Bioinformatics analysis of gene expression profiles of Inclusion body myositis

Inclusion body myositis (IBM) is a disease with a poor prognosis and limited treatment options. This study aimed at exploring gene expression profile alterations, investigating the underlying mechanisms and identifying novel targets for IBM. We analysed two microarray datasets (GSE39454 and GSE128470) derived from the Gene Expression Omnibus (GEO) database. The GEO2R tool was used to screen out differentially expressed genes (DEGs) between IBM and normal samples. Gene Ontology（GO）function and Kyoto Encyclopedia of Genes and Genomes（KEGG）pathway enrichment analysis were performed using the Database for Annotation, Visualization and Integrated Discovery to identify the pathways and functional annotation of DEGs. Finally, protein-protein interaction (PPI) networks were constructed using STRING and Cytoscape, in order to identify hub genes. A total of 144 upregulated DEGs and one downregulated DEG were identified. The GO enrichment analysis revealed that the immune response was the most significantly enriched term within the DEGs. The KEGG pathway analysis identified 22 significant pathways, the majority of which could be divided into the immune and infectious diseases. Following the construction of PPI networks, ten hub genes with high degrees of connectivity were picked out, namely PTPRC, IRF8, CCR5, VCAM1, HLA-DRA, TYROBP, C1QB, HLA-DRB1, CD74 and CXCL9. Our research hypothesizes that autoimmunity plays an irreplaceable role in the pathogenesis of IBM. The novel DEGs and pathways identified in this study may provide new insight into the underlying mechanisms of IBM at the molecular level.     

Comparison of Implant Quality between Loose and Intra-operatively Linked Iodine-125 Seeds in Prostate Cancer Brachytherapy

From 2007 to 2010, 230 patients had iodine-125 seeds implanted (loose or intra-operatively linked into seed trains with variable seed-to-seed spacing). The primary aim was to evaluate differences in implant quality by comparing the intra-operative and post-implant dosimetry in patients treated with loose and intra-operatively linked seeds. The secondary aim was to evaluate the "learning curve" for the procedure. The following parameters were compared: the radiation dose to 90% of the prostate volume (D90), the radiation dose to 30% of the urethral volume (DU30), the percentage of the prostate volume receiving 100% or 200% of the prescribed dose (V100 or V200, respectively), the percentage of the rectal volume receiving 100% of the prescribed dose (VR100), and the homogeneity index (HI). We obtained the following results for loose vs. intra-operatively linked seeds: D90 (Gy), 184.7 ± 15.0 vs. 177.9 ± 12.7 (p = 0.002); V100 (%), 95.5 ± 2.4 vs. 94.9 ± 3.2 (p = 0.206); V200 (%), 35.1 ± 7.5 vs. 24.3 plusmn; 6,9 (p < 0.001); DU30 (Gy), 218.6 ± 24.1 vs. 197.4 ± 19.5 (p = 0.001); VR100 (cm³), 0.6 ± 0.47 vs. 0.3 ± 0.3 (p < 0.001); HI (%), 31.8 ± 7.3 vs. 44.0 ± 9.8 (p < 0.001). The advantages of intra-operatively linked seed implantation over loose seed implantation are a more homogeneous prostate dose and lower urethral and rectal doses. The disadvantage is a lower post-implant D90. Sufficient experience with the loose seed implantation procedure was obtained after the first 40 patients. There was essentially no learning curve when a new implantation method using intra-operatively linked seeds was subsequently initiated.     

Long-term results of high-dose-rate brachytherapy and external-beam radiotherapy in the primary treatment of endometrial cancer

In this report we update our long-term follow-up results of the prospective study whose aim was to evaluate the efficacy of high-dose-rate (HDR) brachytherapy in combination with external-beam radiotherapy (EBRT) in the treatment of medically inoperable endometrial cancer. Between 1995 and 1998, 29 patients with stages I-III medically inoperable carcinoma of endometrium were treated with definitive irradiation. All patients underwent combined intracavitary HDR brachytherapy and EBRT. The EBRT dose was 50 Gy with midline shield from 16 Gy. The HDR brachytherapy dose was 50 Gy, delivered in 5 fractions in a weekly schedule. Overall survival (OS) at 5 and 10 years was 48.3% and 20.7%, respectively. Disease-specific survival (DSS) at 5 and 10 years was 73.5% and 67.9%, respectively. The 10-year DSS rate was 73.5% for all stages, 85.7% for Stage I disease, 71.4% for Stage II, and 16.7% for stage III disease. Late Grade 1-2 radiation complications were observed in 4 patients (13.8%). Our long-term follow-up confirms that HDR brachytherapy with EBRT appears to be an effective and safe treatment for stage I and II medically inoperable endometrial cancer.     

