Loneliness, social support and cardiovascular reactivity to laboratory stress

Self-reported or explicit loneliness and social support have been inconsistently associated with cardiovascular reactivity (CVR) to stress. The present study aimed to adapt an implicit measure of loneliness, and use it alongside the measures of explicit loneliness and social support, to investigate their correlations with CVR to laboratory stress. Twenty-five female volunteers aged between 18 and 39 years completed self-reported measures of loneliness and social support, and an Implicit Association Test (IAT) of loneliness. The systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) reactivity indices were measured in response to psychosocial stress induced in the laboratory. Functional support indices of social support were significantly correlated with CVR reactivity to stress. Interestingly, implicit, but not explicit, loneliness was significantly correlated with DBP reactivity after one of the stressors. No associations were found between structural support and CVR indices. Results are discussed in terms of validity of implicit versus explicit measures and possible factors that affect physiological outcomes

DNA Structure Modulates the Oligomerization Properties of the AAV Initiator Protein Rep68

Rep68 is a multifunctional protein of the adeno-associated virus (AAV), a parvovirus that is mostly known for its promise as a gene therapy vector. In addition to its role as initiator in viral DNA replication, Rep68 is essential for site-specific integration of the AAV genome into human chromosome 19. Rep68 is a member of the superfamily 3 (SF3) helicases, along with the well-studied initiator proteins simian virus 40 large T antigen (SV40-LTag) and bovine papillomavirus (BPV) E1. Structurally, SF3 helicases share two domains, a DNA origin interaction domain (OID) and an AAA+ motor domain. The AAA+ motor domain is also a structural feature of cellular initiators and it functions as a platform for initiator oligomerization. Here, we studied Rep68 oligomerization in vitro in the presence of different DNA substrates using a variety of biophysical techniques and cryo-EM. We found that a dsDNA region of the AAV origin promotes the formation of a complex containing five Rep68 subunits. Interestingly, non-specific ssDNA promotes the formation of a double-ring Rep68, a known structure formed by the LTag and E1 initiator proteins. The Rep68 ring symmetry is 8-fold, thus differing from the hexameric rings formed by the other SF3 helicases. However, similiar to LTag and E1, Rep68 rings are oriented head-to-head, suggesting that DNA unwinding by the complex proceeds bidirectionally. This novel Rep68 quaternary structure requires both the DNA binding and AAA+ domains, indicating cooperativity between these regions during oligomerization in vitro. Our study clearly demonstrates that Rep68 can oligomerize through two distinct oligomerization pathways, which depend on both the DNA structure and cooperativity of Rep68 domains. These findings provide insight into the dynamics and oligomeric adaptability of Rep68 and serve as a step towards understanding the role of this multifunctional protein during AAV DNA replication and site-specific integration

A meta-analysis of long-term effects of conservation agriculture on maize grain yield under rain-fed conditions

Conservation agriculture involves reduced tillage, permanent soil cover and crop rotations to enhance soil fertility and to supply food from a dwindling land resource. Recently, conservation agriculture has been promoted in Southern Africa, mainly for maize-based farming systems. However, maize yields under rain-fed conditions are often variable. There is therefore a need to identify factors that influence crop yield under conservation agriculture and rain-fed conditions. Here, we studied maize grain yield data from experiments lasting 5 years and more under rain-fed conditions. We assessed the effect of long-term tillage and residue retention on maize grain yield under contrasting soil textures, nitrogen input and climate. Yield variability was measured by stability analysis. Our results show an increase in maize yield over time with conservation agriculture practices that include rotation and high input use in low rainfall areas. But we observed no difference in system stability under those conditions. We observed a strong relationship between maize grain yield and annual rainfall. Our meta-analysis gave the following findings: (1) 92% of the data show that mulch cover in high rainfall areas leads to lower yields due to waterlogging; (2) 85% of data show that soil texture is important in the temporal development of conservation agriculture effects, improved yields are likely on well-drained soils; (3) 73% of the data show that conservation agriculture practices require high inputs especially N for improved yield; (4) 63% of data show that increased yields are obtained with rotation but calculations often do not include the variations in rainfall within and between seasons; (5) 56% of the data show that reduced tillage with no mulch cover leads to lower yields in semi-arid areas; and (6) when adequate fertiliser is available, rainfall is the most important determinant of yield in southern Africa. It is clear from our results that conservation agriculture needs to be targeted and adapted to specific biophysical conditions for improved impact

