Humans Sensitivity Distribution in Perceptual Space by a Wearable Haptic Sleeve

It is very important to understand humans’ perception when the other communication modalities like vision and audition are partially or fully impaired. Therefore, this paper tries to give a brief overview on humans’ sensitivity distribution in perceptual space. During our experiments, a wearable haptic sleeve consisted of 7 vibro-actuators was used to stimulate subjects arm to convey haptic feedback. The basic research questions in this study are: 1) whether humans’ perception linearly correlated with the actuation frequency, haptic feedback in our scenario 2) humans’ ability to generalise templates via the wearable haptic sleeve. Those findings would be useful to increase humans’ perception when humans have to work with fully or partially impaired perception in their day-to-day life

Structural basis for CRISPR RNA-guided DNA recognition by Cascade

The CRISPR (clustered regularly interspaced short palindromic repeats) immune system in prokaryotes uses small guide RNAs to neutralize invading viruses and plasmids. In Escherichia coli, immunity depends on a ribonucleoprotein complex called Cascade. Here we present the composition and low-resolution structure of Cascade and show how it recognizes double-stranded DNA (dsDNA) targets in a sequence-specific manner. Cascade is a 405-kDa complex comprising five functionally essential CRISPR-associated (Cas) proteins (CasA1B2C6D1E1) and a 61-nucleotide CRISPR RNA (crRNA) with 5′-hydroxyl and 2′,3′-cyclic phosphate termini. The crRNA guides Cascade to dsDNA target sequences by forming base pairs with the complementary DNA strand while displacing the noncomplementary strand to form an R-loop. Cascade recognizes target DNA without consuming ATP, which suggests that continuous invader DNA surveillance takes place without energy investment. The structure of Cascade shows an unusual seahorse shape that undergoes conformational changes when it binds target DNA.

Uncovering treatment burden as a key concept for stroke care: a systematic review of qualitative research

<b>Background</b> Patients with chronic disease may experience complicated management plans requiring significant personal investment. This has been termed ‘treatment burden’ and has been associated with unfavourable outcomes. The aim of this systematic review is to examine the qualitative literature on treatment burden in stroke from the patient perspective.<p></p> <b>Methods and findings</b> The search strategy centred on: stroke, treatment burden, patient experience, and qualitative methods. We searched: Scopus, CINAHL, Embase, Medline, and PsycINFO. We tracked references, footnotes, and citations. Restrictions included: English language, date of publication January 2000 until February 2013. Two reviewers independently carried out the following: paper screening, data extraction, and data analysis. Data were analysed using framework synthesis, as informed by Normalization Process Theory. Sixty-nine papers were included. Treatment burden includes: (1) making sense of stroke management and planning care, (2) interacting with others, (3) enacting management strategies, and (4) reflecting on management. Health care is fragmented, with poor communication between patient and health care providers. Patients report inadequate information provision. Inpatient care is unsatisfactory, with a perceived lack of empathy from professionals and a shortage of stimulating activities on the ward. Discharge services are poorly coordinated, and accessing health and social care in the community is difficult. The study has potential limitations because it was restricted to studies published in English only and data from low-income countries were scarce.<p></p> <b>Conclusions</b> Stroke management is extremely demanding for patients, and treatment burden is influenced by micro and macro organisation of health services. Knowledge deficits mean patients are ill equipped to organise their care and develop coping strategies, making adherence less likely. There is a need to transform the approach to care provision so that services are configured to prioritise patient needs rather than those of health care systems

Phage-Induced Expression of CRISPR-Associated Proteins Is Revealed by Shotgun Proteomics in Streptococcus thermophilus

The CRISPR/Cas system, comprised of clustered regularly interspaced short palindromic repeats along with their associated (Cas) proteins, protects bacteria and archaea from viral predation and invading nucleic acids. While the mechanism of action for this acquired immunity is currently under investigation, the response of Cas protein expression to phage infection has yet to be elucidated. In this study, we employed shotgun proteomics to measure the global proteome expression in a model system for studying the CRISPR/Cas response in S. thermophilus DGCC7710 infected with phage 2972. Host and viral proteins were simultaneously measured following inoculation at two different multiplicities of infection and across various time points using two-dimensional liquid chromatography tandem mass spectrometry. Thirty-seven out of forty predicted viral proteins were detected, including all proteins of the structural virome and viral effector proteins. In total, 1,013 of 2,079 predicted S. thermophilus proteins were detected, facilitating the monitoring of host protein synthesis changes in response to virus infection. Importantly, Cas proteins from all four CRISPR loci in the S. thermophilus DGCC7710 genome were detected, including loci previously thought to be inactive. Many Cas proteins were found to be constitutively expressed, but several demonstrated increased abundance following infection, including the signature Cas9 proteins from the CRISPR1 and CRISPR3 loci, which are key players in the interference phase of the CRISPR/Cas response. Altogether, these results provide novel insights into the proteomic response of S. thermophilus, specifically CRISPR-associated proteins, upon phage 2972 infection

