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STUDY DESIGN.: A cohort study analyzing the cervical range of motion of subjects with anterior cervical decompression and fusion operation (ACDF). OBJECTIVE.: The purpose of this study was to compare the cervical range of motion of subjects who underwent an ACDF operation to age-matched healthy nonoperative subjects. Subjects were divided according to the number of operated levels, postoperative time point, and level of disability. SUMMARY OF BACKGROUND DATA.: ACDF is an operative treatment aimed at expansion of the spinal canal and relief of cord compression. In addition to alleviating pain, 2 common tools are used to measure postoperative success; cervical range of motion kinematic analysis and subjective evaluation questionnaires (Neck Disability Index [NDI]). METHODS.: This study involved 25 preoperative and 110 postoperative ACDF subjects as well as 18 control volunteers with no prior history of neck complaints. ACDF subjects were divided according to the number of operated levels; 1-, 2-, 3-, and 4-levels as well as time of their clinical visit; preoperative, early, and late postoperative. Before kinematic testing, the subjects were asked to complete the NDI survey. A virtual reality assisted electromagnetic tracking was used to measure an active voluntary motion of the head relative to the torso. The subjects' maximum range of motion was calculated and compared as they executed 3 to 5 consecutive cycles of the primary motions, flexion/extension, axial rotation, and lateral bending. An analysis of variance statistical test (P < 0.01) was used to determine significant differences between study groups. RESULTS.: Subject's range of motion decreased relative to control as the number of operated levels increased. Moreover, 1- and 2-level subjects increased their range motion relative to preoperative. Finally, there was a decrease in range of motion as the subject's level of disability increased as measured by an NDI score but all subjects reported a lower score relative to preoperative time point. CONCLUSION.: The active range of motion of subjects who underwent an ACDF surgery increased postoperative and was dependent on the number of operated levels. In addition, there was an improvement in the disability level after the surgery as measured by the NDI score. [ABSTRACT FROM AUTHOR]

BACKGROUND: In anterior cruciate ligament (ACL) reconstruction using hamstring grafts, the graft can be looped, resulting in an increased graft diameter but reducing graft length within the tunnels. HYPOTHESIS: After 6 and 12 weeks, structural properties and knee kinematics after soft tissue ACL reconstruction with 15 mm within the femoral tunnel will be significantly inferior when compared with the properties of ACL reconstruction with 25 mm in the tunnel. STUDY DESIGN: Controlled laboratory study. METHODS: In an intra-articular goat model, 36 ACL reconstructions using an Achilles tendon split graft were performed with 15-mm (18 knees) and 25-mm (18 knees) graft length in the femoral tunnel. Animals were sacrificed 6 weeks and 12 weeks after surgery and knee kinematics was tested. In situ forces as well as the structural properties were determined and compared with those in an intact control group. Histologic analyses were performed in 2 animals in each group 6 and 12 weeks postoperatively. Statistical analysis was performed using a 2-factor analysis of variance test. RESULTS: Anterior cruciate ligament reconstructions with 15 mm resulted in significantly less anterior tibial translation after 6 weeks (P < .05) but not after 12 weeks. Kinematics after 12 weeks and in situ forces of the replacement grafts at both time points showed no statistically significant differences. Stiffness, ultimate failure load, and ultimate stress revealed no statistically significant differences between the 15-mm group and the 25-mm group. CONCLUSION: The results suggest that there is no negative correlation between short graft length (15 mm) in the femoral tunnel and the resulting knee kinematics and structural properties. CLINICAL RELEVANCE: Various clinical scenarios exist in which the length of available graft that could be pulled into the bone tunnel (femoral or tibial) could be in question. To address this concern, this study showed that reducing the tendon graft length in the femoral bone tunnel from 25 mm to 15 mm did not have adverse affects in a goat model. [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate childhood sexual abuse (CSA), adulthood sexual victimization (ASV), and adulthood sexual assault experiences in a comparison sample of female military veterans (n = 142) and civilian community members (n = 81). Women veterans were significantly more likely than civilian women to report adult sexual assault. Although comparable rates of CSA and ASV were found across groups, veterans more frequently reported having been sexually abused by a parental figure, reported longer durations of CSA, and significantly greater severity of ASV than civilians. Implications for mental health professionals providing sexual trauma services to female military personnel and veterans are discussed. [ABSTRACT FROM AUTHOR]

STUDY DESIGN.: A cohort study analyzing the cervical range of motion (ROM) of subjects with 4- or 5-level posterior laminectomy and fusion or anterior and posterior decompression and fusion operation. OBJECTIVE.: The purpose of this study was to evaluate the effect of extending a C3-C7 fusion to C3-T1 on subject's ROM and level of disability. SUMMARY OF BACKGROUND DATA.: Cadaveric studies show a reduction in the ROM of C3-C7 cervical fusion spines. In vivo, surgeons treat symptomatic cervical subaxial spine with either a C3-C7 fusion or C3-T1 fusion. While in some cases extending the fusion level to T1 is merited due to pathology, most cases are due to surgeon's preference to avoid future degeneration and reoperation of the C7-T1 junction. METHODS.: This study involved 44 4-level fusion and 20 5-level fusion subjects along with 18 nonoperative controls. Operative subjects were divided according to early or late postoperative clinical visit. Subjects were asked to complete the neck disability index survey and their maximum ROM during flexion/extension, axial rotation, and lateral bending was measured using a virtual reality assisted electromagnetic tracking system. In addition, the helical axis of motion was calculated for flexion and extension motions. An analysis of variance statistical test was used to determine significant differences between study groups. RESULTS.: Five- level subjects had significantly less ROM than 4-level subjects and both groups were significantly less than control group during all motions. There was no effect of postoperative time on subject's ROM. In addition, there was no difference in the center of helical axis of rotation across the 3 groups. Finally, both operative groups exhibited similar levels of mild disability as measured by the neck disability index. CONCLUSIONS.: Extending the subaxial fusion from C3-C7 to include C7-T1 resulted in a significant loss of ROM, while postoperative time healing, center of rotation, and level of disability were similar across groups. This finding merits further investigation of the intersegmental motions of the cervical spine. [ABSTRACT FROM AUTHOR]

Background: Double bundle ACL reconstruction has been demonstrated to decrease rotational knee laxity. However, there is no simple, commercially-available device to measure knee rotation. The investigators developed a simple, non-invasive device to measure knee rotation. In conjunction with a rigid boot to rotate the tibia and a force/moment sensor to allow precise determination of torque about the knee, a magnetic tracking system measures the axial rotation of the tibia with respect to the femur. This device has been shown to have acceptable levels of test re-test reliability to measure knee rotation in cadaveric knees.Methods: The objective of this study was to determine reliability of the device in measuring knee rotation of human subjects. Specifically, the intra-tester reliability within a single testing session, test-retest reliability between two testing sessions, and inter-tester reliability were assessed for 11 male subjects with normal knees.Results: The 95% confidence interval for rotation was less than 5 degrees for intra-tester, test-retest, and inter-tester reliability, and the standard error of measurement for the differences between left and right knees was found to be less than 3 degrees .Conclusion: It was found that the knee rotation measurements obtained with this device have acceptable limits of reliability for clinical use and interpretation. [ABSTRACT FROM AUTHOR]