Longitudinal Numbers-Needed-To-Treat (NNT) for Achieving Various Levels of Analgesic Response and Improvement with Etoricoxib, Naproxen, and Placebo in Ankylosing Spondylitis

<p>Abstract</p> <p>Background</p> <p>Clinical analgesic trials typically report response as group mean results. However, research has shown that few patients are average and most have responses at the extremes. Moreover, group mean results do not convey response levels and thus have limited value in representing the benefit-risk at an individual level. Responder analyses and numbers-needed-to-treat (NNT) are considered more relevant for evaluating treatment response. We evaluated levels of analgesic response and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score improvement and the associated NNTs.</p> <p>Methods</p> <p>This was a post-hoc analysis of a 6-week, randomized, double-blind study (N = 387) comparing etoricoxib 90 mg, etoricoxib 120 mg, naproxen 1000 mg, and placebo in AS. Spine pain and BASDAI were measured on a 100-mm visual analog scale. The number and percentage of patients achieving ≥30% and ≥50% improvement in both BASDAI and spine pain were calculated and used to determine the corresponding NNTs. Patients who discontinued from the study for any reason were assigned zero improvement beyond 7 days of the time of discontinuation.</p> <p>Results</p> <p>For etoricoxib 90 mg, etoricoxib 120 mg and naproxen 1000 mg, the NNTs at 6 weeks compared with placebo were 2.0, 2.0, and 2.7 respectively for BASDAI ≥30% improvement, and 3.2, 2.8, and 4.1 for ≥50% improvement. For spine pain, the NNTs were 1.9, 2.0, and 3.2, respectively, for ≥30% improvement, and 2.7, 2.5, and 3.7 for ≥50% improvement. The differences between etoricoxib and naproxen exceeded the limit of ±0.5 units described as a clinically meaningful difference for pain. Response rates and NNTs were generally similar and stable over 2, 4, and 6 weeks.</p> <p>Conclusions</p> <p>For every 2 patients treated with etoricoxib, 1 achieved a clinically meaningful (≥30%) improvement in spine pain and BASDAI beyond that expected from placebo, whereas the corresponding values were approximately 1 in every 3 patients treated with naproxen. Use of NNTs and responder analyses provide additional, complementary information beyond population mean responses when assessing efficacy compared to placebo and amongst active therapies.</p

Potent Neutralization of Influenza A Virus by a Single-Domain Antibody Blocking M2 Ion Channel Protein

Influenza A virus poses serious health threat to humans. Neutralizing antibodies against the highly conserved M2 ion channel is thought to offer broad protection against influenza A viruses. Here, we screened synthetic Camel single-domain antibody (VHH) libraries against native M2 ion channel protein. One of the isolated VHHs, M2-7A, specifically bound to M2-expressed cell membrane as well as influenza A virion, inhibited replication of both amantadine-sensitive and resistant influenza A viruses in vitro, and protected mice from a lethal influenza virus challenge. Moreover, M2-7A showed blocking activity for proton influx through M2 ion channel. These pieces of evidence collectively demonstrate for the first time that a neutralizing antibody against M2 with broad specificity is achievable, and M2-7A may have potential for cross protection against a number of variants and subtypes of influenza A viruses

Effectiveness and costs of implementation strategies to reduce acid suppressive drug prescriptions: a systematic review

