The field of the genetics of polycystic ovary syndrome (PCOS) has relatively recently moved into the era of genome-wide association studies. This has led to the discovery of 16 robust loci for PCOS. ...Some loci contain genes with clear roles in reproductive ( LHCGR , FSHR , and FSHB ) and metabolic ( INSR and HMGA2 ) dysfunction in the syndrome. The next challenge facing the field is the identification of causal variants and genes and the role they play in PCOS pathophysiology. The potential for gene discovery to improve diagnosis and treatment of PCOS is promising, though there is much to be done in the field before the current findings can be translated to the clinic.
Circadian rhythms provide organisms with an adaptive advantage, allowing them to regulate physiological and developmental events so that they occur at the most appropriate time of day. In plants, as ...in other eukaryotes, multiple transcriptional feedback loops are central to clock function. In one such feedback loop, the Myb-like transcription factors CCA1 and LHY directly repress expression of the pseudoresponse regulator TOC1 by binding to an evening element (EE) in the TOC1 promoter. Another key regulatory circuit involves CCA1 and LHY and the TOC1 homologs PRR5, PRR7, and PRR9. Purification of EE-binding proteins from plant extracts followed by mass spectrometry led to the identification of RVE8, a homolog of CCA1 and LHY. Similar to these well-known clock genes, expression of RVE8 is circadian-regulated with a dawn phase of expression, and RVE8 binds specifically to the EE. However, whereas cca1 and lhy mutants have short period phenotypes and overexpression of either gene causes arrhythmia, rve8 mutants have long-period and RVE8-OX plants have short-period phenotypes. Light input to the clock is normal in rve8, but temperature compensation (a hallmark of circadian rhythms) is perturbed. RVE8 binds to the promoters of both TOC1 and PRR5 in the subjective afternoon, but surprisingly only PRR5 expression is perturbed by overexpression of RVE8. Together, our data indicate that RVE8 promotes expression of a subset of EE-containing clock genes towards the end of the subjective day and forms a negative feedback loop with PRR5. Thus RVE8 and its homologs CCA1 and LHY function close to the circadian oscillator but act via distinct molecular mechanisms.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Genome wide association studies (GWAS) have revealed 11 independent risk loci for polycystic ovary syndrome (PCOS), a common disorder in young women characterized by androgen excess and ...oligomenorrhea. To put these risk loci and the single nucleotide polymorphisms (SNPs) therein into functional context, we measured DNA methylation and gene expression in subcutaneous adipose tissue biopsies to identify PCOS-specific alterations. Two genes from the LHCGR region, STON1-GTF2A1L and LHCGR, were overexpressed in PCOS. In analysis stratified by obesity, LHCGR was overexpressed only in non-obese PCOS women. Although not differentially expressed in the entire PCOS group, INSR was underexpressed in obese PCOS subjects only. Alterations in gene expression in the LHCGR, RAB5B and INSR regions suggest that SNPs in these loci may be functional and could affect gene expression directly or indirectly via epigenetic alterations. We identified reduced methylation in the LHCGR locus and increased methylation in the INSR locus, changes that are concordant with the altered gene expression profiles. Complex patterns of meQTL and eQTL were identified in these loci, suggesting that local genetic variation plays an important role in gene regulation. We propose that non-obese PCOS women possess significant alterations in LH receptor expression, which drives excess androgen secretion from the ovary. Alternatively, obese women with PCOS possess alterations in insulin receptor expression, with underexpression in metabolic tissues and overexpression in the ovary, resulting in peripheral insulin resistance and excess ovarian androgen production. These studies provide a genetic and molecular basis for the reported clinical heterogeneity of PCOS.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Novel strategies to re-engage and retain people living with HIV (PLWH) who are out of care are greatly needed. While mobile clinics have been used effectively for HIV testing and linkage, evidence ...guiding their use in providing HIV care domestically has been limited. To guide the development of a mobile HIV clinic (MHC) model as a strategy to re-engage and retain PLWH who are out of care, we aimed to explore stakeholder perceptions of barriers and facilitators to MHC implementation and use. From June 2019-July 2020, we conducted 41 in-depth interviews with HIV clinic providers, administrators, staff, legal authorities, and community advisory board members, PLWH, AIDS service organizations and city officials in Atlanta, Georgia, and domestic and international