Background Context: Intervertebral disc degeneration (IDD) is a common cause of back pain. Patients who fail conservative management may face the morbidity of surgery. Alternative treatment modalities could have a significant impact on disease progression and patients' quality of life.Purpose: To determine if the injection of a virus vector carrying a therapeutic gene directly into the nucleus pulposus improves the course of IDD.Study Design: Prospective randomized controlled animal study.Methods: Thirty-four skeletally mature New Zealand white rabbits were used. In the treatment group, L2-L3, L3-L4, and L4-L5 discs were punctured in accordance with a previously validated rabbit annulotomy model for IDD and then subsequently treated with adeno-associated virus serotype 2 (AAV2) vector carrying genes for either bone morphogenetic protein 2 (BMP2) or tissue inhibitor of metalloproteinase 1 (TIMP1). A nonoperative control group, nonpunctured sham surgical group, and punctured control group were also evaluated. Serial magnetic resonance imaging (MRI) studies at 0, 6, and 12 weeks were obtained, and a validated MRI analysis program was used to quantify degeneration. The rabbits were sacrificed at 12 weeks, and L4-L5 discs were analyzed histologically. Viscoelastic properties of the L3-L4 discs were analyzed using uniaxial load-normalized displacement testing. Creep curves were mathematically modeled according to a previously validated two-phase exponential model. Serum samples obtained at 0, 6, and 12 weeks were assayed for biochemical evidence of degeneration.Results: The punctured group demonstrated MRI and histologic evidence of degeneration as expected. The treatment groups demonstrated less MRI and histologic evidence of degeneration than the punctured group. The serum biochemical marker C-telopeptide of collagen type II increased rapidly in the punctured group, but the treated groups returned to control values by 12 weeks. The treatment groups demonstrated several viscoelastic properties that were distinct from control and punctured values.Conclusions: Treatment of punctured rabbit intervertebral discs with AAV2-BMP2 or AAV2-TIMP1 helps delay degenerative changes, as seen on MRI, histologic sampling, serum biochemical analysis, and biomechanical testing. Although data from animal models should be extrapolated to the human condition with caution, this study supports the potential use of gene therapy for the treatment of IDD. [ABSTRACT FROM AUTHOR]

Premature ovarian insufficiency is a common form of female infertility affecting up to 4% of women and characterised by amenorrhea with elevated gonadotropin before the age of 40. Oocytes require controlled DNA breakage and repair for homologous recombination and the maintenance of oocyte integrity. Biallelic disruption of the DNA damage repair gene, Fanconi anemia complementation group A (FANCA), is a common cause of Fanconi anaemia, a syndrome characterised by bone marrow failure, cancer predisposition, physical anomalies and POI. There is ongoing dispute about the role of heterozygous FANCA variants in POI pathogenesis, with insufficient evidence supporting causation. Here, we have identified biallelic FANCA variants in French sisters presenting with POI, including a novel missense variant of uncertain significance and a likely pathogenic deletion that initially evaded detection. Functional studies indicated no discernible effect on DNA damage sensitivity in patient lymphoblasts. These novel FANCA variants add evidence that heterozygous loss of one allele is insufficient to cause DNA damage sensitivity and POI. We propose that intragenic deletions, that are relatively common in FANCA, may be missed without careful analysis, and could explain the presumed causation of heterozygous variants. Accurate variant curation is critical to optimise patient care and outcomes., (© 2024 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.)

Theory suggests that intolerance of uncertainty (IU), a tendency to perceive uncertain events as threatening, may serve as a potential risk factor for increased intimate partner violence (IPV) perpetration; however, few studies have investigated this association, and none have taken a longitudinal approach. We investigated the issue in two longitudinal online investigations (initial N  = 282 and 1,118), with time periods ranging from just before the COVID-19 pandemic to the fourth pandemic wave, approximately 1.5 years later. IU was a significant predictor of IPV cross-sectionally, and in the short term longitudinally (i.e., over periods of weeks); however, it did not predict IPV over the longer term (i.e., over periods of months or years). In addition, our longitudinal design allowed assessment of IPV trends across pandemic waves. Physical IPV rates remained low and steady across time. Psychological IPV rates showed an increase in the early days of the pandemic, but then dropped and stabilized, albeit at a somewhat higher rate than pre-pandemic. Study 2 had ample representation of LGBTQ+ respondents and showed that the patterns and processes worked similarly for LGBTQ+ and non-LGBTQ+ individuals., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interests with respect to the authorship and/or publication of this article.

Assessing physical activity is important in the treatment of chronic conditions, including chronic low back pain (cLBP). ActiGraph™, a widely used physical activity monitor, collects raw acceleration data, and processes these data through proprietary algorithms to produce physical activity measures. The purpose of this study was to replicate ActiGraph™ algorithms in MATLAB and test the validity of this method with both healthy controls and participants with cLBP. MATLAB code was developed to replicate ActiGraph™'s activity counts and step counts algorithms, to sum the activity counts into counts per minute (CPM), and categorize each minute into activity intensity cut points. A free-living validation was performed where 24 individuals, 12 cLBP and 12 healthy, wore an ActiGraph™ GT9X on their non-dominant hip for up to seven days. The raw acceleration data were processed in both ActiLife™ (v6), ActiGraph™'s data analysis software platform, and through MATLAB (2022a). Percent errors between methods for all 24 participants, as well as separated by cLBP and healthy, were all less than 2%. ActiGraph™ algorithms were replicated and validated for both populations, based on minimal error differences between ActiLife™ and MATLAB, allowing researchers to analyze data from any accelerometer in a manner comparable to ActiLife™.