<p>Abstract</p> <p>Background</p> <p>Evaluation of evidence for the effectiveness of implementation strategies aimed at reducing prescriptions for the use of acid suppressive drugs (ASD).</p> <p>Methods</p> <p>A systematic review of intervention studies with a design according to research quality criteria and outcomes related to the effect of reduction of ASD medication retrieved from Medline, Embase and the Cochrane Library. Outcome measures were the strategy of intervention, quality of methodology and results of treatment to differences of ASD prescriptions and costs.</p> <p>Results</p> <p>The intervention varied from a single passive method to multiple active interactions with GPs. Reports of study quality had shortcomings on subjects of data-analysis. Not all outcomes were calculated but if so rction of prescriptions varied from 8% up to 40% and the cost effectiveness was in some cases negative and in others positive. Few studies demonstrated good effects from the interventions to reduce ASD.</p> <p>Conclusion</p> <p>Poor quality of some studies is limiting the evidence for effective interventions. Also it is difficult to compare cost-effectiveness between studies. However, RCT studies demonstrate that active interventions are required to reduce ASD volume. Larger multi-intervention studies are necessary to evaluate the most successful intervention instruments.</p

Substitution of adeno-associated virus Rep protein binding and nicking sites with human Chromosome 19 sequences

<p>Abstract</p> <p>Background</p> <p>Adeno-associated virus type 2 (AAV2) preferentially integrates its DNA at a ~2 kb region of human chromosome 19, designated <it>AAVS1 </it>(also known as <it>MBS85</it>). Integration at <it>AAVS1 </it>requires the AAV2 replication (Rep) proteins and a DNA sequence within <it>AAVS1 </it>containing a 16 bp Rep recognition sequence (RRS) and closely spaced Rep nicking site (also referred to as a terminal resolution site, or <it>trs</it>). The AAV2 genome is flanked by inverted terminal repeats (ITRs). Each ITR contains an RRS and closely spaced <it>trs</it>, but the sequences differ from those in <it>AAVS1</it>. These ITR sequences are required for replication and packaging.</p> <p>Results</p> <p>In this study we demonstrate that the <it>AAVS1 </it>RRS and <it>trs </it>can function in AAV2 replication, packaging and integration by replacing a 61 bp region of the AAV2 ITR with a 49 bp segment of <it>AAVS1 </it>DNA. Modifying one or both ITRs did not have a large effect on the overall virus titers. These modifications did not detectably affect integration at <it>AAVS1</it>, as measured by semi-quantitative nested PCR assays. Sequencing of integration junctions shows the joining of the modified ITRs to <it>AAVS1 </it>sequences.</p> <p>Conclusions</p> <p>The ability of these <it>AAVS1 </it>sequences to substitute for the AAV2 RRS and <it>trs </it>provides indirect evidence that the stable secondary structure encompassing the <it>trs </it>is part of the AAV2 packaging signal.</p

Healthy people with nature in mind

This is the final version of the article. Available from the publisher via the DOI in this record.BACKGROUND: The global disease burden resulting from climate change is likely to be substantial and will put further strain on public health systems that are already struggling to cope with demand. An up- stream solution, that of preventing climate change and associated adverse health effects, is a promising approach, which would create win-win-situations where both the environment and human health benefit. One such solution would be to apply methods of behaviour change to prompt pro-environmentalism, which in turn benefits health and wellbeing. DISCUSSION: Based on evidence from the behavioural sciences, we suggest that, like many social behaviours, pro- environmental behaviour can be automatically induced by internal or external stimuli. A potential trigger for such automatic pro-environmental behaviour would be natural environments themselves. Previous research has demonstrated that natural environments evoke specific psychological and physiological reactions, as demonstrated by self-reports, epidemiological studies, brain imaging techniques, and various biomarkers. This suggests that exposure to natural environments could have automatic behavioural effects, potentially in a pro-environmental direction, mediated by physiological reactions. Providing access and fostering exposure to natural environments could then serve as a public health tool, together with other measures, by mitigating climate change and achieving sustainable health in sustainable ecosystems. However, before such actions are implemented basic research is required to elucidate the mechanisms involved, and applied investigations are needed to explore real world impacts and effect magnitudes. As environmental research is still not sufficiently integrated within medical or public health studies there is an urgent need to promote interdisciplinary methods and investigations in this critical field. Health risks posed by anthropogenic climate change are large, unevenly distributed, and unpredictable. To ameliorate negative impacts, pro-environmental behaviours should be fostered. Potentially this could be achieved automatically through exposure to favourable natural environments, with an opportunity for cost-efficient nature-based solutions that provide benefits for both the environment and public health