mobile health clinics to explore barriers and facilitators to use of MHCs. Interviews were transcribed, coded and thematically analysed. Barriers raised include potential for: breach of confidentiality with resulting heightened stigmatization, fractured continuity of care, safety concerns, staffing challenges, and low community acceptance of MHC presence in their locality. Participants provided suggestions regarding appropriate exterior design, location, timing, and co-delivery of non-HIV services that could facilitate MHC acceptance and address the concerns. In identifying key barriers and facilitators to MHC use, this study informs design and implementation of an MHC as a novel strategy for re-engaging and retaining PLWH who are out of care.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Approximately half of the people with HIV (PWH) in the United States are retained in HIV care and only 57% have achieved viral suppression, due to barriers including transportation access, stigma, ...poor mental health, substance use, and medical mistrust. Community-based HIV care models have potential to address the diverse needs of patients and to improve retention in care, but their success is contingent on acceptance by patients and key community stakeholders. Recognizing that the preferences of PWH who are out-of-care (PWH-OOC) likely differ from those retained in care, we conducted a mixed-methods study from June 2019 to May 2021 composed of surveys with PWH-OOC (n = 50) and in-depth interviews with key clinic and community stakeholders (n = 41) to examine the relative preference and perceived advantages and disadvantages for six different community-based HIV care models versus the traditional fixed-clinic model. Survey data was analyzed to assess average rank preference for each care model and interview transcripts were thematically coded to examine factors influencing model acceptance. The highest preference for care delivery was via a mobile clinic, followed by community-based peer navigation, primary care clinics, telemedicine, traditional HIV subspeciality clinic, homeless shelter, and drug treatment center. Common factors influencing preference included convenience, accessibility, potential to preserve confidentiality, quality of care assurance, opportunity to develop rapport with their HIV care provider, access to a smart device, and potential to alleviate versus exacerbate HIV stigma. Participants discussed need for integration of care models and for individuals to choose different care models at different times. Providers and patients differed in preference for care model and weighting of relative advantages and disadvantages of each. Findings highlight the need to integrate alternative, community-based care models into the national plan to end the HIV epidemic and to allow for PWH-OOC to choose the model most fitting based on individual circumstances.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Epithelial ovarian cancer (EOC) is a heterogeneous disease with a major heritable component. The different histotypes of invasive disease – high grade serous, clear cell, endometrioid and mucinous – ...are associated with different underlying genetic susceptibility and epidemiological and lifestyle risk factors, all of which contribute to the different biology and clinical characteristics of each histotype. A combination of familial and population based sequencing studies, and genome wide association studies (GWAS) have identified a range of genetic susceptibility alleles for EOC comprising rare but highly penetrant genes (e.g. BRCA1, BRCA2) that are responsible for familial clustering of ovarian cancer cases; more moderate penetrance susceptibility genes (e.g. BRIP1, RAD51C/D, MSH6); and multiple common but low penetrance susceptibility alleles identified by GWAS. Identifying genetic risk alleles for ovarian cancer has had a significant impact on disease prevention strategies; for example it is now routine clinical practice for individuals with germline BRCA1 and BRCA2 mutations to undergo risk reducing salpingo-oophorectomy. Because ovarian cancers are commonly diagnosed at a late clinical stage when the prognosis is poor, the continued development of genetic risk prediction and prevention strategies will represent an important approach to reduce mortality due to ovarian cancer. Advances in genomics technologies that enable more high-throughput genetic testing, combined with research studies that identify additional EOC risk alleles will likely provide further opportunities to establish polygenic risk prediction approaches, based on combinations of rare high/moderate penetrance susceptibility genes and common, low penetrance susceptibility alleles. This article reviews the current literature describing the genetic and epidemiological components of ovarian cancer risk, and discusses both the opportunities and challenges in using this information for clinical risk prediction and prevention.