Research Question: Premature ovarian insufficiency (POI) is characterised by amenorrhea associated with elevated follicle stimulating hormone (FSH) under the age of 40 years and affects 1-3.7% women. Genetic factors explain 20-30% of POI cases, but most causes remain unknown despite genomic advancements., Design: We used whole exome sequencing (WES) in four Iranian families, validated variants via Sanger sequencing, and conducted the Acyl-cLIP assay to measure HHAT enzyme activity., Results: Despite ethnic homogeneity, WES revealed diverse genetic causes, including a novel homozygous nonsense variant in SYCP2L, impacting synaptonemal complex (SC) assembly, in the first family. Interestingly, the second family had two independent causes for amenorrhea - the mother had POI due to a novel homozygous loss-of-function variant in FANCM (required for chromosomal stability) and her daughter had primary amenorrhea due to a novel homozygous GNRHR (required for gonadotropic signalling) frameshift variant. WES analysis also provided cytogenetic insights. WES revealed one individual was in fact 46, XY and had a novel homozygous missense variant of uncertain significance in HHAT, potentially responsible for complete sex reversal although functional assays did not support impaired HHAT activity. In the remaining individual, WES indicated likely mosaic Turners with the majority of X chromosome variants having an allelic balance of ∼85% or ∼15%. Microarray validated the individual had 90% 45,XO., Conclusions: This study demonstrates the diverse causes of amenorrhea in a small, isolated ethnic cohort highlighting how a genetic cause in one individual may not clarify familial cases. We propose that, in time, genomic sequencing may become a single universal test required for the diagnosis of infertility conditions such as POI., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The objective of this study is to assess women's vulnerability to becoming involved with the legal system as it relates to their exposure, sensitivity, and resiliency to specific experiences associated with incarceration before, during, and after their confinement using the vulnerability framework. We sampled 12 women who self-identified as Latina mothers from local jail annexes, probation department offices, and substance use treatment centers in South Central Texas. We conducted a qualitative, secondary analysis. Three overarching themes emerged: (1) "[The abuse] just kept happening;" (2) "[Incarceration] was an excessive interference;" and (3) "I wasn't there back then [for my children], but now I can be [there for them] in some way." We also identified subthemes. More research and culturally tailored programming are needed to bridge services across legal system sites (jails, prisons, probation) that interact with this population of women to provide supportive services. PUBLIC CONTRIBUTION: We would like to recognize community stakeholders who work in the local jail, probation, and medication treatment centers who helped with the distribution of fliers and participant recruitment along with the women who shared their experiences following incarceration for the original study's data used in this secondary analysis., (© 2023 Wiley Periodicals LLC.)

Disruption of meiosis and DNA repair genes is associated with female fertility disorders like premature ovarian insufficiency (POI). In this study, we identified a homozygous missense variant in the HELQ gene (c.596 A>C; p.Gln199Pro) through whole exome sequencing in a POI patient, a condition associated with disrupted ovarian function and female infertility. HELQ, an enzyme involved in DNA repair, plays a crucial role in repairing DNA cross-links and has been linked to germ cell maintenance, fertility, and tumour suppression in mice. To explore the potential association of the HELQ variant with POI, we used CRISPR/Cas9 to create a knock-in mouse model harbouring the equivalent of the human HELQ variant identified in the POI patient. Surprisingly, Helq knock-in mice showed no discernible phenotype, with fertility levels, histological features, and follicle development similar to wild-type mice. Despite the lack of observable effects in mice, the potential role of HELQ in human fertility, especially in the context of POI, should not be dismissed. Larger studies encompassing diverse ethnic populations and alternative functional approaches will be necessary to further examine the role of HELQ in POI. Our results underscore the potential uncertainties associated with genomic variants and the limitations of in vivo animal modelling.

Objective: Biomechanics represents the common final output through which all biopsychosocial constructs of back pain must pass, making it a rich target for phenotyping. To exploit this feature, several sites within the NIH Back Pain Consortium (BACPAC) have developed biomechanics measurement and phenotyping tools. The overall aims of this article were to: 1) provide a narrative review of biomechanics as a phenotyping tool; 2) describe the diverse array of tools and outcome measures that exist within BACPAC; and 3) highlight how leveraging these technologies with the other data collected within BACPAC could elucidate the relationship between biomechanics and other metrics used to characterize low back pain (LBP)., Methods: The narrative review highlights how biomechanical outcomes can discriminate between those with and without LBP, as well as among levels of severity of LBP. It also addresses how biomechanical outcomes track with functional improvements in LBP. Additionally, we present the clinical use case for biomechanical outcome measures that can be met via emerging technologies., Results: To answer the need for measuring biomechanical performance, our "Results" section describes the spectrum of technologies that have been developed and are being used within BACPAC., Conclusion and Future Directions: The outcome measures collected by these technologies will be an integral part of longitudinal and cross-sectional studies conducted in BACPAC. Linking these measures with other biopsychosocial data collected within BACPAC increases our potential to use biomechanics as a tool for understanding the mechanisms of LBP, phenotyping unique LBP subgroups, and matching these individuals with an appropriate treatment paradigm., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Academy of Pain Medicine.)

As a member of the Back Pain Consortium (BACPAC), the University of Pittsburgh Mechanistic Research Center's research goal is to phenotype chronic low back pain using biological, biomechanical, and behavioral domains using a prospective, observational cohort study. Data will be collected from 1,000 participants with chronic low back pain according to BACPAC-wide harmonized and study-specific protocols. Participation lasts 12 months with one required in person baseline visit, an optional second in person visit for advanced biomechanical assessment, and electronic follow ups at months 1, 2, 3, 4, 5, 6, 9, and 12 to assess low back pain status and response to prescribed treatments. Behavioral data analysis includes a battery of patient-reported outcomes, social determinants of health, quantitative sensory testing, and physical activity. Biological data analysis includes omics generated from blood, saliva, and spine tissue. Biomechanical data analysis includes a physical examination, lumbopelvic kinematics, and intervertebral kinematics. The statistical analysis includes traditional unsupervised machine learning approaches to categorize participants into groups and determine the variables that differentiate patients. Additional analysis includes the creation of a series of decision rules based on baseline measures and treatment pathways as inputs to predict clinical outcomes. The characteristics identified will contribute to future studies to assist clinicians in designing a personalized, optimal treatment approach for each patient., (© The Author(s) 2023. Published by Oxford University Press on behalf of the American Academy of Pain Medicine.)

Critically ill infants and children with rare diseases need equitable access to rapid and accurate diagnosis to direct clinical management. Over 2 years, the Acute Care Genomics program provided whole-genome sequencing to 290 families whose critically ill infants and children were admitted to hospitals throughout Australia with suspected genetic conditions. The average time to result was 2.9 d and diagnostic yield was 47%. We performed additional bioinformatic analyses and transcriptome sequencing in all patients who remained undiagnosed. Long-read sequencing and functional assays, ranging from clinically accredited enzyme analysis to bespoke quantitative proteomics, were deployed in selected cases. This resulted in an additional 19 diagnoses and an overall diagnostic yield of 54%. Diagnostic variants ranged from structural chromosomal abnormalities through to an intronic retrotransposon, disrupting splicing. Critical care management changed in 120 diagnosed patients (77%). This included major impacts, such as informing precision treatments, surgical and transplant decisions and palliation, in 94 patients (60%). Our results provide preliminary evidence of the clinical utility of integrating multi-omic approaches into mainstream diagnostic practice to fully realize the potential of rare disease genomic testing in a timely manner., (© 2023. The Author(s).)

