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Purpose The purpose of this review is to perform a meta-analysis of studies reporting meniscus repair outcomes. Pooled analyses of such studies will provide an accurate estimate of the outcomes that can be expected following meniscal repair at various postoperative time points. Methods A meta-analysis of meniscal repair failure (defined as persistent symptoms, lack of healing on magnetic resonance imaging or revision surgery) and other clinical outcomes was performed following meniscal repair. Patients included had traumatic, nondegenerative meniscal tears, were skeletally mature, and had specific time-points after surgery. Repairs included were performed either in isolation, or with concomitant ACL reconstruction. Because of the inherent heterogeneity of single-arm meta-analyses, pooled analyses were performed using a random-effects model. Results Rates of all-cause meniscal repair failure was pooled to be 12% at 0-1 years (95% CI: .09-.16), 15% at 2-3 years (95% CI: .11-.20), and 19% at 4-6 years (95% CI: .13-.24). Sensitivity analysis for studies performing meniscal repair entirely on patients with concomitant ACL reconstruction (ACLR) showed comparable rates of failure at similar time intervals. Development of osteoarthritis, in patients with knees previously free from articular pathologies, was 4% at 2-3 years (95% CI: .02-.07), and 10% at 4-6 years (95% CI: .03-.25). Conclusion Meniscus repair for traumatic injuries have an all-cause failure rate that increases from 12% to 19% through a time period ranging from 1-6 years following surgery. The failure rates were comparable for patients with meniscal repairs performed with concomitant ACLRs. Level of Evidence IV; Systematic Review of Level II-IV Studies.

Terminal osseous dysplasia with pigmentary defects (TODPD), also known as digitocutaneous dysplasia, is one of the X-linked filaminopathies caused by a variety of FLNA-variants. TODPD is characterized by skeletal defects, skin fibromata and dysmorphic facial features. So far, only a single recurrent variant (c.5217G>A;p.Val1724_Thr1739del) in FLNA has found to be responsible for TODPD. We identified a novel c.5217+5G>C variant in FLNA in a female proband with skeletal defects, skin fibromata, interstitial lung disease, epilepsy, and restrictive cardiomyopathy. This variant causes mis-splicing of exon 31 predicting the production of a FLNA-protein with an in-frame-deletion of 16 residues identical to the miss-splicing-effect of the recurrent TODPD c.5217G>A variant. This mis-spliced transcript was explicitly detected in heart tissue, but was absent from blood, skin, and lung. X-inactivation analyses showed extreme skewing with almost complete inactivation of the mutated allele (>90%) in these tissues, except for heart. The mother of the proband, who also has fibromata and skeletal abnormalities, is also carrier of the FLNA-variant and was diagnosed with noncompaction cardiomyopathy after cardiac screening. No other relevant variants in cardiomyopathy-related genes were found. Here we describe a novel variant in FLNA (c.5217+5G>C) as the second pathogenic variant responsible for TODPD. Cardiomyopathy has not been described as a phenotypic feature of TODPD before.

Introduction: Carbohydrate intake and physical activity are related to glucose homeostasis, both being influenced by individual genetic makeup. However, the interactions between these 2 factors, as affected by genetics, on glycaemia have been scarcely reported. Objective: We focused on analysing the interplay between carbohydrate intake and physical activity levels on blood glucose, taking into account a genetic risk score (GRS), based on SNPs related to glucose/energy metabolism. Methods: A total of 1,271 individuals from the Food4Me cohort, who completed the nutritional intervention, were evaluated at baseline. We collected dietary information by using an online-validated food frequency questionnaire, a questionnaire on physical activity, blood biochemistry by analysis of dried blood spots, and by analysis of selected SNPs. Fifteen out of 31 SNPs, with recognized participation in carbohydrate/energy metabolism, were included in the component analyses. The GRS included risk alleles involved in the control of glycaemia or energy-yielding processes. Results: Data concerning anthropometric, clinical, metabolic, dietary intake, physical activity, and genetics related to blood glucose levels showed expected trends in European individuals of comparable sex and age, being categorized by lifestyle, BMI, and energy/carbohydrate intakes, in this Food4Me population. Blood glucose was inversely associated with physical activity level (β = −0.041, p = 0.013) and positively correlated with the GRS values (β = 0.015, p = 0.047). Interestingly, an interaction affecting glycaemia, concerning physical activity level with carbohydrate intake, was found (β = −0.060, p = 0.033), which also significantly depended on the genetic background (GRS). Conclusions: The relationships of carbohydrate intake and physical activity are important in understanding glucose homeostasis, where a role for the genetic background should be ascribed.

Objectives We explored efficacy and safety of IVIg as first-line treatment in patients with an idiopathic inflammatory myopathy. Methods In this investigator-initiated phase 2 open-label study, we included 20 adults with a newly diagnosed, biopsy-proven idiopathic inflammatory myopathy, and a disease duration of less than 9 months. Patients with IBM and prior use of immunosuppressants were excluded. The standard treatment regimen consisted of IVIg (Privigen) monotherapy for 9 weeks: a loading dose (2 g/kg body weight) and two subsequent maintenance doses (1 g/kg body weight) with a 3-week interval. The primary outcome was the number of patients with at least moderate improvement on the 2016 ACR/EULAR Total Improvement Score. Secondary outcomes included time to improvement, the number of patients requiring rescue medication and serious adverse events. Results We included patients with DM (n = 9), immune-mediated necrotizing myopathy (n = 6), non-specific myositis/overlap myositis (n = 4) and anti-synthetase syndrome (n = 1). One patient was excluded from analyses because of minimal weakness resulting in a ceiling effect. Eight patients (8/19 = 42.0%; Clopper–Pearson 95% CI: 19.6, 64.6) had at least moderate improvement by 9 weeks. Of these, six reached improvement by 3 weeks. Seven patients required rescue medication due to insufficient efficacy and prematurely ended the study. Three serious adverse events occurred, of which one was pulmonary embolism. Conclusion First-line IVIg monotherapy led to at least moderate improvement in nearly half of patients with a fast clinical response in the majority of responders. Trial registration Netherlands Trial Register identifier, NTR6160.

Background and purpose — Platelet-rich plasma (PRP) is broadly used in the treatment of knee osteoarthritis, but clinical outcomes are highly variable. We evaluated the effectiveness of intra-articular injections with Autologous Conditioned Plasma (ACP), a commercially available form of platelet-rich plasma, in a tertiary referral center. Second, we aimed to identify which patient factors are associated with clinical outcome. Patients and methods — 140 patients (158 knees) with knee osteoarthritis (Kellgren and Lawrence grade 0–4) were treated with 3 intra-articular injections of ACP. The Knee Injury and Osteoarthritis Outcome Score (KOOS), pain (Numeric Rating Scale; NRS), and general health (EuroQol 5 Dimensions; EQ5D) were assessed at baseline and 3, 6, and 12 months’ follow-up. The effect of sex, age, BMI, Kellgren and Lawrence grade, history of knee trauma, and baseline KOOS on clinical outcome at 6 and 12 months was determined using linear regression. Results — Mean KOOS increased from 37 at baseline to 44 at 3 months, 45 at 6 months, and 43 at 12 months’ follow-up. Mean NRS-pain decreased from 6.2 at baseline to 5.3 at 3 months, 5.2 at 6 months, and 5.3 at 12 months. EQ5D did not change significantly. There were no predictors of clinical outcome. Interpretation — ACP does not lead to a clinically relevant improvement (exceeding the minimal clinically important difference) in patients suffering from knee osteoarthritis. None of the investigated factors predicts clinical outcome.

There is limited data comparing the outcomes of knee arthroplasty for arthritis secondary to meniscus root tear versus primary osteoarthritis. The aim of this 2:1 matched case control series was to compare outcomes in patients who underwent arthroplasty for arthritis following a meniscus root tear (root tear cohort—“RTC”) with a control group of patients with primary osteoarthritis (primary osteoarthritis—“controls”). The authors hypothesized that the meniscus root tear patients would have similar clinical outcomes, return to activity, complication and reoperation rates as their matched controls. A consecutive series of patients who had a clinically and radiographically confirmed meniscus root tear between 2002 and 2017 at a mean 4.8 year follow-up that developed secondary arthritis were matched 2:1 by laterality, surgery, age at surgery, date of surgery, sex, and surgeon to a control group of patients with primary osteoarthritis, without a root tear, who underwent arthroplasty. No patients were lost to follow-up. Patient demographics, Kellgren–Lawrence grades at the time of surgery, pre- and post-operative Knee Society Score pain and function scores, Tegner score, complications, and survival free of reoperation were analyzed between groups. A total of 225 subjects were identified, including 75 root tear cohort patients (13 UKA, 62 TKA) and 150 control patients. The root tear cohort had significantly lower Kellgren–Lawrence grades than the control group at the time of arthroplasty (p ≤ 0.001), but similar baseline pre-operative Knee Society Score pain, Knee Society Score function, and Tegner activity scale score. Post-operatively, Knee Society Score pain scores were comparable, and root tear cohort Knee Society Score function scores statistically significantly improved (p ≤ 0.007). Complication rates and survival free of reoperation at final follow-up were not statistically significantly different between groups. Patients treated with arthroplasty for secondary arthritis after a meniscus root tear demonstrated less severe radiographic arthritis, but similar pre-operative pain levels compared to matched controls with primary osteoarthritis. The root tear cohort patients demonstrated improved outcomes with respect to function, and similar outcomes with respect to pain, activity level, complication rates, and reoperation rates. The authors conclude that arthroplasty can be a reliable option for selected patients with an irreparable root tear and ongoing pain and dysfunction refractory to non-operative management, even in the setting of less advanced osteoarthritis on X-ray. III.

