Perbandingan Efektivitas Terapi Injeksi Intra-artikular HA, LP-PRP, dan LR-PRP Terhadap Keluhan Nyeri Lutut Pada Osteoarthritis: Meta-analysis

Background: Osteoarthritis can reduce a person's quality of life due to pain and limitation of motion. Treatment of OA using analgesic and anti-inflammatory drugs has the risk of causing gastric bleeding. Invasive therapy with IA injection has become an option, but because of the risks due to injection and the high cost, it is necessary to conduct a meta-analysis to determine which one is the most effective in reducing pain in knee osteoarthritis (KOA) patients. The results of this study are expected to assist the selection of intra-articular injection therapy that is more effective and appropriate in providing therapy to KOA patients. Method: Search for RCT articles assessing the effectiveness of IA PRP (LP-PRP or LR-PRP) with IA-HA on pain, with WOMAC score as an outcome measure, from Pubmed, Cochrane, Proquest, ScienceDirect, Clinical Key, and EBSCO hosts. Articles are rated for quality on the JADAD scale. Then the selected will be carried out meta-analysis. The flow of article selection will be presented in the PRISMA flow chart. Results: Six studies met the eligibility criteria separated based on their variable, leukocyte poor platelet rich plasma and HA and leukocyte rich platelet rich plasma and HA. There is a significant mean difference of WOMAC score in LR-PRP compared to HA (mean difference -5,24) and LP-PRP compared to HA (mean difference-3,82). Conclusion: The findings of this meta-analysis reveal that intra-articular injection therapy with LR-PRP is superior to LP-PRP and HA at 6 and 12 months, especially for symptomatic knee pain. Keywords: Knee pain · Knee osteoarthritis · PRP · Platelet-rich plasma · Hyaluronic acid · Meta-analysis · Systematic review · Leukocyte Poor Platelet Rich Plasma · Leukocyte Rich Platelet Rich Plasma ·Latar Belakang: Osteoarthritis dapat mengurangi kualitas hidup seseorang akibat nyeri dan keterbatasan gerak. Pengobatan OA menggunakan obat analgesik dan antiinflamasi berisiko mengakibatkan perdarahan pada lambung. Terapi invasif dengan penyuntikan IA menjadi pilihan yang baik namun karena risiko akibat penyuntikan dan biaya yang cukup mahal sehingga perlu melakukan metaanalisis untuk menentukan mana yang paling efektif mengurangi nyeri pada pasien KOA. Hasil penelitian ini diharapkan dapat membantu pemilihan terapi injeksi intra artikular yang lebih efektif dan tepat dalam memberikan terapi pada pasien KOA. Metode: Pencarian artikel RCT yang menilai efektifitas IA PRP (LP-PRP atau LR-PRP) dengan IA-HA, terhadap nyeri dengan skor WOMAC sebagai alat ukur, dari Pubmed, Cochrane, Proquest, ScienceDirect, Clinical Key, dan EBSCO host. Artikel dinilai kualitasnya dengan skala JADAD. Lalu yang terpilih akan dilakukan meta analisis. Alur pemilihan artikel akan disajikan dalam PRISMA flow chart. Hasil: Enam penelitian memenuhi kriteria kelayakan yang dipisahkan berdasarkan variabelnya, leukocyte poor platelet rich plasma dan HA dan leukocyte rich platelet rich plasma dan HA. Terdapat perbedaan rerata skor WOMAC yang signifikan pada LR-PRP dibandingkan dengan HA (mean difference -5,24) dan LP-PRP dibandingkan dengan HA (mean difference -3,82). Kesimpulan: Hasil meta-analisis ini dapat disimpulkan bahwa terapi injeksi intra-artikular dengan LR-PRP lebih unggul daripada LP-PRP dan HA pada 6 dan 12 bulan, terutama untuk nyeri lutut simtomatik. Kata Kunci: Nyeri Lutut · Osteoarthritis lutut · PRP · Platelet-rich plasma · Asam Hialuronat · Meta-analysis · Systematic review · Leukocyte Poor Platelet Rich Plasma · Leukocyte Rich Platelet Rich Plasma

Allelic Expression Imbalance Promoting a Mutant PEX6 Allele Causes Zellweger Spectrum Disorder

