Coast-to-Coast Spread of SARS-CoV-2 during the Early Epidemic in the United States.

The novel coronavirus SARS-CoV-2 was first detected in the Pacific Northwest region of the United States in January 2020, with subsequent COVID-19 outbreaks detected in all 50 states by early March. To uncover the sources of SARS-CoV-2 introductions and patterns of spread within the United States, we sequenced nine viral genomes from early reported COVID-19 patients in Connecticut. Our phylogenetic analysis places the majority of these genomes with viruses sequenced from Washington state. By coupling our genomic data with domestic and international travel patterns, we show that early SARS-CoV-2 transmission in Connecticut was likely driven by domestic introductions. Moreover, the risk of domestic importation to Connecticut exceeded that of international importation by mid-March regardless of our estimated effects of federal travel restrictions. This study provides evidence of widespread sustained transmission of SARS-CoV-2 within the United States and highlights the critical need for local surveillance.

Mapping partner drug resistance to guide antimalarial combination therapy policies in sub-Saharan Africa.

Resistance to artemisinin-based combination therapies (ACTs) threatens the global control of Plasmodium falciparum malaria. ACTs combine artemisinin-derived compounds with partner drugs to enable multiple mechanisms of clearance. Although ACTs remain widely effective in sub-Saharan Africa, long-standing circulation of parasite alleles associated with reduced partner drug susceptibility may contribute to the development of clinical resistance. We fitted a hierarchical Bayesian spatial model to data from over 500 molecular surveys to predict the prevalence and frequency of four key markers in transporter genes (pfcrt 76T and pfmdr1 86Y, 184F, and 1246Y) in first-level administrative divisions in sub-Saharan Africa from the uptake of ACTs (2004 to 2009) to their widespread usage (2010 to 2018). Our models estimated that the pfcrt 76T mutation decreased in prevalence in 90% of regions; the pfmdr1 N86 and D1246 wild-type genotypes increased in prevalence in 96% and 82% of regions, respectively; and there was no significant directional selection at the pfmdr1 Y184F locus. Rainfall seasonality was the strongest predictor of the prevalence of wild-type genotypes, with other covariates, including first-line drug policy and transmission intensity more weakly associated. We lastly identified regions of high priority for enhanced surveillance that could signify decreased susceptibility to the local first-line ACT. Our results can be used to infer the degree of molecular resistance and magnitude of wild-type reversion in regions without survey data to inform therapeutic policy decisions.

Food environment around schools and adolescent consumption of unhealthy foods in Addis Ababa, Ethiopia.

Adolescent diets may be influenced by the retail food environment around schools. However, international research to examine associations between the proximity of retail food outlets to schools and diet provides equivocal support for an association. This study aims to understand the school food environment and drivers for adolescents' consumption of unhealthy foods in Addis Ababa, Ethiopia. Mixed-methods research was conducted, 1200 adolescents (10-14 years) from randomly selected government schools were surveyed, along with vendors within 5-min' walk of the schools and focus group discussions (FGDs) with adolescent groups. Mixed-effect logistic regression investigated the relationship between the number of vendors around the schools and the consumption of selected unhealthy foods. Thematic analysis was used to summarize findings from the FGDs. Consumption of sweets and sugar-sweetened beverages (S-SSB) and deep-fried foods (DFF) at least once a week was reported by 78.6% and 54.3% of the adolescents, respectively. Although all schools were surrounded by food vendors selling DFF and S-SSB, consumption was not associated with the number of vendors available around the school. However, adolescents' awareness and perception of healthy food, and their concerns about the safety of foods in the market, influenced their dietary choices and behaviours. Lack of financial resources to purchase food as desired also played a role in their selection of food and eating habits. Reported unhealthy food consumption is high among adolescents in Addis Ababa. Thus, further research is warranted to come up with school-based interventions that promote access and healthy food choices among adolescents.

Burden and contributing factors to overweight and obesity in young adolescents in Addis Ababa, Ethiopia.