Cartilage injuries in the knee are common and can occur in isolation or in combination with limb malalignment, meniscus, ligament, and bone deficiencies. Each of these problems must be addressed to achieve a successful outcome for any cartilage restoration procedure. If nonsurgical management fails, surgical treatment is largely based on the size and location of the cartilage defect. Preservation of the patient's native cartilage is preferred if an osteochondral fragment can be salvaged. Chondroplasty and osteochondral autograft transfer are typically used to treat small (

Pompe disease is a metabolic disorder caused by a deficiency of the glycogen-hydrolyzing lysosomal enzyme acid α-glucosidase (GAA), which leads to progressive muscle wasting. This autosomal-recessive disorder is the result of disease-associated variants located in the GAA gene. In the present study, we performed extended molecular diagnostic analysis to identify novel disease-associated variants in six suspected Pompe patients from four different families for which conventional diagnostic assays were insufficient. Additional assays, such as a generic-splicing assay, minigene analysis, SNP array analysis, and targeted Sanger sequencing, allowed the identification of an exonic deletion, a promoter deletion, and a novel splicing variant located in the 5' UTR. Furthermore, we describe the diagnostic process for an infantile patient with an atypical phenotype, consisting of left ventricular hypertrophy but no signs of muscle weakness or motor problems. This led to the identification of a genetic mosaicism for a very severe GAA variant caused by a segmental uniparental isodisomy (UPD). With this study, we aim to emphasize the need for additional analyses to detect new disease-associated GAA variants and non-Mendelian genotypes in Pompe disease where conventional DNA diagnostic assays are insufficient. ispartof: MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT vol:17 pages:337-348 ispartof: location:United States status: published

Background: Recent evidence indicates that insulin resistance (IR) in obesity may develop independently in different organs, representing different etiologies toward type 2 diabetes and other cardiometabolic diseases. The aim of this study was to investigate whether IR in the liver and IR in skeletal muscle are associated with distinct metabolic profiles. Methods: This study includes baseline data from 634 adults with overweight or obesity (BMI ≥ 27 kg/m 2) (≤65 years; 63% women) without diabetes of the European Diogenes Study. Hepatic insulin resistance index (HIRI) and muscle insulin sensitivity index (MISI), were derived from a five-point OGTT. At baseline 17 serum metabolites were identified and quantified by nuclear-magnetic-resonance spectroscopy. Linear mixed model analyses (adjusting for center, sex, body mass index (BMI), waist-to-hip ratio) were used to associate HIRI and MISI with these metabolites. In an independent sample of 540 participants without diabetes (BMI ≥ 27 kg/m 2; 40–65 years; 46% women) of the Maastricht Study, an observational prospective population-based cohort study, 11 plasma metabolites and a seven-point OGTT were available for validation. Results: Both HIRI and MISI were associated with higher levels of valine, isoleucine, oxo-isovaleric acid, alanine, lactate, and triglycerides, and lower levels of glycine (all p < 0.05). HIRI was also associated with higher levels of leucine, hydroxyisobutyrate, tyrosine, proline, creatine, and n-acetyl and lower levels of acetoacetate and 3-OH-butyrate (all p < 0.05). Except for valine, these results were replicated for all available metabolites in the Maastricht Study. Conclusions: In persons with obesity without diabetes, both liver and muscle IR show a circulating metabolic profile of elevated (branched-chain) amino acids, lactate, and triglycerides, and lower glycine levels, but only liver IR associates with lower ketone body levels and elevated ketogenic amino acids in circulation, suggestive of decreased ketogenesis. This knowledge might enhance developments of more targeted tissue-specific interventions to prevent progression to more severe disease stages.

Background Patients with the clinical symptoms of knee or hip osteoarthritis without solid X-ray features present a therapeutic dilemma. The question arises whether the decision for a surgical treatment should be based on the clinical presentation or the X-ray. Objective To determine prognostic patient factors for knee and hip arthroplasty when the X-ray does only show Kellgren and Lawrence grade 0–2 osteoarthritis. Study design Nationwide prospective cohort study. Methods Participants of the Cohort Hip and Cohort Knee (CHECK) with KL 0–2 osteoarthritis on the X-ray were contacted to determine whether any knee or hip arthroplasty had taken place. A Cox proportional hazards regression analysis was performed to find baseline patient factors predicting the decision for arthroplasty. Results Regarding the knee, sex HR 0.207 P = 0.030, BMI HR 1.081 P = 0.018 and WOMAC total sum score HR 1.022 P = 0.017 were statistically significant predictors of the outcome arthroplasty. Age was not a significant predictor (P = 0.079). Concerning the hip, sex HR 2.103 P = 0.012, age HR 1.062 P = 0.022 and WOMAC total sum score HR 1.019 P = 0.029 were found to be statistically significant predictors for arthroplasty. BMI (P = 0.576), contralateral pain (P = 0.877) and health perception (P = 0.405) did not predict the end point hip arthroplasty. Conclusion Predictors for knee arthroplasty were being female, having a higher BMI and a higher WOMAC total sum score. Predictors for hip arthroplasty were being male, having a higher age and a higher WOMAC total sum score. The incidence of arthroplasty was 5.1% (10.2 years) for the knee and 10.2% (9.7 years) for the hip.

BACKGROUND Spontaneous osteonecrosis of the knee has recently been termed subchondral insufficiency fracture of the knee (SIFK) to appropriately recognize the etiology of mechanical overloading of the subchondral bone. The purpose of this study was to assess clinical outcomes of SIFK based on progression to surgical treatment and arthroplasty, and to evaluate the risk factors that increase the progression to arthroplasty. METHODS A retrospective review was performed on patients with a diagnosis of SIFK, as confirmed with use of magnetic resonance images (MRIs). Baseline and final radiographs were reviewed. Baseline MRIs were also reviewed for injury characteristics. Failure was defined as progression to surgical treatment or conversion to arthroplasty. RESULTS Two hundred twenty-three patients (71% female) with a mean age of 65.1 years were included. SIFK affected 154 femora (69%) and 123 tibiae (55%), with medial compartment involvement in 198 knees (89%); 74% of medial menisci had root or radial tears, with a mean extrusion of 3.6 mm. Varus malalignment was identified in 54 (69%) of 78 knees. Seventy-six (34%) of all patients progressed to surgical intervention at 2.7 years, and 66 (30%) underwent arthroplasty at 3.0 years. The rates of conversion to surgical intervention and arthroplasty increased to 47% (37 of 79; p = 0.04) and 37% (29 of 79; p = 0.09), respectively, in patients with >5 years of follow-up. The 10-year survival rate free of arthroplasty for patients with SIFK on the medial femoral condyle (p < 0.01), SIFK on the medial tibial plateau (p < 0.01), medial meniscal extrusion (p = 0.01), varus alignment (p = 0.02), and older age (per year older; p = 0.003) was significantly higher than the survival rates of those without each respective condition. CONCLUSIONS Subchondral insufficiency fractures predominantly involve the medial compartment of the knee and commonly present with medial meniscal root and radial tears. Approximately one-third of patients progressed to total knee arthroplasty. Baseline arthritis, older age, location of the insufficiency fracture on both the medial femoral condyle and medial tibial plateau, meniscal extrusion, and varus malalignment were all associated with progression to arthroplasty. LEVEL OF EVIDENCE Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

BACKGROUND: Emotion recognition constitutes a pivotal process of social cognition. It involves decoding social cues (e.g., facial expressions) to maximise social adjustment. Current theoretical models posit the relationship between social withdrawal factors (social disengagement, lack of social interactions and loneliness) and emotion decoding.OBJECTIVE: To investigate the role of social withdrawal in patients with schizophrenia (SZ) or probable Alzheimer's disease (AD), neuropsychiatric conditions associated with social dysfunction.METHODS: A sample of 156 participants was recruited: schizophrenia patients (SZ; n = 53), Alzheimer's disease patients (AD; n = 46), and two age-matched control groups (SZc, n = 29; ADc, n = 28). All participants provided self-report measures of loneliness and social functioning, and completed a facial emotion detection task.RESULTS: Neuropsychiatric patients (both groups) showed poorer performance in detecting both positive and negative emotions compared with their healthy counterparts (p CONCLUSIONS: Our findings help to detail the similarities and differences in social function and facial emotion recognition in two disorders rarely studied in parallel, AD and SZ. Transdiagnostic patterns in these results suggest that social withdrawal is associated with heightened sensitivity to negative emotion expressions, potentially reflecting hypervigilance to social threat. Across the neuropsychiatric groups specifically, this hypervigilance associated with social withdrawal extended to positive emotion expressions, an emotional-cognitive bias that may impact social functioning in people with severe mental illness.

