Prehabilitation for frail patients undergoing colorectal surgery: lessons learnt from a randomised feasibility study

There is substantial interest by clinicians to improve the health outcomes of older and frail patients followingmajor surgery, with prehabilitation a potential and important component of future standard patient care. We studied the feasibility of a randomised controlled trial of pre-operative prehabilitation in frail patients scheduled for colorectal surgery in regional Australia. We conducted a single blind, parallel arm, randomised controlled trial in a regional referral centre where colorectal surgical patients aged over 50 were invited to participate and screened for frailty. Frail patients were randomised to undertake either a 4-week supervised exercise program with dietary advice, or usual care. The primary outcome was 6-min-walk-distance at baseline, pre-surgery (4 weeks later) and at follow-up (4–6 weeks post-operation). Secondary outcomes included physical activity level, health-related quality of life, and post-surgical complications. Feasibility outcomes were numbers of patients reaching each stage and barriers or reasons for withdrawal. Of 106 patients eligible for screening during the 2-year study period, only five were able to be randomised, of which one alone completed the entire study to follow-up. Fewer patients than expected met the frailty criteria (23.6%), and many (22.6%) were offered surgery in a shorter timeframe than the required 4 weeks. Physical and psychological aspects of frailty and logistical issues were key for patients declining study participation and/or not complying with the intervention and/or all outcome assessments. Feasibility for a large randomised controlled trial of prehabilitation for frail colorectal patients was poor (~5%) for our regional location. Addressing barriers, examination of a large, dense population base, and utilisation of a frailty-screening tool validated in surgical patients are necessary for future studies to identify the impact of prehabilitation for frail patients

Composite RNA aptamers as functional mimics of proteins

Individual RNA aptamers are often used to modulate the function of their target proteins, and multi-valent aptamers have been constructed to enhance their activity. To expand the utility of aptamers in manipulating and controlling biological processes, here we advance a general method for the design and construction of composite aptamers. The resulting molecular constructs resemble proteins in that they can form specific interactions with three or more different partners and be readily integrated into existing protein regulatory networks. As the first embodiment of this method, we created a tetra-valent aptamer that simultaneously binds to two molecules of the Drosophila protein B52 and two copies of streptavidin, thus mimicking the function of an antibody in immunochemical assays. We demonstrated that the performance of this ‘aptabody’ rivals that of a monoclonal antibody against B52 in these assays. While this study was performed in vitro and the composite aptamer we made was intended to mimic an existing protein, the same method can be used to accommodate arbitrary combinations of individual aptamers in composite molecular contexts, and these constructs can be delivered into living cells, where they are able to utilize existing cellular infrastructure for their production and processing

High frequency of Plasmodium falciparum chloroquine resistance marker (pfcrt T76 mutation) in Yemen: An urgent need to re-examine malaria drug policy

<p>Abstract</p> <p>Background</p> <p>Malaria remains a significant health problem in Yemen with <it>Plasmodium falciparum </it>being the predominant species which is responsible for 90% of the malaria cases. Despite serious concerns regarding increasing drug resistance, chloroquine is still used for the prevention and treatment of malaria in Yemen. This study was carried out to determine the prevalence of choloroquine resistance (CQR) of <it>P. falciparum </it>isolated from Yemen based on the <it>pfcrt </it>T76 mutation.</p> <p>Methods</p> <p>A cross-sectional study was carried out among 511 participants from four governorates in Yemen. Blood samples were screened using microscopic and species-specific nested PCR based on the 18S rRNA gene to detect and identify <it>Plasmodium </it>species. Blood samples positive for <it>P. falciparum </it>were used for detecting the <it>pfcrt </it>T76 mutation using nested-PCR.</p> <p>Results</p> <p>The prevalence of <it>pfcrt </it>T76 mutation was 81.5% (66 of 81 isolates). Coastal areas/foothills had higher prevalence of <it>pfcrt </it>T76 mutation compared to highland areas (90.5% <it>vs </it>71.8%) (p = 0.031). The <it>pfcrt </it>T76 mutation had a significant association with parasitaemia (p = 0.045). Univariate analysis shows a significant association of <it>pfcrt </it>T76 mutation with people aged > 10 years (OR = 9, 95% CI = 2.3 - 36.2, p = 0.001), low household income (OR = 5, 95% CI = 1.3 - 19.5, p = 0.027), no insecticide spray (OR = 3.7, 95% CI = 1.16 - 11.86, p = 0.025) and not sleeping under insecticide treated nets (ITNs) (OR = 4.8, 95% CI = 1.38 - 16.78, p = 0.01). Logistic regression model confirmed age > 10 years and low household income as predictors of <it>pfcrt </it>T76 mutation in Yemen <it>P. falciparum </it>isolates.</p> <p>Conclusions</p> <p>The high prevalence of <it>pfcrt </it>T76 mutation in Yemen could be a predictive marker for the prevalence of <it>P. falciparum </it>CQR. This finding shows the necessity for an in-vivo therapeutic efficacy test for CQ.<it> P. falciparum </it>CQR should be addressed in the national strategy to control malaria.</p