The prevalence of overweight/obesity in adolescents has increased globally, including in low- and middle-income countries. Early adolescence provides an opportunity to develop and encourage positive health and behavioural practices, yet it is an understudied age group with limited information to guide and inform appropriate interventions. This study aims to determine the prevalence of overweight/obesity in young adolescents, aged between 10 and 14 years attending public schools in Addis Ababa, Ethiopia, and to explore the contributing factors. A cross-sectional school-based study was conducted. Adolescents completed individual questionnaires. Weight (kg) and height (m) measurements were converted to BMI-for-age and gender z-scores. Multivariate regression analysis was conducted to determine the associated factors. The overall prevalence of overweight/obesity was 8% among adolescents aged 10-14 years and it was significantly higher in females (13%) than males (2%). The diet quality for the majority of the adolescents was inadequate, putting them at risk for poor health outcomes. The contributors to overweight/obesity were different between males and females. Age and no access to a flush toilet were negatively associated with overweight/obesity in males and access to a computer, laptop or tablet was positively associated. In females, menarche was positively associated with overweight/obesity. Living with only their mother or another female adult and an increase in physical activity were negatively associated with overweight/obesity. There is a need to improve the diet quality of young adolescents in Ethiopia and understand the reasons why females are less physically active to limit the risk of poor diet-related health outcomes.

Integrating private health facilities in government-led health systems: a case study of the public-private mix approach in Ethiopia.

BACKGROUND: Private health care facilities working in partnership with the public health sector is one option to create sustainable health systems and ensure health and well-being for all in low-income countries. As the second-most populous country in Africa with a rapidly growing economy, demand for health services in Ethiopia is increasing and one-quarter of its health facilities are privately owned. The Private Health Sector Program (PHSP), funded by the United States Agency for International Development, implemented a series of public-private partnership in health projects from 2004 to 2020 to address several public health priorities, including tuberculosis, malaria, HIV/AIDS, and family planning. We assessed PHSP's performance in leadership and governance, access to medicines, health management information systems, human resources, service provision, and finance. METHODS: The World Health Organization's health systems strengthening framework, which is organized around six health system building blocks, guided the assessment. We conducted 50 key informant interviews and a health facility assessment at 106 private health facilities supported by the PHSP to evaluate its performance. RESULTS: All six building blocks were addressed by the program and key informants shared that several policy and strategic changes were conducive to supporting the functioning of private health facilities. The provision of free medicines from the public pharmaceutical logistics system, relaxation of strict regulatory policies that restricted service provision through the private sector, training of private providers, and public-private mix guidelines developed for tuberculosis, malaria, and reproductive, maternal, newborn, child, and adolescent health helped increase the use of services at health facilities. CONCLUSIONS: Some challenges and threats to sustainability remain, including fragile partnerships between public and private bodies, resource constraints, mistrust between the public and private sectors, limited incentives for the private sector, and oversight of the quality of services. To continue with gains in the policy environment, service accessibility, and other aspects of the health system, the government and international communities must work collaboratively to address public-private partnerships in health areas that can be strengthened. Future efforts should emphasize a mechanism to ensure that the private sector is capable, incentivized, and supervised to deliver continuous, high-quality and equitable services.

DYNAMICS OF FIBROTIC CHANGES IN THE LIVER AFTER THE SUCCESSFUL ERADICATION OF HEPATITIS C VIRUS IN PATIENTS WITH NAFLD.

OBJECTIVE: The aim: To assess the dynamics of serum levels of angiopoietin-2 and transforming growth factor-ß1 in patients with chronic hepatitis C (CHC) with concomitant nonalcoholic fatty liver disease (NAFLD) after successful DAAs. PATIENTS AND METHODS: Materials and methods: 82 patients with CHC were examined, of which 56 were diagnosed with NAFLD and increased body weight. Ang-2, TGF-ß1, leptin, adiponectin, and the degree of liver fibrosis were determined for all participants. The patients were divided into groups: 1 gr. (n=23) - CHС + increased body weight + hepatic steatosis, 2 gr. (n=33) - СНС + increased body weight + nonalcoholic steatohepatitis, 3rd gr. (n=26) - CHC. All patients received DAAs for 12 weeks. RESULTS: Results: From 82 patients F3-4 had 31 people, F1-2 - 25, F0-1 - 11, F0 -15 patients. F3-4 and steatosis S2-3 (p<0.05) was more common in patients of 2 gr.. Serum Ang-2 levels were higher (p<0.05) in patients of 2 gr. with F3-4, than in patients with F0-2. Fibrosis regression occurred more often in patients with 1 and 3 gr. with F1-2 than in patients 2 gr. and F3-4 and was accompanied by a decrease in Ang-2 and TGF-ß1 levels. CONCLUSION: Conclusions: High levels of Ang-2 and TGF-ß1 are registered in patients with CHC+NAFLD, which correlate with the degree of liver fibrosis and significantly decrease after successful DAAs in patients with low initial stages of liver fibrosis and normal body weight.