Objectives: Social dysfunction is one of the most common signs of major neuropsychiatric disorders. The Default Mode Network (DMN) is crucially implicated in both psychopathology and social dysfunction, although the transdiagnostic properties of social dysfunction remains unknown. As part of the pan-European PRISM (Psychiatric Ratings using Intermediate Stratified Markers) project, we explored cross-disorder impact of social dysfunction on DMN connectivity. Methods: We studied DMN intrinsic functional connectivity in relation to social dysfunction by applying Independent Component Analysis and Dual Regression on resting-state fMRI data, among schizophrenia (SZ; N=48), Alzheimer disease (AD; N=47) patients and healthy controls (HC; N=55). Social dysfunction was operationalised via the Social Functioning Scale (SFS) and De Jong-Gierveld Loneliness Scale (LON). Results: Both SFS and LON were independently associated with diminished DMN connectional integrity within rostromedial prefrontal DMN subterritories (pcorrected range=0.02–0.04). The combined effect of these indicators (Mean.SFS + LON) on diminished DMN connectivity was even more pronounced (both spatially and statistically), independent of diagnostic status, and not confounded by key clinical or sociodemographic effects, comprising large sections of rostromedial and dorsomedial prefrontal cortex (pcorrected =0.01). Conclusions: These findings pinpoint DMN connectional alterations as putative transdiagnostic endophenotypes for social dysfunction and could aid personalised care initiatives grounded in social behaviour, The project leading to this application has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115916. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. This publication reflects only the author’s views and neither the IMI 2JU nor EFPIA nor the European Commission are liable for any use that may be made of the information contained therein

The exact immunopathophysiology of community-acquired pneumonia (CAP) caused by SARS-CoV-2 (COVID-19) remains clouded by a general lack of relevant disease controls. The scarcity of single-cell investigations in the broader population of patients with CAP renders it difficult to distinguish immune features unique to COVID-19 from the common characteristics of a dysregulated host response to pneumonia. We performed integrated single-cell transcriptomic and proteomic analyses in peripheral blood mononuclear cells from a matched cohort of eight patients with COVID-19, eight patients with CAP caused by Influenza A or other pathogens, and four non-infectious control subjects. Using this balanced, multi-omics approach, we describe shared and diverging transcriptional and phenotypic patterns-including increased levels of type I interferon-stimulated natural killer cells in COVID-19, cytotoxic CD8 T EMRA cells in both COVID-19 and influenza, and distinctive monocyte compositions between all groups-and thereby expand our understanding of the peripheral immune response in different etiologies of pneumonia., peer-reviewed

ObjectivesTo describe the combination of spinocerebellar ataxia (SCA) types 3 and 6 and sporadic inclusion body myositis (IBM).MethodsA description of five patients with SCA type 3 and 6 who were diagnosed with IBM. We explore possible mechanisms explaining the coexistence of both diseases.ResultsThe patients with SCA-3 (n=4) and SCA-6 (n=1) developed asymmetric muscle weakness in a pattern suggestive of IBM in the course of their disease. Based on findings of neurological examination and additional investigations (muscle ultrasound, muscle biopsy), the diagnosis of IBM was made in all patients.ConclusionWe report on five patients with concomitant SCA and IBM. Our cases may merely illustrate coincidental co-occurrence of IBM and SCA-3/SCA-6. However, the presence of SCA mutations could predispose to the development of IBM in some SCA patients, or, the presence of toxic aggregates and malfunctioning of cellular quality control processes in both diseases could indicate a convergence of disease mechanisms.

Obesity-related insulin resistance (IR) may develop in multiple organs, representing various etiologies for cardiometabolic diseases. We identified abdominal subcutaneous adipose tissue (ScAT) transcriptome profiles in liver or muscle IR by means of RNA sequencing in overweight or obese participants of the Diet, Obesity, and Genes (DiOGenes) (NCT00390637, ClinicalTrials.gov) cohort (n = 368). Tissue-specific IR phenotypes were derived from a 5-point oral glucose tolerance test. Hepatic and muscle IR were characterized by distinct abdominal ScAT transcriptome profiles. Genes related to extracellular remodeling were upregulated in individuals with primarily hepatic IR, while genes related to inflammation were upregulated in individuals with primarily muscle IR. In line with this, in two independent cohorts, the Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) (n = 325) and the Maastricht Study (n = 685), an increased systemic low-grade inflammation profile was specifically related to muscle IR but not to liver IR. We propose that increased ScAT inflammatory gene expression may translate into an increased systemic inflammatory profile, linking ScAT inflammation to the muscle IR phenotype. These distinct IR phenotypes may provide leads for more personalized prevention of cardiometabolic diseases.

Candida auris (C. auris) is an emerging fungal pathogen causing invasive infections and outbreaks that have been difficult to control in healthcare facilities worldwide. There is a lack of current evidence for pragmatic infection prevention and control recommendations. The aim of this paper was to review the epidemiology of C. auris and identify best practices with a panel of experts, in order to provide guidance and recommendations for infection prevention and control measures based on available scientific evidence, existing guidelines and expert opinion. The Infection Prevention and Control working group of the International Society of Antimicrobial Chemotherapy organised an expert meeting with infection prevention and mycology experts to review recommendations for healthcare workers on infection prevention and control measures for C. auris at inpatient healthcare facilities. The most common interventions included: screening, standard precautions, cleaning and disinfection, inpatient transfer, outbreak management, decolonisation, and treatment.

Contains fulltext : 207009.pdf (Publisher’s version ) (Closed access) The diagnosis and classification of idiopathic inflammatory myopathies are based mainly on clinical and histological features. The discovery of myositis-specific and myositis-associated antibodies has simplified the (sub)classification of inflammatory myopathies. Patients suspected of having an idiopathic inflammatory myopathy should undergo routine antibody testing to gain more insight into distinct phenotypes, comorbidities, treatment response and prognosis. Furthermore, autoantibody testing can help in patients with atypical patterns of weakness or with an unresolved limb-girdle myopathic phenotype, or interstitial lung disease. However, some important technical and methodological issues can hamper the interpretation of antibody testing; for example, some antibodies are not included in the widely available line blots. We aim to provide a practical review of the use of autoantibody testing in idiopathic inflammatory myopathies in clinical practice.

Background Single photon emission computed tomography (SPECT/CT) is a diagnostic option for knee osteoarthritis patients without osteoarthritic features on X-ray; however, the added value of SPECT/CT remains debatable in the diagnostic algorithm. Objective To review the added value of SPECT/CT in the diagnostic algorithm of knee osteoarthritis. Study Design Systematic review Methods A systematic search was carried out in the databases EMBASE, MEDLINE, and the Cochrane collaboration. The retrieved articles were screened for relevance on title and abstract. This was followed by a full-text study quality appraisal of the remaining articles. Finally, a total of 9 trials were included. Results The use of SPECT/CT might objectify some clinical knee osteoarthritis symptoms. It could correlate with findings on plain radiography and magnetic resonance imaging. Furthermore, there is some evidence SPECT/CT gives additional information compared with these imaging modalities; however, superiority is not proven. The uptake on SPECT could predict the intraoperative macroscopic findings. Yet the clinical relevance remains unclear. Conclusion There is no strong evidence SPECT/CT should play a role in the diagnosing and decision-making processes of knee osteoarthritis. Yet there is evidence suggesting SPECT/CT might give additional information in the diagnosing process. More research would be of added value to answer this research question.