Premature ovarian insufficiency (POI) is a common cause of infertility in women, characterised by amenorrhea and elevated FSH under the age of 40 years. In some cases, POI is syndromic in association with other features such as sensorineural hearing loss in Perrault syndrome. POI is a heterogeneous disease with over 80 causative genes known so far; however, these explain only a minority of cases. Using whole-exome sequencing (WES), we identified a MRPL50 homozygous missense variant (c.335T > A; p.Val112Asp) shared by twin sisters presenting with POI, bilateral high-frequency sensorineural hearing loss, kidney and heart dysfunction. MRPL50 encodes a component of the large subunit of the mitochondrial ribosome. Using quantitative proteomics and western blot analysis on patient fibroblasts, we demonstrated a loss of MRPL50 protein and an associated destabilisation of the large subunit of the mitochondrial ribosome whilst the small subunit was preserved. The mitochondrial ribosome is responsible for the translation of subunits of the mitochondrial oxidative phosphorylation machinery, and we found patient fibroblasts have a mild but significant decrease in the abundance of mitochondrial complex I. These data support a biochemical phenotype associated with MRPL50 variants. We validated the association of MRPL50 with the clinical phenotype by knockdown/knockout of mRpL50 in Drosophila, which resulted abnormal ovarian development. In conclusion, we have shown that a MRPL50 missense variant destabilises the mitochondrial ribosome, leading to oxidative phosphorylation deficiency and syndromic POI, highlighting the importance of mitochondrial support in ovarian development and function., (© 2023. The Author(s).)

Chondrocytes and osteoblasts differentiated from induced pluripotent stem cells (iPSCs) will provide insights into skeletal development and genetic skeletal disorders and will generate cells for regenerative medicine applications. Here, we describe a method that directs iPSC-derived sclerotome to chondroprogenitors in 3D pellet culture then to articular chondrocytes or, alternatively, along the growth plate cartilage pathway to become hypertrophic chondrocytes that can transition to osteoblasts. Osteogenic organoids deposit and mineralize a collagen I extracellular matrix (ECM), mirroring in vivo endochondral bone formation. We have identified gene expression signatures at key developmental stages including chondrocyte maturation, hypertrophy, and transition to osteoblasts and show that this system can be used to model genetic cartilage and bone disorders.

Context: Premature ovarian insufficiency (POI) is a common form of female infertility that usually presents as an isolated condition but can be part of various genetic syndromes. Early diagnosis and treatment of POI can minimize comorbidity and improve health outcomes., Objective: We aimed to determine the genetic cause of syndromic POI, intellectual disability, neutropenia, and cataracts., Methods: We performed whole-exome sequencing (WES) followed by functional validation via RT-PCR, RNAseq, and quantitative proteomics, as well as clinical update of previously reported patients with variants in the caseinolytic peptidase B (CLPB) gene., Results: We identified causative variants in CLPB, encoding a mitochondrial disaggregase. Variants in this gene are known to cause an autosomal recessive syndrome involving 3-methylglutaconic aciduria, neurological dysfunction, cataracts, and neutropenia that is often fatal in childhood; however, there is likely a reporting bias toward severe cases. Using RNAseq and quantitative proteomics we validated causation and gained insight into genotype:phenotype correlation. Clinical follow-up of patients with CLPB deficiency who survived to adulthood identified POI and infertility as a common postpubertal ailment., Conclusion: A novel splicing variant is associated with CLPB deficiency in an individual who survived to adulthood. POI is a common feature of postpubertal female individuals with CLPB deficiency. Patients with CLPB deficiency should be referred to pediatric gynecologists/endocrinologists for prompt POI diagnosis and hormone replacement therapy to minimize associated comorbidities., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

Premature ovarian insufficiency (POI) is a leading form of female infertility, characterised by menstrual disturbance and elevated follicle-stimulating hormone before age 40. It is highly heterogeneous with variants in over 80 genes potentially causative, but the majority of cases having no known cause. One gene implicated in POI pathology is TP63. TP63 encodes multiple p63 isoforms, one of which has been shown to have a role in the surveillance of genetic quality in oocytes. TP63 C-terminal truncation variants and N-terminal duplication have been described in association with POI, however, functional validation has been lacking. Here we identify three novel TP63 missense variants in women with nonsyndromic POI, including one in the N-terminal activation domain, one in the C-terminal inhibition domain, and one affecting a unique and poorly understood p63 isoform, TA*p63. Via blue-native page and luciferase reporter assays we demonstrate that two of these variants disrupt p63 dimerization, leading to constitutively active p63 tetramer that significantly increases the transcription of downstream targets. This is the first evidence that TP63 missense variants can cause isolated POI and provides mechanistic insight that TP63 variants cause POI due to constitutive p63 activation and accelerated oocyte loss in the absence of DNA damage., (© 2022 The Authors. Human Mutation published by Wiley Periodicals LLC.)

Background: Clinical exome sequencing typically achieves diagnostic yields of 30%-57.5% in individuals with monogenic rare diseases. Undiagnosed diseases programmes implement strategies to improve diagnostic outcomes for these individuals., Aim: We share the lessons learnt from the first 3 years of the Undiagnosed Diseases Program-Victoria, an Australian programme embedded within a clinical genetics service in the state of Victoria with a focus on paediatric rare diseases., Methods: We enrolled families who remained without a diagnosis after clinical genomic (panel, exome or genome) sequencing between 2016 and 2018. We used family-based exome sequencing (family ES), family-based genome sequencing (family GS), RNA sequencing (RNA-seq) and high-resolution chromosomal microarray (CMA) with research-based analysis., Results: In 150 families, we achieved a diagnosis or strong candidate in 64 (42.7%) (37 in known genes with a consistent phenotype, 3 in known genes with a novel phenotype and 24 in novel disease genes). Fifty-four diagnoses or strong candidates were made by family ES, six by family GS with RNA-seq, two by high-resolution CMA and two by data reanalysis., Conclusion: We share our lessons learnt from the programme. Flexible implementation of multiple strategies allowed for scalability and response to the availability of new technologies. Broad implementation of family ES with research-based analysis showed promising yields post a negative clinical singleton ES. RNA-seq offered multiple benefits in family ES-negative populations. International data sharing strategies were critical in facilitating collaborations to establish novel disease-gene associations. Finally, the integrated approach of a multiskilled, multidisciplinary team was fundamental to having diverse perspectives and strategic decision-making., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Previous animal models of intervertebral disc degeneration (IDD) rely on open surgical approaches, which confound the degenerative response and pain behaviors due to injury to surrounding tissues during the surgical approach. To overcome these challenges, we developed a minimally invasive percutaneous puncture procedure to induce IDD in a rat model., Methods: Ten Fischer 344 male rats underwent percutaneous annular puncture of lumbar intervertebral discs (IVDs) at L2-3, L3-4, and L4-5. Ten unpunctured rats were used as controls. Magnetic resonance imagings (MRIs), serum biomarkers, and behavioral tests were performed at baseline and 6, 12, and 18 weeks post puncture. Rats were sacrificed at 18 weeks and disc histology, immunohistochemistry, and glycosaminoglycan (GAG) assays were performed., Results: Punctured IVDs exhibited significant reductions in MRI signal intensity and disc volume. Disc histology, immunohistochemistry, and GAG assay results were consistent with features of IDD. IVD-punctured rats demonstrated significant changes in pain-related behaviors, including total distance moved, twitching frequency, and rearing duration., Conclusions: This is the first reported study of the successful establishment of a reproducible rodent model of a percutaneous lumbar annular puncture resulting in discogenic pain. This model will be useful to test therapeutics and elucidate the basic mechanisms of IDD and discogenic pain., Competing Interests: The authors declare no conflicts of interest., (© 2022 The Authors. JOR Spine published by Wiley Periodicals LLC on behalf of Orthopaedic Research Society.)

