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Autophagy, a self-defense mechanism, has been found to be associated with drug resistance in hepatocellular carcinoma (HCC). Our study was designed to investigate the role and related mechanisms of autophagy in matrine-induced apoptosis in hepatoma cells of HepG2 and Bel7402. Cell apoptosis was detected by flow cytometry analysis (Annexin V–FITC/PI double-staining assay), the activity and activating cleavages of caspase-3, -8, and -9. MTT assay and colony forming assay were used to assess the effect of matrine on growth and proliferation of HCC cells. Autophagic flux in HCC cells was analyzed using the expression of LC3BI/II and p62/SQSTM1, GFP-LC3 transfection, and transmission electron microscopy. Moreover, regarding to the associated mechanisms, the effects of matrine on the phosphoinositide 3-kinase/AKT/mTOR pathway and beclin-1 were studied. Our results showed that: (1) both autophagy and apoptosis could be induced by treatment with matrine; (2) using the autophagic inhibitor chloroquine and beclin-1 small-interfering RNA, cell apoptosis induced by matrine could be enhanced in a caspase-dependent manner; and (3) autophagy was induced via inhibition of PI3K/AKT/mTOR pathway and up-regulation of beclin-1. In conclusion, inhibition of autophagy could enhance matrine-induced apoptosis in human hepatoma cells.

Orofacial clefts (OFCs), which include non-syndromic cleft lip with or without cleft palate (CL/P), are among the most common birth defects in humans, affecting approximately 1 in 700 newborns. CL/P is phenotypically heterogeneous and has a complex etiology caused by genetic and environmental factors. Previous genome-wide association studies (GWASs) have identified at least 15 risk loci for CL/P. As these loci do not account for all of the genetic variance of CL/P, we hypothesized the existence of additional risk loci. We conducted a multiethnic GWAS in 6480 participants (823 unrelated cases, 1700 unrelated controls and 1319 case-parent trios) with European, Asian, African and Central and South American ancestry. Our GWAS revealed novel associations on 2p24 near FAM49A, a gene of unknown function (P = 4.22 × 10-8), and 19q13 near RHPN2, a gene involved in organizing the actin cytoskeleton (P = 4.17 × 10-8). Other regions reaching genome-wide significance were 1p36 (PAX7), 1p22 (ARHGAP29), 1q32 (IRF6), 8q24 and 17p13 (NTN1), all reported in previous GWASs. Stratification by ancestry group revealed a novel association with a region on 17q23 (P = 2.92 × 10-8) among individuals with European ancestry. This region included several promising candidates including TANC2, an oncogene required for development, and DCAF7, a scaffolding protein required for craniofacial development. In the Central and South American ancestry group, significant associations with loci previously identified in Asian or European ancestry groups reflected their admixed ancestry. In summary, we have identified novel CL/P risk loci and suggest new genes involved in craniofacial development, confirming the highly heterogeneous etiology of OFCs. Orofacial clefts (OFCs), which include non-syndromic cleft lip with or without cleft palate (CL/P), are among the most common birth defects in humans, affecting approximately 1 in 700 newborns. CL/P is phenotypically heterogeneous and has a complex etiology caused by genetic and environmental factors. Previous genome-wide association studies (GWASs) have identified at least 15 risk loci for CL/P. As these loci do not account for all of the genetic variance of CL/P, we hypothesized the existence of additional risk loci. We conducted a multiethnic GWAS in 6480 participants (823 unrelated cases, 1700 unrelated controls and 1319 case-parent trios) with European, Asian, African and Central and South American ancestry. Our GWAS revealed novel associations on 2p24 near FAM49A, a gene of unknown function (P = 4.22 × 10(-8)), and 19q13 near RHPN2, a gene involved in organizing the actin cytoskeleton (P = 4.17 × 10(-8)). Other regions reaching genome-wide significance were 1p36 (PAX7), 1p22 (ARHGAP29), 1q32 (IRF6), 8q24 and 17p13 (NTN1), all reported in previous GWASs. Stratification by ancestry group revealed a novel association with a region on 17q23 (P = 2.92 × 10(-8)) among individuals with European ancestry. This region included several promising candidates including TANC2, an oncogene required for development, and DCAF7, a scaffolding protein required for craniofacial development. In the Central and South American ancestry group, significant associations with loci previously identified in Asian or European ancestry groups reflected their admixed ancestry. In summary, we have identified novel CL/P risk loci and suggest new genes involved in craniofacial development, confirming the highly heterogeneous etiology of OFCs.