THE CLINICAL EXPERIENCE OF THE EFFECTIVE USE OF DAPAGLIFLOZIN IN COMORBID CARDIAC PATIENTS WITH CONCOMITANT TYPE 2 DIABETES MELLITUS AND ARTERIAL HYPERTENSION ON THE BACKGROUND OF OVERWEIGHT IN OUTPATIENT SETTING.

OBJECTIVE: The aim: To assess the efficacy and safety of dapagliflozin in the treatment of comorbid cardiac patients with type 2 diabetes mellitus (T2DM) in combination with arterial hypertension (AH) and overweight in outpatient setting. PATIENTS AND METHODS: Materials and methods: Under observation were 19 patients who were treated in outpatient setting during 2019-2021 for AH and had T2DM, overweight or obesity. As part of complex treatment, patients received dapagliflozin 10 mg once a day for 12 months. RESULTS: Results: The normalization of blood pressure, elimination of heart failure symptoms on the background of increased ejection fraction, improved indicators of the functional capacity of the kidneys, and a decrease in the degree of proteinuria/albuminuria were noted after treatment. The patients had an easier time losing weight (body mass index and waist circumference decreased; p<0.05) and decreased levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C). None of the monitored patients had cases of hypoglycemia or urinary tract infection. The number and/or doses of antihypertensive, hypouricemic and diuretic drugs were gradually reduced. CONCLUSION: Conclusions: Using dapagliflozin in a standard dose of 10 mg/day in the complex therapy of patients with T2DM in combination with arterial hypertension and overweight contributes not only to the normalization of blood pressure, but also to a reduction in body weight and waist circumference. The proposed therapy can be an alternative for the treatment of patients with T2DM with concomitant overweight or obesity, arterial hypertension, with or without heart and/or renal failure as a first-line antidiabetic drug.

SARS-CoV-2 in Nursing Homes after 3 Months of Serial, Facilitywide Point Prevalence Testing, Connecticut, USA.

Nursing homes house populations that are highly vulnerable to coronavirus disease. Point prevalence surveys (PPSs) provide information on the severe acute respiratory syndrome coronavirus 2 infection status of staff and residents in nursing homes and enable isolation of infectious persons to halt disease spread. We collected 16 weeks of public health surveillance data on a subset of nursing homes (34/212) in Connecticut, USA. We fit a Poisson regression model to evaluate the association between incidence and time since serial PPS onset, adjusting for decreasing community incidence and other factors. Nursing homes conducted a combined total of 205 PPSs in staff and 232 PPSs in residents. PPS was associated with 41%-80% reduction in incidence rate in nursing homes. Our findings provide support for the use of repeated PPSs in nursing home staff and residents, combined with strong infection prevention measures such as cohorting, in contributing to outbreak control.

Effectiveness of the Pfizer-BioNTech COVID-19 Vaccine Among Residents of Two Skilled Nursing Facilities Experiencing COVID-19 Outbreaks - Connecticut, December 2020-February 2021.

Residents of long-term care facilities (LTCFs), particularly those in skilled nursing facilities (SNFs), have experienced disproportionately high levels of COVID-19-associated morbidity and mortality and were prioritized for early COVID-19 vaccination (1,2). However, this group was not included in COVID-19 vaccine clinical trials, and limited postauthorization vaccine effectiveness (VE) data are available for this critical population (3). It is not known how well COVID-19 vaccines protect SNF residents, who typically are more medically frail, are older, and have more underlying medical conditions than the general population (1). In addition, immunogenicity of the Pfizer-BioNTech vaccine was found to be lower in adults aged 65-85 years than in younger adults (4). Through the CDC Pharmacy Partnership for Long-Term Care Program, SNF residents and staff members in Connecticut began receiving the Pfizer-BioNTech COVID-19 vaccine on December 18, 2020 (5). Administration of the vaccine was conducted during several on-site pharmacy clinics. In late January 2021, the Connecticut Department of Public Health (CT DPH) identified two SNFs experiencing COVID-19 outbreaks among residents and staff members that occurred after each facility's first vaccination clinic. CT DPH, in partnership with CDC, performed electronic chart review in these facilities to obtain information on resident vaccination status and infection with SARS-CoV-2, the virus that causes COVID-19. Partial vaccination, defined as the period from >14 days after the first dose through 7 days after the second dose, had an estimated effectiveness of 63% (95% confidence interval [CI] = 33%-79%) against SARS-CoV-2 infection (regardless of symptoms) among residents within these SNFs. This is similar to estimated effectiveness for a single dose of the Pfizer-BioNTech COVID-19 vaccine in adults across a range of age groups in noncongregate settings (6) and suggests that to optimize vaccine impact among this population, high coverage with the complete 2-dose series should be recommended for SNF residents and staff members.