Verbal arguments often precede physical dating violence perpetration, and research is needed to better understand the content and evolution of arguments in dating relationships in order to develop more targeted dating violence prevention programming. This multisite project qualitatively investigated the content of verbal arguments preceding physical dating violence perpetration reported by 30 undergraduate students. Participants completed a semi-structured interview inquiring about events preceding participants' most recent dating violence episode. Interviews were analyzed using a thematic analysis approach. Verbal arguments often preceded participants' most recent episode of physical dating violence perpetration, with a wide range of argument topics reported, including jealousy, partner noncompliance, and substance use. Findings highlight the need for research to better understand the context of verbal arguments that precipitate dating violence perpetration., (© Copyright 2022 Springer Publishing Company, LLC.)

The dependency-possessiveness model proposes that individuals who are highly dependent on their intimate partner and fear partner abandonment, particularly among those with emotion dysregulation problems, may be at heightened risk for intimate partner aggression (IPA) perpetration. Despite prior research establishing a link between relationship dependency and male IPA perpetration, it is unknown whether this association extends to female-perpetrated aggression, occurs in dating relationships, and is moderated by emotion dysregulation. Thus, the purpose of the current study was to investigate the association between relationship dependency and female-perpetrated dating aggression and determine if emotion dysregulation moderated this hypothesized relationship. Female undergraduate students ( N = 119) completed measures assessing relationship dependency, emotion dysregulation, and female-perpetrated physical and psychological dating aggression as part of a larger study investigating the context of dating aggression episodes. Anxious attachment was significantly correlated with female-perpetrated psychological and physical dating aggression. Regression analyses indicated a significant interaction between the Spouse-Specific Dependency Scale [SSDS] Anxious Attachment subscale and emotion dysregulation predicting female-perpetrated physical dating aggression, suggesting moderation. There was a positive association between anxious attachment relationship dependency and female-perpetrated physical dating aggression at high levels of emotion dysregulation. A significant interaction was also found between the SSDS Emotional Dependency subscale and emotion dysregulation predicting female-perpetrated physical dating aggression, such that among those with low scores in emotion dysregulation, there was a positive relationship between emotional dependency and female-perpetrated physical dating aggression. Findings suggest that the ability to regulate emotions may play an important role in the association between relationship dependency and female-perpetrated dating aggression.

The nuclear pore complex (NPC) is a multi-protein complex that regulates the trafficking of macromolecules between the nucleus and cytoplasm. Genetic variants in components of the NPC have been shown to cause a range of neurological disorders, including intellectual disability and microcephaly. Translocated promoter region, nuclear basket protein (TPR) is a critical scaffolding element of the nuclear facing interior of the NPC. Here, we present two siblings with biallelic variants in TPR who present with a phenotype of microcephaly, ataxia and severe intellectual disability. The variants result in a premature truncation variant, and a splice variant leading to a 12-amino acid deletion respectively. Functional analyses in patient fibroblasts demonstrate significantly reduced TPR levels, and decreased TPR-containing NPC density. A compensatory increase in total NPC levels was observed, and decreased global RNA intensity in the nucleus. The discovery of variants that partly disable TPR function provide valuable insight into this essential protein in human disease, and our findings suggest that TPR variants are the cause of the siblings' neurological disorder., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Premature ovarian insufficiency (POI), affecting 1 in 100 women, is characterised by loss of ovarian function associated with elevated gonadotropin, before the age of 40. In addition to infertility, patients face increased risk of comorbidities such as heart disease, osteoporosis, cancer and/or early mortality. We used whole exome sequencing to identify the genetic cause of POI in seven women. Each had biallelic candidate variants in genes with a primary role in DNA damage repair and/or meiosis. This includes two genes, REC8 and HROB, not previously associated with autosomal recessive POI. REC8 encodes a component of the cohesin complex and HROB encodes a factor that recruits MCM8/9 for DNA damage repair. In silico analyses, combined with concordant mouse model phenotypes support these as new genetic causes of POI. We also identified novel variants in MCM8, NUP107, STAG3 and HFM1 and a known variant in POF1B. Our study highlights the pivotal role of meiosis in ovarian function. We identify novel variants, consolidate the pathogenicity of variants previously considered of unknown significance, and propose HROB and REC8 variants as new genetic causes while exploring their link to pathogenesis., (© 2021. The Author(s), under exclusive licence to European Society of Human Genetics.)

