End points for sickle cell disease clinical trials: patient-reported outcomes, pain, and the brain

To address the global burden of sickle cell disease (SCD) and the need for novel therapies, the American Society of Hematology partnered with the US Food and Drug Administration to engage the work of 7 panels of clinicians, investigators, and patients to develop consensus recommendations for clinical trial end points. The panels conducted their work through literature reviews, assessment of available evidence, and expert judgment focusing on end points related to: patient-reported outcomes (PROs), pain (non-PROs), the brain, end-organ considerations, biomarkers, measurement of cure, and low-resource settings. This article presents the findings and recommendations of the PROs, pain, and brain panels, as well as relevant findings and recommendations from the biomarkers panel. The panels identify end points, where there were supporting data, to use in clinical trials of SCD. In addition, the panels discuss where further research is needed to support the development and validation of additional clinical trial end points

Exploring the effects of telehealth on medical human resources supply: a qualitative case study in remote regions

BACKGROUND: The availability of medical human resource supply is a growing concern for rural and remote communities in many countries. In the last decade, various telehealth experiences in Canada have highlighted the potential impact of this technology on professional practice. The purpose of this study was to explore physicians' and managers' perceptions regarding the potential of telehealth to support recruitment and retention of physicians in remote and rural regions. METHODS: A case study in Eastern Quebec was performed to explore this complex phenomenon. The analytical framework was based on two literature reviews and a Delphi study. Data were collected from semi-structured interviews with 41 physicians and 22 managers. Transcripts were produced and interview content was coded independently by two judges and validated by an expert panel. RESULTS: Interviews have highlighted the potential impact of telehealth on several factors influencing the recruitment and retention of physicians in rural and remote regions. The potential effects of telehealth on physicians' choice of practice location could be seen at the professional, organizational, educational and individual levels. For instance, telehealth could improve work satisfaction by allowing a regional on-call duty system and a better follow-up of patients. However, there are also certain limits related to telehealth, such as the fear that it would eventually replace all continuing medical education activities and onsite specialists in remoteregions. CONCLUSION: Telehealth is likely to have an impact on several factors related to medical workforce supply in remote and rural regions. However, the expected benefits will materialize if and only if this technology is properly integrated into organizations as a support to professional practice

A Population-Based Evaluation of a Publicly Funded, School-Based HPV Vaccine Program in British Columbia, Canada: Parental Factors Associated with HPV Vaccine Receipt

Analysis of a telephone survey by Gina Ogilvie and colleagues identifies the parental factors associated with HPV vaccine uptake in a school-based program in Canada

Binary and Millisecond Pulsars at the New Millennium

We review the properties and applications of binary and millisecond pulsars. Our knowledge of these exciting objects has greatly increased in recent years, mainly due to successful surveys which have brought the known pulsar population to over 1300. There are now 56 binary and millisecond pulsars in the Galactic disk and a further 47 in globular clusters. This review is concerned primarily with the results and spin-offs from these surveys which are of particular interest to the relativity community.Comment: 59 pages, 26 figures, 5 tables. Accepted for publication in Living Reviews in Relativity (http://www.livingreviews.org

Biopsy-based calibration of T2* magnetic resonance for estimation of liver iron concentration and comparison with R2 Ferriscan.

BACKGROUND: There is a need to standardise non-invasive measurements of liver iron concentrations (LIC) so clear inferences can be drawn about body iron levels that are associated with hepatic and extra-hepatic complications of iron overload. Since the first demonstration of an inverse relationship between biopsy LIC and liver magnetic resonance (MR) using a proof-of-concept T2* sequence, MR technology has advanced dramatically with a shorter minimum echo-time, closer inter-echo spacing and constant repetition time. These important advances allow more accurate calculation of liver T2* especially in patients with high LIC. METHODS: Here, we used an optimised liver T2* sequence calibrated against 50 liver biopsy samples on 25 patients with transfusional haemosiderosis using ordinary least squares linear regression, and assessed the method reproducibility in 96 scans over an LIC range up to 42 mg/g dry weight (dw) using Bland-Altman plots. Using mixed model linear regression we compared the new T2*-LIC with R2-LIC (Ferriscan) on 92 scans in 54 patients with transfusional haemosiderosis and examined method agreement using Bland-Altman approach. RESULTS: Strong linear correlation between ln(T2*) and ln(LIC) led to the calibration equation LIC = 31.94(T2*)-1.014. This yielded LIC values approximately 2.2 times higher than the proof-of-concept T2* method. Comparing this new T2*-LIC with the R2-LIC (Ferriscan) technique in 92 scans, we observed a close relationship between the two methods for values up to 10 mg/g dw, however the method agreement was poor. CONCLUSIONS: New calibration of T2* against liver biopsy estimates LIC in a reproducible way, correcting the proof-of-concept calibration by 2.2 times. Due to poor agreement, both methods should be used separately to diagnose or rule out liver iron overload in patients with increased ferritin

Cesarean delivery on maternal request: Can the ethical problem be solved by the principlist approach?