EXPERIMENTAL MODEL OF AN INTEGRATED APPROACH TO THE TRAINING OF LEGAL AND HEALTH CARE PROFESSIONALS ON ISSUES OF INFECTION WITH ESPECIALLY DANGEROUS INFECTIOUS DISEASES.

OBJECTIVE: The aim: Developing integration training (educational) programs for medical and legal students, interns, masters, doctors. PATIENTS AND METHODS: Material and methods: When performing the work, on a set of search and analytical methods: analytical, bibliographic, systemic, informational, statistical; interdisciplinary interactive teaching methods for students of Sumy State University. RESULTS: Results: The results of the integrated training course are the formation of a new style of interdisciplinary relations between participants of the educational process and practical medicine and jurisprudence; new educational environment; classes with multi - and transdisciplinary experts-consultants; development of personal attitudes, future professional contacts, and practical skills. CONCLUSION: Conclusions: The introduction of new teaching methods using an interdisciplinary integrated approach increases the level of education quality (35.8% higher than the initial result) and conduct applied research in the field of public health, jurisprudence.

PRKCQ inhibition enhances chemosensitivity of triple-negative breast cancer by regulating Bim.

BACKGROUND: Protein kinase C theta, (PRKCQ/PKCθ) is a serine/threonine kinase that is highly expressed in a subset of triple-negative breast cancers (TNBC) and promotes their growth, anoikis resistance, epithelial-mesenchymal transition (EMT), and invasion. Here, we show that PRKCQ regulates the sensitivity of TNBC cells to apoptosis triggered by standard-of-care chemotherapy by regulating levels of pro-apoptotic Bim. METHODS: To determine the effects of PRKCQ expression on chemotherapy-induced apoptosis, shRNA and cDNA vectors were used to modulate the PRKCQ expression in MCF-10A breast epithelial cells or triple-negative breast cancer cells (MDA-MB231Luc, HCC1806). A novel PRKCQ small-molecule inhibitor, 17k, was used to inhibit kinase activity. Viability and apoptosis of cells treated with PRKCQ cDNA/shRNA/inhibitor +/-chemotherapy were measured. Expression levels of Bcl2 family members were assessed. RESULTS: Enhanced expression of PRKCQ is sufficient to suppress apoptosis triggered by paclitaxel or doxorubicin treatment. Downregulation of PRKCQ also enhanced the apoptosis of chemotherapy-treated TNBC cells. Regulation of chemotherapy sensitivity by PRKCQ mechanistically occurs via regulation of levels of Bim, a pro-apoptotic Bcl2 family member; suppression of Bim prevents the enhanced apoptosis observed with combined PRKCQ downregulation and chemotherapy treatment. Regulation of Bim and chemotherapy sensitivity is significantly dependent on PRKCQ kinase activity; overexpression of a catalytically inactive PRKCQ does not suppress Bim or chemotherapy-associated apoptosis. Furthermore, PRKCQ kinase inhibitor treatment suppressed growth, increased anoikis and Bim expression, and enhanced apoptosis of chemotherapy-treated TNBC cells, phenocopying the effects of PRKCQ downregulation. CONCLUSIONS: These studies support PRKCQ inhibition as an attractive therapeutic strategy and complement to chemotherapy to inhibit the growth and survival of TNBC cells.

Investigating selected host and parasite factors potentially impacting upon seasonal malaria chemoprevention in Bama, Burkina Faso.