A Blueberry-Enriched Diet Attenuates Nephropathy in a Rat Model of Hypertension via Reduction in Oxidative Stress

To assess renoprotective effects of a blueberry-enriched diet in a rat model of hypertension. Oxidative stress (OS) appears to be involved in the development of hypertension and related renal injury. Pharmacological antioxidants can attenuate hypertension and hypertension-induced renal injury; however, attention has shifted recently to the therapeutic potential of natural products as antioxidants. Blueberries (BB) have among the highest antioxidant capacities of fruits and vegetables.Male spontaneously hypertensive rats received a BB-enriched diet (2% w/w) or an isocaloric control diet for 6 or 12 weeks or 2 days. Compared to controls, rats fed BB-enriched diet for 6 or 12 weeks exhibited lower blood pressure, improved glomerular filtration rate, and decreased renovascular resistance. As measured by electron paramagnetic resonance spectroscopy, significant decreases in total reactive oxygen species (ROS), peroxynitrite, and superoxide production rates were observed in kidney tissues in rats on long-term dietary treatment, consistent with reduced pathology and improved function. Additionally, measures of antioxidant status improved; specifically, renal glutathione and catalase activities increased markedly. Contrasted to these observations indicating reduced OS in the BB group after long-term feeding, similar measurements made in rats fed the same diet for only 2 days yielded evidence of increased OS; specifically, significant increases in total ROS, peroxynitrite, and superoxide production rates in all tissues (kidney, brain, and liver) assayed in BB-fed rats. These results were evidence of "hormesis" during brief exposure, which dissipated with time as indicated by enhanced levels of catalase in heart and liver of BB group.Long-term feeding of BB-enriched diet lowered blood pressure, preserved renal hemodynamics, and improved redox status in kidneys of hypertensive rats and concomitantly demonstrated the potential to delay or attenuate development of hypertension-induced renal injury, and these effects appear to be mediated by a short-term hormetic response

Multifunctional Adaptive NS1 Mutations Are Selected upon Human Influenza Virus Evolution in the Mouse

The role of the NS1 protein in modulating influenza A virulence and host range was assessed by adapting A/Hong Kong/1/1968 (H3N2) (HK-wt) to increased virulence in the mouse. Sequencing the NS genome segment of mouse-adapted variants revealed 11 mutations in the NS1 gene and 4 in the overlapping NEP gene. Using the HK-wt virus and reverse genetics to incorporate mutant NS gene segments, we demonstrated that all NS1 mutations were adaptive and enhanced virus replication (up to 100 fold) in mouse cells and/or lungs. All but one NS1 mutant was associated with increased virulence measured by survival and weight loss in the mouse. Ten of twelve NS1 mutants significantly enhanced IFN-β antagonism to reduce the level of IFN β production relative to HK-wt in infected mouse lungs at 1 day post infection, where 9 mutants induced viral yields in the lung that were equivalent to or significantly greater than HK-wt (up to 16 fold increase). Eight of 12 NS1 mutants had reduced or lost the ability to bind the 30 kDa cleavage and polyadenylation specificity factor (CPSF30) thus demonstrating a lack of correlation with reduced IFN β production. Mutant NS1 genes resulted in increased viral mRNA transcription (10 of 12 mutants), and protein production (6 of 12 mutants) in mouse cells. Increased transcription activity was demonstrated in the influenza mini-genome assay for 7 of 11 NS1 mutants. Although we have shown gain-of-function properties for all mutant NS genes, the contribution of the NEP mutations to phenotypic changes remains to be assessed. This study demonstrates that NS1 is a multifunctional virulence factor subject to adaptive evolution

Risk of surgical site infection and efficacy of antibiotic prophylaxis: a cohort study of appendectomy patients in Thailand

