (695) were followed for 2 years. Two rehabilitation-related factors were found to influence outcome. First, patients who were prescribed an ACL brace for their return to sports had a significantly better Knee injury and Osteoarthritis Outcome Score (KOOS) for sports and recreational activities at 2 years (odds ratio [OR] =1.50, 95% confidence interval [CI] = 1.07 to 2.11; p = 0.019). Second, patients prescribed an ACL brace for the postoperative rehabilitation period were 2.3 times more likely to have subsequent surgery by 2 years (OR = 2.26, 95% CI = 1.11 to 4.60; p = 0.024). The odds of a graft rerupture were not affected by any type of brace wear.ConclusionsRehabilitation-related factors that the physician can control at the time of an ACL reconstruction have the ability to influence clinical outcomes at 2 years. Weight-bearing and motion can be initiated immediately postoperatively. Bracing during the early postoperative period is not helpful. Use of a functional brace early in the postoperative period was associated with an increased risk of a reoperation. Use of a functional brace for a return to sports improved the KOOS on the sports/recreation subscale.Level of evidencePrognostic Level I. See Instructions for Authors for a complete description of levels of evidence.

Next-generation sequencing is a powerful tool for the discovery of genes related to neurodevelopmental disorders (NDDs). Here, we report the identification of a distinct syndrome due to de novo or inherited heterozygous mutations in Tousled-like kinase 2 (TLK2) in 38 unrelated individuals and two affected mothers, using whole-exome and whole-genome sequencing technologies, matchmaker databases, and international collaborations. Affected individuals had a consistent phenotype, characterized by mild-borderline neurodevelopmental delay (86%), behavioral disorders (68%), severe gastro-intestinal problems (63%), and facial dysmorphism including blepharophimosis (82%), telecanthus (74%), prominent nasal bridge (68%), broad nasal tip (66%), thin vermilion of the upper lip (62%), and upslanting palpebral fissures (55%). Analysis of cell lines from three affected individuals showed that mutations act through a loss-of-function mechanism in at least two case subjects. Genotype-phenotype analysis and comparison of computationally modeled faces showed that phenotypes of these and other individuals with loss-of-function variants significantly overlapped with phenotypes of individuals with other variant types (missense and C-terminal truncating). This suggests that haploinsufficiency of TLK2 is the most likely underlying disease mechanism, leading to a consistent neurodevelopmental phenotype. This work illustrates the power of international data sharing, by the identification of 40 individuals from 26 different centers in 7 different countries, allowing the identification, clinical delineation, and genotype-phenotype evaluation of a distinct NDD caused by mutations in TLK2.

To examine the association between rehabilitation utilization within 12 months of breast cancer diagnosis and out-of-pocket costs in the second year (12-24mo after diagnosis). Secondary analysis of the 2009-2019 Surveillance, Epidemiology and End Results-Medicare linked database. Individuals who received rehabilitation services were propensity-score matched to individuals who did not receive services. Overall and health care service-specific models were examined using generalized linear models with a gamma distribution. Inpatient and outpatient medical facilities. A total of 35,212 individuals diagnosed with nonmetastatic breast cancer and were continuously enrolled in Medicare Fee-For Service (parts A, B, and D) in the 12 months before and 24 months postdiagnosis. Not applicable. Individual cost responsibility, a proxy for out-of-pocket costs, which was defined as deductibles, coinsurance, and copayments during the second year after diagnosis (12-24mo postdiagnosis). The mean individual cost responsibility was higher in individuals who used rehabilitation than those who did not ($4013 vs $3783), although it was not a clinically meaningful difference (d =0.06). Individuals who received rehabilitative services had significantly higher costs attributed to individual provider care ($1634 vs $1476), institutional outpatient costs ($886 vs $812), and prescription drugs ($959 vs $906), and significantly lower costs attributed to institutional inpatient costs ($455 vs $504), and durable medical equipment ($81 vs $86). Older adults with breast cancer who received rehabilitation services had higher cost responsibility during the second year after diagnosis than those who did not. Future work is needed to examine the relationship between rehabilitation and out-of-pocket costs across longer periods of time and in conjunction with perceived benefit. [ABSTRACT FROM AUTHOR]

Living donor kidney transplant is the ideal treatment option for end-stage renal disease; however, the decision to pursue living donor kidney transplant is complex and challenging. Measurement invariance of living donor kidney transplant Decisional Balance and Self-Efficacy across gender (male/female), race (Black/White), and education level (no college/college or higher) were examined using a sequential approach. Full strict invariance was found for Decisional Balance and Self-Efficacy for gender and partial strict invariance was found for Decisional Balance and Self-Efficacy across race and education level. This information will inform tailored feedback based on these constructs in future intervention studies targeting behavior change among specific demographic subgroups.