School,Supervision and Adolescent-Sensitive Clinic Care: Combination Social Protection and Reduced Unprotected Sex Among HIV-Positive Adolescents in South Africa

Social protection can reduce HIV-risk behavior in general adolescent populations, but evidence among HIV-positive adolescents is limited. This study quantitatively tests whether social protection is associated with reduced unprotected sex among 1060 ART-eligible adolescents from 53 government facilities in South Africa. Potential social protection included nine ‘cash/cash-in-kind’ and ‘care’ provisions. Analyses tested interactive/additive effects using logistic regressions and marginal effects models, controlling for covariates. 18 % of all HIV-positive adolescents and 28 % of girls reported unprotected sex. Lower rates of unprotected sex were associated with access to school (OR 0.52 95 % CI 0.33–0.82 p = 0.005), parental supervision (OR 0.54 95 % CI 0.33–0.90 p = 0.019), and adolescent-sensitive clinic care (OR 0.43 95 % CI 0.25–0.73 p = 0.002). Gender moderated the effect of adolescent-sensitive clinic care. Combination social protection had additive effects amongst girls: without any provisions 49 % reported unprotected sex; with 1–2 provisions 13–38 %; and with all provisions 9 %. Combination social protection has the potential to promote safer sex among HIV-positive adolescents, particularly girls.     

Two years after lockdown: reviewing the effects of COVID‐19 on health services and support for adolescents living with HIV in South Africa

IntroductionSouth Africa''s progress towards the 95‐95‐95 goals has been significantly slower among adolescents living with HIV (ALHIV), among whom antiretroviral therapy (ART) adherence, retention in care and viral suppression remain a concern. After 2 years of living with COVID‐19, it is important to examine the direct and indirect effects of the pandemic on healthcare resources, access to HIV services and availability of support structures, to assess their impact on HIV care for ALHIV.DiscussionThe COVID‐19 response in South Africa has shifted healthcare resources towards combatting COVID‐19, affecting the quality and availability of HIV services—especially for vulnerable populations, such as ALHIV. The healthcare system''s response to COVID‐19 has threatened to diminish fragile gains in engaging ALHIV with HIV services, especially as this group relies on overburdened public health facilities for their HIV care. Reallocation of limited health resources utilized by ALHIV disrupted healthcare workers’ capacity to form and maintain therapeutic relationships with ALHIV and monitor ALHIV for ART‐related side effects, treatment difficulties and mental health conditions, affecting their ability to retain ALHIV in HIV care. Prevailing declines in HIV surveillance meant missed opportunities to identify and manage opportunistic infections and HIV disease progression in adolescents. “Lockdown” restrictions have limited access to healthcare facilities and healthcare workers for ALHIV by reducing clinic appointments and limiting individual movement. ALHIV have had restricted access to social, psychological and educational support structures, including national feeding schemes. This limited access, coupled with reduced opportunities for routine maternal and sexual and reproductive health services, may place adolescent girls at greater risk of transactional sex, child marriages, unintended pregnancy and mother‐to‐child HIV transmission.ConclusionsAdolescent HIV care in South Africa is often overlooked; however, ART adherence among ALHIV in South Africa is particularly susceptible to the consequences of a world transformed by COVID‐19. The current structures in place to support HIV testing, ART initiation and adherence have been reshaped by disruptions to health structures, new barriers to access health services and the limited available education and psychosocial support systems. Reflecting on these limitations can drive considerations for minimizing these barriers and retaining ALHIV in HIV care.     

Abnormal Cochlear Potentials from Deaf Patients with Mutations in the Otoferlin Gene

Otoferlin is involved in neurotransmitter release at the synapse between inner hair cells (IHCs) and auditory nerve fibres, and mutations in the OTOF gene result in severe to profound hearing loss. Abnormal sound-evoked cochlear potentials were recorded with transtympanic electrocochleography from four children with otoferlin (OTOF) mutations to evaluate physiological effects in humans of abnormal neurotransmitter release from IHCs. The subjects were profoundly deaf with absent auditory brainstem responses and preserved otoacoustic emissions consistent with auditory neuropathy. Two children were compound heterozygotes for mutations c.2732_2735dupAGCT and p.Ala964Glu; one subject was homozygous for mutation p.Phe1795Cys, and one was compound heterozygote for two novel mutations c.1609delG in exon 16 and c.1966delC in exon 18. Cochlear potentials evoked by clicks from 60 to 120 dB peak equivalent sound pressure level were compared to recordings obtained from 16 normally hearing children. Cochlear microphonic (CM) was recorded with normal amplitudes from all but one ear. After cancelling CM, cochlear potentials were of negative polarity with reduced amplitude and prolonged duration compared to controls. These cochlear potentials were recorded as low as 50–90 dB below behavioural thresholds in contrast to the close correlation in controls between cochlear potentials and behavioural threshold. Summating potential was identified in five out of eight ears with normal latency whilst auditory nerve compound action potentials were either absent or of low amplitude. Stimulation at high rates reduced amplitude and duration of the prolonged potentials, consistent with neural generation. This study suggests that mechano-electrical transduction and cochlear amplification are normal in patients with OTOF mutations. The low-amplitude prolonged negative potentials are consistent with decreased neurotransmitter release resulting in abnormal dendritic activation and impairment of auditory nerve firing.