Quantifying Cancer Absolute Risk and Cancer Mortality in the Presence of Competing Events after a Myotonic Dystrophy Diagnosis

Recent studies show that patients with myotonic dystrophy (DM) have an increased risk of specific malignancies, but estimates of absolute cancer risk accounting for competing events are lacking. Using the Swedish Patient Registry, we identified 1,081 patients with an inpatient and/or outpatient diagnosis of DM between 1987 and 2007. Date and cause of death and date of cancer diagnosis were extracted from the Swedish Cause of Death and Cancer Registries. We calculated non-parametric estimates of absolute cancer risk and cancer mortality accounting for the high non-cancer competing mortality associated with DM. Absolute cancer risk after DM diagnosis was 1.6% (95% CI=0.4-4%), 5% (95% CI=3-9%) and 9% (95% CI=6-13%) at ages 40, 50 and 60 years, respectively. Females had a higher absolute risk of all cancers combined than males: 9% (95% CI=4-14), and 13% (95% CI=9-20) vs. 2% (95%CI= 0.7-6) and 4% (95%CI=2-8) by ages 50 and 60 years, respectively) and developed cancer at younger ages (median age =51 years, range=22-74 vs. 57, range=43-84, respectively, p=0.02). Cancer deaths accounted for 10% of all deaths, with an absolute cancer mortality risk of 2% (95%CI=1-4.5%), 4% (95%CI=2-6%), and 6% (95%CI=4-9%) by ages 50, 60, and 70 years, respectively. No gender difference in cancer-specific mortality was observed (p=0.6). In conclusion, cancer significantly contributes to morbidity and mortality in DM patients, even after accounting for high competing DM mortality from non-neoplastic causes. It is important to apply population-appropriate, validated cancer screening strategies in DM patients.     

Noninvasive Digital Detection of Fetal DNA in Plasma of 4-Week-Pregnant Women following In Vitro Fertilization and Embryo Transfer

The discovery of cell-free fetal DNA (cfDNA) circulating in the maternal blood has provided new opportunities for noninvasive prenatal diagnosis (NIPD). However, the extremely low levels of cfDNA within a high background of the maternal DNA in maternal circulation necessitate highly sensitive molecular techniques for its reliable use in NIPD. In this proof of principle study, we evaluated the earliest possible detection of cfDNA in the maternal plasma by a bead-based emulsion PCR technology known as BEAMing (beads, emulsion, amplification, magnetics). Blood samples were collected from in vitro fertilization (IVF) patients at 2 to 6 weeks following embryo transfer (i.e., 4 to 8 week pregnancies) and plasma DNA was extracted. The genomic regions of both X and Y chromosome-specific sequences (AMELX and AMELY) were concurrently amplified in two sequential PCRs; first by conventional PCR then by BEAMing. The positive beads either for AMELX or AMELY gene sequences were counted by a flow cytometer. Our results showed that the pregnancies yielding boys had significantly higher plasma AMELY gene fractions (0.512 ± 0.221) than the ones yielding girls (0.028 ± 0.003) or non-pregnant women (0.020 ± 0.005, P= 0.0059). Here, we clearly demonstrated that the BEAMing technique is capable of reliably detecting cfDNA in the blood circulation of 4-week-pregnant women, which is only two weeks after the embryo transfer. BEAMing technique can also be used to early detect fetal DNA alterations in other pregnancy-associated disorders.     

Integrating multiple data sources for assessing blue whale abundance and distribution in Chilean Northern Patagonia

Aim

Species distribution models are useful tools for depicting important habitat, assessing abundance and orienting conservation efforts. For small populations in poorly studied ecosystems, available data are often scarce and patchy. To overcome this limitation, we aim to evaluate the use of different data types within a hierarchical Bayesian framework with the goal of modelling the abundance and distribution of a small and highly migratory population of blue whale (BW, Balaenoptera musculus) summering in Chilean Northern Patagonian (CNP).

Location

CNP, Eastern South Pacific (ESP).

Methods

We constructed a Bayesian hierarchical species distribution Model (HSDM), combining a binomial N‐mixture model used to model BW groups counts in line‐transect data (2009, 2012 and 2014) with a logistic regression for modelling presence‐availability data (2009–2016), allowing both models to share covariate parameters for borrowing strength in estimations.

Results

Distance to areas of high chlorophyll‐a concentration during spring before summering season (AHCC‐s) was the most important and consistent explanatory variable for assessing BW abundance and distribution in CNP. Incorporating accessorial presence‐only data reduced uncertainty in parameters estimation when comparing with a model using only line‐transect data, although other covariates of secondary importance failed to be retained in this model.

Main conclusions

Our results remark the capability of HSDM for integrating different data types providing a potential powerful tool when data are limited and heterogeneous. Results indicate that AHCC‐s, and possibly thermal fronts, could modulate BW abundance and distribution patterns in CNP. Preliminary model‐based delimitations of possible priority conservation areas for BW in CNP overlap with highly used vessel navigation routes and areas destined to aquaculture.

