Relationship between vertebral fractures, bone mineral density, and osteometabolic profile in HIV and Hepatitis B and C-infected patients treated with ART

Objective: The purpose of our study was to evaluate the alterations of bone metabolism and the prevalence of vertebral fractures in the population with HIV and hepatitis B and C seropositivity in treatment with antiretroviral drugs (HAART). Methods: We selected 83 patients with diagnosis of HIV, HBV, HCV infection. In all these patients biochemical examinations of phospho-calcium metabolism and a densitometry of lumbar spine were performed. We also evaluated lateral spine X-rays in order to analyze the presence of vertebral deformities and to define their severity. As a control group we analyzed the prevalence of vertebral fractures in a group of 40 non-infectious patients. Results: We selected 82 seropositive patients, 46 males and 37 females, with a median age of 55 \ub1 10 years. Out of these patients, 55 were infected by HIV, 12 were infected by HBV, 11 presented HIV and HCV co-infection and 4 were HCV+. The prevalence of hypovitaminosis D in the studied population was 53%, while the prevalence of osteoporosis and osteopenia was 14 and 48%, respectively. The average T-score in the fractured population was -1.9 SD. The viral load and the CD4+ cell count were respectively, directly, and inversely correlated with the number and severity of vertebral fractures. Antiretroviral therapy regimen containing TDF and PI was a significant determinant of the presence of vertebral deformities. The use of these drugs was also associated with lower levels of vitamin D and higher bone turnover levels compared to other antiretroviral drugs. Conclusions: HIV patients suffer from bone fragility, particularly at spine, independently by the level of bone mineral density. In this population, the T-score threshold for the risk of fracture is higher than that usually used in general population. For this reason, it would be indicated to perform an X-ray of the spine in order to detect vertebral deformities even in patients with a normal or slighlty reduced bone mineral density

Fully Immunocompetent CD8+ T Lymphocytes Are Present in Autologous Haematopoietic Stem Cell Transplantation Recipients Despite an Ineffectual T-Helper Response

BACKGROUND: Reduced CD4 T lymphocytes counts can be observed in HIV infection and in patients undergoing autologous haematopoietic stem cell transplantation (ASCT). Nevertheless, whereas opportunistic infections (OI) are frequent in HIV-infected individuals with low cell counts, OI are uncommon in ASCT patients. METHODOLOGY/PRINCIPAL FINDINGS: To verify whether this observation could be secondary to intrinsic HIV-correlated T cell defects, we performed in-depth immunologic analyses in 10 patients with comparable CD4 counts in whom lymphopenia was secondary either to HIV-infection or ASCT-associated immunosuppressive therapy and compared them to age-matched healthy subjects. Results showed the presence of profound alterations in CD4+ T lymphocytes in both groups of patients with respect to healthy controls. Thus, a low percentage of CCR7+ CD4+ T cells and a compensative expansion of CD45RA-CCR7- CD4+ T cells, a reduced IL-2/IFN-gamma cytokine production and impaired recall antigens-specific proliferative responses were detected both in ASCT and HIV patients. In stark contrast, profound differences were detected in CD8+ T-cells between the two groups of patients. Thus, mature CD8+ T cell prevailed in ASCT patients in whom significantly lower CD45RA-CCR7- cells, higher CD45RA+CCR7- CD8+ cells, and an expansion of CCR7+CD8+ cells was detected; this resulted in higher IFN-gamma +/TNFalpha production and granzyme CD8+ expression. The presence of strong CD8 T cells mediated immune responses justifies the more favorable clinical outcome of ASCT compared to HIV patients. CONCLUSION/SIGNIFICANCE: These results indicate that CD8 T cells maturation and functions can be observed even in the face of a profound impairment of CD4+ T lymphocytes in ASCT but not in HIV patients. Primary HIV-associated CD8 defects or an imprinting by an intact CD4 T cell system in ASCT could justify these results

An explainable model of host genetic interactions linked to COVID-19 severity

We employed a multifaceted computational strategy to identify the genetic factors contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing (WES) dataset of a cohort of 2000 Italian patients. We coupled a stratified k-fold screening, to rank variants more associated with severity, with the training of multiple supervised classifiers, to predict severity based on screened features. Feature importance analysis from tree-based models allowed us to identify 16 variants with the highest support which, together with age and gender covariates, were found to be most predictive of COVID-19 severity. When tested on a follow-up cohort, our ensemble of models predicted severity with high accuracy (ACC = 81.88%; AUCROC = 96%; MCC = 61.55%). Our model recapitulated a vast literature of emerging molecular mechanisms and genetic factors linked to COVID-19 response and extends previous landmark Genome-Wide Association Studies (GWAS). It revealed a network of interplaying genetic signatures converging on established immune system and inflammatory processes linked to viral infection response. It also identified additional processes cross-talking with immune pathways, such as GPCR signaling, which might offer additional opportunities for therapeutic intervention and patient stratification. Publicly available PheWAS datasets revealed that several variants were significantly associated with phenotypic traits such as "Respiratory or thoracic disease", supporting their link with COVID-19 severity outcome.A multifaceted computational strategy identifies 16 genetic variants contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing dataset of a cohort of Italian patients