Collaboration from previous work institution. Free PMC article: https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/30737479/ Analyses in our diagnostic DNA laboratory include genes involved in autosomal recessive (AR) lysosomal storage disorders such as glycogenosis type II (Pompe disease) and mucopolysaccharidosis type I (MPSI, Hurler disease). We encountered 4 cases with apparent homozygosity for a disease-causing sequence variant that could be traced to one parent only. In addition, in a young child with cardiomyopathy, in the absence of other symptoms, a diagnosis of Pompe disease was considered. Remarkably, he presented with different enzymatic and genotypic features between leukocytes and skin fibroblasts. All cases were examined with microsatellite markers and SNP genotyping arrays. We identified one case of total uniparental disomy (UPD) of chromosome 17 leading to Pompe disease and three cases of segmental uniparental isodisomy (UPiD) causing Hurler-(4p) or Pompe disease (17q). One Pompe patient with unusual combinations of features was shown to have a mosaic segmental UPiD of chromosome 17q. The chromosome 17 UPD cases amount to 11% of our diagnostic cohort of homozygous Pompe patients (plus one case of pseudoheterozygosity) where segregation analysis was possible. We conclude that inclusion of parental DNA is mandatory for reliable DNA diagnostics. Mild or unusual phenotypes of AR diseases should alert physicians to the possibility of mosaic segmental UPiD. SNP genotyping arrays are used in diagnostic workup of patients with developmental delay. Our results show that even small Regions of Homozygosity that include telomeric areas are worth reporting, regardless of the imprinting status of the chromosome, as they might indicate segmental UPiD. info:eu-repo/semantics/publishedVersion

Background: The adipose tissue (AT) is a secretory organ producing a wide variety of factors that participate in the genesis of metabolic disorders linked to excess fat mass. Weight loss improves obesity-related disorders.Objectives: Transcriptomic studies on human AT, and a combination of analyses of transcriptome and proteome profiling of conditioned media from adipocytes and stromal cells isolated from human AT, have led to the identification of apolipoprotein M (apoM) as a putative adipokine. We aimed to validate apoM as novel adipokine, investigate the relation of AT APOM expression with metabolic syndrome and insulin sensitivity, and study the regulation of its expression in AT and secretion during calorie restriction-induced weight loss.Methods: We examined APOM mRNA level and secretion in AT from 485 individuals enrolled in 5 independent clinical trials, and in vitro in human multipotent adipose-derived stem cell adipocytes. APOM expression and secretion were measured during dieting.Results: APOM was expressed in human subcutaneous and visceral AT, mainly by adipocytes. ApoM was released into circulation from AT, and plasma apoM concentrations correlate with AT APOM mRNA levels. In AT, APOM expression inversely correlated with adipocyte size, was lower in obese compared to lean individuals, and reduced in subjects with metabolic syndrome and type 2 diabetes. Regardless of fat depot, there was a positive relation between AT APOM expression and systemic insulin sensitivity, independently of fat mass and plasma HDL cholesterol. In human multipotent adipose-derived stem cell adipocytes, APOM expression was enhanced by insulin-sensitizing peroxisome proliferator-activated receptor agonists and inhibited by tumor necrosis factor a, a cytokine that causes insulin resistance. In obese individuals, calorie restriction increased AT APOM expression and secretion.Conclusions: ApoM is a novel adipokine, the expression of which is a hallmark of healthy AT and is upregulated by calorie restriction. AT apoM deserves further investigation as a potential biomarker of risk for diabetes and cardiovascular diseases.

Background: Anterior cruciate ligament (ACL) injury is one of the most frequent orthopaedic injuries and reasons for time loss in sports and carries significant implications, including posttraumatic osteoarthritis (OA). Instability associated with ACL injury has been linked to the development of secondary meniscal tears (defined as tears that develop after the initial ACL injury). To date, no study has examined secondary meniscal tears after ACL injury and their effect on OA and arthroplasty risk. Purpose: To describe the rates and natural history of secondary meniscal tears after ACL injury and to determine the effect of meniscal tear treatment on the development of OA and conversion to total knee arthroplasty (TKA). Study Design: Cohort study; Level of evidence, 3. Methods: A geographic database of >500,000 patients was reviewed to identify patients with primary ACL injuries between January 1, 1990, and December 31, 2005. Information was collected with regard to ACL injury treatment, rates/characteristics of the secondary meniscal tears, and outcomes, including development of OA and conversion to TKA. Kaplan-Meier and adjusted multivariate survival analyses were performed to test for the effect of meniscal treatment on survivorship free of OA and TKA. Results: Of 1398 primary ACL injuries, the overall rate of secondary meniscal tears was 16%. Significantly lower rates of secondary meniscal tears were noted among patients undergoing acute ACL reconstruction within 6 months (7%) as compared with patients with delayed ACL reconstruction (33%, P < .01) and nonoperative ACL management (19%, P < .01). Of the 235 secondary meniscal tears identified (196 patients), 11.5% underwent repair, 73% partial meniscectomy, and 16% were treated nonoperatively. Tears were most often medial in location (77%) and complex in morphology (56% of medial tears, 54% of lateral tears). At the time of final follow-up, no patient undergoing repair of a secondary meniscal tear (0%) underwent TKA, as opposed to 10.9% undergoing meniscectomy and 6.1% receiving nonoperative treatment ( P = .28). Conclusion: Secondary meniscal tears after ACL injury are most common among patients undergoing delayed surgical or nonoperative treatment of their primary ACL injuries. Secondary tears often present as complex tears of the medial meniscus and result in high rates of partial meniscectomy.

Anterior cruciate ligament (ACL) injuries are frequent, as >200,000 injuries occur in the United States alone each year. Owing to the risks for associated meniscus and cartilage damage, ACL injuries are a significant source of both orthopedic care and research. Given the extended recovery course after ACL injury, which often lasts 1-2 years, and is associated with limited participation in sports and activities of daily living for patients, there is a critical need for the evolution of new and improved methods for ACL repair. Subsequently, animal models of ACL reconstruction (ACLR) play a key role in the development and initial trialing of novel ACL interventions. This article provides a clear operative description and associated illustrations for a validated, institutional animal care and use committee, and veterinarian approved and facile model of ACLR to serve researchers investigating ACLR.

Background: Meniscal repair is desirable over resection to prevent postmeniscectomy arthritis, especially among young and active patients. However, long-term data are currently lacking following isolated meniscal repair, particularly in the pediatric population. Purpose/Hypothesis: To report long-term follow-up of isolated meniscal tears treated by meniscal repair in a pediatric and adolescent population and to compare those results with previous midterm follow-up data reported. The authors hypothesized that these patients would have satisfactory function and reoperation rates at long-term follow-up. Study Design: Case series; Level of evidence, 4. Methods: Forty-four patients aged ≤18 years undergoing repair of an isolated meniscal tear (without concomitant anterior cruciate ligament injury) between 1990 and 2005 were included. At the time of final follow-up, recurrent tear, reoperations, and International Knee Documentation Committee (IKDC) and Tegner scores were determined. With logistic regression, the overall failure among tear types was calculated. Wilcoxon rank sum analysis were performed to calculate the differences in clinical outcome for different time points, and Spearman coefficients were calculated for Tegner and IKDC with different variables. Results: At a mean follow-up of 17.6 years (range, 13.1-25.9 years), 32 patients with 33 isolated meniscal repairs (29 male, 3 female) with a mean age of 16.1 years (range, 9.9-18.7 years) at surgery were included in this study. At early follow-up, the overall failure rate was 14 of 33 (42%); complex tears (80%) and bucket-handle tears (47%) had higher overall failure rates when compared with simple tears (18.2%), although only complex tears had a significantly higher failure rate. However, no further failures occurred since midterm follow-up with any tear type. At final follow-up, the mean IKDC score was 92.3, which was significantly increased when compared with preoperative (65.3, P < .0001) and midterm (90.2, P = .01) scores. The mean Tegner score (6.5) was significantly lower than both preoperative (8.3, P < .0001) and midterm (8.4, P < .0001) scores. There was no difference in Tegner or IKDC score for patients with successful versus failed repair. Conclusion: In conclusion, while there was a high early failure rate, this study demonstrated overall good to excellent long-term clinical outcomes after isolated meniscal repair in an adolescent population, even for those requiring reoperation. Early failure and reoperation rates were variable, depending on tear type, with complex multiplanar tears having more failures at short-term follow-up. However, at long-term follow-up, IKDC and Tegner scores were not significantly different for those with complex tears as compared with other tear types.

Hundreds of genetic variants have been associated with Body Mass Index (BMI) through genome-wide association studies (GWAS) using observational cohorts. However, the genetic contribution to efficient weight loss in response to dietary intervention remains unknown. We perform a GWAS in two large low-caloric diet intervention cohorts of obese participants. Two loci close to NKX6.3/MIR486 and RBSG4 are identified in the Canadian discovery cohort (n = 1166) and replicated in the DiOGenes cohort (n = 789). Modulation of HGTX (NKX6.3 ortholog) levels in Drosophila melanogaster leads to significantly altered triglyceride levels. Additional tissue-specific experiments demonstrate an action through the oenocytes, fly hepatocyte-like cells that regulate lipid metabolism. Our results identify genetic variants associated with the efficacy of weight loss in obese subjects and identify a role for NKX6.3 in lipid metabolism, and thereby possibly weight control., Individuals show large variability in their capacity to lose weight and maintain this weight. Here, the authors perform GWAS in two weight loss intervention cohorts and identify two genetic loci associated with weight loss that are taken forward for Bayesian fine-mapping and functional assessment in flies.

