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Measuring pelvic tilt and pelvic obliquity during functional positions is important for surgical planning of total hip arthroplasty as these orientations affect optimal acetabular cup position and post-operative hip stability. The objective of this study was to compare pelvic tilt, pelvic obliquity, and pelvic mobility across 3 cohorts of age-matched patients: 1) healthy controls 2) THA patients without spinal fusion and 3) patients with instrumented spinal fusions. We hypothesized that (1) the healthy and THA cohorts would demonstrate similar pelvic mobility across the range of position demand and (2) individuals with spinal fusions would have significantly less pelvic mobility than both the healthy and THA cohorts. We compared 10 patients in each of these cohorts using stereo radiography to quantify pelvic tilt and pelvic obliquity across a range of clinically relevant poses of varying demand on pelvic mobility. Results demonstrated that the overall pelvic mobility of the spinal fusion cohort was consistently similar in magnitude to health controls but biased anteriorly by 6.5% and 33.5% compared to the healthy and total hip cohorts, primarily due to less posterior tilting across the functional positions (Healthy: 39.6° ± 10.2°; Spinal fusion: 39.5° ± 7.3°; Total hip: 37.8° ± 7.6°). Obliquity angles varied substantially between some clinically relevant pose combinations. Low and high coronal plane mobility patients were identified in each of the three cohorts, with mobility ranging between 4.4° and 28.3°, respectively, across positions. Substantial intragroup variability was exhibited within each cohort across the six functional poses, highlighting the patient-specific nature of the spinopelvic relationship regardless of previous surgery at the hip or spine. The larger pelvic tilt angles demonstrated during more demanding poses in seated and standing highlights the importance of imaging patients in poses that capture the full extent of pelvic mobility.

The cytokines IL-1α and IL-1β exert powerful pro-inflammatory actions throughout the body, mediated primarily by the intracellular signaling capacity of the interleukin-1 receptor (IL-1R1). Although Il1r1 knockout mice have been informative with respect to a requirement for IL-1R1 signaling in inflammatory events, the constitutive nature of gene elimination has limited their utility in the assessment of temporal and spatial patterns of cytokine action. To pursue such questions, we have generated C57Bl/6J mice containing a floxed Il1r1 gene (Il1r1loxP/loxP), with loxP sites positioned to flank exons 3 and 4 and thereby the ability to spatially and temporally eliminate Il1r1 expression and signaling. We found that Il1r1loxP/loxP mice breed normally and exhibit no gross physical or behavioral phenotypes. Moreover, Il1r1loxP/loxP mice exhibit normal IL-1R1 receptor expression in brain and spleen, as well as normal IL-1R1-dependent increases in serum IL-6 following IL-1α injections. Breeding of Il1r1loxP/loxP mice to animals expressing a cytomegalovirus (CMV)-driven Cre recombinase afforded efficient excision at the Il1r1 locus. The Il1r1loxP/loxP line should be a valuable tool for the assessment of contributions made by IL-1R1 signaling in diverse cell types across development.

Sex-related differences in psychopathology are known phenomena, with externalizing and internalizing symptoms typically more common in boys and girls, respectively. However, the neural correlates of these sex-by-psychopathology interactions are underinvestigated, particularly in adolescence. Participants were 14 years of age and part of the IMAGEN study, a large ( = 1526) community-based sample. To test for sex-by-psychopathology interactions in structural grey matter volume (GMV), we used whole-brain, voxel-wise neuroimaging analyses based on robust non-parametric methods. Psychopathological symptom data were derived from the Strengths and Difficulties Questionnaire (SDQ). We found a sex-by-hyperactivity/inattention interaction in four brain clusters: right temporoparietal-opercular region ( < 0.01, Cohen's = -0.24), bilateral anterior and mid-cingulum ( < 0.05, Cohen's = -0.18), right cerebellum and fusiform ( < 0.05, Cohen's = -0.20) and left frontal superior and middle gyri ( < 0.05, Cohen's = -0.26). Higher symptoms of hyperactivity/inattention were associated with lower GMV in all four brain clusters in boys, and with higher GMV in the temporoparietal-opercular and cerebellar-fusiform clusters in girls. Using a large, sex-balanced and community-based sample, our study lends support to the idea that externalizing symptoms of hyperactivity/inattention may be associated with different neural structures in male and female adolescents. The brain regions we report have been associated with a myriad of important cognitive functions, in particular, attention, cognitive and motor control, and timing, that are potentially relevant to understand the behavioural manifestations of hyperactive and inattentive symptoms. This study highlights the importance of considering sex in our efforts to uncover mechanisms underlying psychopathology during adolescence.