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

A first update on mapping the human genetic architecture of COVID-19

peer reviewe

UPAYA DINAS SOSIAL DALAM PEMBINAAN PENGEMIS DI KAWASAN MEGA MALL KOTA BENGKULU

Penelitian ini bertujuan untuk mendekripsikan Upaya Dinas Sosial dalam Pembinaan Pengemis di Kawasan Mega Mall Kota Bengkulu di Kelurahan Pasar Melintang Kota Bengkulu. Subjek dalam penelitian ini adalah Kepada Dinas Sosial Kota Bengkulu (Ir.Syahrul Tamzie), Ketua Bidang Tuna Sosial (Itera Hasti, So.Sos), Seksi Bidang Tuna Sosial dan Perdagangan Anak (Fitri Alvo,S.ST), serta tiga orang masyarakat yang berdagang di Kawasan Mega Mall Kota Bengkulu (Ibuk Ema, Pak Anto dan Mbak Nur). Teknik pengumpulan data dalam penelitian ini wawancara, observasi dan dokumentasi. Analisis data dilakukan dengan reduksi data, penyajian data dan penarikan kesimpulan. Pemeriksaan keabsahan data menggunakan teknik triangulasi, mulai dari triangulasi subjek, trianggulasi waktu dan triangulasi teknik. Dari Hasil penelitian, ditemukan bahwa pertama Upaya yang dilakukan oleh Dinas Sosial Kota Bengkulu dalam melakukan pembinaan misalnya,Razia, setalah dilakukan Razia pengemis di kumpulkan di tempat penampungan atau panti asuhan, pembinaan. Kedua Hambatan yang dihadapi oleh pihak dinas sosial dalam pembinaan pengemis misalnya, belum ada tempat atau lokasi khusus untuk pembinaan pengemis, belum ada peraturan daerah khusus tentang pengemis dan hambatan lain seperti pengemis itu sendiri yang tidak mau berubah. Ketiga Solusi yang digunakan pihak dinas sosial terhadap hambatan dalam melakukan pembinaan pengemis di Kota Bengkulu khususnya di kawasan Mega Mall Kota Bengkulu yaitu: (1) Dana, pihak dinas sosial hanya menyusun dan menjalankan program pembinaan sesuai dengan anggaran dana yang ada.(2)Lokasi atau tempat yaitu pembinaan tahap awal di lakukan di kantor dinas dan Pihak dinas sosial Kota Bengkulu bekerja dengan pihak panti asuhan sebagai tempat penampungan sementara. (3) Belum ada peraturan daerah khusus tentang pengemis sehingga pihak Dinas Sosial masih menggunakan Peraturan Daerah Nomor 03 Tahun 2008 tentang Ketentraman dan Ketertiban Umum dalam Wilayah Kota Bengkulu pasal 27. (4) Pengemis itu sendiri yang sulit atau tidak mau berubah, disini pihak dinas sosial melakukan pendekatan saat melakukan pembinaan. Keempat Persepsi masyarakat yang berdagang di Kawasan Mega Mall Kota Bengkulu tentang keberadaan pengemis tersebut, pengemis mengganggu lalu lintas di lahan parkir, merusak pemandangan, pengunjung merasa risih. Kata kunci : Upaya, Hambatan, Solusi, Persepsi, Pengemis, Dinas Sosial

The CDK Inhibitor Dinaciclib Improves Cisplatin Response in Nonseminomatous Testicular Cancer: A Preclinical Study

Background: Most patients with testicular germ cell tumors (GCTs) are treated with cisplatin (CP)-based chemotherapy. However, some of them may develop CP resistance and therefore represent a clinical challenge. Cyclin-dependent kinase 5 (CDK5) is involved in chemotherapy resistance in different types of cancer. Here, we investigated the possible role of CDK5 and other CDKs targeted by dinaciclib in nonseminoma cell models (both CP-sensitive and CP-resistant), evaluating the potential of the CDK inhibitor dinaciclib as a single/combined agent for the treatment of advanced/metastatic testicular cancer (TC). Methods: The effects of dinaciclib and CP on sensitive and resistant NT2/D1 and NCCIT cell viability and proliferation were evaluated using MTT assays and direct count methods. Flow cytometry cell-cycle analysis was performed. The protein expression was assessed via Western blotting. The in vivo experiments were conducted in zebrafish embryos xenografted with TC cells. Results: Among all the CDKs analyzed, CDK5 protein expression was significantly higher in CP-resistant models. Dinaciclib reduced the cell viability and proliferation in each cell model, inducing changes in cell-cycle distribution. In drug combination experiments, dinaciclib enhances the CP effect both in vitro and in the zebrafish model. Conclusions: Dinaciclib, when combined with CP, could be useful for improving nonseminoma TC response to CP