Mitochondrial disorders are collectively common, genetically heterogeneous disorders in both pediatric and adult populations. They are caused by molecular defects in oxidative phosphorylation, failure of essential bioenergetic supply to mitochondria, and apoptosis. Here, we present three affected individuals from a consanguineous family of Pakistani origin with variable seizures and intellectual disability. Both females display primary ovarian insufficiency (POI), while the male shows abnormal sex hormone levels. We performed whole exome sequencing and identified a recessive missense variant c.694C > T, p.Arg232Cys in TFAM that segregates with disease. TFAM (mitochondrial transcription factor A) is a component of the mitochondrial replisome machinery that maintains mtDNA transcription and replication. In primary dermal fibroblasts, we show depletion of mtDNA and significantly altered mitochondrial function and morphology. Moreover, we observed reduced nucleoid numbers with significant changes in nucleoid size or shape in fibroblasts from an affected individual compared to controls. We also investigated the effect of tfam impairment in zebrafish; homozygous tfam mutants carrying an in-frame c.141&#95;149 deletion recapitulate the mtDNA depletion and ovarian dysgenesis phenotypes observed in affected humans. Together, our genetic and functional data confirm that TFAM plays a pivotal role in gonad development and expands the repertoire of mitochondrial disease phenotypes., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Pediatric and adolescent athletes are a large demographic undergoing anterior cruciate ligament reconstruction (ACL-R). Postoperative rehabilitation is critical, requiring patients to complete home exercise programs (HEPs). To address obstacles to HEP adherence, we developed an interactive health technology, interACTION (iA), to monitor knee-specific rehabilitation. iA is a web-based platform that incorporates wearable motion sensors and a mobile app that provides feedback and allows remote monitoring. The Wheel of Sukr is a gamification mechanism that includes numerous behavioral elements., Objective: This study aims to use a user-centered design process to incorporate behavioral change strategies derived from self-management theory into iA using the Wheel of Sukr, with the aim of influencing patient behavior., Methods: In total, 10 athletes aged 10-18 years with a history of ACL-R were included in this study. Patients were between 4 weeks and 1 year post-ACL-R. Participants underwent a 60-minute triphasic interview. Phase 1 focused on elements of gaming that led to high participation and information regarding surgery and recovery. In phase 2, participants were asked to think aloud and rank cards representing the components of the Wheel of Sukr in order of interest. In phase 3, the patients reviewed the current version of iA. Interviews were recorded, transcribed, and checked for accuracy. Qualitative content analysis segmented the data and tagged meaningful codes until descriptive redundancy was achieved; next, 2 coders independently coded the data set. These elements were categorized according to the Wheel of Sukr framework. The mean age of participants was 12.8 (SD 1.32) years, and 70% (7/10) were female. Most participants (7/10, 70%) reported attending sessions twice weekly. All patients were prescribed home exercises. Self-reported HEP compliance was 75%-100% in 40% (4/10), 50%-75% in 40% (4/10), and 25%-50% of prescribed exercises in 20% (2/10) of the participants., Results: The participants responded positively to an app that could track home exercises. Desirable features included exercise demonstrations, motivational components, and convenience. The participants listed sports specificity, competition, notifications, reminders, rewards, and social aspects of gameplay as features to incorporate. In the Wheel of Sukr card sort exercise, motivation was ranked first; self-management, second; and growth, esteem, and fun tied for the third position. The recommended gameplay components closely followed the themes from the Wheel of Sukr card sort activity., Conclusions: The participants believe iA is a helpful addition to recovery and want the app to include exercise movement tracking and encouragement. Despite the small number of participants, thematic saturation was reached, suggesting the sample was sufficient to obtain a representative range of perspectives. Future work will implement motivation; self-management; and growth, confidence, and fun in the iA user experience. Young athlete ACL-R patients will complete typical clinical scenarios using increasingly developed prototypes of the gamified iA in a controlled setting., (©Michael McClincy, Liliana G Seabol, Michelle Riffitts, Ethan Ruh, Natalie E Novak, Rachel Wasilko, Megan E Hamm, Kevin M Bell. Originally published in JMIR Serious Games (https://games.jmir.org), 27.08.2021.)

In vitro biomechanical studies of the osteoligamentous spine are widely used to characterize normal biomechanics, identify injury mechanisms, and assess the effects of degeneration and surgical instrumentation on spine mechanics. The objective of this study was to determine how well four standards in vitro loading paradigms replicate in vivo kinematics with regards to the instantaneous center of rotation and arthrokinematics in relation to disc deformation. In vivo data were previously collected from 20 asymptomatic participants (45.5 ± 5.8 years) who performed full range of motion neck flexion-extension (FE) within a biplane x-ray system. Intervertebral kinematics were determined with sub-millimeter precision using a validated model-based tracking process. Ten cadaveric spines (51.8 ± 7.3 years) were tested in FE within a robotic testing system. Each specimen was tested under four loading conditions: pure moment, axial loading, follower loading, and combined loading. The in vivo and in vitro bone motion data were directly compared. The average in vitro instant center of rotation was significantly more anterior in all four loading paradigms for all levels. In general, the anterior and posterior disc heights were larger in the in vitro models than in vivo. However, after adjusting for gender, the observed differences in disc height were not statistically significant. This data suggests that in vitro biomechanical testing alone may fail to replicate in vivo conditions, with significant implications for novel motion preservation devices such as cervical disc arthroplasty implants., (© 2020 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Muscle contraction is a fundamental biological process where molecular interactions between the myosin molecular motor and actin filaments result in contraction of a whole muscle, a process spanning size scales differing in eight orders of magnitude. Since unique behavior is observed at every scale in between these two extremes, to fully understand muscle function it is vital to develop multi-scale models. Based on simulations of classic measurements of muscle heat generation as a function of work, and shortening rate as a function of applied force, we hypothesize that a model based on molecular measurements must be modified to include a weakly-bound interaction between myosin and actin in order to fit measurements at the muscle fiber or whole muscle scales. This hypothesis is further supported by the model's need for a weakly-bound state in order to qualitatively reproduce the force response that occurs when a muscle fiber is rapidly stretched a small distance. We tested this hypothesis by measuring steady-state force as a function of shortening velocity, and the force transient caused by a rapid length step in Drosophila jump muscle fibers. Then, by performing global parameter optimization, we quantitatively compared the predictions of two mathematical models, one lacking a weakly-bound state and one with a weakly-bound state, to these measurements. Both models could reproduce our force-velocity measurements, but only the model with a weakly-bound state could reproduce our force transient measurements. However, neither model could concurrently fit both measurements. We find that only a model that includes weakly-bound cross-bridges with force-dependent detachment and an elastic element in series with the cross-bridges is able to fit both of our measurements. This result suggests that the force response after stretch is not a reflection of distinct steps in the cross-bridge cycle, but rather arises from the interaction of cross-bridges with a series elastic element. Additionally, the model suggests that the curvature of the force-velocity relationship arises from a combination of the force-dependence of weakly- and strongly-bound cross-bridges. Overall, this work presents a minimal cross-bridge model that has predictive power at the fiber level., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Freeman-Sheldon syndrome (FSS) is characterized by congenital contractures resulting from dominant point mutations in the embryonic isoform of muscle myosin. To investigate its disease mechanism, we used Drosophila models expressing FSS myosin mutations Y583S or T178I in their flight and jump muscles. We isolated these muscles from heterozygous mutant Drosophila and performed skinned fiber mechanics. The most striking mechanical alteration was an increase in active muscle stiffness. Y583S/+ and T178I/+ fibers' elastic moduli increased 70 and 77%, respectively. Increased stiffness contributed to decreased power generation, 49 and 66%, as a result of increased work absorbed during the lengthening portion of the contractile cycle. Slower muscle kinetics also contributed to the mutant phenotype, as shown by 17 and 32% decreases in optimal frequency for power generation, and 27 and 41% slower muscle apparent rate constant 2πb. Combined with previous measurements of slower in vitro actin motility, our results suggest a rate reduction of at least one strongly bound cross-bridge cycle transition that increases the time myosin spends strongly bound to actin, t on . Increased t on was further supported by decreased ATP affinity and a 16% slowing of jump muscle relaxation rate in T178I heterozygotes. Impaired muscle function caused diminished flight and jump ability of Y583S/+ and T178I/+ Drosophila. Based on our results, assuming that our model system mimics human skeletal muscle, we propose that one mechanism driving FSS is elevated muscle stiffness arising from prolonged t on in developing muscle fibers., (Copyright © 2021 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