Introduction Noncommunicable diseases are one of the main challenges that affect health worldwide and have been found to be increasing in both low- and middle-income countries compared with high-income countries. The aim of this study was to assess the impact of financial incentives and a comprehensive care program focusing on patients' behavior and self-management of uncontrolled type 2 diabetes (glycosylated hemoglobin [HbA1c] ≥ 7), as well as modifiable risk factors for disease complications in a Saudi Arabian population. Methods This quasiexperimental study, using a pre- and postevaluation approach, was used to compare the level of HbA1c among patients with uncontrolled diabetes before and after the financial incentives and comprehensive care program were implemented. Financial awards were given to patients who achieved a significantly greater decrease in HbA1c levels with his/her responsible physician. The study population included 702 Saudi Arabian patients with type 2 diabetes from 14 regions and 34 primary healthcare centers in the Kingdom of Saudi Arabia. All of these patients (≥ 15 years old) with uncontrolled type 2 diabetes who attended local primary healthcare centers in Saudi Arabia for a follow-up visit from February to October 2018. Results The mean age, in years, of the sample was 56.14 (± SD = 9.909); slightly more than half of the patients 401 (57.1%) were females. Most of the participants 645 (91.9%) were married, and 381(54.3%) patients were housewives. Linear mixed modeling revealed that all groups showed improvements over time in the primary outcome of HbA1c levels (p = 0.009), Including the secondary outcomes of body mass index and systolic and diastolic blood pressure (p = 0.04, < 0.001, 0.019 respectively). Conclusions Patient behavior was improved, which was reflected by decreases in HbA1c, body mass index, and blood pressure levels. A comprehensive care program is recommended by healthcare providers to increase awareness among patients with diabetes to reduce other risk factors. These kinds of interventions positively motivate patients with diabetes to control their health measurements and to adopt a healthy lifestyle.

In this secondary analysis of the DiOGenes study, we investigated whether physical activity (PA) contributes to diet-induced weight loss and helps to reduce subsequent regain. We also studied the associations of PA with changes in cardiometabolic variables. Adults with overweight were included and followed an 8-week low-calorie diet (LCD). When successful (>8% weight loss), participants were randomized to different ad libitum diet groups and were advised to maintain their weight loss over the 6-month intervention period. Body weight (BW), body composition, cardiometabolic variables and subjectively-assessed PA were measured at baseline, at the end of weight loss and at the end of the intervention. BW was reduced by the LCD (from 99.8 ± 16.7 to 88.4 ± 14.9 kg; P < 0.001). This reduction was maintained during the weight maintenance period (89.2 ± 16.0 kg). Total PA (sum score of the three subscales of the Baecke questionnaire) increased during the weight loss period (from 8.16 ± 0.83 to 8.39 ± 0.78; P < 0.001) and this increase was subsequently maintained (8.42 ± 0.90). We found no evidence that baseline PA predicted weight loss. However, a higher level of baseline PA predicted a larger weight-loss-induced improvement in total cholesterol, triglycerides, glucose and CRP, and in post-prandial insulin sensitivity (Matsuda index). Subsequent weight and fat mass maintenance were predicted by the post-weight loss level of PA and associated with changes in PA during the weight maintenance phase. In conclusion, despite the fact that higher baseline levels of PA did not predict more weight loss during the LCD, nor that an increase in PA during the LCD was associated with more weight loss, higher PA levels were associated with more improvements in several cardiometabolic variables. The positive effect of higher PA on weight loss maintenance seems in contrast to randomized controlled trials that have not been able to confirm a positive effect of exercise training programmes on weight loss maintenance. This analysis supports the notion that higher self-imposed levels of PA may improve the cardiometabolic risk profile during weight loss and help to maintain weight loss afterwards.

Lifestyle intervention, combining calorie restriction and physical activity to induce weight loss, is the frontline treatment for overweight or obesity and well-known to reduce waist circumference (WC). Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) associated with WC adjusted for body mass index (WCadjBMI), but it remains unclear whether these SNPs relate to the change in WCadjBMI with lifestyle intervention. Here, we examined whether 59 SNPs previously associated with WCadjBMI in GWAS predicted change in WCadjBMI at one year in 5 lifestyle intervention trials and at 8-10 weeks in two lifestyle intervention trials. Look AHEAD, Diabetes Prevention Program, Diabetes Prevention Study, DIETFITS, and PrediMed Plus contributed one-year data, and NUGENOB and DiOGenes contributed 8-10 week data. Genetic risk scores (GRS) combined associated alleles for each SNP weighted by association with WCadjBMI from Shungin et al, 2015 and meta-analyses with random effects for each trial were used to pool results. Among White participants, higher GRS related to smaller year one change in WCadjBMI in the lifestyle intervention arms, and thus predicted poorer response (p=0.009). With a point estimate of 0.002 (SE=0.001) across trials, for a person with an initial BMI of 34 and a year 1 reduction in BMI of 2.5, each weighted risk allele in the GRS contributed to a 0.06 cm (SE=0.03) higher WC at year 1. With a 25th%ile, median, and 75th%ile GRS of 42.77, 46.75, and 50.48, this translates to 0.46 cm less change in WC between the 25th%ile and 75th%ile. No significant findings emerged in men and women separately, in the African-American subset, for the 8-10 week outcomes, or for the individuals SNPs after correcting for multiple comparisons. These results may help to define the molecular pathways through which lifestyle intervention impacts central adiposity. Disclosure J. Mccaffery: None. T. Hansen: None. T. O. Kilpelainen: None. D. Corella: None. W. H. M. Saris: Advisory Panel; Self; Friesland Campina International, Consultant; Self; Nutrition et sante. T. I. A. Sørensen: None. J. Tuomilehto: None. R. R. Wing: None. T. Agurs-collins: None. K. A. Jablonski: None. Q. Pan: None. A. Astrup: Consultant; Self; Groupe Éthique et Santé, France, Employee; Self; Novo Nordisk Foundation, Other Relationship; Self; Flaxslim ApS, Denmark, Gelesis, Personalized Weight Management Research Consortium ApS (Gluco-Diet. dk). M. R. Christiansen: None. L. M. Corso: None. J. C. Florez: Consultant; Self; Goldfinch Bio, Inc., Other Relationship; Self; Novo Nordisk. P. W. Franks: Advisory Panel; Self; Zoe Global Limited, Consultant; Self; Eli Lilly and Company, Novo Nordisk. C. D. Gardner: None. Funding WESTAT/National Cancer Institute

Parkinson’s disease (PD) is the most prevalent movement disorder known and predominantly affects the elderly. It is a progressive neurodegenerative disease wherein α-synuclein, a neuronal protein, aggregates to form toxic structures in nerve cells. The cause of Parkinson’s disease (PD) remains unknown. Intestinal dysfunction and changes in the gut microbiota, common symptoms of PD, are evidently linked to the pathogenesis of PD. Although a multitude of studies have investigated microbial etiologies of PD, the microbial role in disease progression remains unclear. Here, we show that Gram-negative sulfate-reducing bacteria of the genus Desulfovibrio may play a potential role in the development of PD. Conventional and quantitative real-time PCR analysis of feces from twenty PD patients and twenty healthy controls revealed that all PD patients harbored Desulfovibrio bacteria in their gut microbiota and these bacteria were present at higher levels in PD patients than in healthy controls. Additionally, the concentration of Desulfovibrio species correlated with the severity of PD. Desulfovibrio bacteria produce hydrogen sulfide and lipopolysaccharide, and several strains synthesize magnetite, all of which likely induce the oligomerization and aggregation of α-synuclein protein. The substances originating from Desulfovibrio bacteria likely take part in pathogenesis of PD. These findings may open new avenues for the treatment of PD and the identification of people at risk for developing PD.

BACKGROUNDChondromas are benign cartilaginous tumors that are rarely seen in the brain.OBSERVATIONSA 58-year-old woman had undergone routine brain imaging after a motor vehicle accident and was incidentally found to have a right falcine lesion. Contrast magnetic resonance imaging showed a mostly nonenhancing mass with discontinuous rim enhancement. She was taken to the operating room and pathology revealed a chondroma.LESSONSFalcine intracranial chondromas are rare and typically misdiagnosed as meningiomas. Chondromas should be in the differential for patients presenting with nonenhancing falcine lesions.

