The Emerging Role of Two-Pore Domain Potassium Channels in Breast Cancer

Potassium ion channels are transmembrane proteins that selectively facilitate ion flow down an electrochemical gradient between intracellular and extracellular environments. There is accumulating evidence which suggest that potassium channel protein activity is important in the pathophysiology of cancer, and associations of the two-pore domain family of potassium channels and breast cancer are currently emerging. The aim of this review is to summarize data on mechanisms of action related to oncogenic properties and examine the role of the two-pore domain family in breast cancer

An assessment of prevalence and expenditure associated with discharge brain MRI in preterm infants

To assess national expenditure associated with preterm-infant brain MRI and potential impact of reduction per Choosing Wisely campaign 2015 recommendation to “avoid routine screening term-equivalent or discharge brain MRIs in preterm-infants”. Cross-sectional U.S. trend data from the Agency for Healthcare Research and Quality (AHRQ), Healthcare Cost and Utilization Project (HCUP) Kids’ Inpatient Database (KID) database (2006, 2009, 2012, 2016) was used to estimate overall national expenditure associated with brain MRI among infants with gestational age (GA) ≤36 weeks, and also when classified as ‘not indicated’ (NI-MRI) i.e., equivalent to routine use without clinical indications and regarded as low-value service (LVS). Associated cost was determined by querying CMS-database for physician-fee-schedules to find the highest global procedure-cost per cycle, then adjusting for inflation. Sensitivity-analyses were conducted to account for additional clinical charges associated with NI-MRI. 3,768 (0.26%) of 1,472,236 preterm-infants had brain MRI across all cycles (inflation-adjusted total $3,690,088). Overall proportion of brain MRIs increased across 2006–2012 from 0.25$1,299,130 (95% CI: $987,505,$1,610,755); 2009, $1,194,208 (95$873,487, $1,516,154); 2012,$931,836 (95% CI: $666,114,$1,197,156); and 2016, $264,648 (95$172,061, $357,280). Prevalence for NI-MRI in 2006, 2009, 2012 and 2016 was 86$1,190,919/$518,343, for 2012/2016 cycles respectively. National MRI prevalence in preterm infants (both overall and LVS) and associated expenditure decreased substantially post recommendation; however, annual savings are modest and unlikely to be \u3e$1.2 million

Using Genetic Technologies To Reduce, Rather Than Widen, Health Disparities

Evidence shows that both biological and nonbiological factors contribute to health disparities. Genetics, in particular, plays a part in how common diseases manifest themselves. Today, unprecedented advances in genetically based diagnoses and treatments provide opportunities for personalized medicine. However, disadvantaged groups may lack access to these advances, and treatments based on research on non-Hispanic whites might not be generalizable to members of minority groups. Unless genetic technologies become universally accessible, existing disparities could be widened. Addressing this issue will require integrated strategies, including expanding genetic research, improving genetic literacy, and enhancing access to genetic technologies among minority populations in a way that avoids harms such as stigmatization

Use of electronic personal health record systems to encourage HIV screening: an exploratory study of patient and provider perspectives

<p>Abstract</p> <p>Background</p> <p>When detected, HIV can be effectively treated with antiretroviral therapy. Nevertheless in the U.S. approximately 25% of those who are HIV-infected do not know it. Much remains unknown about how to increase HIV testing rates. New Internet outreach methods have the potential to increase disease awareness and screening among patients, especially as electronic personal health records (PHRs) become more widely available. In the US Department of Veterans' Affairs medical care system, 900,000 veterans have indicated an interest in receiving electronic health-related communications through the PHR. Therefore we sought to evaluate the optimal circumstances and conditions for outreach about HIV screening. In an exploratory, qualitative research study we examined patient and provider perceptions of Internet-based outreach to increase HIV screening among veterans who use the Veterans Health Administration (VHA) health care system.</p> <p>Findings</p> <p>We conducted two rounds of focus groups with veterans and healthcare providers at VHA medical centers. The study's first phase elicited general perceptions of an electronic outreach program to increase screening for HIV, diabetes, and high cholesterol. Using phase 1 results, outreach message texts were drafted and then presented to participants in the second phase. Analysis followed modified grounded theory.</p> <p>Patients and providers indicated that electronic outreach through a PHR would provide useful information and would motivate patients to be screened for HIV. Patients believed that electronic information would be more convenient and understandable than information provided verbally. Patients saw little difference between messages about HIV versus about diabetes and cholesterol. Providers, however, felt patients would disapprove of HIV-related messages due to stigma. Providers expected increased workload from the electronic outreach, and thus suggested adding primary care resources and devising methods to smooth the flow of patients getting screened. When provided a choice between unsecured emails versus PHRs as the delivery mechanism for disease screening messages, both patients and providers preferred PHRs.</p> <p>Conclusions</p> <p>There is considerable potential to use PHR systems for electronic outreach and social marketing to communicate to patients about, and increase rates of, disease screening, including for HIV. Planning for direct-to-patient communications through PHRs should include providers and address provider reservations, especially about workload increases.</p

