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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.)

Background: The coronal alignment of the lower limb is generally accepted as a major determinant of surgical outcome in total knee arthroplasty (TKA). To achieve the ideal post-operative alignment, surgeons need to be aware of the influence that weight-bearing positions have on the final knee alignment. Therefore, this review aims to define the effect of varying weight-bearing positions on the coronal alignment of the lower limb. We hypothesized that a coronal alignment deformity increases with loading., Methods: The PubMed, Medline and google scholar databases were searched systematically in June 2022. Only studies which compared coronal alignment with a standardized radiographic protocol in the single leg, double leg and supine positions were included. To obtain pooled estimates of the effect of different weight-bearing positions, random-effect analysis were fitted using SAS., Results: Compared to the supine position, double leg weight-bearing positions were found to be associated with a more pronounced varus deformity (mean difference in HKA is 1,76° (95% CI 1,32: 2,21), p < 0.0001)). The mean difference in HKA between double leg and single leg weight-bearing conditions was 1.43° (95% CI (-0,042;2,90), p = 0.0528)., Conclusion: The overall knee alignment was found to be influenced by the weight-bearing position. An average difference of 1.76° in HKA-angle was found between a double leg-stance and supine position, tending to increased varus in the former weight-bearing position. It is therefore possible that the deformity could increase by 1.76° if knee surgeons only follow a pre-op planning based on double-leg stance full length radiographs., 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 © 2023 Elsevier B.V. All rights reserved.)

Introduction: The concept of restoring the constitutional, pre-diseased alignment has gained lots of interest among knee surgeons. Previous attempts to use the contralateral limb to bridge the gap between the arthritic and the constitutional alignment were unsuccessful. We investigated the usability of a mathematical formula to predict the constitutional (pre-diseased) coronal alignment once arthritis has occurred. It is our hypothesis that by using the KL grade, CPAK classification and four radiographic measurements of the arthritic knee, the pre-diseased coronal alignment could be predicted., Material and Methods: Hundred arthritic patients with consecutive X-rays were used to determine a mathematical formula. Five alignment parameters were determined on full-length X-rays: HKA angle, mechanical lateral distal femoral angle (mLDFA), medial proximal tibial angle (MPTA), joint line convergence angle (JLCA) and the tibial joint line angle (TJLA). A refinement of the algorithm was implemented based on a reference cohort, consisted of 250 young adults aged between 20 and 27 years. Moreover, all knees were subdivided based on their CPAK-phenotype and the Kellgren-Lawrence scale (KL scale). An independent arthritic cohort of 289 patients scheduled for primary total knee arthroplasty was included to verify the accuracy of the predicted HKAs (HKA PRED )., Results: In CPAK type 1, the HKA PRED was 3.86° varus (STD 1.39) and the HKA YHA was 4.0° varus. In CPAK type 2, the HKA PRED was 1.68° varus (STD 1.95) compared to a HKA YHA of 1.34° (STD 0.81). The average constitutional HKA is not different in both CPAK 1 (p = 0.61) and CPAK 2 (p = 0.25), and the difference in the mean is estimated to be equal to - 0.14 (95CI - 0.68 to 0.40) in CPAK 1 and 0.35 (95CI - 0.06 to 0.75) in CPAK 2., Conclusion: Using the KL grade, CPAK classification and four radiographic measurements of the arthritic knee, the pre-diseased coronal alignment can be predicted in 80% of the varus knees with an accuracy of ≤ 0.5°. The predicted HKA (HKA PRED ) can be very useful in the current and future clinical practice., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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.)

Introduction: High-grade varus osteoarthrosis (OA) is characterized by a pronounced intra-articular varus deformity and associated insufficiency of the lateral ligamentous complex. When performing a total knee arthroplasty (TKA) in such a knee, traditionally the alignment is restored to neutral, and the medial soft tissue structures are released to compensate for the lateral laxity and balance the joint. However, another option would be to leave the medial soft tissues untouched and accept the lateral laxity but to compensate for it using an ML-stabilized constrained-condylar knee (CCK) design. Our aim was to prove our hypothesis that such knees would demonstrate better clinical stability and better functionality as well as subjective outcome scores., Materials and Methods: We searched our bicenter database of 912 primary TKAs (from 2016 to 2019) for primary TKA patients with a preoperative varus alignment of > 8°. After inclusion, 60 patients were divided into three groups by implant design: CCK (n = 21), posterior-stabilized (PS) (n = 20) and cruciate-retaining (CR) (n = 19). Oxford Knee Score (OKS), Forgotten Joint Score (FJS), Knee Society Score (KSS), UCLA-activity score, ML instability scores and both radiographic and clinical data were compared between groups., Results: ML stability was significantly better in CCK designs (86% grade 0) compared to CR (37% grade 0) (p = 0.004) but not PS (70% grade 0) designs. No grade II instability was present in CCK and PS implants compared to 16% of CR implants. KSS and UCLA-activity score were higher in CCK designs compared to PS (p = 0.027, p = 0.041) and CR designs (p < 0.001, p = 0.007). OKS and FJS were higher in CCK designs compared to CR (p = 0.025, p = 0.008) but not to PS., Conclusion: The use of a CCK design to compensate for the lateral laxity in high-grade varus OA knees allowed to refrain from a medial release. CCK designs displayed improved clinical stability and better functionality as well as subjective outcome scores compared to less-constrained designs., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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).)

