Changes in Mycobacterium tuberculosis Genotype Families Over 20 Years in a Population-Based Study in Northern Malawi

BACKGROUND: Despite increasing interest in possible differences in virulence and transmissibility between different genotypes of M. tuberculosis, very little is known about how genotypes within a population change over decades, or about relationships to HIV infection. METHODS AND PRINCIPAL FINDINGS: In a population-based study in rural Malawi we have examined smears and cultures from tuberculosis patients over a 20-year period using spoligotyping. Isolates were grouped into spoligotype families and lineages following previously published criteria. Time trends, HIV status, drug resistance and outcome were examined by spoligotype family and lineage. In addition, transmissibility was examined among pairs of cases with known epidemiological contact by assessing the proportion of transmissions confirmed for each lineage, on the basis of IS6110 RFLP similarity of the M tuberculosis strains. 760 spoligotypes were obtained from smears from 518 patients from 1986-2002, and 377 spoligotypes from cultures from 347 patients from 2005-2008. There was good consistency in patients with multiple specimens. Among 781 patients with first episode tuberculosis, the majority (76%) had Lineage 4 ("European/American") strains; 9% had Lineage 3 ("East-African/Indian"); 8% Lineage 1 ("Indo-Oceanic"); and 2% Lineage 2 ("East-Asian"); others unclassifiable. Over time the proportion of Lineage 4 decreased from >90% to 60%, with an increase in the other 3 lineages (p<0.001). Lineage 1 strains were more common in those with HIV infection, even after adjusting for age, sex and year. There were no associations with drug resistance or outcome, and no differences by lineage in the proportion of pairs in which transmission was confirmed. CONCLUSIONS: This is the first study to describe long term trends in the four M. tuberculosis lineages in a population. Lineage 4 has probably been longstanding in this population, with relatively recent introductions and spread of Lineages1-3, perhaps influenced by the HIV epidemic

The dynamic relationships between the three events that release individual Na+ ions from the Na+/K+-ATPase

© Macmillan Publishers Limited, 2012. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Nature Communications 3 (2012): 669, doi:10.1038/ncomms1673.Na+/K+ pumps move net charge through the cell membrane by mediating unequal exchange of intracellular Na+ and extracellular K+. Most charge moves during transitions that release Na+ to the cell exterior. When pumps are constrained to bind and release only Na+, a membrane voltage-step redistributes pumps among conformations with zero, one, two or three bound Na+, thereby transiently generating current. By applying rapid voltage steps to squid giant axons, we previously identified three components in such transient currents, with distinct relaxation speeds: fast (which nearly parallels the voltage-jump time course), medium speed (τm=0.2–0.5 ms) and slow (τs=1–10 ms). Here we show that these three components are tightly correlated, both in their magnitudes and in the time courses of their changes. The correlations reveal the dynamics of the conformational rearrangements that release three Na+ to the exterior (or sequester them into their binding sites) one at a time, in an obligatorily sequential manner.This research was directly supported by the Intramural Research Program of the National Institutes of Health (NIH), NINDS, grants NIH HL36783 to D.C.G., and NIH U54GM087519 and R01GM030376 to F.B

Early transmission and case fatality of Ebola virus at the index site of the 2013-16 west African Ebola outbreak: a cross-sectional seroprevalence survey.

BACKGROUND: To date, epidemiological studies at the index site of the 2013-16 west African Ebola outbreak in Meliandou, Guinea, have been restricted in their scope. We aimed to determine the occurrence of previously undocumented Ebola virus disease (EVD) cases and infections, and to reconstruct transmission events. METHODS: This cross-sectional seroprevalence survey of the adult population of Meliandou used a highly specific oral fluid test and detailed interviews of all households in the village and key informants. Each household was interviewed, with all members prompted to describe the events of the outbreak, any illness within the household, and possible contact with suspected cases. Information for deceased individuals was provided by relatives living in the same household. Symptoms were based on Ebola virus Makona variant EVD case definitions (focusing on fever, vomiting, and diarrhoea). For antibody testing, we used an Ebola virus glycoprotein IgG capture enzyme immunoassay developed from a previously validated assay. A maximum exposure level was assigned to every participant using a predetermined scale. We used a generalised linear model (logit function) to estimate odds ratios for the association of sociodemographic variables and exposure level with Ebola virus infection. We adjusted estimates for age and maximum exposure, as appropriate. FINDINGS: Between June 22, and July 9, 2017, we enrolled 237 participants from 27 households in Meliandou. Two households refused to participate and one was absent. All adults in participating households who were present for the interview provided an oral fluid swab for testing, of which 224 were suitable for analysis. In addition to the 11 EVD deaths described previously, on the basis of clinical description and oral fluid testing, we found two probable EVD deaths and eight previously unrecognised anti-Ebola virus IgG-positive survivors, including one who had mild symptoms and one who was asymptomatic, resulting in a case fatality of 55·6% (95% CI 30·8-78·5) for adults. Health-care work (adjusted odds ratio 6·64, 1·54-28·56; p=0·001) and level of exposure (odds ratio adjusted for linear trend across five levels 2·79, 1·59-4·883; p<0·0001) were independent risk factors for infection. INTERPRETATION: Ebola virus infection was more widespread in this spillover population than previously recognised (21 vs 11 cases). We show the first serological evidence of survivors in this population (eight anti-Ebola virus IgG seropositive) and report a case fatality lower than previously reported (55·6% vs 100% in adults). These data show the high community coverage achievable by using a non-invasive test and, by accurately documenting the beginnings of the west African Ebola virus outbreak, reveal important insight into transmission dynamics and risk factors that underpin Ebola virus spillover events. FUNDING: US Food and Drug Administration, Wellcome Trust, and German Research Council