Nemaline myopathy (NM) is a genetic muscle disorder characterized by muscle dysfunction and electron-dense protein accumulations (nemaline bodies) in myofibers. Pathogenic mutations have been described in 9 genes to date, but the genetic basis remains unknown in many cases. Here, using an approach that combined whole-exome sequencing (WES) and Sanger sequencing, we identified homozygous or compound heterozygous variants in LMOD3 in 21 patients from 14 families with severe, usually lethal, NM. LMOD3 encodes leiomodin-3 (LMOD3), a 65-kDa protein expressed in skeletal and cardiac muscle. LMOD3 was expressed from early stages of muscle differentiation; localized to actin thin filaments, with enrichment near the pointed ends; and had strong actin filament-nucleating activity. Loss of LMOD3 in patient muscle resulted in shortening and disorganization of thin filaments. Knockdown of lmod3 in zebrafish replicated NM-associated functional and pathological phenotypes. Together, these findings indicate that mutations in the gene encoding LMOD3 underlie congenital myopathy and demonstrate that LMOD3 is essential for the organization of sarcomeric thin filaments in skeletal muscle.

Research on the integrated collaborative care team (ICCT) model, a version of an integrated youth service, with youths and families is needed to evaluate its effectiveness in improving mental health functioning compared with hospital outpatient treatment as usual (TAU). To test the benefits of the ICCT in improving youth functioning compared with TAU, to assess youths' general psychopathology symptoms and substance use problems, and to quantify health service access, use, and satisfaction. This 2-group pragmatic randomized clinical trial enrolled youths (14-17 years) and caregivers in Canada from September 2016 to March 2020. Participants were randomized to either 1 of 5 outpatient mental health hospital programs or 1 of 3 community ICCTs. Data analyses began on July 12, 2021, and concluded on November 12, 2023. Youths were offered services in the ICCT or TAU groups. Outcomes were assessed at baseline, 6 months, and 12 months. The primary outcome was change in youth-reported mental health functioning as measured with the Columbia Impairment Scale (CIS). Secondary outcomes included the following: (1) caregiver-reported functioning and youth- and caregiver-reported general psychopathology and substance use, (2) mental health service satisfaction, and (3) health service access and use. Linear mixed-effects and generalized estimating equation models were used to compare outcomes in intention-to-treat analyses. This study included 247 youths; 124 were randomized to the ICCT and 123 were randomized to TAU. There were no baseline differences between groups; youths had a mean (SD) age of 15.7 (1.1) years. A total of 85 (34.4%) youths identified as boys or men, 157 (63.6%) identified as girls or women, and 5 (2.0%) identified as transgender, reported diverse gender identities, or were missing these data. CIS scores improved over the 12 months for both the ICCT group (Cohen d = -3.59 [95% CI, -4.99 to -2.20]; P < .001) and the TAU group (Cohen d = -2.59 [95% CI, -4.01 to -1.18]; P < .001). Significant differences in changes between groups were not observed (unadjusted CIS model, partial η2 = 0.002; P = .59). Both groups had mean scores suggesting satisfaction with services. The ICCT group accessed services sooner (median, 9 days; IQR, 5-16 days) compared with the TAU group (median, 27 days; IQR, 14-57 days) (Cohen d = 0.54 [95% CI, 0.27-0.81]; P < .001, t test). Fewer youths in the ICCT group saw a psychiatrist compared with youths in the TAU group (22 [17.5%] vs 104 [82.5%]; P < .001, χ2 test; φ = -0.67). Although no clinical differences between groups were observed in this trial, youths receiving ICCT care improved in multiple metrics, accessed services sooner, and used fewer psychiatric resources than those in TAU programs. Future research should focus on how ICCT models can integrate and collaborate with hospital outpatient services. ClinicalTrials.gov Identifier: NCT02836080.