Purpose: Implementation of morphometric reference data from the contralateral, unaffected lower limb is suggested when reconstructing the coronal plane alignment in TKA. Limited information, however, is available which confirms this left-to-right symmetry in coronal alignment based upon radiographs. The purpose of the study was, therefore, (1) to verify if a left-to-right symmetry is present and (2) to assess whether the contralateral lower limb would be a reliable reference for reconstructing the frontal plane alignment., Methods: Full-leg standing radiographs of 250 volunteers (male, 125; female,125) were reviewed for three alignment parameters (Hip-Knee-Ankle angle (HKA), Femoral Mechanical Angle (FMA) and Tibial Mechanical Angle (TMA)). Evaluation of assumed left-to-right symmetry was performed according to two coronal alignment classifications (HKA subdivisions (HKA) and limb, femoral and tibial phenotypes (HKA, FMA and TMA)). Inter- and within-subject variability was calculated, along with correlations coefficients (r) and coefficients of determination (r 2 ). Reliability of the contralateral limb as a personalized reference to reconstruct the constitutional alignment was investigated by intervals, expanding by 1° increments (0.5° increment both to varus and valgus) around the right knee alignment parameters. Subsequently, it was verified whether or not the left knee parameters fell within this interval., Results: Symmetrical distribution in coronal alignment was found in 79% (HKA subdivision) and 59% (limb phenotype) of the cohort. Gender differences were present for the most common symmetric limb phenotypes (VAR HKA 3° (23.2%) in males and NEU HKA 0° (38.4%) in females). Inter-subject variability was more prominent than the within-subject side differences for all parameters. Correlations analyses revealed mostly moderate correlations between the alignment measurements. Coefficients of determination showed overall weak left-to-right relationship, except for a moderate predictability for HKA (r 2  = 0.538, p < 0.001) and FMA (r 2  = 0.618, p < 0.001) in females. FMA and TMA marked weak predictive values for contralateral HKA. Only 60% of left knees were referenced within a 3° interval around the right knee., Conclusion: No strict left-to-right symmetry was observed in coronal alignment measurements. There is insufficient left-to-right agreement to consider the concept of the contralateral unaffected limb as an idealized reference for frontal plane alignment reconstruction based upon full-leg standing radiographs., Level of Evidence: I., (© 2020. European Society of Sports Traumatology, Knee Surgery, Arthroscopy (ESSKA).)

Purpose: The influence of type and intensity of sports during growth on knee alignment was investigated. The second aim was to ascertain whether the distal femur or proximal tibia contribute most to knee alignment. Also, the influence of field position and leg dominancy on knee alignment in soccer players was audited., Methods: Standardized full-leg standing digital radiographs were obtained from 100 males and 100 females on which 8 different alignment parameters were measured. Participants were questioned on their sports activities during different stages of growth. Sports activities were graded according to the Tegner score., Results: The mean (±SD) hip-knee-ankle angle (HKA) was significantly lower (p < 0.001) in high-activity male athletes (-2.8° ± 2.4°) than in low-activity male athletes (-0.9° ± 1.9°). No differences in HKA were observed between different activity levels in females. Males who practiced soccer between 10-12 years and 15-17 years had, in turn, a lower HKA than athletes practicing other high-activity sports in these age categories (mean difference ≥1.2°, p ≤ 0.046). The most contributing factor for the varus alignment in male soccer players was a lower medial proximal tibial angle (MPTA)., Conclusion: High-activity sports participation during youth is associated with varus alignment at the end of growth in males. The most pronounced bowlegs were observed in male soccer players, and this was primarily determined by the proximal tibia. Adjustments in loads applied to the knees during skeletal growth in males might prevent the development of varus alignment and associated pathology, but further studies are required., Level of Evidence: Diagnostic study, Level III.