Litegebew Yitayeh,1 Addisu Gize,2 Melkayehu Kassa,2 Misrak Neway,1 Aschalew Afework,1 Mulugeta Kibret,3 Wondemagegn Mulu4 1GAMBY Teaching General Hospital, Bahir Dar, Ethiopia; 2Department of Microbiology, St. Paul’s Hospital Millennium Medical College, Addis Ababa, Ethiopia; 3Department of Biology, Science College, Bahir Dar University, Bahir Dar, Ethiopia; 4Department of Medical Laboratory Science, College of Medicine and Health Sciences, Bahir Dar University, Bahir Dar, EthiopiaCorrespondence: Addisu Gize Email addisu.gize@sphmmc.edu.etBackground: Infections with multi-drug resistant (MDR) bacteria are serious threats to many low-income countries associated with overuse and misuse of antibiotics. This study determined the antibiogram profiles of bacteria isolated from different body site infections among patients admitted to GAMBY Teaching General Hospital, Bahir Dar, Northwest Ethiopia.Methods: A hospital-based cross-sectional study was done between November 2015 and May 2018. Various clinical specimens were sampled from patients and analyzed for aerobic bacterial isolation and Kirby–Bauer disk diffusion susceptibility testing. Chi-square test was calculated to see association among variables, and P-value < 0.05 was taken as a cutoff value for statistical significance.Results: From the 716 clinical specimens processed, 134 (18.7%) were culture-positive for aerobic bacterial pathogens. Culture-confirmed positivity was higher in ear discharge (27.3%) and urine (26.3%) samples. The prevalence of infection was significantly highest among females (P = 0.001). Escherichia coli 63 (47.4%) and 10 (7.4%) of Klebsiella spp. from Gram-negative bacteria were the predominant bacterial isolates, while Staphylococcus saprophyticus 17 (12.6%) and S. aureus 14 (10.4%) were from Gram-positive bacteria. Overall, 61.8% of the isolates were found to be MDR. The proportion of MDR among Klebsiella spp., S. aureus and E. coli isolates was 90.9%, 60.9% and 50%, respectively. Gram-positive bacteria demonstrated 20%, 48.6% and 100% of resistance against norfloxacin, ciprofloxacin and clindamycin, respectively. Gram-negative bacteria also revealed from 20% resistance for the antibiotic nitrofurantoin and 100% of resistance for ampicillin and penicillin.Conclusion: Infections with bacterial isolates resistant to the majority of antibiotics are a major issue in the study area. Most of the identified bacteria were resistant to the routinely used antibiotics, and MDR isolates are alarmingly high. Therefore, clinicians should practice rational choice of antibiotics and treatment should be guided by antimicrobial susceptibility testing.Keywords: bacterial isolates, antibiogram, clinical specimen, GAMBY, Bahir Dar, Ethiopia