Zellweger spectrum disorders (ZSDs) are autosomal-recessive disorders that are caused by defects in peroxisome biogenesis due to bi-allelic mutations in any of 13 different PEX genes. Here, we identified seven unrelated individuals affected with an apparent dominant ZSD in whom a heterozygous mutant PEX6 allele (c.2578C&gt;T [p.Arg860Trp]) was overrepresented due to allelic expression imbalance (AEI). We demonstrated that AEI of PEX6 is a common phenomenon and is correlated with heterozygosity for a frequent variant in the 3' untranslated region (UTR) of the mutant allele, which disrupts the most distal of two polyadenylation sites. Asymptomatic parents, who were heterozygous for PEX c.2578C&gt;T, did not show AEI and were homozygous for the 3' UTR variant. Overexpression models confirmed that the overrepresentation of the pathogenic PEX6 c.2578T variant compared to wild-type PEX6 c.2578C results in a peroxisome biogenesis defect and thus constitutes the cause of disease in the affected individuals. AEI promoting the overrepresentation of a mutant allele might also play a role in other autosomal-recessive disorders, in which only one heterozygous pathogenic variant is identified.</p

A pan-cancer clinical platform to predict immunotherapy outcomes and prioritize immuno-oncology combinations in early-phase trials

Immunooncology; Predictive biomarkers; Tumor microenvironmentInmunooncología; Biomarcadores predictivos; Microambiente tumoralImmunooncologia; Biomarcadors predictius; Microambient tumoralBackground Immunotherapy is effective, but current biomarkers for patient selection have proven modest sensitivity. Here, we developed VIGex, an optimized gene signature based on the expression level of 12 genes involved in immune response with RNA sequencing. Methods We implemented VIGex using the nCounter platform (Nanostring) on a large clinical cohort encompassing 909 tumor samples across 45 tumor types. VIGex was developed as a continuous variable, with cutoffs selected to detect three main categories (hot, intermediate-cold and cold) based on the different inflammatory status of the tumor microenvironment. Findings Hot tumors had the highest VIGex scores and exhibited an increased abundance of tumor-infiltrating lymphocytes as compared with the intermediate-cold and cold. VIGex scores varied depending on tumor origin and anatomic site of metastases, with liver metastases showing an immunosuppressive tumor microenvironment. The predictive power of VIGex-Hot was observed in a cohort of 98 refractory solid tumor from patients treated in early-phase immunotherapy trials and its clinical performance was confirmed through an extensive metanalysis across 13 clinically annotated gene expression datasets from 877 patients treated with immunotherapy agents. Last, we generated a pan-cancer biomarker platform that integrates VIGex categories with the expression levels of immunotherapy targets under development in early-phase clinical trials. Conclusions Our results support the clinical utility of VIGex as a tool to aid clinicians for patient selection and personalized immunotherapy interventions.A.H.C. would like to acknowledge fellowship funding from the Spanish Society of Medical Oncology (SEOM), CRIS Contra el Cancer and Hold'em For Life Oncology Fellowship. This research has been funded by the Comprehensive Program of Cancer Immunotherapy & Immunology II (CAIMI-II) supported by the BBVA Foundation (grant 53/2021) and the 2020–2021 Division of Medical Oncology and Hematology (DMOH) Fellowship award at Princess Margaret Cancer Centre. VHIO would like to acknowledge the Cellex Foundation for providing research facilities and equipment and the CERCA Programme from the Generalitat de Catalunya for their support of this research. Authors from VHIO acknowledge the State Agency for Research (Agencia Estatal de Investigación) for providing financial support as a Center of Excellence Severo Ochoa (CEX2020-001024-S/AEI/10.13039/501100011033). A.V. was the recipient of a project award from the FAECC (AVP/18/AECC/3219) and received funding from the Advanced Molecular Diagnostic (DIAMAV) program from the FERO Foundation. Graphical abstract was created with BioRender.com. Diagram in Figure 3B was created with SankeyMATIC (sankeymatic.com)

Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy

Phosphoinositides are lipids that play a critical role in processes such as cellular signalling, ion channel activity and membrane trafficking. When mutated, several genes that encode proteins that participate in the metabolism of these lipids give rise to neurological or developmental phenotypes. PI4KA is a phosphoinositide kinase that is highly expressed in the brain and is essential for life. Here we used whole exome or genome sequencing to identify 10 unrelated patients harbouring biallelic variants in PI4KA that caused a spectrum of conditions ranging from severe global neurodevelopmental delay with hypomyelination and developmental brain abnormalities to pure spastic paraplegia. Some patients presented immunological deficits or genito-urinary abnormalities. Functional analyses by western blotting and immunofluorescence showed decreased PI4KA levels in the patients' fibroblasts. Immunofluorescence and targeted lipidomics indicated that PI4KA activity was diminished in fibroblasts and peripheral blood mononuclear cells. In conclusion, we report a novel severe metabolic disorder caused by PI4KA malfunction, highlighting the importance of phosphoinositide signalling in human brain development and the myelin sheath

The genetic study of three population microisolates in South Tyrol (MICROS): study design and epidemiological perspectives