     

Epilation for Minor Trachomatous Trichiasis: Four-Year Results of a Randomised Controlled Trial

BackgroundTrachomatous trichiasis (TT) needs to be managed to reduce the risk of vision loss. The long-term impact of epilation (a common traditional practice of repeated plucking of lashes touching the eye) in preventing visual impairment and corneal opacity from TT is unknown. We conducted a randomized controlled trial of epilation versus surgery for the management of minor TT (fewer than six lashes touching the eye) in Ethiopia. Here we report the four-year outcome and the effect on vision and corneal opacity.

Methodology/ Principal Findings

1300 individuals with minor TT were recruited and randomly assigned to quality trichiasis surgery or repeated epilation using high quality epilation forceps by a trained person with good near vision. Participants were examined six-monthly for two-years, and then at four-years after randomisation. At two-years all epilation arm participants were offered free surgery. At four-years 1151 (88.5%) were re-examined: 572 (88%) and 579 (89%) from epilation and surgery arms, respectively. At that time, 21.1% of the surgery arm participants had recurrent TT; 189/572 (33%) of the epilation arm had received surgery, while 383 (67%) declined surgery and had continued epilating (“epilation-only”). Among the epilation-only group, 207 (54.1%) fully controlled their TT, 166 (43.3%) had minor TT and 10 (2.6%) had major TT (>5 lashes). There were no differences between participants in the epilation-only, epilation-to-surgery and surgery arm participants in changes in visual acuity and corneal opacity between baseline and four-years.

Conclusions/ Significance

Most minor TT participants randomised to the epilation arm continued epilating and controlled their TT. Change in vision and corneal opacity was comparable between surgery and epilation-only participants. This suggests that good quality epilation with regular follow-up is a reasonable second-line alternative to surgery for minor TT for individuals who either decline surgery or do not have immediate access to surgical treatment.     

Telomere length and risk of glioma

BackgroundTelomere length in blood or buccal cell DNA has been associated with risk of various cancers. Glioma can be a highly malignant brain tumor and has few known risk factors. Genetic variants in or near RTEL1 and TERT, key components of telomere biology, are associated with glioma risk. Therefore, we evaluated the association between relative telomere length (RTL) and glioma in a prospective study.Materials and methodsWe performed a nested case-control study within the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. RTL was determined by quantitative PCR on blood or buccal cell DNA obtained at least 2 years prior to diagnosis from 101 individuals with glioma cases. Healthy controls (n = 198) were matched to cases (2:1) on age, gender, smoking status, calendar year, and DNA source. Conditional logistic regression was used to investigate the association between RTL and glioma.ResultsAs expected, RTL declined with increasing age in both cases and controls. There was no statistically significant association between RTL and glioma overall. An analysis stratified by gender suggested that short RTL (1st tertile) in males was associated with glioma (odds ratio, [OR] = 2.29, 95% confidence interval [CI] 1.02–5.11); this association was not observed for females (OR = 0.41, 95% CI 0.14–1.17).ConclusionsThis prospective study did not identify significant associations between RTL and glioma risk, but there may be gender-specific differences. Larger, prospective studies are needed to evaluate these findings.     

Regulation of protein kinase CK1alphaLS by dephosphorylation in response to hydrogen peroxide

Low levels of hydrogen peroxide (H(2)O(2)) are mitogenic to mammalian cells and stimulate the hyperphosphorylation of heterogeneous nuclear ribonucleoprotein C (hnRNP-C) by protein kinase CK1alpha. However, the mechanisms by which CK1alpha is regulated have been unclear. Here it is demonstrated that low levels of H(2)O(2) stimulate the rapid dephosphorylation of CK1alphaLS, a nuclear splice form of CK1alpha. Furthermore, it is demonstrated that either treatment of endothelial cells with H(2)O(2), or dephosphorylation of CK1alphaLS in vitro enhances the association of CK1alphaLS with hnRNP-C. In addition, dephosphorylation of CK1alphaLS in vitro enhances the kinase's ability to phosphorylate hnRNP-C. While CK1alpha appears to be present in all metazoans, analysis of CK1alpha genomic sequences from several species reveals that the alternatively spliced nuclear localizing L-insert is unique to vertebrates, as is the case for hnRNP-C. These observations indicate that CK1alphaLS and hnRNP-C represent conserved components of a vertebrate-specific H(2)O(2)-responsive nuclear signaling pathway.     

Inclusion and human rights in health policies: comparative and benchmarking analysis of 51 policies from Malawi, Sudan, South Africa and Namibia

While many health services strive to be equitable, accessible and inclusive, peoples' right to health often goes unrealized, particularly among vulnerable groups. The extent to which health policies explicitly seek to achieve such goals sets the policy context in which services are delivered and evaluated. An analytical framework was developed--EquiFrame--to evaluate 1) the extent to which 21 Core Concepts of human rights were addressed in policy documents, and 2) coverage of 12 Vulnerable Groups who might benefit from such policies. Using this framework, analysis of 51 policies across Malawi, Namibia, South Africa and Sudan, confirmed the relevance of all Core Concepts and Vulnerable Groups. Further, our analysis highlighted some very strong policies, serious shortcomings in others as well as country-specific patterns. If social inclusion and human rights do not underpin policy formation, it is unlikely they will be inculcated in service delivery. EquiFrame facilitates policy analysis and benchmarking, and provides a means for evaluating policy revision and development.