Contains fulltext : 204838.pdf (Publisher’s version ) (Open Access) The human social brain is complex. Current knowledge fails to define the neurobiological processes underlying social behaviour involving the (patho-) physiological mechanisms that link system-level phenomena to the multiple hierarchies of brain function. Unfortunately, such a high complexity may also be associated with a high susceptibility to several pathogenic interventions. Consistently, social deficits sometimes represent the first signs of a number of neuropsychiatric disorders including schizophrenia (SCZ), Alzheimer's disease (AD) and major depressive disorder (MDD) which leads to a progressive social dysfunction. In the present review we summarize present knowledge linking neurobiological substrates sustaining social functioning, social dysfunction and social withdrawal in major psychiatric disorders. Interestingly, AD, SCZ, and MDD affect the social brain in similar ways. Thus, social dysfunction and its most evident clinical expression (i.e., social withdrawal) may represent an innovative transdiagnostic domain, with the potential of being an independent entity in terms of biological roots, with the perspective of targeted interventions.

Background and aims: Body mass index (BMI) and waist circumference (WC) are commonly used markers of cardiometabolic risk. However, sagittal abdominal diameter (SAD) has been proposed as a possibly more sensitive marker of intra-abdominal obesity. We investigated differences in how SAD, WC, and BMI were correlated with cardiometabolic risk markers.Methods and results: This cross-sectional study investigated anthropometric and metabolic baseline measurements of individuals from six trials. Multiple linear regression and (partial) correlation coefficients were used to investigate associations between SAD, WC, and BMI and cardiometabolic risk markers, including components of the metabolic syndrome as well as insulin resistance, blood lipids, and low-grade inflammation.In total 1516 mostly overweight or obese individuals were included in the study. SAD was significantly more correlated with TG than WC for all studies, and overall increase in correlation was 0.05 (95% CI (0.02; 0.08). SAD was significantly more correlated with the markers TG and DBP 0.11 (95% CI (0.08, 0.14)) and 0.04 (95% CI (0.006, 0.07), respectively compared to BMI across all or most studies.Conclusion: This study showed that no single anthropometric indicator was consistently more strongly correlated across all markers of cardiometabolic risk. However, SAD was significantly more strongly correlated with TG than WC and significantly more strongly correlated with DBP and TG than BMI. (C) 2020 Published by Elsevier B.V. on behalf of The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University.

Contains fulltext : 238504.pdf (Publisher’s version ) (Open Access) OBJECTIVE: To assess anti-cytosolic 5'-nucleotidase 1A (anti-cN-1A) autoantibodies in children with juvenile dermatomyositis (DM) and healthy controls, using 3 different methods of antibody detection, as well as verification of the results in an independent cohort. METHODS: Anti-cN-1A reactivity was assessed in 34 Dutch juvenile DM patients and 20 healthy juvenile controls using the following methods: a commercially available full-length cN-1A enzyme-linked immunosorbent assay (ELISA), a synthetic peptide ELISA, and immunoblotting with a lysate from cN-1A-expressing HEK 293 cells. Sera from juvenile DM patients with active disease and those with disease in remission were analyzed. An independent British cohort of 110 juvenile DM patients and 43 healthy juvenile controls was assessed using an in-house full-length cN-1A ELISA. RESULTS: Anti-cN-1A reactivity was not present in sera from juvenile DM patients or healthy controls when tested with the commercially available full-length cN-1A ELISA or by immunoblotting, in either active disease or disease in remission. Additionally, in the British juvenile DM cohort, anti-cN-1A reactivity was not detected. Three Dutch juvenile DM patients had weakly positive results for 1 of 3 synthetic cN-1A peptides measured by ELISA. CONCLUSION: Juvenile DM patients and young healthy individuals did not show anti-cN-1A reactivity as assessed by different antibody detection techniques.

Articular cartilage defects cause pain and progression to osteoarthritis, and there remains a critical need for safe and cost-effective interventions. Historically available treatments for articular cartilage defects are limited in success, in part due to the native biology of the cartilage, which has limited healing potential, as well as due to the inability to create a favorable signaling and cell environment. The evolution of cartilage treatment has been rapid, with emerging options for treatment and repair. Recent advances in platelet-rich plasma (PRP) have demonstrated efficacy in growth factor delivery as well as symptom modulation. Furthermore, cell-based approaches such as autologous chondrocyte implantation (ACI) and stem/stromal cell therapies have ushered in a new era of treatments which can be responsive to and interact with the local intra-articular environment. Finally, the technovolution of this field has led to the development of single-stage combination autologous/allogeneic treatments which have the potential to overcome logistical and recovery limitations of two-stage treatments while providing trophic factors, signaling orchestration, and autologous cells for defect repair.

To assess articular cartilage in vivo, a noninvasive measurement is proposed to evaluate damage of the cartilage. It is hypothesized that glycosaminoglycan chemical exchange saturation transfer (gagCEST) can be applied as a noninvasive imaging technique as it would relate to electromechanical indentation and GAG content as measured with biochemical assays. This pilot study applies gagCEST MRI in total knee arthroplasty (TKA) patients to assess substantially damaged articular cartilage. The outcome was verified against electromechanical indentation and biochemical assays to assess the potential of gagCEST MRI. Five TKA patients were scanned on a 7.0 T MRI with a gagCEST sequence. Articular resurfacing cuts after TKA were obtained for electromechanical and biochemical analyses. The gagCEST MRI measurements on the medial condyle showed a moderate correlation with the GAG content, although sensitivity on the lateral condyle was lacking. Additionally, a strong negative correlation of gagCEST MRI with the electromechanical measurements was observed in the regression analysis. Correlation of gagCEST MRI with electromechanical measurements was shown, but the correlation of gagCEST MRI with GAG content was not convincing. In conclusion, gagCEST could be a useful tool to assess the GAG content in articular cartilage noninvasively, although the mismatch in heterogeneity requires further investigation., This pilot study applies gagCEST MRI in vivo in five total knee arthroplasty patients to assess substantially damaged articular cartilage. GagCEST MRI measurements show a moderate correlation with GAG content on the medial condyle and a strong correlation with electromechanical measurements. In conclusion, gagCEST could be a useful tool to assess the GAG content in articular cartilage noninvasively, although the mismatch in heterogeneity requires further investigation.

Meniscus and cartilage injuries of the knee joint lead to cartilage degeneration and osteoarthritis (OA). The research on biomaterials and artificial implants as substitutes in reconstruction and regeneration has become a main international focus in order to solve clinical problems such as irreparable meniscus injury, postmeniscectomy syndrome, osteochondral lesions and generalised chronic OA. In this review, we provide a summary of biomaterials currently used in clinical practice as well as state-of-the-art tissue engineering strategies and technologies that are developed for articular cartilage and meniscus repair and regeneration. The literature was reviewed over the last 5 years on clinically used meniscus and cartilage repair biomaterials, such as Collagen Meniscal Implant, Actifit, NUsurface, TruFit, Agili-C and MaioRegen. There are clinical advantages for these biomaterials and the application of these treatment options should be considered individually. Standardised evaluation protocols are needed for biological and mechanical assessment and comparison between different scaffolds, and long-term randomised independent clinical trials with large study numbers are needed to provide more insight into the use of these biomaterials. Surgeons should become familiar and stay up to date with evolving repair options to improve their armamentarium for meniscal and cartilage defects.

Background Articular cartilage defects in the knee have poor intrinsic healing capacity and may lead to functional disability and osteoarthritis (OA). “Instant MSC Product accompanying Autologous Chondron Transplantation” (IMPACT) combines rapidly isolated recycled autologous chondrons with allogeneic MSCs in a one-stage surgery. IMPACT was successfully executed in a first-in-man investigator-driven phase I/II clinical trial in 35 patients. The purpose of this study is to compare the efficacy of IMPACT to nonsurgical treatment for the treatment of large (2–8 cm2) articular cartilage defects in the knee. Methods Sixty patients will be randomized to receive nonsurgical care or IMPACT. After 9 months of nonsurgical care, patients in the control group are allowed to receive IMPACT surgery. The Knee Injury and Osteoarthritis Outcome Score (KOOS), pain (numeric rating scale, NRS), and EuroQol five dimensions five levels (EQ5D-5 L) will be used to compare outcomes at baseline and 3, 6, 9, 12, and 18 months after inclusion. Cartilage formation will be assessed at baseline, and 6 and 18 months after inclusion using MRI. An independent rheumatologist will monitor the onset of a potential inflammatory response. (Severe) adverse events will be recorded. Lastly, the difference between IMPACT and nonsurgical care in terms of societal costs will be assessed by monitoring healthcare resource use and productivity losses during the study period. A health economic model will be developed to estimate the incremental cost-effectiveness ratio of IMPACT vs. nonsurgical treatment in terms of costs per quality adjusted life year over a 5-year time horizon. Discussion This study is designed to evaluate the efficacy of IMPACT compared to nonsurgical care. Additionally, safety of IMPACT will be assessed in 30 to 60 patients. Lastly, this study will evaluate the cost-effectiveness of IMPACT compared to nonsurgical care. Trial registration NL67161.000.18 [Registry ID: CCMO] 2018#003470#27 [EU-CTR; registered on 26 March 2019] NCT04236739 [ClinicalTrials.gov] [registered after start of inclusion; 22 January 2020]

