The Race of 10 Synthetic RNAi-Based Drugs to the Pharmaceutical Market

Ten years after Fire and Melo’s Nobel Prize for discovery of gene silencing by double-stranded RNA, a remarkable progress was achieved in RNA interference (RNAi). Changes in the chemical structure of synthetic oligonucleotides make them more stable and specific, and new delivery strategies became progressively available. The attention of pharmaceutical industry rapidly turned to RNAi, as an opportunity to explore new drug targets. This review addresses nine small-interfering RNAs (siRNAs) and one unique microRNA (miRNA) inhibitor, which entered the phase 2–3 clinical trials. The siRNAs in focus are PF-04523655, TKM-080301, Atu027, SYL040012, SYL1001, siG12D-LODER (phase 2), QPI-1002, QPI-1007, and patisiran (phase 3). Regarding miRNAs, their content can be down- or up-regulated, by using miRNA inhibitors (AntimiRs) or miRNA mimics. Miravirsen is an AntimiR-122 for hepatitis C virus infection. The flexibility of RNAi technology is easily understood taking into account: (i) the different drug targets (i.e. p53, caspase 2, PKN3, β2-adrenergic receptor, mutated KRAS, microRNAs); (ii) therapeutic conditions, including ophthalmic diseases, kidney injury, amyloidosis, pancreatic cancer, viral hepatitis; and (iii) routes of administration (ocular, intravenous, subcutaneous, intratumoral). Although some issues are still matters of concern (delivery, toxicity, cost, and biological barriers), RNAi definitively opens a wide avenue for drug development.     

Coping Strategies for HIV-Related Stigma in Liuzhou,China

This study explores the feelings, experiences, and coping strategies of people living with HIV (PLHIV) in Liuzhou, China. In a southwestern Chinese city with high HIV prevalence, we conducted semi-structured in-depth interviews with 47 PLHIV selected to represent individuals who had acquired HIV via different acquisition routes. Many participants felt severely stigmatized; they commonly reported having very low self-esteem and feelings of despair. Based on style of coping and whether it occurred at the interpersonal or intrapersonal level, four types of coping that participants used to deal with HIV-associated stigma were identified: (1) Compassion (Passive/Avoidant—Interpersonal); (2) Hiding HIV status (Passive/Avoidant—Intrapersonal); (3) Social support (Active/Problem-focused—Interpersonal; and (4) Self-care (Active/Problem-focused—Intrapersonal). Educational and stigma-reduction interventions targeting potential social support networks for PLHIV (e.g., family, close friends, and peers) could strengthen active interpersonal PLHIV coping strategies. Interventions teaching self-care to PLHIV would encourage active intrapersonal coping, both of which may enhance PLHIV quality of life in Liuzhou, China.     

Neonatal Outcomes of Pregnancy with Immune Thrombocytopenia

Neonates born to mothers with immune thrombocytopenia (ITP) have an increased risk for neonatal thrombocytopenia and hemorrhagic complications. The aim of this study was to determine the maternal and neonatal outcomes of pregnancies with ITP and also to identify risk factors that predicts neonatal thrombocytopenia. We performed a retrospective analysis of 40 pregnancies with ITP and their 40 neonates. Among the 40 neonates, thrombocytopenia (platelet count of less than 150 × 10⁹/L) was detected in 15 neonates (37.5 %) whom 8 of them had severe thrombocytopenia (platelet count of less than 50 × 10⁹/L). Ten of the 15 neonates with thrombocytopenia required treatment to increase the platelet counts. There was statistically significant association between neonatal thrombocytopenia and maternal splenectomy history and maternal duration of thrombocytopenia. There was no statistically significant correlation between maternal platelet count and neonatal platelet count. Clinicians should pay special attention in these neonates because of risk for development of neonatal thrombocytopenia. Maternal and neonatal outcomes in patients with idiopathic thrombocytopenic purpura is generally good.     

Biomechanical investigation of titanium elastic nail prebending for treating diaphyseal long bone fractures

This study numerically investigated the deformation of titanium elastic nails prebent at various degrees during implantation into the intramedullary canal of fractured bones and the mechanism by which this prebending influenced the stability of the fractured bone. Three degrees of prebending the implanted portions of the nails were used: equal to, two times, and three times the diameter of the intramedullary canal. Furthermore, a simulated diaphyseal fracture with a 5-mm gap was created in the middle shaft portion of the bone fixed with two elastic nails in a double C-type configuration. End caps were simulated using a constraint equation. To confirm that the simulation process is able to present the mechanical response of the nail inside the intramedullary, an experiment was conducted by using sawbone for validation. The results indicated that increasing the degrees of nail prebending facilitated straightening the nails against the inner aspect of canal after implantation, with increase in stability under torsion. Furthermore, reducing nail prebending caused a larger portion of the nails to move closer to the loading site and center of bone after implantation; the use of end caps prevented the nail tips from collapsing and increased axial stability. End cap use was critical for preventing the nail tips from collapsing and for increasing the stability of the nails prebent at a degree equal to the diameter of the canal with insufficient frictional force between the nail and canal. Therefore, titanium elastic nail prebending in a double C-type configuration with a degree three times the diameter of the canal represents a superior solution for treating transverse fractures without a gap, whereas that with a degree equal to the diameter of the intramedullary canal and combined with end cap use represents an advanced solution for treating comminuted fractures in a diaphyseal long bone fracture.     