•Contribution of high and moderate penetrant genes to ovarian cancer heritability•Contribution of common low risk alleles to ovarian cancer heritability•Implications of genetic risk discovery for clinical risk prediction and prevention
Missing values in proteomic data sets have real consequences on downstream data analysis and reproducibility. Although several imputation methods exist to handle missing values, no single imputation ...method is best suited for a diverse range of data sets, and no clear strategy exists for evaluating imputation methods for clinical DIA-MS data sets, especially at different levels of protein quantification. To navigate through the different imputation strategies available in the literature, we have established a strategy to assess imputation methods on clinical label-free DIA-MS data sets. We used three DIA-MS data sets with real missing values to evaluate eight imputation methods with multiple parameters at different levels of protein quantification: a dilution series data set, a small pilot data set, and a clinical proteomic data set comparing paired tumor and stroma tissue. We found that imputation methods based on local structures within the data, like local least-squares (LLS) and random forest (RF), worked well in our dilution series data set, whereas imputation methods based on global structures within the data, like BPCA, performed well in the other two data sets. We also found that imputation at the most basic protein quantification levelfragment levelimproved accuracy and the number of proteins quantified. With this analytical framework, we quickly and cost-effectively evaluated different imputation methods using two smaller complementary data sets to narrow down to the larger proteomic data set’s most accurate methods. This acquisition strategy allowed us to provide reproducible evidence of the accuracy of the imputation method, even in the absence of a ground truth. Overall, this study indicates that the most suitable imputation method relies on the overall structure of the data set and provides an example of an analytic framework that may assist in identifying the most appropriate imputation strategies for the differential analysis of proteins.
Abstract
Objective
To evaluate the impact of integrating patient-reported outcomes (PROs) into routine clinics, from the perspective of patients with RA, clinicians and other staff.
Methods
We ...conducted a prospective cohort study using a mixed methods sequential explanatory design at an academic arthritis clinic. RA patients completed selected Patient-Reported Outcomes Measurement Information System measures on tablets in the waiting room. Results were immediately available to discuss during the visit. Post-visit surveys with patients and physicians evaluated topics discussed and their impact on decision making; patients rated confidence in treatment. Focus groups or interviews with patients, treating rheumatologists and clinic staff were conducted to understand perspectives and experiences.
Results
Some 196 patients and 20 rheumatologists completed post-visit surveys at 816 and 806 visits, respectively. Focus groups were conducted with 24 patients, 10 rheumatologists and 4 research/clinic staff. PROs influenced medical decision-making and RA treatment changes (38 and 18% of visits, respectively). Patients reported very high satisfaction and treatment confidence. Impact on clinical workflow was minimal after a period of initial adjustment. PROs were valued by patients and physicians, and provided new insight into how patients felt and functioned over time. Reviewing results together improved communication, and facilitated patient-centred care, shared decision making, and the identification of new symptoms and contributing psychosocial/behavioural factors.
Conclusion
PRO use at RA visits was feasible, increased understanding of how disease affects how patients feel and function, facilitated shared decision-making, and was associated with high patient satisfaction and treatment confidence.
We performed the first studies of analytic sensitivity, analytic specificity, and dynamic range for the new Xpert MTB/RIF assay, a nucleic acid amplification-based diagnostic system that detects ...Mycobacterium tuberculosis and rifampin (RIF) resistance in under 2 h. The sensitivity of the assay was tested with 79 phylogenetically and geographically diverse M. tuberculosis isolates, including 42 drug-susceptible isolates and 37 RIF-resistant isolates containing 13 different rpoB mutations or mutation combinations. The specificity of the assay was tested with 89 nontuberculosis bacteria, fungi, and viruses. The Xpert MTB/RIF assay correctly identified all 79 M. tuberculosis isolates and correctly excluded all 89 nontuberculosis isolates. RIF resistance was correctly identified in all 37 resistant isolates and in none of the 42 susceptible isolates. Dynamic range was assessed by adding 10² to 10⁷ CFU of M. tuberculosis into M. tuberculosis-negative sputum samples. The assay showed a log-linear relationship between cycle threshold and input CFU over the entire concentration range. Resistance detection in the presence of different mixtures of RIF-resistant and RIF-susceptible DNA was assessed. Resistance detection was dependent on the particular mutation and required between 65% and 100% mutant DNA to be present in the sample for 95% certainty of resistance detection. Finally, we studied whether assay specificity could be affected by cross-contaminating amplicons generated by the GenoType MTBDRplus assay. M. tuberculosis was not detected until at least 10⁸ copies of an MTBDRplus amplicon were spiked into 1 ml of sputum, suggesting that false-positive results would be unlikely to occur.
PDF