Eating disorders are serious mental disorders with increasing prevalence. Without early identification and treatment, eating disorders may run a long-term course. To characterize any associations among disordered eating behaviors (DEBs) and other mental health disorders and to identify early associations with the development of symptoms over time. This multicenter, population-based, longitudinal cohort study used data from baseline (collected in 2010), follow-up 1 (collected in 2012), and follow-up 2 (collected in 2015) of the IMAGEN Study, which included adolescents recruited from 8 European sites. The present study assessed data from 1623 healthy adolescents, aged 14 years at baseline, recruited from high schools. Data analyses were performed from January 2018 to September 2019. Body mass index (BMI), mental health symptoms, substance use behaviors, and personality variables were investigated as time-varying associations of DEBs (dieting, binge eating, and purging) or change in BMI over time. Polygenic risk scores were calculated to investigate genetic contributions associated with BMI, attention-deficit/hyperactivity disorder (ADHD) and neuroticism to DEBs. In this cohort study of 1623 adolescents (829 girls [51.1%]) recruited at a mean (SD) age of 14.5 (0.4) years and followed up at ages 16 and 19 years, 278 adolescents (17.1%) reported binge eating, 334 adolescents (20.6%) reported purging, and 356 adolescents (21.9%) reported dieting at 14, 16, or 19 years. Among the precursors of DEBs, high BMI was associated with future dieting (OR, 3.44; 95% CI, 2.09-5.65). High levels of neuroticism (OR, 1.04; 95% CI, 1.01-1.06), conduct problems (OR, 1.41; 95% CI, 1.17-1.69), and deliberate self-harm (OR, 2.18; 95% CI, 1.37-3.45) were associated with future binge eating. Low agreeableness (OR, 0.95; 95% CI, 0.92-0.97), deliberate self-harm (OR, 2.59; 95% CI, 1.69-3.95), conduct problems (OR, 1.42; 95% CI, 1.20-1.68), alcohol misuse (OR, 1.31; 95% CI, 1.10-1.54), and drug abuse (OR, 2.91; 95% CI, 1.78-4.74) were associated with future purging. Polygenetic risk scores for BMI were associated with dieting (at 14 years: OR, 1.27; lower bound 95% CI, 1.08; at 16 years: OR, 1.38; lower bound 95% CI, 1.17); ADHD, with purging (at 16 years: OR, 1.25; lower bound 95% CI, 1.08; at 19 years, OR, 1.23; lower bound 95% CI, 1.06); and neuroticism, with binge eating (at 14 years: OR, 1.32; lower bound 95% CI, 1.11; at 16 years: OR, 1.24; lower bound 95% CI, 1.06), highlighting distinct etiologic overlaps between these traits. The DEBs predated other mental health problems, with dieting at 14 years associated with future symptoms of depression (OR, 2.53; 95% CI, 1.56-4.10), generalized anxiety (OR, 2.27; 95% CI, 1.14-4.51), deliberate self-harm (OR, 2.10; 95% CI, 1.51-4.24), emotional problems (OR, 1.24; 95% CI, 1.08-1.43), and smoking (OR, 2.16; 95% CI, 1.36-3.48). Purging at 14 years was also associated with future depression (OR, 2.87; 95% CI, 1.69-5.01) and anxiety (OR, 2.48; 95% CI, 1.49-4.12) symptoms. The findings of this study delineate temporal associations and shared etiologies among DEBs and other mental health disorders and emphasize the potential of genetic and phenotypical assessments of obesity, behavioral disorders, and neuroticism to improve early and differential diagnosis of eating disorders.

The cytokines IL-1[alpha] and IL-1[Beta] exert powerful pro-inflammatory actions throughout the body, mediated primarily by the intracellular signaling capacity of the interleukin-1 receptor (IL-1R1). Although Il1r1 knockout mice have been informative with respect to a requirement for IL-1R1 signaling in inflammatory events, the constitutive nature of gene elimination has limited their utility in the assessment of temporal and spatial patterns of cytokine action. To pursue such questions, we have generated C57Bl/6J mice containing a floxed Il1r1 gene (Il1r1loxP/loxP), with loxP sites positioned to flank exons 3 and 4 and thereby the ability to spatially and temporally eliminate Il1r1 expression and signaling. We found that Il1r1loxP/loxP mice breed normally and exhibit no gross physical or behavioral phenotypes. Moreover, Il1r1loxP/loxP mice exhibit normal IL-1R1 receptor expression in brain and spleen, as well as normal IL-1R1-dependent increases in serum IL-6 following IL-1[alpha] injections. Breeding of Il1r1loxP/loxP mice to animals expressing a cytomegalovirus (CMV)-driven Cre recombinase afforded efficient excision at the Il1r1 locus. The Il1r1loxP/loxP line should be a valuable tool for the assessment of contributions made by IL-1R1 signaling in diverse cell types across development.