Impact Factor: outdated artefact or stepping-stone to journal certification?

A review of Garfield's journal impact factor and its specific implementation as the Thomson Reuters Impact Factor reveals several weaknesses in this commonly-used indicator of journal standing. Key limitations include the mismatch between citing and cited documents, the deceptive display of three decimals that belies the real precision, and the absence of confidence intervals. These are minor issues that are easily amended and should be corrected, but more substantive improvements are needed. There are indications that the scientific community seeks and needs better certification of journal procedures to improve the quality of published science. Comprehensive certification of editorial and review procedures could help ensure adequate procedures to detect duplicate and fraudulent submissions.Comment: 25 pages, 12 figures, 6 table

Topoisomerase II alpha expression and the benefit of adjuvant chemotherapy for postoperative patients with non-small cell lung cancer

<p>Abstract</p> <p>Background</p> <p>Adjuvant chemotherapy has been shown to improve survival rates of postoperative patients with non-small cell lung cancer (NSCLC). Biomarkers could help select an appropriate chemotherapy for NSCLC patients or predict the efficacy of chemotherapy. The objective of this study was to explore the possible prognostic and predictive role of topoisomerase II alpha (TopIIα) expression level in postoperative NSCLC patients who received adjuvant chemotherapy.</p> <p>Methods</p> <p>Patients with stage I-III NSCLC, who underwent surgery in our hospital from January 2004 to December 2007 and who also received adjuvant chemotherapy after surgery, were analyzed in this study. Expression of TopIIα and Ki67 in paraffin-embedded tissues was detected by immunohistochemistry (IHC). The relationships between clinicopathological characteristics, chemotherapy regimens, the expression of biomarkers and disease free survival (DFS) were analyzed.</p> <p>Results</p> <p>TopIIα and Ki67 were highly expressed in 22.5% and 36.4% of the 151 patients, respectively. Univariate survival analysis showed that male sex (P = 0.036), non-adenocarcinoma (P = 0.004), earlier pathological TNM stage (P = 0.001) or pathological N stage (P < 0.001), and high expression of TopIIα (P = 0.012) were correlated with better DFS, whereas age, smoking history, different chemotherapy regimens, T stage and expression level of Ki67 were of no prognostic significance. Further stratified analysis showed that vinorelbine (NVB)-containing adjuvant regimens were generally associated with better DFS than regimens without NVB in patients with low TopIIα expression, though the difference was not statistically significant (P = 0.065). Pairwise comparisons for patients with low TopIIα expression indicated that the NVB-containing regimen was associated with better DFS than the docetaxel (TXT)-containing regimen (P = 0.047). COX multivariate analysis showed that pathological TNM stage, histological subtype and expression level of TopIIα to be independent of risk factors affecting DFS in postoperative NSCLC patients who received chemotherapy.</p> <p>Conclusions</p> <p>High TopIIα expression was discovered to be correlated with better DFS for postoperative NSCLC patients who received adjuvant chemotherapy. The NVB-containing chemotherapy regimen was more effective than the TXT-containing regimen in improving DFS in patients with low TopIIα expression. TopIIα could be considered to be an independent prognostic biomarker of DFS in postoperative NSCLC patients who received adjuvant chemotherapy.</p