The DNA-binding protein PRDM9 directs positioning of the double-strand breaks (DSBs) that initiate meiotic recombination in mice and humans. Prdm9 is the only mammalian speciation gene yet identified and is responsible for sterility phenotypes in male hybrids of certain mouse subspecies. To investigate PRDM9 binding and its role in fertility and meiotic recombination, we humanized the DNA-binding domain of PRDM9 in C57BL/6 mice. This change repositions DSB hotspots and completely restores fertility in male hybrids. Here we show that alteration of one Prdm9 allele impacts the behaviour of DSBs controlled by the other allele at chromosome-wide scales. These effects correlate strongly with the degree to which each PRDM9 variant binds both homologues at the DSB sites it controls. Furthermore, higher genome-wide levels of such 'symmetric' PRDM9 binding associate with increasing fertility measures, and comparisons of individual hotspots suggest binding symmetry plays a downstream role in the recombination process. These findings reveal that subspecies-specific degradation of PRDM9 binding sites by meiotic drive, which steadily increases asymmetric PRDM9 binding, has impacts beyond simply changing hotspot positions, and strongly support a direct involvement in hybrid infertility. Because such meiotic drive occurs across mammals, PRDM9 may play a wider, yet transient, role in the early stages of speciation.

The impacts of war and displacement on executive function (EF)--what we might call the cognitive signatures of "minds under siege"--are little known. We surveyed a gender-balanced sample of 12- to 18-year-old Syrian refugees (n = 240) and Jordanian non-refugees (n = 210) living in Jordan. We examined the relative contributions of poverty, trauma exposure, posttraumatic stress, and insecurity to variance in inhibitory control and working memory. We observed associations between poverty and WM, suggesting that, even in populations exposed to substantial violence and fear, poverty is a specific pathway to WM deficit. We did not, however, find associations between EFs and exposures to trauma. Careful distinction between childhood adversities may illuminate which neurocognitive pathways matter for measures of cognitive function.

BackgroundKnees undergoing revision anterior cruciate ligament reconstruction (rACLR) have a high prevalence of articular cartilage lesions.HypothesisThe prevalence of chondrosis at the time of rACLR is associated with meniscal status and lower extremity alignment.Study designCross-sectional study; Level of evidence, 3.MethodsData from the prospective Multicenter ACL Revision Study (MARS) cohort were reviewed to identify patients with preoperative lower extremity alignment films. Lower extremity alignment was defined by the weightbearing line (WBL) as a percentage of the tibial plateau width, while the chondral and meniscal status of each weightbearing compartment was recorded at the time of surgery. Multivariable proportional odds models were constructed and adjusted for relevant factors to examine which risk factors were independently associated with the degree of medial and lateral compartment chondrosis.ResultsThe cohort included 246 patients with lower extremity alignment films at the time of rACLR. Mean (±SD) patient age was 26.9 ± 9.5 years and body mass index (BMI) was 26.4 ± 4.6. The medial compartment had more chondrosis (grade 2/3, 42%; grade 4, 6.5%) than did the lateral compartment (grade 2/3, 26%; grade 4, 6.5%). Disruption of the meniscus was noted in 35% of patients on the medial side and 16% in the lateral side. The mean WBL was 0.43 ± 0.13. Medial compartment chondrosis was associated with BMI (P = .025), alignment (P = .002), and medial meniscal status (P = .001). None of the knees with the WBL lateral to 0.625 had grade 4 chondrosis in the medial compartment. Lateral compartment chondrosis was significantly associated with age (P = .013) and lateral meniscal status (P < .001). Subjects with "intact" menisci were found to decrease their odds of having chondrosis by 64% to 84%.ConclusionThe status of articular cartilage in the tibiofemoral compartments at the time of rACLR is related to meniscal status. Lower extremity alignment and BMI are associated with medial compartment chondrosis.