Variations in CCL3L gene cluster sequence and non-specific gene copy numbers

<p>Abstract</p> <p>Background</p> <p>Copy number variations (CNVs) of the gene CC chemokine ligand 3-like1 (<it>CCL3L1</it>) have been implicated in HIV-1 susceptibility, but the association has been inconsistent. <it>CCL3L1 </it>shares homology with a cluster of genes localized to chromosome 17q12, namely <it>CCL3</it>, <it>CCL3L2</it>, and, <it>CCL3L3</it>. These genes are involved in host defense and inflammatory processes. Several CNV assays have been developed for the <it>CCL3L1 </it>gene.</p> <p>Findings</p> <p>Through pairwise and multiple alignments of these genes, we have shown that the homology between these genes ranges from 50% to 99% in complete gene sequences and from 70-100% in the exonic regions, with <it>CCL3L1 </it>and <it>CCL3L3 </it>being identical. By use of MEGA 4 and BioEdit, we aligned sense primers, anti-sense primers, and probes used in several previously described assays against pre-multiple alignments of all four chemokine genes. Each set of probes and primers aligned and matched with overlapping sequences in at least two of the four genes, indicating that previously utilized RT-PCR based CNV assays are not specific for only <it>CCL3L1</it>. The four available assays measured median copies of 2 and 3-4 in European and African American, respectively. The concordance between the assays ranged from 0.44-0.83 suggesting individual discordant calls and inconsistencies with the assays from the expected gene coverage from the known sequence.</p> <p>Conclusions</p> <p>This indicates that some of the inconsistencies in the association studies could be due to assays that provide heterogenous results. Sequence information to determine CNV of the three genes separately would allow to test whether their association with the pathogenesis of a human disease or phenotype is affected by an individual gene or by a combination of these genes.</p

Effect of a female community health volunteer-delivered intervention to increase cervical cancer screening uptake in Nepal:a cluster randomized controlled trial

This study aimed to assess the effect of Female Community Health Volunteer (FCHV)-delivered intervention to increase cervical cancer screening uptake among Nepalese women. A community-based, open-label, 2-group, cluster randomized controlled trial (CRCT) was conducted in a semi-urban setting in Western Nepal. Fourteen clusters (1:1) were randomly assigned to the intervention group, which received a 12-month intervention delivered by FCHVs or the control group (usual care). Between April and June 2019, 690 women aged 30–60 years were recruited for CRCT during the baseline survey. A follow-up assessment was conducted after the completion of the 12 months intervention. The primary outcome was the change in cervical cancer screening from baseline to 12-month follow-up. Of 690 women, 646 women completed the trial. 254 women in the intervention group and 385 women in the control group were included in the primary outcome analysis. There was a significant increase in cervical cancer screening uptake in the intervention group [relative risk (RR), 1.48; 95 % confidence interval (CI) 1.32, 1.66; P < 0.01)], compared to the control group. The secondary outcome was the change in median knowledge score among women that increased from 2 [interquartile range (IQR) 1–4] (baseline) to 6 [IQR 3–9] (follow-up) in the intervention group. However, the median knowledge score remained almost the same among women in the control group 2 [IQR 1–5] to 3 [IQR 2–5]. Our study findings reported that an FCHV-delivered intervention significantly increased cervical cancer screening uptake among women living in a semi-urban setting in Nepal. Trial registration: ClinicalTrials.gov NCT03808064

Association of chemokine receptor gene (CCR2-CCR5) haplotypes with acquisition and control of HIV-1 infection in Zambians

<p>Abstract</p> <p>Background</p> <p>Polymorphisms in chemokine (C-C motif) receptors 2 and 5 genes (<it>CCR2 </it>and <it>CCR5</it>) have been associated with HIV-1 infection and disease progression. We investigated the impact of <it>CCR2-CCR5 </it>haplotypes on HIV-1 viral load (VL) and heterosexual transmission in an African cohort. Between 1995 and 2006, cohabiting Zambian couples discordant for HIV-1 (index seropositive and HIV-1 exposed seronegative {HESN}) were monitored prospectively to determine the role of host genetic factors in HIV-1 control and heterosexual transmission. Genotyping for eight <it>CCR2 </it>and <it>CCR5 </it>variants resolved nine previously recognized haplotypes. By regression and survival analytic techniques, controlling for non-genetic factors, we estimated the effects of these haplotypic variants on a) index partner VL, b) seroconverter VL, c) HIV-1 transmission by index partners, d) HIV-1 acquisition by HESN partners.</p> <p>Results</p> <p>Among 567 couples, 240 virologically linked transmission events had occurred through 2006. HHF*2 homozygosity was associated with significantly lower VL in seroconverters (mean beta = -0.58, log₁₀<it>P </it>= 0.027) and the HHD/HHE diplotype was associated with significantly higher VL in the seroconverters (mean beta = 0.54, log₁₀<it>P </it>= 0.014) adjusted for age and gender in multivariable model. HHD/HHE was associated with more rapid acquisition of infection by the HESNs (HR = 2.0, 95% CI = 1.20-3.43, <it>P </it>= 0.008), after adjustments for index partner VL and the presence of genital ulcer or inflammation in either partner in Cox multivariable models. The HHD/HHE effect was stronger in exposed females (HR = 2.1, 95% CI = 1.14-3.95, <it>P </it>= 0.018).</p> <p>Conclusions</p> <p>Among Zambian discordant couples, HIV-1 coreceptor gene haplotypes and diplotypes appear to modulate HIV-1 VL in seroconverters and alter the rate of HIV-1 acquisition by HESNs. These associations replicate or resemble findings reported in other African and European populations.</p