Predicting prostate tumour location from multiparametric MRI using Gaussian kernel support vector machines: a preliminary study

The performance of a support vector machine (SVM) algorithm was investigated to predict prostate tumour location using multi-parametric MRI (mpMRI) data. The purpose was to obtain information of prostate tumour location for the implementation of bio-focused radiotherapy. In vivo mpMRI data were collected from 16 patients prior to radical prostatectomy. Sequences included T2-weighted imaging, diffusion-weighted imaging and dynamic contrast enhanced imaging. In vivo mpMRI was registered with ‘ground truth’ histology, using ex vivo MRI as an intermediate registration step to improve accuracy. Prostate contours were delineated by a radiation oncologist and tumours were annotated on histology by a pathologist. Five patients with minimal imaging artefacts were selected for this study. A Gaussian kernel SVM was trained and tested on different patient data subsets. Parameters were optimised using leave-oneout cross validation. Signal intensities of mpMRI were used as features and histology annotations as true labels. Prediction accuracy, as well as area under the curve (AUC) of the receiver operating characteristics (ROC) curve, were used to assess performance. Results demonstrated the prediction accuracy ranged from 70.4 to 87.1% and AUC of ROC ranged from 0.81 to 0.94. Additional investigations showed the apparent diffusion coefficient map from diffusion weighted imaging was the most important imaging modality for predicting tumour location. Future work will incorporate additional patient data into the framework to increase the sensitivity and specificity of the model, and will be extended to incorporate predictions of biological characteristics of the tumour which will be used in bio-focused radiotherapy optimisation.     

Impact of a Romantic Relationships Counseling Group Project on Deaf Male Adolescents in a Deaf School

To date, limited research has been conducted on and few educational tools exist regarding the romantic relationships of deaf adolescents. Although deaf male adolescents are supposed to pursue partners according to social norms, they are often afraid of expressing their feelings and being rejected. In particular, deaf male adolescents at deaf schools are accustomed to following their superiors and suppressing their autonomy. This study established a group counseling project to discuss the romantic relationships of deaf male adolescents in a deaf school, and understand the impacts of the counseling to later refine the project. The group was facilitated by three leaders who were assisted by a sign language interpreter, and ran for a total of 25 h over 12 sessions. Eight male adolescents joined the group. A mixed-method design, which emphasizes a qualitative approach, was adopted to collect and examine the data. Interviews with the group members and the teachers of members were conducted for qualitative content analysis, supplemented with score changes in the members’ satisfaction between the midterm and final group counseling sessions. The results indicated that joining the group helped the deaf male adolescents learn new ways to care for their partners, improved their interactions with partners, peers, and teachers, and enhanced their esteem for themselves and other people. Finally, suggestions of themes to explore in the group, and the leadership skills required for romantic relationship group counseling targeted at deaf male adolescents, are provided.     

Religiousness and health in Europe

Recent research suggests that epidemiological forces in religion and health can have opposed effects. Using longitudinal data of people aged 50+ included in wave 1 (2004–2005) of the Survey of Health, Ageing and Retirement in Europe (SHARE), and followed up through waves 2 (2006–2007), 4 (2011) and 5 (2013), we examined two forms of religious internalization and their association with health. Multivariate logistic regressions were used to examine all associations. Taking part in a religious organization was associated with lower odds of GALI (global activity limitation index) (OR = 0.86, 95% CI 0.75, 0.98) and depressive symptoms 0.80 (95% CI 0.69, 0.93), whereas being religiously educated lowered odds of poor self-rated health (SRH) 0.81 (95% CI 0.70, 0.93) and long-term health problems 0.84 (95% CI 0.74, 0.95). The more religious had lower odds of limitations with activities of daily living 0.76 (95% CI 0.58, 0.99) and depressive symptoms 0.77 (95% CI 0.64, 0.92) than other respondents, and compared to people who only prayed and did not have organizational involvement, they had lower odds of poor SRH 0.71 (95% CI 0.52, 0.97) and depressive symptoms 0.66 (95% CI 0.50, 0.87). Conversely, people who only prayed had higher odds of depressive symptoms than non-religious people 1.46 (95% CI 1.15, 1.86). Our findings suggest two types of religiousness: 1. Restful religiousness (praying, taking part in a religious organization and being religiously educated), which is associated with good health, and 2. Crisis religiousness (praying without other religious activities), which is associated with poor health.     

Some Refinements of a Methodology for Examining the Influence of Overt and Covert Self-Rules on Task Completion

The purpose of this study was to evaluate the role of overt and covert self-rule statements on the execution of a chained task by participants with developmental disabilities. A multiple baseline design across participants with multi-element phases embedded was used to evaluate the effects of overt and covert self-rules, alternating with blocking and nonblocking phases, on skill acquisition, generalization, and maintenance, in the absence of explicit reinforcement contingencies for accurate performance. All three participants demonstrated acquisition of the chained task and generalization to novel stimuli. Performance was shown to be only moderately disrupted for some participants during conditions in which the emission of overt and covert self-rules were blocked, raising questions regarding the degree to which a functional relationship between task completion and self-rule statements was obtained. Results are discussed in terms of the practical utility of teaching individuals to respond as listeners to their own emission of overt and covert self-rules as speakers.