<p>Abstract</p> <p>Background</p> <p>There is increasing evidence of the important role that small, isolated populations could play in finding genes involved in the etiology of diseases. For historical and political reasons, South Tyrol, the northern most Italian region, includes several villages of small dimensions which remained isolated over the centuries.</p> <p>Methods</p> <p>The MICROS study is a population-based survey on three small, isolated villages, characterized by: old settlement; small number of founders; high endogamy rates; slow/null population expansion. During the stage-1 (2002/03) genealogical data, screening questionnaires, clinical measurements, blood and urine samples, and DNA were collected for 1175 adult volunteers. Stage-2, concerning trait diagnoses, linkage analysis and association studies, is ongoing. The selection of the traits is being driven by expert clinicians. Preliminary, descriptive statistics were obtained. Power simulations for finding linkage on a quantitative trait locus (QTL) were undertaken.</p> <p>Results</p> <p>Starting from participants, genealogies were reconstructed for 50,037 subjects, going back to the early 1600s. Within the last five generations, subjects were clustered in one pedigree of 7049 subjects plus 178 smaller pedigrees (3 to 85 subjects each). A significant probability of familial clustering was assessed for many traits, especially among the cardiovascular, neurological and respiratory traits. Simulations showed that the MICROS pedigree has a substantial power to detect a LOD score ≥ 3 when the QTL specific heritability is ≥ 20%.</p> <p>Conclusion</p> <p>The MICROS study is an extensive, ongoing, two-stage survey aimed at characterizing the genetic epidemiology of Mendelian and complex diseases. Our approach, involving different scientific disciplines, is an advantageous strategy to define and to study population isolates. The isolation of the Alpine populations, together with the extensive data collected so far, make the MICROS study a powerful resource for the study of diseases in many fields of medicine. Recent successes and simulation studies give us confidence that our pedigrees can be valuable both in finding new candidates loci and to confirm existing candidate genes.</p

Systematic Collaborative Reanalysis of Genomic Data Improves Diagnostic Yield in Neurologic Rare Diseases

Altres ajuts: Generalitat de Catalunya, Departament de Salut; Generalitat de Catalunya, Departament d'Empresa i Coneixement i CERCA Program; Ministerio de Ciencia e Innovación; Instituto Nacional de Bioinformática; ELIXIR Implementation Studies (CNAG-CRG); Centro de Investigaciones Biomédicas en Red de Enfermedades Raras; Centro de Excelencia Severo Ochoa; European Regional Development Fund (FEDER).Many patients experiencing a rare disease remain undiagnosed even after genomic testing. Reanalysis of existing genomic data has shown to increase diagnostic yield, although there are few systematic and comprehensive reanalysis efforts that enable collaborative interpretation and future reinterpretation. The Undiagnosed Rare Disease Program of Catalonia project collated previously inconclusive good quality genomic data (panels, exomes, and genomes) and standardized phenotypic profiles from 323 families (543 individuals) with a neurologic rare disease. The data were reanalyzed systematically to identify relatedness, runs of homozygosity, consanguinity, single-nucleotide variants, insertions and deletions, and copy number variants. Data were shared and collaboratively interpreted within the consortium through a customized Genome-Phenome Analysis Platform, which also enables future data reinterpretation. Reanalysis of existing genomic data provided a diagnosis for 20.7% of the patients, including 1.8% diagnosed after the generation of additional genomic data to identify a second pathogenic heterozygous variant. Diagnostic rate was significantly higher for family-based exome/genome reanalysis compared with singleton panels. Most new diagnoses were attributable to recent gene-disease associations (50.8%), additional or improved bioinformatic analysis (19.7%), and standardized phenotyping data integrated within the Undiagnosed Rare Disease Program of Catalonia Genome-Phenome Analysis Platform functionalities (18%)

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Tingkat Kecemasan Siswa yang Mempunyai Orang Tua Tunggal dalam Menghadapi Ujian

Anxiety is the narrowing of the field of perception but still may be directed to others. This study aimed to identify the anxiety levels of students who have single parents in the exam. Method: Descriptive research design. The population was 31 students who have single parents. The sample was 31 students. The Sampling technique was total sampling. The Instrument used Hars questionnaires. Result: The results showed that 87% students experiencing anxiety in susceptible adaptive anxiety which makes the child’s motivation to achieve the goal. Based on the results, there were three things that stand out, namely the onset of anxiety disorders of sleep (not sleep soundly) 30%, impaired intelligence (poor memory, difficulty concentrating) 26%, and anxiety (a bad feeling before the exam) 17%. Discussion: It was expected that counseling can determine the level of anxiety felt by the class XII students who have single parents and allows students to uncover the feelings of the problem so that the learning process will increase