Collective physician perspectives on non-oral medication approaches for the management of clinically relevant unresolved issues in Parkinson's disease: Consensus from an international survey and discussion program

Navigate PD was an educational program established to supplement existing guidelines and provide recommendations on the management of Parkinson's disease (PD) refractory to oral/transdermal therapies. It involved 103 experts from 13 countries overseen by an International Steering Committee (ISC) of 13 movement disorder specialists. The ISC identified 71 clinical questions important for device-aided management of PD. Fifty-six experts responded to a web-based survey, rating 15 questions as ‘critically important;’ these were refined to 10 questions by the ISC to be addressed through available evidence and expert opinion. Draft guidance was presented at international/national meetings and revised based on feedback. Key take-home points are: • Patients requiring levodopa >5 times daily who have severe, troublesome ‘off’ periods (>1–2 h/day) despite optimal oral/transdermal levodopa or non-levodopa-based therapies should be referred for specialist assessment even if disease duration is <4 years. • Cognitive decline related to non-motor fluctuations is an indication for device-aided therapies. If cognitive impairment is mild, use deep brain stimulation (DBS) with caution. For patients who have cognitive impairment or dementia, intrajejunal levodopa infusion is considered as both therapeutic and palliative in some countries. Falls are linked to cognitive decline and are likely to become more frequent with device-aided therapies. • Insufficient control of motor complications (or drug-resistant tremor in the case of DBS) are indications for device-aided therapies. Levodopa-carbidopa intestinal gel infusions or subcutaneous apomorphine pump may be considered for patients aged >70 years who have mild or moderate cognitive impairment, severe depression or other contraindications to DBS

Meta-analysis of type 2 Diabetes in African Americans Consortium

Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15 × 10(-94)<P<5 × 10(-8), odds ratio (OR)  = 1.09 to 1.36). Fine-mapping revealed that 88 of 158 previously identified T2D or glucose homeostasis loci demonstrated nominal to highly significant association (2.2 × 10(-23) < locus-wide P<0.05). These novel and previously identified loci yielded a sibling relative risk of 1.19, explaining 17.5% of the phenotypic variance of T2D on the liability scale in African Americans. Overall, this study identified two novel susceptibility loci for T2D in African Americans. A substantial number of previously reported loci are transferable to African Americans after accounting for linkage disequilibrium, enabling fine mapping of causal variants in trans-ethnic meta-analysis studies.Peer reviewe

Dysregulated non-coding telomerase RNA component and associated exonuclease XRN1 in leucocytes from women developing preeclampsia-possible link to enhanced senescence

Senescence in placenta/fetal membranes is a normal phenomenon linked to term parturition. However, excessive senescence which may be induced by telomere attrition, has been associated with preeclampsia (PE). We hypothesized that the telomerase complex in peripheral blood mononuclear cells (PBMC) and circulating telomere associated senescence markers would be dysregulated in women with PE. We measured long non-coding (nc) RNA telomerase RNA component (TERC) and RNAs involved in the maturation of TERC in PBMC, and the expression of TERC and 5′–3′ Exoribonuclease 1 (XRN1) in extracellular vesicles at 22–24 weeks, 36–38 weeks and, 5-year follow-up in controls and PE. We also measured telomere length at 22–24 weeks and 5-year follow-up. The circulating senescence markers cathelicidin antimicrobial peptide (CAMP), β-galactosidase, stathmin 1 (STMN1) and chitotriosidase/CHIT1 were measured at 14–16, 22–24, 36–38 weeks and at 5-year follow-up in the STORK study and before delivery and 6 months post-partum in the ACUTE PE study. We found decreased expression of TERC in PBMC early in pregnant women who subsequently developed PE. XRN1 involved in the maturation of TERC was also reduced in pregnancy and 5-year follow-up. Further, we found that the senescence markers CAMP and β-galactosidase were increased in PE pregnancies, and CAMP remained higher at 5-year follow-up. β-galactosidase was associated with atherogenic lipid ratios during pregnancy and at 5-year follow-up, in PE particularly. This study suggests a potential involvement of dysfunctional telomerase biology in the pathophysiology of PE, which is not restricted to the placenta

Fast Offline Partial Evaluation of Large Logic Programs

There are two main approaches to partial evaluation [6], a well-known technique for program specialisation. Online partial evaluators basically include an augmented interpreter that tries to evaluate the program constructs as much as possible—using the partially known input data—while still ensuring the terminatio