Background/objectives: To investigate (1) the association of four VDR polymorphisms (TaqI/rs731236, ApaI/rs7975232, FokI/rs10735810, and Bsml/rs1544410) with markers of adiposity and tissue-specific insulin resistance at baseline, after weight loss and weight maintenance; (2) the effect of the VDR polymorphisms in the SAT transcriptome in overweight/obese Caucasians of the DiOGenes cohort. Methods: We included 553 adult obese individuals (mean BMI 34.8 kg/m 2), men (n = 197) and women (n = 356) at baseline, following an 8-week weight loss intervention and 26 weeks weight maintenance. Genotyping was performed using an Illumina 660W-Quad SNP chip on the Illumina iScan Genotyping System. Tissue-specific IR was determined using Hepatic Insulin Resistance Index (HIRI), Muscle Insulin Sensitivity Index (MISI), and Adipose Tissue Insulin Resistance Index (Adipo-IR). Expression quantitative trait loci (eQTL) analysis was performed to determine the effect of SNPs on SAT gene expression. Results: None of the VDR polymorphisms were associated with HIRI or MISI. Interestingly, carriers of the G allele of VDR FokI showed higher Adipo-IR (GG + GA 7.8 ± 0.4 vs. AA 5.6 ± 0.5, P = 0.010) and higher systemic FFA (GG + GA: 637.8 ± 13.4 vs. AA: 547.9 ± 24.7 µmol/L, P = 0.011), even after adjustment with age, sex, center, and FM. However, eQTL analysis showed minor to no effect of these genotypes on the transcriptional level in SAT. Also, VDR polymorphisms were not related to changes in body weight and IR as result of dietary intervention (P > 0.05 for all parameters). Conclusions: The VDR Fokl variant is associated with elevated circulating FFA and Adipo-IR at baseline. Nevertheless, minor to no effect of VDR SNPs on the transcriptional level in SAT, indicating that putative mechanisms of action remain to be determined. Finally, VDR SNPs did not affect dietary intervention outcome in the present cohort.

Weight loss aims to improve glycemic control in obese but strong variability is observed. Using a multi-omics approach, we investigated differences between 174 responders and 201 non-responders, that had lost >8% body weight following a low-caloric diet (LCD, 800 kcal/d for 8 weeks). The two groups were comparable at baseline for body composition, glycemic control, adipose tissue transcriptomics and plasma ketone bodies. But they differed significantly in their response to LCD, including improvements in visceral fat, overall insulin resistance (IR) and tissue-specific IR. Transcriptomics analyses found down-regulation in key lipogenic genes (e.g. SCD, ELOVL5) in responders relative to non-responders; metabolomics showed increase in ketone bodies; while proteomics revealed differences in lipoproteins. Findings were consistent between genders; with women displaying smaller improvements owing to a better baseline metabolic condition. Integrative analyses identified a plasma omics model that was able to predict non-responders with strong performance (on a testing dataset, the Receiving Operating Curve Area Under the Curve (ROC AUC) was 75% with 95% Confidence Intervals (CI) [67%, 83%]). This model was based on baseline parameters without the need for intrusive measurements and outperformed clinical models (p = 0.00075, with a +14% difference on the ROC AUCs). Our approach document differences between responders and non-responders, with strong contributions from liver and adipose tissues. Differences may be due to de novo lipogenesis, keto-metabolism and lipoprotein metabolism. These findings are useful for clinical practice to better characterize non-responders both prior and during weight loss.

Atherosclerotic plaque development in the carotid artery bifurcation elevates the risk for stroke, which is often initiated by plaque rupture. The risk-to-rupture of a plaque is related to its composition. Two-dimensional non-invasive carotid elastography studies have found a correlation between wall strain and plaque composition. This study introduces a technique to perform non-invasive volumetric elastography in vivo. Three-dimensional ultrasound data of carotid artery bifurcations were acquired in four asymptomatic individuals using an electrocardiogram-triggered multislice acquisition device that scanned over a length of 35 mm (350 slices) using a linear transducer (L11-3, fc = 9 MHz). For each slice, three-angle ultrasound plane wave data were acquired and beamformed. A correction for breathing-induced motion was applied to spatially align the slices, enabling 3-D cross-correlation-based compound displacement, distensibility and strain estimation. Distensibility values matched with previously published values, while the corresponding volumetric principal strain maps revealed locally elevated compressive and tensile strains. This study presents for the first time 3-D elastography of carotid arteries in vivo.

Contains fulltext : 205507.pdf (Publisher’s version ) (Open Access) Atrophy and fatty infiltration are important causes of muscle weakness in inclusion body myositis (IBM). Muscle weakness can also be caused by reduced specific force; i.e. the amount of force generated per unit of residual muscle tissue. This study investigates in vivo specific force of the quadriceps and ex vivo specific force of single muscle fibers in patients with IBM. We included 8 participants with IBM and 12 healthy controls, who all underwent quantitative muscle testing, quantitative MRI of the quadriceps and paired muscle biopsies of the quadriceps and tibialis anterior. Single muscle fibers were isolated to measure muscle fiber specific force and contractile properties. Both in vivo quadriceps specific force and ex vivo muscle fiber specific force were reduced. Muscle fiber dysfunction was accompanied by reduced active stiffness, which reflects a decrease in the number of attached actin-myosin cross-bridges during activation. Myosin concentration was reduced in IBM fibers. Because reduced specific force contributes to muscle weakness in patients with IBM, therapeutic strategies that augment muscle fiber strength may provide benefit to patients with IBM.

Heterozygous gain of function mutations in the ZIC1 gene have been described with syndromic craniosynostosis, variable cerebral or cerebellar abnormalities and mild to moderate developmental delay. Deletion of chromosome 3q25.1 including both adjacent ZIC1 and ZIC4 genes have been described as a cause of variable cerebellar abnormalities including Dandy-Walker malformation. We report two siblings presenting with neonatal microcephaly, agenesis of the corpus callosum, brachycephaly with reduced volume of the posterior fossa, cerebellar and pons hypoplasia, scoliosis and tethered cord (closed neural tube defect). One of the siblings had apparent partial rhombencephalosynapsis. Trio analysis of exome sequencing data revealed a novel heterozygous frameshift mutation in ZIC1 at the end of exon 3 in one sibling and was confirmed by Sanger sequencing in both children. The mutation was not detected in DNA of both parents, which suggests parental gonadal mosaicism. We show that expression of the mutant allele leads to synthesis of a stable abnormal transcript in patient cells, without evidence for nonsense-mediated decay. Craniosynostosis was not present at birth, which explains why ZIC1 mutations were not initially considered. This severe brain malformation indicates that premature closure of sutures can be independent of the abnormal brain development in subjects with pathogenic variants in ZIC1.

Objective Non‐invasive prenatal testing (NIPT) detects placental chromosome aberrations. When amniocentesis reveals a normal karyotype, confined placental mosaicism (CPM) may be assumed. In order to confirm this, placental cytogenetic studies were performed. Method NIPT was conducted in the course of the Dutch TRIDENT study. Placentas of 10 cases with NIPT results indicating an autosomal trisomy and showing a normal (N = 9) or low mosaic karyotype (N = 1) in amniotic fluid (AF) were investigated. The cytotrophoblast as well as the mesenchymal core of two to four placental chorionic villi biopsies were studied with single nucleotide polymorphism (SNP) array. Clinical outcome data were collected. Results In 10/10 cases, CPM was proven. In 3/10 cases trisomy/uniparental disomy (UPD)/biparental disomy (BPD) mosaicism was discovered. In 2/3 cases, all three cell lines were present in the placenta, whereas BPD was found in AF. In 1/3 cases trisomy 22/UPD22 was present in AF while trisomy 22/BPD22 mosaicism was found in the placenta. Five of 10 pregnancies were affected with pre‐eclampsia, low birth weight, preterm delivery, and/or congenital malformations. Conclusion The presence of trisomy/UPD/BPD mosaicism in 3/10 cases that we investigated proves that trisomic zygote rescue may involve multiple rescue events during early embryogenesis. UPD mosaicism, when present in crucial fetal tissues, may explain the abnormal phenotype in undiagnosed cases., What's already known about this topic? Trisomic zygote rescue is the main mechanism for uniparental disomy (UPD) formation.Confined placental mosaicism (CPM) is the major source of discordant NIPT results.CPM is associated with a risk for adverse pregnancy outcome. What does this study add? Trisomic zygote rescue may involve multiple rescue events based on the co‐occurrence of a trisomy‐, UPD‐, and BPD‐cell line in half of the rescued cases as revealed by placental studies.