BACKGROUND: Since 2014, seasonal malaria chemoprevention (SMC) with amodiaquine-sulfadoxine-pyrimethamine (AQ-SP) has been implemented on a large scale during the high malaria transmission season in Burkina Faso. This paper reports the prevalence of microscopic and submicroscopic malaria infection at the outset and after the first round of SMC in children under 5 years old in Bama, Burkina Faso, as well as host and parasite factors involved in mediating the efficacy and tolerability of SMC. METHODS: Two sequential cross-sectional surveys were conducted in late July and August 2017 during the first month of SMC in a rural area in southwest Burkina Faso. Blood smears and dried blood spots were collected from 106 to 93 children under five, respectively, at the start of SMC and again 3 weeks later. Malaria infection was detected by microscopy and by PCR from dried blood spots. For all children, day 7 plasma concentrations of desethylamodiaquine (DEAQ) were measured and CYP2C8 genetic variants influencing AQ metabolism were genotyped. Samples were additionally genotyped for pfcrt K76T and pfmdr1 N86Y, molecular markers associated with reduced amodiaquine susceptibility. RESULTS: 2.8% (3/106) of children were positive for Plasmodium falciparum infection by microscopy and 13.2% (14/106) by nested PCR within 2 days of SMC administration. Three weeks after SMC administration, in the same households, 4.3% (4/93) of samples were positive by microscopy and 14.0% (13/93) by PCR (p = 0.0007). CYP2C8*2, associated with impaired amodiaquine metabolism, was common with an allelic frequency of 17.1% (95% CI 10.0-24.2). Day 7 concentration of DEAQ ranged from 0.48 to 362.80 ng/mL with a median concentration of 56.34 ng/mL. Pfmdr1 N86 predominated at both time points, whilst a non-significant trend towards a higher prevalence of pfcrt 76T was seen at week 3. CONCLUSION: This study showed a moderate prevalence of low-level malaria parasitaemia in children 3 weeks following SMC during the first month of administration. Day 7 concentrations of the active DEAQ metabolite varied widely, likely reflecting variability in adherence and possibly metabolism. These findings highlight factors that may contribute to the effectiveness of SMC in children in a high transmission setting.

Eight-Year Incidence of Open-Angle Glaucoma in the Tema Eye Survey.

PURPOSE: To determine the incidence of open-angle glaucoma (OAG) and its risk factors in the Tema Eye Survey in Ghana, West Africa. DESIGN: Longitudinal, observational population-based study. PARTICIPANTS: One thousand two hundred five of 1500 participants 40 years of age or older selected randomly from 5603 participants originally drawn from the population and who had undergone a baseline examination. METHODS: All participants underwent baseline and follow-up ophthalmologic examinations 8 years apart. Glaucoma diagnosis was determined based on the International Society for Geographical and Epidemiologic Ophthalmology criteria. MAIN OUTCOME MEASURES: Incidence and odds ratio (OR). RESULTS: The response rate was 80.3%. Of 1101 nonglaucomatous participants at baseline who had complete follow-up data, 4.6% (95% confidence interval [CI], 3.7%-5.2%) demonstrated OAG over the 8-year period, or 0.58% (95% CI, 0.4%-0.8%) per year. The 8-year incidence increased with age from 3.1% in those 40 to 49 years old to 7.0% in those 60 to 69 years old. Baseline risk factors for incident OAG were male gender (OR, 2.1; 95% CI, 1.1-4.0; P = 0.025), older age relative to those 40 to 49 years old (those 50-50 years old: OR, 2.6; 95% CI, 1.2-5.7; those 60-69 years old: OR, 4.3; 95% CI, 2.0-8.8; and for those 70 years of age and older: OR, 6.3; 95% CI, 2.6-15.4; all P < 0.001), higher intraocular pressure (IOP; OR, 1.4; 95% CI, 1.1-1.8; P < 0.001), larger vertical cup-to-disc ratio (OR, 5.8; 95% CI, 5.2-6.6; P < 0.001), and thinner central cornea (OR, 1.2; 95% CI, 1.03-1.5; P = 0.013). A separate analysis performed with central corneal thickness-based IOP correction did not change the outcome of the associative model of incident glaucoma. CONCLUSIONS: The incidence of OAG is higher in this population than reported in nonblack populations outside Africa. This is important not only in Ghana and probably other West African countries but also wherever people of the West African diaspora reside. These data enhance our understanding of the epidemiologic factors of OAG in this setting and may serve as reference for public health policy and planning.

Study of the lifestyle of economically active population of the chernivtsi region: the prevalence of risk factors among business entities in the market.