Aim/Purpose: This study was conducted to examine the rate of delay, explanatory causes, and coping strategies of PhD candidates at Addis Ababa University, Ethiopia’s premier university, over the last ten years. Background: Delayed graduation is a common theme in doctoral education around the world. It continues to draw the concern of governments, universities, and the candidates themselves, calling for different forms of intervention. Addressing these challenges is key to resolving the many obstacles into doctoral education. Methodology: Ten-year archival data consisting of 1,711 PhD students and in-depth interviews with ten PhD candidates were used as data-generation tools. The data collection focused on progression patterns, reasons for study delays, and the coping mechanisms used by doctoral students when they face challenges. While the candidates were interviewed to narrate their lived experience pertinent to the objectives of the study, the archival data regarding the PhD students were collected from the Registrar Office of the University under study. Contribution: Amid an ongoing global debate about best practices in doctoral education, the research on study delays contributes not only to filling the existing empirical gap in the area but also in identifying factors, for example, related to financial matters, family commitment, and student-supervisor rapport, that help address the challenges faced and improving the provision of doctoral education. Findings: The findings of this study revealed that the cumulative average completion time for a PhD study was 6.19 years— over two years more than the four years given as the optimum duration for completing a PhD program. The institutional pattern of delays over the last ten years indicates that doctoral students are requiring more and more years to complete their PhDs. The study further revealed that completing a PhD in time is a process that can be influenced by many interacting factors, which include student commitment and preparation, favourable academic and research environment, and positive student-supervisor rapport. Recommendations for Practitioners: It is important for practitioners and higher education institutions to find ways to improve the on-time completion of doctoral programmes in order to minimise the continued financial, emotional, and opportunity costs the higher education sector is currently incurring. Recommendation for Researchers: The fact that this study was limited to a single institution by itself warrants more studies about time-to-degree in PhD programs and causes for study delays as well as studies about successful interventions in doctoral education. Future research should particularly explore the nature of the advisor/advisee relationship and other critical factors that appear to have a significant role in addressing the challenges of study delay. Impact on Society: The expansion of PhD programmes is an encouraging development in Ethiopia. The findings of this study may help improve completion rates of doctoral students and reduce program duration, which would have significant implication to minimise the ensuing financial, emotional, and opportunity costs involved at individual, national, and institutional levels. Future Research: Given the growing number of universities in Ethiopia and their possible diversity, PhD students’ profiles, backgrounds, and expectations, more research is needed to examine how this diversity may impact doctoral students’ progression and persistence.

AbstractSurvival at high altitude requires adapting to extreme conditions such as environmental hypoxia. To understand high-altitude adaptations in a primate, we assembled the genome of the gelada (Theropithecus gelada), an endemic Ethiopian monkey, and complemented it with population resequencing, hematological, and morphometric data. Unexpectedly, we identified a novel karyotype that may contribute to reproductive isolation between gelada populations. We also identified genomic elements including protein-coding sequences and gene families that exhibit accelerated changes in geladas and may contribute to high-altitude adaptation. Our findings lend insight into mechanisms of speciation and adaptation while providing promising avenues for functional hypoxia research.

The Korean clinical practice guideline recently developed by the Korean Breast Cancer Society to address the national clinical situation is currently under revision ahead of a seventh recommendation. A second consensus conference was held to further develop this guideline by soliciting opinions regarding important issues related to surgery, radiotherapy, and medical oncology. Several issues were discussed, and the discussion progressed to pros and cons in the context of cases in various clinical situations. The panels discussed and voted on issues regarding surgical treatment for non-axillary regional lymph nodes, regional nodal irradiation of pN1 disease, and ovarian functional suppression (OFS) as an adjuvant treatment in premenopausal patients with hormone receptor-positive breast cancer. Regarding the surgical treatment of non-axillary regional lymph node, most panelists agreed with the recommendation of preoperative chemotherapy and postoperative radiotherapy for patients with biopsy-diagnosed metastases, whereas surgery or radiotherapy of non-axillary regional lymph nodes was suggested for clinical partial responders. Discussions on radiotherapy addressed the need for adjuvant radiotherapy and radiation field of regional lymph node in the context of various N1 breast cancer cases. The participants reached a consensus to recommend that N1 patients should receive regional nodal irradiation for a large tumor burden (e.g., three positive nodes, perinodal extension, or large primary tumor). Finally, the panels favored OFS in addition to endocrine therapy for premenopausal women with high risk factors such as a large tumor size, involvement of more than three nodes, and a high histologic grade.

