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Abstract Objectives Cerebral palsy (CP) is the most common childhood motor disability, yet its link to single‐gene disorders is under‐characterized. To explore the genetic landscape of CP, we conducted whole exome sequencing (WES) in a cohort of patients with CP. Methods We performed comprehensive phenotyping and WES on a prospective cohort of individuals with cryptogenic CP (who meet criteria for CP; have no risk factors), non‐cryptogenic CP (who meet criteria for CP; have at least one risk factor), and CP masqueraders (who could be diagnosed with CP, but have regression/progressive symptoms). We characterized motor phenotypes, ascertained medical comorbidities, and classified brain MRIs. We analyzed WES data using an institutional pipeline. Results We included 50 probands in this analysis (20 females, 30 males). Twenty‐four had cryptogenic CP, 20 had non‐cryptogenic CP, five had CP masquerader classification, and one had unknown classification. Hypotonic‐ataxic subtype showed a difference in prevalence across the classification groups (p = 0.01). Twenty‐six percent of participants (13/50) had a pathogenic/likely pathogenic variant in 13 unique genes (ECHS1, SATB2, ZMYM2, ADAT3, COL4A1, THOC2, SLC16A2, SPAST, POLR2A, GNAO1, PDHX, ACADM, ATL1), including one patient with two genetic disorders (ACADM, PDHX) and two patients with a SPAST‐related disorder. The CP masquerader category had the highest diagnostic yield (n = 3/5, 60%), followed by the cryptogenic CP category (n = 7/24, 29%). Fifteen percent of patients with non‐cryptogenic CP (n = 3/20) had a Mendelian disorder on WES. Interpretation WES demonstrated a significant prevalence of Mendelian disorders in individuals clinically diagnosed with CP, including in individuals with known CP risk factors.

Background: Most knee surgeons have believed during TKA neutral mechanical alignment should be restored. A number of patients may exist, however, for whom neutral mechanical alignment is abnormal. Patients with so-called "constitutional varus" knees have had varus alignment since they reached skeletal maturity. Restoring neutral alignment in these cases may in fact be abnormal and undesirable and would likely require some degree of medial soft tissue release to achieve neutral alignment.Questions/purposes: We investigated what percentage of the normal population has constitutional varus knees and what are the contributing factors.Subjects and Methods: We recruited a cohort of 250 asymptomatic adult volunteers between 20 and 27 years old for this cross-sectional study. All volunteers had full-leg standing digital radiographs on which 19 alignment parameters were analyzed. The incidence of constitutional varus alignment was determined and contributing factors were analyzed using multivariate prediction models.Results: Thirty-two percent of men and 17% of women had constitutional varus knees with a natural mechanical alignment of 3° varus or more. Constitutional varus was associated with increased sports activity during growth, increased femoral varus bowing, an increased varus femoral neck-shaft angle, and an increased femoral anatomic mechanical angle.Conclusions: An important fraction of the normal population has a natural alignment at the end of growth of 3° varus or more. This might be a consequence of Hueter-Volkmann's law. Restoration of mechanical alignment to neutral in these cases may not be desirable and would be unnatural for them. [ABSTRACT FROM AUTHOR]

BackgroundRecent studies have sought to describe HIV infection and transmission characteristics around the world. Identification of early HIV-1 infection is essential to proper surveillance and description of regional transmission trends. In this study we compare people recently infected (RI) with HIV-1, as defined by Serologic Testing Algorithm for Recent HIV Seroconversion (STARHS), to those with chronic infection.Methodology/principal findingsSubjects were identified from 2002-2004 at four testing sites in São Paulo. Of 485 HIV-1-positive subjects, 57 (12%) were defined as RI. Of the participants, 165 (34.0%) were aware of their serostatus at the time of HIV-1 testing. This proportion was statistically larger (p59 years-old age strata (pConclusions/significanceIn this study, we evaluated RI individuals and discovered that HIV-1 has been spreading among younger individuals in São Paulo and preventive approaches should, therefore, target this age stratum.

Knee osteoarthritis is a whole joint disease highlighting the coupling of cartilage and bone adaptations. However, the structural properties of the subchondral bone plate (SBP) and underlying subchondral trabecular bone (STB) in the femoral compartment have received less attention compared to the tibial side. Furthermore, how the properties in the femoral compartment relate to those in the corresponding tibial site is unknown. Therefore, this study aimed to quantify the structural bone and cartilage morphology in the femoral compartment and investigate its association with those of the tibial plateau. Specifically, tibial plateaus and femoral condyles were retrieved from 28 patients with end-stage knee-osteoarthritis (OA) and varus deformity. The medial condyle of tibial plateaus and the distal part of the medial femoral condyles were micro-CT scanned (20.1 μm/voxel). Cartilage thickness (Cart.Th), SBP, and STB microarchitecture were quantified. Significant ( P  < <.001; 0.79 ≤  r  ≤ 0.97) correlations with a relative difference within 10% were found between the medial side of the femoral and tibial compartments. The highest correlations were found for SBP porosity ( r  = 0.97, mean absolute difference of 0.50%, and mean relative difference of 9.41%) and Cart.Th ( r  = 0.96, mean absolute difference of 0.18 mm, and relative difference of 7.08%). The lowest correlation was found for trabecular thickness ( r  = 0.79, mean absolute difference of 21.07 μm, and mean relative difference of 5.17%) and trabecular number ( r  = 0.79, mean absolute difference of 0.18 mm- 1 , and relative difference of 5.02%). These findings suggest that the distal femur is affected by OA in a similar way as the proximal tibia. Given that bone adaptation is a response to local mechanical forces, our results suggest that varus deformity similarly affects the stress distribution of the medial tibial plateau and the medial distal femur., Competing Interests: All authors state that they have no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