OBJECTIVE: Introduction: To reduce the burden of non-communicable diseases (NCDs) and premature mortality, it is necessary to influence the risks of their occurrence at all stages of life. Economically active population, which can be more at risk, is required the special attention. The aim of the study is to investigate the prevalence for risk factors of major NCDs among the economically active population of the Chernivtsi region in the example of business entities in the market. PATIENTS AND METHODS: Materials and methods: The survey of the Chernivtsi business entities (n = 633) conducted in 2017-2018 on the territory of ME CSC (the Municipal Enterprise City Shopping Complex) "Kalynivskyi market" has been used in the research. RESULTS: Results: There is the high level of the prevalence of the main risk factors for NCDs (unhealthy diet, lack of physical activity, smoking) among those working in the territory of the market. Only 17% consume a sufficient amount of fruit and fish. Only 35% of respondents systematically do physical exercises and special physical exercises. The most common unhealthy diet has been found among young men (25-44 years), in this group, about 40% are smoking. An acute problem of female smoking (25%) among market workers has been revealed. It is shown that, in general (taking into account passive smoking), 65% of respondents suffer from harmful effects of tobacco. CONCLUSION: Conclusions: The established features of the lifestyle of workers indicate the need to make maximum efforts to focus on improving medical literacy and the formation of motivation to preserve health.

Association between migraine and suicidal behavior among Ethiopian adults.

BACKGROUND: Despite the significant impact of migraine on patients and societies, few studies in low- and middle-income countries (LMICs) have investigated the association between migraine and suicidal behavior. The objective of our study is to examine the extent to which migraines are associated with suicidal behavior (including suicidal ideation, plans, and attempts) in a well-characterized study of urban dwelling Ethiopian adults. METHODS: We enrolled 1060 outpatient adults attending St. Paul hospital in Addis Ababa, Ethiopia. Standardized questionnaires were used to collect data on socio-demographics, and lifestyle characteristics. Migraine classification was based on the International Classification of Headache Disorders-2 diagnostic criteria. The Composite International Diagnostic Interview (CIDI) was used to assess depression and suicidal behaviors (i.e. ideation, plans and attempts). Multivariable logistic regression models were used to estimate adjusted odds ratio (AOR) and 95% confidence intervals (95% CIs). RESULTS: The prevalence of suicidal behavior was 15.1%, with a higher suicidal behavior among those who had migraines (61.9%). After adjusting for confounders including substance use and socio-demographic factors, migraine was associated with a 2.7-fold increased odds of suicidal behavior (AOR = 2.7; 95% CI 1.88-3.89). When stratified by their history of depression in the past year, migraine without depression was significantly associated with suicidal behavior (AOR: 2.27, 95% Cl: 1.49-3.46). The odds of suicidal behavior did not reach statistical significance in migraineurs with depression (AOR: 1.64, 95% CI: 0.40-6.69). CONCLUSION: Our study indicates that migraine is associated with increased odds of suicidal behavior in this population. Given the serious public health implications this has, attention should be given to the treatment and management of migraine at a community level.

Inferred miRNA activity identifies miRNA-mediated regulatory networks underlying multiple cancers.

MOTIVATION: MicroRNAs (miRNAs) play a key role in regulating tumor progression and metastasis. Identifying key miRNAs, defined by their functional activities, can provide a deeper understanding of biology of miRNAs in cancer. However, miRNA expression level cannot accurately reflect miRNA activity. RESULTS: We developed a computational approach, ActMiR, for identifying active miRNAs and miRNA-mediated regulatory mechanisms. Applying ActMiR to four cancer datasets in The Cancer Genome Atlas (TCGA), we showed that (i) miRNA activity was tumor subtype specific; (ii) genes correlated with inferred miRNA activities were more likely to enrich for miRNA binding motifs; (iii) expression levels of these genes and inferred miRNA activities were more likely to be negatively correlated. For the four cancer types in TCGA we identified 77-229 key miRNAs for each cancer subtype and annotated their biological functions. The miRNA-target pairs, predicted by our ActMiR algorithm but not by correlation of miRNA expression levels, were experimentally validated. The functional activities of key miRNAs were further demonstrated to be associated with clinical outcomes for other cancer types using independent datasets. For ER(-)/HER2(-) breast cancers, we identified activities of key miRNAs let-7d and miR-18a as potential prognostic markers and validated them in two independent ER(-)/HER2(-) breast cancer datasets. Our work provides a novel scheme to facilitate our understanding of miRNA. In summary, inferred activity of key miRNA provided a functional link to its mediated regulatory network, and can be used to robustly predict patient's survival. AVAILABILITY AND IMPLEMENTATION: the software is freely available at http://research.mssm.edu/integrative-network-biology/Software.html. CONTACT: jun.zhu@mssm.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PRKCQ promotes oncogenic growth and anoikis resistance of a subset of triple-negative breast cancer cells.