Preference for Human Papillomavirus–Based Cervical Cancer Screening: Results of a Choice-Based Conjoint Study in Zambia

The objective of this study was to assess the conditions under which Zambia women with a history of cervical cancer screening by visual inspection with acetic acid might switch to HPV-based testing in the future

Seasonality and geographical distribution of Kawasaki disease among Black children in the Southeast United States

IntroductionKawasaki Disease (KD) is a leading cause of pediatric acquired heart disease in the United States, affecting up to 7,000 children annually. Seasonal variation, an epidemiological characteristic of KD, has previously been reported predominantly among Asian children; however, little is known about the epidemiology and seasonality of KD of Black children within the U.S.MethodsElectronic medical records were abstracted from 529 hospitalized KD patients admitted to a single tertiary center in Alabama between 2005 and 2019. Medical charts were reviewed to confirm KD diagnosis following American Heart Association criteria. Cases were stratified by the month of diagnosis date to assess seasonality, and statewide distribution of incidence is reported at county level using geographical spatial analysis. Comparisons were performed between Black patients and White patients with KD.ResultsThe average number of KD cases per year was 35. Approximately, 60% were males and 44% were White children (N = 234), 45% were Black children (N = 240) and 11% were other races (N = 55). Black children were younger than White children at KD admission (median age 32 vs. 41 months respectively, p = 0.02). Overall, the highest rates of cases occurred between January and April. When stratifying by race, cases started to rise in December among White children with the highest rates between February and April with a peak in March. Among Black children cases were high during the winter season (January–April) with a peak in April. Similarly high rates also occurred in June, July and November. There were no differences in geographical distribution of cases by race.ConclusionKD incidence among White children in Alabama follows a seasonal cycle similar to other regions in the U.S. However, sustained incidence and additional peaks outside of the usual KD seasonality were seen among Black children with KD. Further studies are needed to investigate differential triggers between races

Spousal migration and human papillomavirus infection among women in rural western Nepal

In April 2014 we investigated the association of migration of a woman's husband with her high-risk human papillomavirus (HR-HPV) infection status and her abnormal cervical cytology status in the Achham district of rural Far-Western Nepal

Attitudes Toward Menstrual Suppression Among Cyclic and Continuous Contraceptive Vaginal Ring Users in Kenya

Objective: Multipurpose prevention technologies (MPTs) are developmental dual-purpose options that would provide women with a contraceptive as well as a prevention modality aimed at sexually transmitted infections. The contraceptive vaginal ring (CVR) has many properties that makes it an ideal MPT candidate. The objective of this study is to understand women’s attitudes towards menstrual suppression, a potential side effect of using a CVR, and how to address these attitudes for MPT vaginal rings in development. Materials and methods: We analyzed data derived from a subset of cohort study participants (n=45) in Thika, Kenya between January 2016- December 2018. The primary study enrolled 121 women 18-40 years with bacterial vaginosis and randomized them to cyclic or continuous CVR use for eight months. During the 6-month follow-up, a questionnaire eliciting attitudes towards menstrual suppression was administered. Responses to the menstrual suppression questionnaire between participants in the cyclic and continuous CVR use groups were compared. Likert-scale responses were summed to create a menstrual suppression attitude summary score, and a hierarchical cluster analysis was conducted to identify similarities in response patterns among all participants. Results: Totally 81.8% of continuous CVR users believed that one was less likely to get pregnant after using hormonal medication to suppress menses, compared to 47.8% of cyclic CVR users (P=0.02), and were more worried it would cause long-term health effects (86.4% vs 60.9%, p = 0.05). The menstrual suppression attitude summary score ranged from 8 to 42, with lower scores indicating negative attitudes. The summary score identified three distinct clusters. When asked if menstrual suppression effects long-term health; 100% of Cluster 3 was worried compared to 80.8% of Cluster 2 and 46.2% of Cluster 1 (p = 0.03). The average summary score among Cluster 3 (Mean = 14.8, SD = 4.6) was lower (p < 0.001) and women were more worried about discomfort during sex (p=0.05) as well as their sexual partners feeling the ring (p=0.02). Conclusion: Women are more likely to have negative attitudes if they believe menstrual suppression hinders future reproductive health. Education on cycle control and fertility could mitigate negative attitudes and improve uptake of CVRs

Genomic alterations associated with mutational signatures, DNA damage repair and chromatin remodeling pathways in cervical carcinoma

Despite recent advances in the prevention of cervical cancer, the disease remains a leading cause of cancer-related deaths in women worldwide. By applying the GISTIC2.0 and/or the MutSig2CV algorithms on 430 whole-exome-sequenced cervical carcinomas, we identified previously unreported significantly mutated genes (SMGs) (including MSN, GPX1, SPRED3, FAS, and KRT8), amplifications (including NFIA, GNL1, TGIF1, and WDR87) and deletions (including MIR562, PVRL1, and NTM). Subset analyses of 327 squamous cell carcinomas and 86 non-squamous cell carcinomas revealed previously unreported SMGs in BAP1 and IL28A, respectively. Distinctive copy number alterations related to tumors predominantly enriched for *CpG- and Tp*C mutations were observed. CD274, GRB2, KRAS, and EGFR were uniquely significantly amplified within the Tp*C-enriched tumors. A high frequency of aberrations within DNA damage repair and chromatin remodeling genes were detected. Facilitated by the large sample size derived from combining multiple datasets, this study reveals potential targets and prognostic markers for cervical cancer.publishedVersio