Rehabilitation has been shown to improve functional outcomes following total knee replacement (TKR). However, its delivery and associated costs are highly variable. The authors have developed and previously validated the accuracy of a remote (wearable) rehabilitation monitoring platform ( interACTION ). The present study's objective was to assess the feasibility of utilizing interACTION for the remote management of rehabilitation after TKR and to determine a preliminary estimate of the effects of the interACTION system on the value of rehabilitation. Specifically, we tested post-operative outpatient rehabilitation supplemented with interACTION (n = 13) by comparing it to a standard post-operative outpatient rehabilitation program (n = 12) using a randomized design. Attrition rates were relatively low and not significantly different between groups, indicating that participants found both interventions acceptable. A small (not statistically significant) decrease in the number of physical therapy visits was observed in the interACTION Group, therefore no significant difference in total cost could be observed. All patients and physical therapists in the interACTION Group indicated that they would use the system again in the future. Therefore, the next steps are to address the concerns identified in this pilot study and to expand the platform to include behavioral change strategies prior to conducting a full-scale randomized controlled trial. Trial registration: ClinicalTrials.gov NCT02646761 " interACTION : A Portable Joint Function Monitoring and Training System for Remote Rehabilitation Following TKA" 6 January 2016.

Recent empirical data suggests that the majority of adolescents and emerging adults utilize digital technology to engage with texting and social media on a daily basis, with many using these mediums to engage in sexting (sending sexual texts, pictures, or videos via digital mediums). While research in the last decade has disproportionately focused on the potential risk factors and negative consequences associated with sexting, the data are limited by failing to differentiate consensual from non-consensual sexting and account for potential influences of intimate partner aggression (IPA) and sexting coercion in these contexts. In the current study, we assessed the positive and negative consequences associated with sexting, using behavioral theory as a framework, to determine the relationship between an individual's personal history of IPA victimization and the perceived consequences. Undergraduate students ( N = 536) who reported consensual sexting completed a series of measures examining their most recent sexting experience, including perceived sexting consequences, and their history of sexting coercion and IPA. Results suggested that those reporting a history of any type of IPA victimization endorsed more negative reinforcing consequences after sending a sext, and those with a history of physical or sexual IPA victimization endorsed more punishing consequences after sending a sext than those without such history. Additionally, experience with IPA was found to be positively correlated with perceived pressure/coercion to send a sext. The implications of these data for research, policy, prevention, and intervention are explored.

Background: Distal arthrogryposis (DA) is a group of autosomal dominant skeletal muscle diseases characterized by congenital contractures of distal limb joints. The most common cause of DA is a mutation of the embryonic myosin heavy chain gene, MYH3. Human phenotypes of DA are divided into the weakest form-DA1, a moderately severe form-DA2B (Sheldon-Hall Syndrome), and a severe DA disorder-DA2A (Freeman-Sheldon Syndrome). As models of DA1 and DA2B do not exist, their disease mechanisms are poorly understood., Methods: We produced the first models of myosin-based DA1 (F437I) and DA2B (A234T) using transgenic Drosophila melanogaster and performed an integrative analysis of the effects of the mutations. Assessments included lifespan, locomotion, ultrastructural analysis, muscle mechanics, ATPase activity, in vitro motility, and protein modeling., Results: We observed significant defects in DA1 and DA2B Drosophila flight and jump ability, as well as myofibril assembly and stability, with homozygotes displaying more severe phenotypes than heterozygotes. Notably, DA2B flies showed dramatically stronger phenotypic defects compared to DA1 flies, mirroring the human condition. Mechanical studies of indirect flight muscle fibers from DA1 heterozygotes revealed reduced power output along with increased stiffness and force production, compared to wild-type controls. Further, isolated DA1 myosin showed significantly reduced myosin ATPase activity and in vitro actin filament motility. These data in conjunction with our sinusoidal analysis of fibers suggest prolonged myosin binding to actin and a slowed step associated with Pi release and/or the power stroke. Our results are supported by molecular modeling studies, which indicate that the F437I and A234T mutations affect specific amino acid residue interactions within the myosin motor domain that may alter interaction with actin and nucleotide., Conclusions: The allele-specific ultrastructural and locomotory defects in our Drosophila DA1 and DA2B models are concordant with the differential severity of the human diseases. Further, the mechanical and biochemical defects engendered by the DA1 mutation reveal that power production, fiber stiffness, and nucleotide handling are aberrant in F437I muscle and myosin. The defects observed in our DA1 and DA2B Drosophila models provide insight into DA phenotypes in humans, suggesting that contractures arise from prolonged actomyosin interactions.

Stretch activation (SA) is a delayed increase in force following a rapid muscle length increase. SA is best known for its role in asynchronous insect flight muscle, where it has replaced calcium's typical role of modulating muscle force levels during a contraction cycle. SA also occurs in mammalian skeletal muscle but has previously been thought to be too low in magnitude, relative to calcium-activated (CA) force, to be a significant contributor to force generation during locomotion. To test this supposition, we compared SA and CA force at different P i concentrations (0-16 mM) in skinned mouse soleus (slow-twitch) and extensor digitorum longus (EDL; fast-twitch) muscle fibers. CA isometric force decreased similarly in both muscles with increasing P i , as expected. SA force decreased with P i in EDL (40%), leaving the SA to CA force ratio relatively constant across P i concentrations (17-25%). In contrast, SA force increased in soleus (42%), causing a quadrupling of the SA to CA force ratio, from 11% at 0 mM P i to 43% at 16 mM P i , showing that SA is a significant force modulator in slow-twitch mammalian fibers. This modulation would be most prominent during prolonged muscle use, which increases P i concentration and impairs calcium cycling. Based upon our previous Drosophila myosin isoform studies and this work, we propose that in slow-twitch fibers a rapid stretch in the presence of P i reverses myosin's power stroke, enabling quick rebinding to actin and enhanced force production, while in fast-twitch fibers, stretch and P i cause myosin to detach from actin.

MicroRNAs (miRNAs) are translational regulatory molecules with recognised roles in heart development and disease. Therefore, it is important to define the human miRNA expression profile in cardiac progenitors and early-differentiated cardiomyocytes and to determine whether critical cardiac transcription factors such as NKX2-5 regulate miRNA expression. We used an NKX2-5 eGFP/w reporter line to isolate both cardiac committed mesoderm and cardiomyocytes. We identified 11 miRNAs that were differentially expressed in NKX2-5 -expressing cardiac mesoderm compared to non-cardiac mesoderm. Subsequent profiling revealed that the canonical myogenic miRNAs including MIR1-1, MIR133A1 and MIR208A were enriched in cardiomyocytes. Strikingly, deletion of NKX2-5 did not result in gross changes in the cardiac miRNA profile, either at committed mesoderm or cardiomyocyte stages. Thus, in early human cardiomyocyte commitment and differentiation, the cardiac myogenic miRNA program is predominantly regulated independently of the highly conserved NKX2-5 -dependant gene regulatory network.

