Monitoring and prediction of an epidemic outbreak using syndromic observations

The paper presents a method for syndromic surveillance of an epidemic outbreak due to an emerging disease, formulated in the context of stochastic nonlinear filtering. The dynamics of the epidemic is modeled using a stochastic compartmental epidemiological model with inhomogeneous mixing. The syndromic (typically non-medical) observations of the number of infected people (e.g. visits to pharmacies, sale of certain products, absenteeism from work/study, etc.) are assumed available for monitoring and prediction of the epidemic. The state of the epidemic, including the number of infected people and the unknown parameters of the model, are estimated via a particle filter. The numerical results indicate that the proposed framework can provide useful early prediction of the epidemic peak if the uncertainty in prior knowledge of model parameters is not excessive.     

Lower lip suspension using bilateral temporalis muscle flaps and fascia lata grafts

Oral incompetence following composite reconstruction of total and subtotal lower lip defects without any functioning lower lip muscle is a difficult problem for reconstructive surgeons. The authors retrospectively reviewed the use of a novel bilateral temporalis suspension technique for oral incompetence following lower lip reconstruction over a 10-year period. The timing of the reconstruction, cause of the defect, period of follow-up, and any complications were noted. Three cases of lower lip resuspension using bilateral temporalis flaps and fascia lata grafts were performed from 2000 to 2010. Two cases were secondary to burn trauma and one was from ballistic trauma. All patients underwent traditional means of reconstruction using free microvascular composite tissue transfer with and without fascial slings. All three patients presented with persistent lower lip incompetence. The average interval between the initial reconstructive operations and the resuspension operations was 1.6 years. All patients achieved dynamic oral competence at the first postoperative visit. At a mean follow-up of 3.6 years, all patients had maintained lower lip function. Dynamic lower lip resuspension with bilateral temporalis flaps and fascia lata grafts is an option for refractory lower lip drooping following total and subtotal loss, especially after conventional static reconstruction and without any functional orbicularis muscle. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V.     

A novel role of RNA helicase A in regulation of translation of type I collagen mRNAs

Type I collagen is composed of two α1(I) polypeptides and one α2(I) polypeptide and is the most abundant protein in the human body. Expression of type I collagen is primarily controlled at the level of mRNA stability and translation. Coordinated translation of α(I) and α2(I) mRNAs is necessary for efficient folding of the corresponding peptides into the collagen heterotrimer. In the 5' untranslated region (5' UTR), collagen mRNAs have a unique 5' stem-loop structure (5' SL). La ribonucleoprotein domain family member 6 (LARP6) is the protein that binds 5' SL with high affinity and specificity and coordinates their translation. Here we show that RNA helicase A (RHA) is tethered to the 5' SL of collagen mRNAs by interaction with the C-terminal domain of LARP6. In vivo, collagen mRNAs immunoprecipitate with RHA in an LARP6-dependent manner. Knockdown of RHA prevents formation of polysomes on collagen mRNAs and dramatically reduces synthesis of collagen protein, without affecting the level of the mRNAs. A reporter mRNA with collagen 5' SL is translated three times more efficiently in the presence of RHA than the same reporter without the 5' SL, indicating that the 5' SL is the cis-acting element conferring the regulation. During activation of quiescent cells into collagen-producing cells, expression of RHA is highly up-regulated. We postulate that RHA is recruited to the 5' UTR of collagen mRNAs by LARP6 to facilitate their translation. Thus, RHA has been discovered as a critical factor for synthesis of the most abundant protein in the human body.     