BACKGROUND: The protein kinase C (PKC) family comprises distinct classes of proteins, many of which are implicated in diverse cellular functions. Protein tyrosine kinase C theta isoform (PRKCQ)/PKCθ, a member of the novel PKC family, may have a distinct isoform-specific role in breast cancer. PKCθ is preferentially expressed in triple-negative breast cancer (TNBC) compared to other breast tumor subtypes. We hypothesized that PRKCQ/PKCθ critically regulates growth and survival of a subset of TNBC cells. METHODS: To elucidate the role of PRKCQ/PKCθ in regulating growth and anoikis resistance, we used both gain and loss of function to modulate expression of PRKCQ. We enhanced expression of PKCθ (kinase-active or inactive) in non-transformed breast epithelial cells (MCF-10A) and assessed effects on epidermal growth factor (EGF)-independent growth, anoikis, and migration. We downregulated expression of PKCθ in TNBC cells, and determined effects on in vitro and in vivo growth and survival. TNBC cells were also treated with a small molecule inhibitor to assess requirement for PKCθ kinase activity in the growth of TNBC cells. RESULTS: PRKCQ/PKCθ can promote oncogenic phenotypes when expressed in non-transformed MCF-10A mammary epithelial cells; PRKCQ/PKCθ enhances anchorage-independent survival, growth-factor-independent proliferation, and migration. PKCθ expression promotes retinoblastoma (Rb) phosphorylation and cell-cycle progression under growth factor-deprived conditions that typically induce cell-cycle arrest of MCF-10A breast epithelial cells. Proliferation and Rb phosphorylation are dependent on PKCθ-stimulated extracellular signal-related kinase (Erk)/mitogen-activated protein kinase (MAPK) activity. Enhanced Erk/MAPK activity is dependent on the kinase activity of PKCθ, as overexpression of kinase-inactive PKCθ does not stimulate Erk/MAPK or Rb phosphorylation or promote growth-factor-independent proliferation. Downregulation of PRKCQ/PKCθ in TNBC cells enhances anoikis, inhibits growth in 3-D MatrigelTM cultures, and impairs triple-negative tumor xenograft growth. AEB071, an inhibitor of PKCθ kinase activity, also inhibits growth and invasive branching of TNBC cells in 3-D cultures, further supporting a role for PKCθ kinase activity in triple-negative cancer cell growth. CONCLUSIONS: Enhanced PRKCQ/PKCθ expression can promote growth-factor-independent growth, anoikis resistance, and migration. PRKCQ critically regulates growth and survival of a subset of TNBC. Inhibition of PKCθ kinase activity may be an attractive therapeutic approach for TNBC, a subtype in need of improved targeted therapies.

Diagnostic validity of the Patient Health Questionnaire-2 (PHQ-2) among Ethiopian adults.

BACKGROUND: The Patient Health Questionnaire-2 (PHQ-2) is an ultra-brief questionnaire widely used by researchers and clinicians to detect major depressive disorder (MDD). Despite its individual and societal impact, MDD is often undetected and untreated particularly among sub-Saharan Africans. We conducted this study to evaluate the reliability and validity of using the PHQ-2 as a screen for MDD among Ethiopian adults. METHODS: A total of 926 adults attending outpatient departments in a major referral hospital in Addis Ababa, Ethiopia participated in this study. Construct validity was assessed by examining associations of PHQ-2 scores with World Health Organization Quality of Life (WHO-QOL) domains. We assessed criterion validity and performance characteristics against an independent, blinded, and psychiatrist administered semi-structured Schedules for Clinical Assessment in Neuropsychiatry (SCAN) interview using measures of sensitivity, specificity and receiver operating characteristics (ROC) curves. RESULTS: The PHQ-2 items showed good reliability (intraclass correlation coefficient=0.92). Quality of life, as reflected by subscale scores for four WHO-QOL domains, was significantly lower among patients with increasing PHQ-2 scores demonstrating good construct validity. ROC analysis and Youden Index showed that a PHQ-2 threshold score of 3 offered optimal discriminatory power with respect to the diagnosis of MDD via the clinical interview (sensitivity=74% and specificity=60%). CONCLUSION: The Amharic language version of the PHQ-2 had good sensitivity and fair specificity for detecting MDD compared against a psychiatrist administered SCAN diagnosis. This study provides evidence for the PHQ-2 as a reliable and valid ultra-brief screening tool for initial identification of MDD.