NF-κB Hyper-Activation by HTLV-1 Tax Induces Cellular Senescence, but Can Be Alleviated by the Viral Anti-Sense Protein HBZ

Activation of I-κB kinases (IKKs) and NF-κB by the human T lymphotropic virus type 1 (HTLV-1) trans-activator/oncoprotein, Tax, is thought to promote cell proliferation and transformation. Paradoxically, expression of Tax in most cells leads to drastic up-regulation of cyclin-dependent kinase inhibitors, p21CIP1/WAF1 and p27KIP1, which cause p53-/pRb-independent cellular senescence. Here we demonstrate that p21CIP1/WAF1-/p27KIP1-mediated senescence constitutes a checkpoint against IKK/NF-κB hyper-activation. Senescence induced by Tax in HeLa cells is attenuated by mutations in Tax that reduce IKK/NF-κB activation and prevented by blocking NF-κB using a degradation-resistant mutant of I-κBα despite constitutive IKK activation. Small hairpin RNA-mediated knockdown indicates that RelA induces this senescence program by acting upstream of the anaphase promoting complex and RelB to stabilize p27KIP1 protein and p21CIP1/WAF1 mRNA respectively. Finally, we show that down-regulation of NF-κB by the HTLV-1 anti-sense protein, HBZ, delay or prevent the onset of Tax-induced senescence. We propose that the balance between Tax and HBZ expression determines the outcome of HTLV-1 infection. Robust HTLV-1 replication and elevated Tax expression drive IKK/NF-κB hyper-activation and trigger senescence. HBZ, however, modulates Tax-mediated viral replication and NF-κB activation, thus allowing HTLV-1-infected cells to proliferate, persist, and evolve. Finally, inactivation of the senescence checkpoint can facilitate persistent NF-κB activation and leukemogenesis

Genetic Variants on Chromosome 1q41 Influence Ocular Axial Length and High Myopia

As one of the leading causes of visual impairment and blindness, myopia poses a significant public health burden in Asia. The primary determinant of myopia is an elongated ocular axial length (AL). Here we report a meta-analysis of three genome-wide association studies on AL conducted in 1,860 Chinese adults, 929 Chinese children, and 2,155 Malay adults. We identified a genetic locus on chromosome 1q41 harboring the zinc-finger 11B pseudogene ZC3H11B showing genome-wide significant association with AL variation (rs4373767, β = −0.16 mm per minor allele, Pmeta = 2.69×10−10). The minor C allele of rs4373767 was also observed to significantly associate with decreased susceptibility to high myopia (per-allele odds ratio (OR) = 0.75, 95% CI: 0.68–0.84, Pmeta = 4.38×10−7) in 1,118 highly myopic cases and 5,433 controls. ZC3H11B and two neighboring genes SLC30A10 and LYPLAL1 were expressed in the human neural retina, retinal pigment epithelium, and sclera. In an experimental myopia mouse model, we observed significant alterations to gene and protein expression in the retina and sclera of the unilateral induced myopic eyes for the murine genes ZC3H11A, SLC30A10, and LYPLAL1. This supports the likely role of genetic variants at chromosome 1q41 in influencing AL variation and high myopia

A common variant near TGFBR3 is associated with primary open angle glaucoma

Primary open angle glaucoma (POAG), a major cause of blindness worldwide, is a complex disease with a significant genetic contribution. We performed Exome Array (Illumina) analysis on 3504 POAG cases and 9746 controls with replication of the most significant findings in 9173 POAG cases and 26 780 controls across 18 collections of Asian, African and European descent. Apart from confirming strong evidence of association at CDKN2B-AS1 (rs2157719 [G], odds ratio [OR] = 0.71, P = 2.81 × 10−33), we observed one SNP showing significant association to POAG (CDC7–TGFBR3 rs1192415, ORG-allele = 1.13, Pmeta = 1.60 × 10−8). This particular SNP has previously been shown to be strongly associated with optic disc area and vertical cup-to-disc ratio, which are regarded as glaucoma-related quantitative traits. Our study now extends this by directly implicating it in POAG disease pathogenesis

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Abstract Primary open angle glaucoma (POAG), a major cause of blindness worldwide, is a complex disease with a significant genetic contribution. We performed Exome Array ), we observed one SNP showing significant association to POAG (CDC7-TGFBR3 rs1192415, OR G-allele = 1.13, P meta = 1.60 × 10 −8 ). This particular SNP has previously been shown to be strongly associated with optic disc area and vertical cup-to-disc ratio, which are regarded as glaucoma-related quantitative traits. Our study now extends this by directly implicating it in POAG disease pathogenesis