In this article, we use the principlist approach to identify, analyse and attempt to solve the ethical problem raised by a pregnant woman's request for cesarean delivery in absence of medical indications

Canadian oncogenic human papillomavirus cervical infection prevalence: Systematic review and meta-analysis

<p>Abstract</p> <p>Background</p> <p>Oncogenic human papillomavirus (HPV) infection prevalence is required to determine optimal vaccination strategies. We systematically reviewed the prevalence of oncogenic cervical HPV infection among Canadian females prior to immunization.</p> <p>Methods</p> <p>We included studies reporting DNA-confirmed oncogenic HPV prevalence estimates among Canadian females identified through searching electronic databases (e.g., MEDLINE) and public health websites. Two independent reviewers screened literature results, abstracted data and appraised study quality. Prevalence estimates were meta-analyzed among routine screening populations, HPV-positive, and by cytology/histology results.</p> <p>Results</p> <p>Thirty studies plus 21 companion reports were included after screening 837 citations and 120 full-text articles. Many of the studies did not address non-response bias (74%) or use a representative sampling strategy (53%).</p> <p>Age-specific prevalence was highest among females aged < 20 years and slowly declined with increasing age. Across all populations, the highest prevalence estimates from the meta-analyses were observed for HPV types 16 (routine screening populations, 8 studies: 8.6% [95% confidence interval 6.5-10.7%]; HPV-infected, 9 studies: 43.5% [28.7-58.2%]; confirmed cervical cancer, 3 studies: 48.8% [34.0-63.6%]) and 18 (routine screening populations, 8 studies: 3.3% [1.5-5.1%]; HPV-infected, 9 studies: 13.6% [6.1-21.1%], confirmed cervical cancer, 4 studies: 17.1% [6.4-27.9%].</p> <p>Conclusion</p> <p>Our results support vaccinating females < 20 years of age, along with targeted vaccination of some groups (e.g., under-screened populations). The highest prevalence occurred among HPV types 16 and 18, contributing a combined cervical cancer prevalence of 65.9%. Further cancer protection is expected from cross-protection of non-vaccine HPV types. Poor study quality and heterogeneity suggests that high-quality studies are needed.</p

Tuning the Mammalian Circadian Clock: Robust Synergy of Two Loops

The circadian clock is accountable for the regulation of internal rhythms in most living organisms. It allows the anticipation of environmental changes during the day and a better adaptation of physiological processes. In mammals the main clock is located in the suprachiasmatic nucleus (SCN) and synchronizes secondary clocks throughout the body. Its molecular constituents form an intracellular network which dictates circadian time and regulates clock-controlled genes. These clock-controlled genes are involved in crucial biological processes including metabolism and cell cycle regulation. Its malfunction can lead to disruption of biological rhythms and cause severe damage to the organism. The detailed mechanisms that govern the circadian system are not yet completely understood. Mathematical models can be of great help to exploit the mechanism of the circadian circuitry. We built a mathematical model for the core clock system using available data on phases and amplitudes of clock components obtained from an extensive literature search. This model was used to answer complex questions for example: how does the degradation rate of Per affect the period of the system and what is the role of the ROR/Bmal/REV-ERB (RBR) loop? Our findings indicate that an increase in the RNA degradation rate of the clock gene Period (Per) can contribute to increase or decrease of the period - a consequence of a non-monotonic effect of Per transcript stability on the circadian period identified by our model. Furthermore, we provide theoretical evidence for a potential role of the RBR loop as an independent oscillator. We carried out overexpression experiments on members of the RBR loop which lead to loss of oscillations consistent with our predictions. These findings challenge the role of the RBR loop as a merely auxiliary loop and might change our view of the clock molecular circuitry and of the function of the nuclear receptors (REV-ERB and ROR) as a putative driving force of molecular oscillations