Access and Unmet Needs of Orphan Drugs in 194 Countries and 6 Areas: A Global Policy Review With Content Analysis.

OBJECTIVES: Three hundred million people living with rare diseases worldwide are disproportionately deprived of in-time diagnosis and treatment compared with other patients. This review provides an overview of global policies that optimize development, licensing, pricing, and reimbursement of orphan drugs. METHODS: Pharmaceutical legislation and policies related to access and regulation of orphan drugs were examined from 194 World Health Organization member countries and 6 areas. Orphan drug policies (ODPs) were identified through internet search, emails to national pharmacovigilance centers, and systematic academic literature search. Texts from selected publications were extracted for content analysis. RESULTS: One hundred seventy-two drug regulation documents and 77 academic publications from 162 countries/areas were included. Ninety-two of 200 countries/areas (46.0%) had documentation on ODPs. Thirty-four subthemes from content analysis were categorized into 6 policy themes, namely, orphan drug designation, marketing authorization, safety and efficacy requirements, price regulation, incentives that encourage market availability, and incentives that encourage research and development. Countries/areas with ODPs were statistically wealthier (gross national income per capita = $10 875 vs$3950, P < .001). Country/area income was also positively correlated with the scope of the respective ODP (correlation coefficient = 0.57, P < .001). CONCLUSIONS: Globally, the number of countries with an ODP has grown rapidly since 2013. Nevertheless, disparities in geographical distribution and income levels affect the establishment of ODPs. Furthermore, identified policy gaps in price regulation, incentives that encourage market availability, and incentives that encourage research and development should be addressed to improve access to available and affordable orphan drugs

Inferring transient particle transport dynamics in live cells

Live-cell imaging and particle tracking provide rich information on mechanisms of intracellular transport. However, trajectory analysis procedures to infer complex transport dynamics involving stochastic switching between active transport and diffusive motion are lacking. We applied Bayesian model selection to hidden Markov modeling to infer transient transport states from trajectories of mRNA-protein complexes in live mouse hippocampal neurons and metaphase kinetochores in dividing human cells. The software is available at http://hmm-bayes.org/.National Institutes of Health (U.S.)National Institute of Mental Health (U.S.) (Grant U01 MH106011)National Science Foundation (U.S.). Physics of Living Systems (Grant PHY 1305537)Leukemia & Lymphoma Society of America (Scholar Award)National Institute of General Medical Sciences (U.S.) (Grant GM088313)Austrian Science Fund (Schroedinger Fellowship

Severe intellectual disability and autistic features associated with microduplication 2q23.1

We report on two patients with developmental delay, hypotonia, and autistic features associated with duplications of chromosome region 2q23.1-2q23.2 detected by chromosome microarray analysis. The duplications include one OMIM Morbid Map gene, MBD5, as well as seven known RefSeq genes (ACVR2A, ORC4L, EPC2, KIF5C, MIR1978, LYPD6B, and LYPD6). MBD5 lies in the minimum area of overlap of the 2q23.1 microdeletion syndrome. This report provides the first detailed clinical examination of two individuals with a duplication of this region and suggests that brain development and cognitive function may be affected by an increased dosage of the genes involved. © 2012 Macmillan Publishers Limited All rights reserved.link_to_OA_fulltex

Which is the optimal risk stratification system for surgically treated localized primary GIST? Comparison of three contemporary prognostic criteria in 171 tumors and a proposal for a modified armed forces institute of pathology risk criteria

10.1245/s10434-008-9969-zAnnals of Surgical Oncology1582153-2163ASON

Defining the optimal systolic phase targets using absolute delay time for reconstructions in dual-source coronary CT angiography.

To define the optimal systolic phase for dual-source computed tomography angiography using an absolute reconstruction delay time after the R-R interval based on the coronary artery motion, we analyzed images reconstructed between 200 and 420 miliseconds (ms) after the R wave at 20 ms increments in 21 patients. Based on the American Heart Association coronary segmentation guidelines, the origin of six coronary artery landmarks (RCA, AM1, PDA, LM, OM1, and D2) were selected to calculate the coronary artery motion velocity. The velocity of the given landmark was defined as the quotient of the route and the length of the time interval. The x, y and z-coordinates of the selected landmark were recorded, and were used for the calculation of the 3D route of coronary artery motion by using a specific equation. Differences in velocities were assessed by analysis of variance for repeated measures; Bonferroni post hoc tests were used for multiple pair wise comparisons. 1488 landmarks were measured (6 locations at 12 systolic time points) in 21 patients and were analyzed. The mean values of the minimum velocities were calculated separately for each heart rate group (i.e. 80 bpm). The mean lowest coronary artery velocities in each segment occurred in the middle period of each time interval of the acquired systolic phase i.e. 280-340 ms. No differences were found in the minimal coronary artery velocities between the three HR groups, with the exception of the AM1 branch (p = 0.00495) between 80 bpm (p = 0.03), and at HRs of 65-80 versus >80 bpm (p = 0.006). During an absolute delay of 200-420 ms after the R-wave, the ideal reconstruction interval varies significantly among coronary artery segments. Decreased velocities occur between 280 to 340 ms. Therefore a narrow range of systolic intervals, rather than a single phase, should be acquired