Expression of the stem cell marker ALDH1 in BRCA1 related breast cancer

Introduction The BRCA1 protein makes mammary stem cells differentiate into mature luminal and myoepithelial cells. If a BRCA1 mutation results in a differentiation block, an enlarged stem cell component might be present in the benign tissue of BRCA1 mutation carriers, and these mammary stem cells could be the origin of BRCA1 related breast cancer. Since ALDH1 is a marker of both mammary stem cells and breast cancer stem cells, we compared ALDH1 expression in malignant tissue of BRCA1 mutation carriers to non-carriers. Methods Forty-one BRCA1 related breast cancers and 41 age-matched sporadic breast cancers were immunohistochemically stained for ALDH1. Expression in epithelium and stroma was scored and compared. Results Epithelial (P=0.001) and peritumoral (P=0.001) ALDH1 expression was significantly higher in invasive BRCA1 related carcinomas compared to sporadic carcinomas. Intratumoral stromal ALDH1 expression was similarly high in both groups. ALDH1 tumor cell expression was an independent predictor of BRCA1 mutation status. Conclusion BRCA1 related breast cancers showed significantly more frequent epithelial ALDH1 expression, indicating that these hereditary tumors have an enlarged cancer stem cell component. Besides, (peritumoral) stromal ALDH1 expression was also more frequent in BRCA1 mutation carriers. ALDH1 may therefore be a diagnostic marker and a therapeutic target of BRCA1 related breast cancer

The association of cardioprotective medications with pneumonia-related outcomes

Introduction: Little research has examined whether cardiovascular medications, other than statins, are associated with improved outcomes after pneumonia. Our aim was to examine the association between the use of beta-blockers, statins, angiotensin converting enzyme (ACE) inhibitors, and angiotensin II receptor blockers (ARBs) with pneumonia-related outcomes. Materials and Methods: We conducted a retrospective population-based study on male patients ≥65 years of age hospitalized with pneumonia and who did not have pre-existing cardiac disease. Our primary analyses were multilevel regression models that examined the association between cardiovascular medication classes and either mortality or cardiovascular events. Results: Our cohort included 21,985 patients: 22% died within 90 days of admission, and 22% had a cardiac event within 90 days. The cardiovascular medications studied that were associated with decreased 90-day mortality included: statins (OR 0.70, 95% CI 0.63-0.77), ACE inhibitors (OR 0.82, 95% CI 0.74-0.91), and ARBs (OR 0.58, 95% CI 0.44-0.77). However, none of the medications were significantly associated with decreased cardiovascular events. Discussion: While statins, ACE inhibitors, and ARBs, were associated with decreased mortality, there was no significant association with decreased CV events. These results indicate that this decreased mortality is unlikely due to their potential cardioprotective effects

Effect of prenatal glucocorticoid treatment on size at birth among infants born at term gestation

ObjectiveTo determine whether prenatal treatment with a single course of glucocorticoids (GCs) affects size at birth among full-term infants independent of fetal size before GC administration or exposure to preterm labor (PTL).Study designIn all, 105 full-term infants were recruited into three study groups (30 GC treated; 60 controls matched for gestational age (GA) at birth and sex; and 15 PTL controls without GC exposure). Size of the infants was estimated before treatment using two-dimensional (2D) ultrasound and by direct measurement at birth.ResultsLength, weight and head circumference at birth were smaller among GC-treated infants compared with matched controls (P's&lt;0.01), although fetal size did not differ before treatment (P's&gt;0.2). Exposure to PTL did not account for this effect.ConclusionsPrenatal treatment with a single course of GCs was associated with a reduction in size at birth among infants born at term gestation. This effect cannot be explained by differences in fetal size before treatment or exposure to PTL

Regional Decline of Coral Cover in the Indo-Pacific: Timing, Extent, and Subregional Comparisons

A number of factors have recently caused mass coral mortality events in all of the world's tropical oceans. However, little is known about the timing, rate or spatial variability of the loss of reef-building corals, especially in the Indo-Pacific, which contains 75% of the world's coral reefs.We compiled and analyzed a coral cover database of 6001 quantitative surveys of 2667 Indo-Pacific coral reefs performed between 1968 and 2004. Surveys conducted during 2003 indicated that coral cover averaged only 22.1% (95% CI: 20.7, 23.4) and just 7 of 390 reefs surveyed that year had coral cover >60%. Estimated yearly coral cover loss based on annually pooled survey data was approximately 1% over the last twenty years and 2% between 1997 and 2003 (or 3,168 km(2) per year). The annual loss based on repeated measures regression analysis of a subset of reefs that were monitored for multiple years from 1997 to 2004 was 0.72 % (n = 476 reefs, 95% CI: 0.36, 1.08).The rate and extent of coral loss in the Indo-Pacific are greater than expected. Coral cover was also surprisingly uniform among subregions and declined decades earlier than previously assumed, even on some of the Pacific's most intensely managed reefs. These results have significant implications for policy makers and resource managers as they search for successful models to reverse coral loss