ObjectiveTo evaluate whether the clinical benefit and relapse rates in anti-muscle-specific kinase (MuSK) myasthenia gravis (MG) differ depending on the protocol of rituximab followed. MethodsThis retrospective multicentre study in patients with MuSK MG compared three rituximab protocols in terms of clinical status, relapse, changes in treatment, and adverse side effects. The primary effectiveness endpoint was clinical relapse requiring a further infusion of rituximab. Survival curves were estimated using Kaplan-Meier methods and survival analyses were undertaken using Cox proportional-hazards models. ResultsTwenty-five patients were included: 11 treated with protocol 4 + 2 (375 mg/m(2)/4 weeks, then monthly for 2 months), five treated with protocol 1 + 1 (two 1 g doses 2 weeks apart), and nine treated with protocol 4 (375 mg/m(2)/4 weeks). Mean follow-up was 5.0 years (SD 3.3). Relapse occurred in 18.2%, 80%, and 33.3%, and mean time to relapse was 3.5 (SD 1.5), 1.1 (SD 0.4), and 2.5 (SD 1.4) years, respectively. Based on Kaplan-Meier estimates, patients treated with protocol 4 + 2 had fewer and later relapses than patients treated with the other two protocols (log-rank test P = 0.0001). Patients treated with protocol 1 + 1 had a higher risk of relapse than patients treated with protocol 4 + 2 (HR 112.8, 95% CI, 5.7-2250.4, P = 0.002). Patients treated with protocol 4 showed a trend to a higher risk of relapse than those treated with protocol 4 + 2 (HR 9.2, 95% CI 0.9-91.8, P = 0.059). InterpretationThis study provides class IV evidence that the 4 + 2 rituximab protocol has a lower clinical relapse rate and produces a more durable response than the 1 + 1 and 4 protocols in patients with MuSK MG.

AbstractThere is now widespread acceptance of the universal coverage approach, presented in the 2010 World Health Report. There are more and more voices for the benefit of creating a single national risk pool. Now, a body of literature is emerging on institutional design and organizational practice for universal coverage, related to management of the three health-financing functions: collection, pooling and purchasing. While all countries can move towards universal coverage, lower-income countries face particular challenges, including scarce resources and limited capacity. Recently, the Lao PDR has been preparing options for moving to a single national health insurance scheme. The aim is to combine four different social health protection schemes into a national health insurance authority (NHIA) with a single national fund- and risk-pool. This paper investigates the main institutional and organizational challenges related to the creation of the NHIA. The paper uses a qualitative approach, drawing on the World Health Organization's institutional and Organizational Assessment for Improving and Strengthening health financing (OASIS) conceptual framework for data analysis. Data were collected from a review of key health financing policy documents and from 17 semi-structured key informant interviews. Policy makers and advisors are confronting issues related to institutional arrangements, funding sources for the authority and government support for subsidies to the demand-side health financing schemes. Compulsory membership is proposed, but the means for covering the informal sector have not been resolved. While unification of existing schemes may be the basis for creating a single risk pool, challenges related to administrative capacity and cross-subsidies remain. The example of Lao PDR illustrates the need to include consideration of national context, the sequencing of reforms and the time-scale appropriate for achieving universal coverage.

AbstractOnly a few studies have assessed the long-term duration of the humoral immune response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).In this nationwide longitudinal study from the Faroe Islands with close to full participation of all individuals on the Islands with PCR confirmed COVID-19 during the two waves of infections in the spring and autumn 2020 (n=172 & n=233), samples were drawn at three longitudinal time points (3, 7 and 12 months and 1, 3 and 7 months after disease onset, respectively).Serum was analyzed with a direct quantitative IgG antibody binding ELISA to detect anti–SARS-CoV-2 spike RBD antibodies and a commercially available qualitative sandwich RBD ELISA kit measuring total antibody binding.The seropositive rate in the convalescent individuals was above 95 % at all sampling time points for both assays. There was an overall decline in IgG titers over time in both waves (p < 0.001). Pairwise comparison showed that IgG declined significantly from the first sample until approximately 7 months in both waves (p < 0.001). After that, the antibody level still declined significantly (p < 0.001), but decelerated with an altered slope remaining fairly stable from 7 months to 12 months after infection. Interestingly, the IgG titers followed a U-shaped curve with higher antibody levels among the oldest (67+) and the youngest (0– 17) age groups compared to intermediate groups (p < 0.001).Our results indicate that COVID-19 convalescent individuals are likely to be protected from reinfection up to 12 months after symptom onset and maybe even longer. We believe our results can add to the understanding of natural immunity and the expected durability of SARS-CoV-2 vaccine immune responses.