Two‐pore Domain Potassium Channel Genes and Breast Cancer in The Cancer Genome Atlas

The overarching goal of this dissertation was to systematically evaluate molecular markers (DNA methylation, gene expression, and copy number changes) of K2P channel genes in relation to breast cancer subtype, clinical covariates and prognosis, using a landscape approach in TCGA breast cancer data. Findings show that overexpression of KCNK5, KCNK9, KCNK10 and KCNK12, and underexpression of KCNK6 and KCNK15, are significantly associated with our primary outcome of TN subtype. Similar patterns of association were also evident for most of the related secondary subtype outcomes. We found CG loci to be associated with nH black race: 4 loci in the promoter region of KCNK15, and 3 more loci near KCNK4, and 2 near KCNK5. CG loci on KCNK2, KCNK5 and KCNK9 were significantly associated with negative expression across all hormone-receptor negative related subtype outcomes. Another locus near KCNK12 also had consistent correlations with positive gene expression across most hormone receptor related negative subtypes. In addition, copy number loss in KCNK10, KCNK13, KCNK16 and KCNK18, and gain in KCNK3, KCNK4, KCNK5, KCNK6, KCNK7, KCNK9, KCNK12, KCNK16, KCNK17 and KCNK18, were common associations across hormone receptor negative subtypes. We found K2P markers together accounted for, or mediated, a substantial proportion of the observed subtype disparity (i.e. increased risk of ER/PR-negative/TN disease) in black women, and gene methylation accounted for the largest proportion mediated. K2P gene markers together also mediated a substantial part of the molecular ER/PR-negative/TN subtype disparity observed with p53 expression. Finally, KCNK4 and KCNK9 may be associated with worse survival. Our study findings are however considered preliminary and need to be validated in additional studies

The value of regional intra-arterial therapy with novel sustained-release ethiodol based preparations for hepatic-neoplastic disease

We continue to search for effective therapies for hepatic-metastatic disease. Loco-regional therapy is attractive because it allows for tumour directed dose intensification without associated increase in systemic toxicity, which may lead to improved efficacy. In addition, the use of sustained-release or depot preparations may obviate the need for continuous infusion via expensive implantable pumps, and may also allow treatment of patients who are unfit for surgery, or who have more advanced disease. The iodinated poppyseed oil, Ethiodol, is selectively retained in liver tumours for weeks to months after hepatic intra-arterial infusion (HAI), and demonstrates ideal properties as a vehicle for development of depot or sustained-release HAI therapies of lipophillic or oil-soluble novel anticancer agents. This project demonstrated the value of Ethiodol for this purpose. A reproducible experimental animal hepatic-metastatic model using Fisher rats and syngenic MADB106 breast adenocarcinoma cells was established, and allowed evaluation of Ethiodol based HAI preparations. Several novel anticancer agents were soluble in Ethiodol and exhibited sustained-release characteristics. These preparations included (a) the topoisomerase-1 inhibitor 9-aminocamptothecin (9AC), (b) the cytokine human recombinant interleukin-2 (Hril2), and (c) several nitric oxide (NO) donors NOR1, NOR2, NOR3, SNAP and sodium nitroprusside. These compounds were effective antitumour agents both in vitro and in vivo, and inhibited tumour engraftment after subcutaneous inoculation with admixed tumour cells. They were well tolerated and eradicated hepatic-metastatic disease when administered as loco-regional HAI therapy, with decreased toxicity compared to equivalent systemic therapy. Investigation of mechanisms of antitimour activity revealed that macrophages appeared to be important for hRIL2 activity, and that NO and cyanide ion production appeared to both contribute to the effects of sodium nitroprusside. Results suggest that clinical studies of these compounds are feasible and warrant further investigation

Disparity in neonatal abstinence syndrome by race/ethnicity, socioeconomic status, and geography, in neonates ≥ 35 weeks gestational age.