Objectives: The idea to aim for an "individualized" alignment, whereby the constitutional alignment is restored, has gained much interest among knee surgeons. This requires insight into the prediseased, natural alignment of our patients' knees. The aim of this study is (1) to determine how the hip-knee-ankle (HKA) angle is influenced during the arthritic process and (2) to investigate the correlation between joint line changes and the progression of osteoarthritis (OA). It is our hypothesis that the most pronounced coronal parameter changes appear at the proximal tibia and at the joint line., Methods: One hundred sequential full-length X-rays with a minimum follow-up of 1 year were retrospectively reviewed from a radiographic joint database. Patients had to be at least 50 years of age needed to have an HKA angle of more than 1.3° varus to be included. Patients with ipsilateral total hip arthroplasty, femoral or tibial fracture, osteotomy, or ligamentous repair were excluded. Fifteen alignment parameters were investigated on the sequential full-length X-rays. Moreover, the relationship between the alignment parameters and the Kellgren-Lawrence grade (KL grade) was determined by using linear mixed models., Results: A progressive KL grade is associated with an increase of the HKA (p < 0.001). Mostly, HKA differs due to decrease of the medial tibial plateau (MPTA) angle (0.93°) and an increase of the joint line angle (JLCA) (0.86°). The mLDFA demonstrated the most pronounced changes in the beginning of OA (KL grade 1-2) (p = 0.049). In particular, the MPTA becomes considerably smaller (p = 0.004) in the later stage of OA (KL grade 3). Also, a progressive increase of the JLCA (p < 0.001) is observed upwards of KL grade 3., Conclusion: By comparing consecutive full-length X-rays in the same patients, it is possible to define the coronal alignment changes during the arthritic process. The HKA angle increases according the arthritic progression, whereby the most pronounced changes appear at the proximal tibia (MPTA) and at the joint line (JLCA).The alignment changes in varus OA knees can be divided in three stadia: (1) erosion of the distal medial femoral condyle, (2) erosion of the medial tibial plateau, and (3) a progressive increase of the joint line angle., Level of Evidence: Therapeutic Study, Level III., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Recent studies highlighted the crucial contribution of subchondral bone to OA development. Yet, only limited data have been reported on the relation between alteration to cartilage morphology, structural properties of the subchondral bone plate (SBP) and underlying subchondral trabecular bone (STB). Furthermore, the relationship between the morphometry of the cartilage and bone in the tibial plateau and the OA-induced changes in the joint's mechanical axis remains unexplored. Therefore, a visualisation and quantification of cartilage and subchondral bone microstructure in the medial tibial plateau was performed. End stage knee-OA patients with varus alignment and scheduled for total knee arthroplasty (TKA) underwent preoperative fulllength radiography to measure the hip-knee-ankle angle (HKA) and the mechanical-axis deviation (MAD). 18 tibial plateaux were μ-CT scanned (20.1 μm/voxel). Cartilage thickness, SBP, and STB microarchitecture were quantified in 10 volumes of interest (VOIs) in each medial tibial plateau. Significant differences (p < 0.001) were found for cartilage thickness, SBP, and STB microarchitecture parameters among the VOIs. Closer to the mechanical axis, cartilage thickness was consistently smaller, while SBP thickness and STB bone volume fraction (BV/TV) were higher. Moreover, trabeculae were also more superior-inferiorly oriented, i.e. perpendicular to the transverse plane of the tibial plateau. As cartilage and subchondral bone changes reflect responses to local mechanical loading patterns in the joint, the results suggested that region-specific subchondral bone adaptations were related to the degree of varus deformity. More specifically, subchondral sclerosis appeared to be most pronounced closer to the mechanical axis of the knee.

Purpose: It is usually assumed that the severity of varus osteoarthritis (OA) of the knee is correlated with the axis deviation of the limb. Despite this, there is currently no clear radiographic definition to define a so-called 'high degree' varus knee, which is characterized by a pronounced lateral ligamentous laxity. The purpose of this study was to radiographically determine if the lateral joint line opening (LJLO) is an indicative parameter when defining so-called high grade varus knees., Methods: Two hundred forty Full length radiographs of patients with end-stage varus osteoarthritis who were scheduled for Total knee arthroplasty (TKA) were evaluated. The Hip-knee-ankle-angle (HKA-angle), Joint-line-convergence-angle (JLCA) and the lateral joint line opening were measured. The lateral joint line opening is the shortest distance between the lateral tibial plateau and the deepest point of the lateral femoral condyle. Linear regression models were used to investigate the relationships between the radiographic measurements., Results: Hip-knee-angle-angle, joint-line-conversion-angle, and lateral joint line opening were all positively correlated (p < 0.001). An increase of 1 mm lateral joint line opening causes an increase of 0.6° joint-line-conversion-angle (p = 0.029) below a cut-off point of 4.7 mm. For lateral opening values beyond 4.7 mm, the gradient increased to 1.2 (p < 0.001). A lateral joint line opening of 4.7 mm corresponds to a hip-knee-ankle-angle of 6.0° (95% CI [5.5; 6.5])., Conclusion: A lateral joint line opening of more than 5 mm in end-stage OA knees is indicative of increased lateral joint laxity. Those knees can be radiographically classified as so-called 'high-grade' varus knees., Level of Evidence: Therapeutic study, Level III., (© 2022. The Author(s).)