Association of suicidal ideation with poor sleep quality among Ethiopian adults.

OBJECTIVE: The objective of this study was to examine the extent to which poor sleep quality is associated with suicidal ideation among Ethiopian adults. METHODS: A cross-sectional study was conducted among 1054 adults attending outpatient clinical facilities in Ethiopia. Standardized questionnaires were utilized to collect data on demographics, sleep quality, lifestyle, and depression status. Depression and suicidal ideation were assessed using the Patient Health Questionnaire-9 (PHQ-9), while the Pittsburgh Sleep Quality Index (PSQI) questionnaire was utilized to assess sleep quality. Multivariate logistic regression models were fit to estimate adjusted odds ratio (AOR) and 95 % confidence intervals (95 % CI). RESULTS: The prevalence of suicidal ideation was 24.3 % while poor sleep quality (PSQI global score of >5 vs. ≤5) was endorsed by 60.2 % of participants. After adjustment for confounders including depression, poor sleep quality was associated with more than 3-fold increased odds of suicidal ideation (AOR = 3.59; 95 % CI 2.34-5.51). When assessed as a continuous variable, each 1-unit increase in the global PSQI score resulted in a 20 % increased odds for suicidal ideation, even after adjusting for depression (AOR = 1.20; 95 % CI 1.14-1.27). Participants with both poor sleep quality and depression had much higher odds (AOR = 23.22, 95 % CI 14.10-38.28) of suicidal ideation as compared with those who had good sleep quality and no depression although inferences from this analysis are limited due to the wide 95 % CI. CONCLUSION: Suicidal ideation and poor sleep quality are highly prevalent. Individuals with poor sleep quality have higher odds of suicidal ideation. If confirmed, mental health services need to address sleep disturbances seriously to prevent suicidal episodes.

Quality of life in patients with nonalcoholic fatty liver disease in combination with essential hypertension considering taste sensitivity to sodium chloride.

INTRODUCTION: Nonalcoholic fatty liver disease and hypertensive disease - is the most common combination of abnormalities that occur in people suffering from metabolic syndrome. Their combination not only causes concurrent damage of the liver and the heart, caused by common pathogenic beginning, and also mutually complicate the disease course of each other. The leading role in the development of nonalcoholic fatty liver disease belongs to abdominal obesity and insulin resistance, and is seen as a manifestation of liver disease in metabolic syndrome. Genetic predisposition, lifestyle, improper nutrition, including excessive use of sodium chloride, lead to excessive formation of visceral adipose tissue with development of abdominal obesity, which is a likely criterion of insulin resistance. The long course of nonalcoholic fatty liver disease in combination with essential hypertension in excessive consumption of sodium chloride may negatively affect their quality of life. The aim of the study is to find out the features of quality of life in patients with nonalcoholic fatty liver disease in combination with hypertensive disease with different taste sensitivity to sodium chloride. MATERIAL AND METHODS: We have investigated the quality of life of 65 patients with nonalcoholic fatty liver disease in combination with hypertensive disease II stage with different taste sensitivity to sodium chloride. Salt taste sensitivity threshold to sodium chloride is determined by the method of R. Henkin. Assessment of quality of life was performed using the Ukrainian version of the questionnaire Medical Outcomes Study Short Form 36 (MO S SF-36). RESULTS: Was revealed that in patients with nonalcoholic fatty liver disease in combination with hypertensive disease II stage with high salt taste sensitivity threshold observed the decline in the quality of life that manifests as a decline in physical condition (especially of the physical functioning, physical role functioning and general health perceptions) and mental health (especially social functioning). Also the increased salt intake and salt appetite in patients with high salt taste sensitivity threshold were noted (p <0,05). CONCLUSIONS: Reducing the use of sodium chloride can be a preventive measure easier than a decrease in body weight, and one that will reduce the body weight, especially in people with nonalcoholic fatty liver disease in combination with hypertensive disease, can reduce the risk of complications and improve quality of life in patients.