Background: The anterior cruciate ligament (ACL) has poor regenerative capacity, and an injury leads to loss of function, limiting quality of life and increasing the incidence of osteoarthritis. Surgical interventions can stabilize the joint and improve functional recovery. The delivery of growth factors (GFs) enhances the healing process; however, this is complex in its regulation, is high in costs, has side effects, and can only be accomplished with supraphysiological concentrations and thus is currently not clinically feasible. However, the immobilization of a patient’s endogenous GFs in biomaterials can overcome these problems. Purpose: To develop a method to capture endogenous bone morphogenetic protein–2 (BMP-2) and ultimately show enhanced ACL healing in vivo using this novel methodology. Study Design: Controlled laboratory study. Methods: BMP-2 binding peptides were synthetized, purified, and immobilized on polycaprolactone (PCL) films. The affinity between the peptide and human BMP-2 (hBMP-2) was confirmed with immunofluorescence and enzyme-linked immunosorbent assay. The C2C12 Luc reporter cell line was used to confirm the bioactivity of immobilized BMP-2. For in vivo experiments, the same functionalization technology was applied to the commercially available Polytape, and the functionalized tape was sutured together with the graft used for ACL reconstruction in rats. Each animal underwent reconstruction with either native Polytape (n = 3) or Polytape with BMP-2 binding peptides (n = 3). At 2 and 6 weeks after surgery, the graft was assessed by histology and micro–computed tomography. Results: The covalent immobilization of the peptide in PCL was successful, allowing the peptide to capture hBMP-2, which remained bioactive and led to the osteogenic differentiation of C2C12. In vivo experiments confirmed the potential of the Polytape functionalized with the BMP-2 binding peptide to capture endogenous BMP-2, leading to enhanced bone formation inside the femoral and tibial tunnels and ultimately improving the graft’s quality. Conclusion: The incorporation of BMP-2 binding peptides into materials used for ACL reconstruction can capture endogenous hBMP-2, which enhances the healing process inside the bone tunnels. Clinical Relevance: These results demonstrate the potential of using synthetic peptides to endow biomaterials with novel biological functions, namely to capture and immobilize endogenous GFs.

Objective Osteochondritis dissecans (OCD) is a knee disorder of predominately pediatric populations. Because of low incidence, it has traditionally been difficult to study OCD. The purpose of this study was to report long-term outcomes of skeletally immature OCD lesions and determine risk factors for persistent knee pain at final follow-up. Design A geographic database of more than 500,000 patients was reviewed to identify patients with knee OCD. Clinical course including operative management, persistent knee pain, and total knee arthroplasty (TKA) were analyzed through review of radiographs, magnetic resonance images, and physician notes. Results A total of 95 skeletally immature patients (70 male, 25 female, mean age 12.5 ± 2.0 years) were followed for a mean of 14 years (range, 2-40 years). Fifty-three patients were treated operatively and 42 were treated nonoperatively. At final follow-up, 13 patients noted persistent knee pain, 8 treated operatively versus 5 treated nonoperatively. Risk factors for knee pain were female gender, patellar lesions, and unstable lesions. Four patients (8%) treated operatively and 2 patients (5%) treated nonoperatively developed symptomatic osteoarthritis at a mean of 28.6 years following diagnosis. Three patients underwent TKA at a mean age of 52 years, significantly younger than that observed for primary TKA at our institution ( P = 0.004). Conclusions Skeletally immature OCD patients have promising histories, with an estimated 14% risk of persistent knee pain, 6% symptomatic osteoarthritis, and 3% conversion to TKA at 14 years’ mean follow-up. Females, patellar lesions, and unstable lesions demonstrated increased persistent knee pain risk. Patients with OCD undergo TKA at a significantly younger age than the general population.

Social withdrawal is one of the first and common signs of early social dysfunction in a number of important neuropsychiatric disorders, likely because of the enormous amount and complexity of brain processes required to initiate and maintain social relationships (Adolphs, 2009). The Psychiatric Ratings using Intermediate Stratified Markers (PRISM) project focusses on the shared and unique neurobiological basis of social withdrawal in schizophrenia, Alzheimer and depression. In this paper, we discuss the working definition of social withdrawal for this study and the selection of objective and subjective rating scales to assess social withdrawal chosen or adapted for this project. We also discuss the MRI and EEG paradigms selected to study the systems and neural circuitry thought to underlie social functioning and more particularly to be involved in social withdrawal in humans, such as the social perception and the social affiliation networks. A number of behavioral paradigms were selected to assess complementary aspects of social cognition. Also, a digital phenotyping method (a smartphone application) was chosen to obtain real-life data., This work was supported by the European Union Horizon 2020 Innovative Medicines Initiative 2 Joint Undertaking grant 115916 for the project ‘Psychiatric ratings using intermediate stratified markers’

Objectives: To compare the overall survival (OS) and cancer specific survival (CSS) by race for women with stage I-III endometrial cancer (EC) by histologic subtype. Methods: This is a retrospective cohort study of women with stage I-III endometrioid, serous, clear cell, and carcinosarcoma who underwent hysterectomy as primary surgical staging as identified within the SEER-Medicare database. Endometrial cancer cases diagnosed between 2000 and 2015 with Medicare enrollment data from 1999-2016 were included. Demographics, cancer data, and survival outcomes were collected. Demographic and treatment factors by race were compared using descriptive analyses. OS and CSS outcomes were stratified by race, stage and histology, then analyzed using log rank tests and multivariate cox modeling (adjusting for age, geographic region, Charlson comorbidity index, post-operative treatment sequencing, FIGO stage, and grade). Results: 24,142 total patients were included in this dataset. 85.5% were White, and 8.5% were BlackBlack. 19,351 stage I, 1,484 stage II, and 3,307 stage III cases were identified. Black women were diagnosed at a younger age bracket (40-69yo) than White patients for endometrioid stage I (40% vs 35%), II (37% vs 31%), and III (31% vs 28%); serous stage I (45% vs 31%) and III (42% vs 28%), and carcinosarcoma stage I (39% vs 27%), p Download : Download high-res image (212KB) Download : Download full-size image Conclusions: Prior studies have reported that BlackBlack women with endometrial cancer have worse survival consistently across stage and histology. However, we did not find this effect when evaluating by CSS and OS. For stage I, BlackBlack women had consistently worse CSS likely related to the disease itself and worse OS in adjusted analyses likely related to poorer overall health outcomes across all histologic subtypes except for clear cell. For stage II and III, racial disparities were seen only for CSS in endometrioid patients in the adjusted analyses, but not OS; and this may have been related to BlackBlack women with stage III cancer receiving less adjuvant therapy. When stratified by stage and histology, BlackBlack women with EC were diagnosed at younger age and with more comorbidities. Overall these findings emphasize the need to intervene in the early stage population, where a disparity exists and the largest population of women is affected.

Hyperkalemic periodic paralysis (HyperPP) is a rare neurological channelopathy caused by gain-of-function mutations in the skeletal muscle sodium channel gene ( SCN4A ) that disrupts sarcolemmal membrane excitability. Clinically, HyperPP is characterised by episodic muscle weakness attacks with associated rise in serum potassium and a degree of myotonia. Attacks are triggered by exercise, stress, potassium-rich food and a fasting state. Therapy of periodic paralysis typically consists of avoiding triggers and the use of prophylactic carbonic anhydrase inhibitors. Although these drugs have shown their efficacy in randomised controlled trials (RCTs), many patients oppose a daily drug intake and side effects are frequently experienced.1 Alternatively, salbutamol has been used as an attack treatment in HyperPP, presumably because catecholamines stimulate the cellular uptake of potassium.2 Still, only a few patients with HyperPP are being treated with salbutamol and the large heterogeneity in individual treatment responses makes it difficult to predict who will benefit from the treatment. We report the results from an N-of-1 trial that compared salbutamol aerosol versus placebo treatment to test whether salbutamol aerosol treatment alone, without prophylactic treatment, reduces weakness attack characteristics to a clinically meaningful degree in a single patient with HyperPP. A randomised, placebo-controlled, double-blind, single patient, multiple cross-over trial (ie, N-of-1 trial) with two (block-randomised) treatment sets: each consisting of a 2-week treatment period of salbutamol and placebo aerosol treatment. The patient ( see online supplemental file 1) preferred attack treatment over daily prophylactic treatment with acetazolamide ( for baseline data see online supplemental file 2, online supplemental efigure 1). We performed an N-of-1 trial because we had no experience with salbutamol treatment in HyperPP and trial evidence on the abortive effect of salbutamol in an out-of-hospital setting was lacking. ### Supplementary data [jnnp-2021-326347supp001.pdf] The patient was instructed to use blinded study inhalators (online supplemental efigure 2) according to the instructions from …