Neonatal abstinence syndrome (NAS) is associated with a range of adverse health outcomes, exorbitant health care costs, and race/ethnicity disparity. We examined key sociodemographic factors that may influence the national race/ethnicity disparity in the prevalence of NAS among Whites, Blacks and Hispanics. 2016 and 2019 cycles of cross-sectional data from HCUP-KID national all-payer pediatric inpatient-care database were used to estimate NAS prevalence (ICD-10CM code P96.1) in newborns ≥ 35 weeks gestational-age, excluding iatrogenic-cases (ICD-10CM code P96.2). Multivariable generalized-linear-models with predictive-margins were used to produce race/ethnicity-specific stratified-estimates for select sociodemographic factors, reported as risk-differences (RD) with 95% confidence-intervals (CI). Final models were adjusted for sex, payer-type, ecologic income-level, and hospital size, type, and region. The overall survey weighted-sample prevalence of NAS was 0.98% (i.e., 6282/638100) and did not differ over cycles. Blacks and Hispanics were significantly more likely than Whites to be in the lowest ecologic income quartile and on Medicaid. In fully-specified models, NAS prevalence among Whites was 1.45% (95% CI: 1.33, 1.57) higher than Blacks and 1.52% (95% CI: 1.39, 1.64) higher than Hispanics; and NAS among Blacks was 0.14% higher than Hispanics (95% CI: 0.03, 0.24). NAS prevalence was highest among Whites on Medicaid (RD: 3.79%; 95% CI: 3.55, 4.03) compared to Whites on private-insurance (RD: 0.33%; 95% CI: 0.27, 0.38), and Blacks (RD: 0.73%; 95% CI: 0.63, 0.83; RD: 0.15%; 95% CI: 0.08, 0.21), or Hispanics, with either payer-type (RD: 0.59%; 95% CI: 0.5, 0.67; RD: 0.09%; 95% CI: 0.03, 0.15) respectively. NAS prevalence was higher among Whites in the lowest income-quartile (RD: 2.22%; 95% CI: 1.99, 2.44) compared with Blacks (RD: 0.51%; 95% CI: 0.41, 0.61) and Hispanics (RD: 0.44%; 95% CI: 0.33, 0.54) in the same quartile, and all subgroups in other quartiles. NAS prevalence was higher among Whites in the Northeast (RD: 2.19%; 95% CI: 1.89, 2.5) compared to Blacks (RD: 0.54%; 95% CI: 0.33, 0.74) and Hispanics (RD: 0.31%; 95% CI: 0.17, 0.45). Although Blacks and Hispanics were more likely to be in the lowest income quartile and have Medicaid insurance, Whites on Medicaid, in the lowest income quartile, and in the Northeast, were found to have the highest NAS prevalence

Feasibility of clinical newborn metabolic screening in a high-volume maternity center in Nepal

Abstract Background Strategic action plans around newborn health evaluation are needed, to address the high neonatal mortality rate in Nepal. Surveillance systems, like Newborn Metabolic Screening (NBS), could reveal unrecognized drivers of neonatal death. NBS is not routinely performed in Nepal. Our objective was to determine the feasibility of establishing NBS, and its acceptability among healthcare providers and parents, in Nepal. Methods This prospective cohort study was conducted between November 2021 and May 2022 in term/late preterm infants born at Paropakar Maternity Hospital, Kathmandu, screening for 6 disorders that can be confirmed and managed locally. Staff were trained on dried-blood spot collection and transport protocols, performance metrics were established, and assays were performed at an accredited laboratory in Bangalore, India. Surveys were developed to determine acceptability among health-care providers and parents. Results Of 835 parents approached for the study, 825 (98.8%) consented. Parental surveys showed that 92% considered “no cost” option most important in choosing to participate in the study. Samples were transported to laboratories in Kathmandu and Bangalore in 36 ± 24 h, and 4.75 ± 1 days, which exceeded expected metrics of 24 and 48 h, respectively. Results were communicated to parents by 9.5 ± 2 days, which was within the expected metric window of 14 days. Abnormalities were reported in 13 infants and included 5 hemoglobinopathy traits (4 Hb E and 1 Hb D), 3 congenital hypothyroidism, 2 glucose-6-phosphate dehydrogenase deficiency, 1 congenital adrenal hyperplasia, 1 elevated acylcarnitine, and 1 biotinidase deficiency. Healthcare providers surveyed (n = 116) showed that 67% reported a moderate understanding of NBS; all indicated that screening would be beneficial. Most cited early diagnosis and treatment, as well as, providing risk to future pregnancies as significant benefits. 90% thought screening should be routinely performed. Conclusions We demonstrate that it is feasible to introduce NBS in Nepal. Transport metrics were longer than expected due to COVID pandemic travel restrictions; however, it was possible to deliver results to families within 2 weeks of birth. Parents overwhelmingly considered “no cost” option as the most important in choosing to screen. A government-sponsored program will be a key factor in establishing NBS in Nepal

Using Genetic Technologies To Reduce, Rather Than Widen, Health Disparities

Evidence shows that both biological and nonbiological factors contribute to health disparities. Genetics, in particular, plays a part in how common diseases manifest themselves. Today, unprecedented advances in genetically based diagnoses and treatments provide opportunities for personalized medicine. However, disadvantaged groups may lack access to these advances, and treatments based on research on non-Hispanic whites might not be generalizable to members of minority groups. Unless genetic technologies become universally accessible, existing disparities could be widened. Addressing this issue will require integrated strategies, including expanding genetic research, improving genetic literacy, and enhancing access to genetic technologies among minority populations in a way that avoids harms such as stigmatization