A Flexible Alternative to the Cox Proportional Hazards Model for Assessing the Prognostic Accuracy of Hospice Patient Survival

Prognostic models are often used to estimate the length of patient survival. The Cox proportional hazards model has traditionally been applied to assess the accuracy of prognostic models. However, it may be suboptimal due to the inflexibility to model the baseline survival function and when the proportional hazards assumption is violated. The aim of this study was to use internal validation to compare the predictive power of a flexible Royston-Parmar family of survival functions with the Cox proportional hazards model. We applied the Palliative Performance Scale on a dataset of 590 hospice patients at the time of hospice admission. The retrospective data were obtained from the Lifepath Hospice and Palliative Care center in Hillsborough County, Florida, USA. The criteria used to evaluate and compare the models'' predictive performance were the explained variation statistic R², scaled Brier score, and the discrimination slope. The explained variation statistic demonstrated that overall the Royston-Parmar family of survival functions provided a better fit (R² = 0.298; 95% CI: 0.236–0.358) than the Cox model (R² = 0.156; 95% CI: 0.111–0.203). The scaled Brier scores and discrimination slopes were consistently higher under the Royston-Parmar model. Researchers involved in prognosticating patient survival are encouraged to consider the Royston-Parmar model as an alternative to Cox.     

Replication slippage versus point mutation rates in short tandem repeats of the human genome

Short tandem repeats (STRs) are subjected to two kinds of mutational modifications: point mutations and replication slippages. The latter is found to be the more frequent cause of STR modifications, but a satisfactory quantitative measure of the ratio of the two processes has yet to be determined. The comparison of entire genome sequences of closely enough related species enables one to obtain sufficient statistics by counting the differences in the STR regions. We analyzed human–chimpanzee DNA sequence alignments to obtain the counts of point mutations and replication slippage modifications. The results were compared with the results of a computer simulation, and the parameters quantifying the replication slippage probability as well as the probabilities of point mutations within the repeats were determined. It was found that within the STRs with repeated units consisting of one, two or three nucleotides, point mutations occur approximately twice as frequently as one would expect on the basis of the 1.2% difference between the human and chimpanzee genomes. As expected, the replication slippage probability is negligible below a 10-bp threshold and grows above this level. The replication slippage events outnumber the point mutations by one or two orders of magnitude, but are still lower by one order of magnitude relative to the mutability of the markers that are used for genotyping purposes.     

Hypertext atlas of fetal and neonatal pathology

Hypertext atlas of fetal and neonatal pathology is a free resource for pregraduate students of medicine, pathologists and other health professionals dealing with prenatal medicine. The atlas can be found at http://www.muni.cz/atlases. The access is restricted to registered users. Concise texts summarize the gross and microscopic pathology, etiology, and clinical signs of both common and rare fetal and neonatal conditions. The texts are illustrated with over 300 images that are accompanied by short comments. The atlas offers histological pictures of high quality. Virtual microscope interface is used to access the high-resolution histological images. Fetal ultrasound video clips are included. Case studies integrate clinical history, prenatal ultrasonographic examination, gross pathology and histological features. The atlas is available in English (and Czech) and equipped with an active index. The atlas is suitable both for medical students and pathologists as a teaching and reference tool. The atlas is going to be further expanded while keeping the high quality of the images.     

Structural basis for sorting mechanism of p62 in selective autophagy

Impairment of autophagic degradation of the ubiquitin- and LC3-binding protein "p62" leads to the formation of cytoplasmic inclusion bodies. However, little is known about the sorting mechanism of p62 to autophagic degradation. Here we identified a motif of murine p62 consisting of 11 amino acids (Ser334-Ser344) containing conserved acidic and hydrophobic residues across species, as an LC3 recognition sequence (LRS). The crystal structure of the LC3-LRS complex at 1.56 angstroms resolution revealed interaction of Trp340 and Leu343 of p62 with different hydrophobic pockets on the ubiquitin fold of LC3. In vivo analyses demonstrated that p62 mutants lacking LC3 binding ability accumulated without entrapping into autophagosomes in the cytoplasm and subsequently formed ubiquitin-positive inclusion bodies as in autophagy-deficient cells. These results demonstrate that the intracellular level of p62 is tightly regulated by autophagy through the direct interaction of LC3 with p62 and reveal that selective turnover of p62 via autophagy controls inclusion body formation.