Premature ovarian insufficiency involves amenorrhea and elevated follicle-stimulating hormone before age 40, and its genetic basis is poorly understood. Here, we study 13 premature ovarian insufficiency (POI) patients using whole-exome sequencing. We identify PREPL and TP63 causative variants, and variants in other potentially novel POI genes. PREPL deficiency is a known cause of syndromic POI, matching the patients' phenotype. A role for TP63 in ovarian biology has previously been proposed but variants have been described in multiorgan syndromes, and not isolated POI. One patient with isolated POI harbored a de novo nonsense TP63 variant in the terminal exon and an unrelated patient had a different nonsense variant in the same exon. These variants interfere with the repression domain while leaving the activation domain intact. We expand the phenotypic spectrum of TP63-related disorders, provide a new genotype:phenotype correlation for TP63 and identify a new genetic cause of isolated POI., (© 2019 Wiley Periodicals, Inc.)

Study Design: In vitro biomechanical analysis., Objectives: Compare the destabilizing effects of anterior discectomy to posterior spinal releases., Summary of Background Data: Posterior release and pedicle screw fixation has become the accepted form of treatment for lumbar and thoracolumbar pediatric scoliotic spinal deformity. A biomechanical evaluation of posterior releases with comparison to traditional anterior releases has not been reported in the lumbar spine., Methods: Eleven fresh-frozen human thoracolumbar specimens (T9-L5) were tested by a robotic manipulator (Staubli RX90; moment target of 5.0 Nm, force target of 50 N) in axial rotation (AR), plus lateral and anterior translation (LT and AT). Specimens underwent either sequential anterior release (partial and full discectomy) or posterior release (inferior facetectomy and wide posterior release) from T10 to L4. Partial discectomy retained the posterior 50% of disc and posterior longitudinal ligament, whereas full discectomy removed all of the disc and PLL. Wide posterior release included total facetectomy plus ligamentum flavum and spinous process resection., Results: Inferior facetectomy produced an average increase of 1.5° ± 1.0° (p = .0625), 1.0 ± 0.8 mm (p = .0313), and 0.2 ± 0.3 mm (p = .156) in AR, LT, and AT, respectively. Compared with partial facetectomy, wide posterior release produced an average additional increase of 8.1° ± 4.0° (p = .0312), 2.0 ± 2.2 mm (p = .4062), and 1.1 ± 1.0 mm (p = .0625) in AR, LT, and AT, respectively. Full discectomy produced 201%, 161%, and 153% of the motion relative to wide posterior release in AR, LT, and AT, respectively (p = .0043, .0087, and .0173). Partial discectomy and wide posterior release proved statistically equivalent., Conclusions: Wide posterior release of the thoracolumbar spine allows significant correction and may be superior to inferior facetectomy in axial rotation. Although complete discectomy with PLL resection would likely allow greater correction, a more clinically realistic partial discectomy confers similar corrective potential in vitro compared with wide posterior release., Level of Evidence: Not applicable., (Copyright © 2018 Scoliosis Research Society. Published by Elsevier Inc. All rights reserved.)

Key Points: Hypertrophic cardiomyopathy (HCM) is a genetic disease that causes thickening of the heart's ventricular walls and is a leading cause of sudden cardiac death. HCM is caused by missense mutations in muscle proteins including myosin, but how these mutations alter muscle mechanical performance in largely unknown. We investigated the disease mechanism for HCM myosin mutation R249Q by expressing it in the indirect flight muscle of Drosophila melanogaster and measuring alterations to muscle and flight performance. Muscle mechanical analysis revealed R249Q decreased muscle power production due to slower muscle kinetics and decreased force production; force production was reduced because fewer mutant myosin cross-bridges were bound simultaneously to actin. This work does not support the commonly proposed hypothesis that myosin HCM mutations increase muscle contractility, or causes a gain in function; instead, it suggests that for some myosin HCM mutations, hypertrophy is a compensation for decreased contractility., Abstract: Hypertrophic cardiomyopathy (HCM) is an inherited disease that causes thickening of the heart's ventricular walls. A generally accepted hypothesis for this phenotype is that myosin heavy chain HCM mutations increase muscle contractility. To test this hypothesis, we expressed an HCM myosin mutation, R249Q, in Drosophila indirect flight muscle (IFM) and assessed myofibril structure, skinned fibre mechanical properties, and flight ability. Mechanics experiments were performed on fibres dissected from 2-h-old adult flies, prior to degradation of IFM myofilament structure, which started at 2 days old and increased with age. Homozygous and heterozygous R249Q fibres showed decreased maximum power generation by 67% and 44%, respectively. Decreases in force and work and slower overall muscle kinetics caused homozygous fibres to produce less power. While heterozygous fibres showed no overall slowing of muscle kinetics, active force and work production dropped by 68% and 47%, respectively, which hindered power production. The muscle apparent rate constant 2πb decreased 33% for homozygous but increased for heterozygous fibres. The apparent rate constant 2πc was greater for homozygous fibres. This indicates that R249Q myosin is slowing attachment while speeding up detachment from actin, resulting in less time bound. Decreased IFM power output caused 43% and 33% decreases in Drosophila flight ability and 19% and 6% drops in wing beat frequency for homozygous and heterozygous flies, respectively. Overall, our results do not support the increased contractility hypothesis. Instead, our results suggest the ventricular hypertrophy for human R249Q mutation is a compensatory response to decreases in heart muscle power output., (© 2019 The Authors. The Journal of Physiology © 2019 The Physiological Society.)

The existence of a ligamentous structure within the anterolateral capsule, which can be injured in combination with the anterior cruciate ligament, has been debated. Therefore, the purpose of this study was to determine the magnitude and direction of the strain in the anterolateral capsule in response to external loads applied to the knee. The anterolateral capsule was hypothesized to not function like a traditional ligament. A 6-degree-of-freedom robotic testing system was used to apply ten external loads to human cadaveric knees (n = 7) in the intact and anterior cruciate ligament (ACL) deficient states. The position of strain markers was recorded on the midsubstance of the anterolateral capsule during the resulting joint kinematics to determine the magnitude and direction of the maximum principal strain. The peak maximum principal strain ranged from 22% to 52% depending on the loading condition. When histograms of strain magnitude values were analyzed to determine strain uniformity, the mean kurtosis was 1.296 ± 0.955, lower than a typical ligament, and the mean variance was 0.015 ± 0.008, higher than a typical ligament. The mean angles of the strain direction vectors compared to the proposed ligament ranged between 38° and 130° (p < 0.05). The magnitude of the maximum principal strain in the anterolateral capsule is much larger than a typical ligament and does not demonstrate a uniform strain distribution. The direction of strain is also not aligned with the proposed ligament. Clinical Significance: Reconstruction methods using tendons will not produce normal joint function due to replacement of a multi-axial structure with a uni-axial structure. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res., (© 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)