BACKGROUND: No data currently exist about use of antibiotics to prevent surgical site infections (SSI) among patients undergoing appendectomy in Thailand. We therefore examined risk factors, use, and efficacy of prophylactic antibiotics for surgical site infection SSI among patients with uncomplicated open appendectomy. METHODS: From July 1, 2003 to June 30, 2004 we conducted a prospective cohort study in eight hospitals in Thailand. We used the National Nosocomial Infection Surveillance (NNIS) system criteria to identify SSI associated with appendectomy. We used logistic regression analysis to obtain relative risk estimates for predictors of SSI. RESULTS: Among 2139 appendectomy patients, we identified 26 SSIs, yielding a SSI rate of 1.2 infections/100 operations. Ninety-two percent of all patients (95% CI, 91.0–93.3) received antibiotic prophylaxis. Metronidazole and gentamicin were the two most common antibiotic agents, with a combined single dose administered in 39% of cases. In 54% of cases, antibiotic prophylaxis was administered for one day. We found that a prolonged duration of operation was significantly associated with an increased SSI risk. Antibiotic prophylaxis was significantly associated with a decreased risk of SSI regardless of whether the antibiotic was administered preoperatively or intraoperatively. Compared with no antibiotic prophylaxis, SSI relative risks for combined single-dose of metronidazole and gentamicin, one-day prophylaxis, and multiple-day antibiotic prophylaxis were 0.28 (0.09–0.90), 0.30 (0.11–0.88) and 0.32 (0.10–0.98), respectively. CONCLUSION: Single-dose combination of metronidazole and gentamicin seems sufficient to reduce SSIs in uncomplicated appendicitis patients despite whether the antibiotic was administered preoperatively or intraoperatively

Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international, randomised controlled trial

Background We designed the EURAMOS-1 trial to investigate whether intensified postoperative chemotherapy for patients whose tumour showed a poor response to preoperative chemotherapy (≥10% viable tumour) improved event-free survival in patients with high-grade osteosarcoma. Methods EURAMOS-1 was an open-label, international, phase 3 randomised, controlled trial. Consenting patients with newly diagnosed, resectable, high-grade osteosarcoma aged 40 years or younger were eligible for randomisation. Patients were randomly assigned (1:1) to receive either postoperative cisplatin, doxorubicin, and methotrexate (MAP) or MAP plus ifosfamide and etoposide (MAPIE) using concealed permuted blocks with three stratification factors: trial group; location of tumour (proximal femur or proximal humerus vs other limb vs axial skeleton); and presence of metastases (no vs yes or possible). The MAP regimen consisted of cisplatin 120 mg/m2, doxorubicin 37·5 mg/m2 per day on days 1 and 2 (on weeks 1 and 6) followed 3 weeks later by high-dose methotrexate 12 g/m2 over 4 h. The MAPIE regimen consisted of MAP as a base regimen, with the addition of high-dose ifosfamide (14 g/m2) at 2·8 g/m2 per day with equidose mesna uroprotection, followed by etoposide 100 mg/m2 per day over 1 h on days 1–5. The primary outcome measure was event-free survival measured in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00134030. Findings Between April 14, 2005, and June 30, 2011, 2260 patients were registered from 325 sites in 17 countries. 618 patients with poor response were randomly assigned; 310 to receive MAP and 308 to receive MAPIE. Median follow-up was 62·1 months (IQR 46·6–76·6); 62·3 months (IQR 46·9–77·1) for the MAP group and 61·1 months (IQR 46·5–75·3) for the MAPIE group. 307 event-free survival events were reported (153 in the MAP group vs 154 in the MAPIE group). 193 deaths were reported (101 in the MAP group vs 92 in the MAPIE group). Event-free survival did not differ between treatment groups (hazard ratio [HR] 0·98 [95% CI 0·78–1·23]); hazards were non-proportional (p=0·0003). The most common grade 3–4 adverse events were neutropenia (268 [89%] patients in MAP vs 268 [90%] in MAPIE), thrombocytopenia (231 [78% in MAP vs 248 [83%] in MAPIE), and febrile neutropenia without documented infection (149 [50%] in MAP vs 217 [73%] in MAPIE). MAPIE was associated with more frequent grade 4 non-haematological toxicity than MAP (35 [12%] of 301 in the MAP group vs 71 [24%] of 298 in the MAPIE group). Two patients died during postoperative therapy, one from infection (although their absolute neutrophil count was normal), which was definitely related to their MAP treatment (specifically doxorubicin and cisplatin), and one from left ventricular systolic dysfunction, which was probably related to MAPIE treatment (specifically doxorubicin). One suspected unexpected serious adverse reaction was reported in the MAP group: bone marrow infarction due to methotrexate. Interpretation EURAMOS-1 results do not support the addition of ifosfamide and etoposide to postoperative chemotherapy in patients with poorly responding osteosarcoma because its administration was associated with increased toxicity without improving event-free survival. The results define standard of care for this population. New strategies are required to improve outcomes in this setting. Funding UK Medical Research Council, National Cancer Institute, European Science Foundation, St Anna Kinderkrebsforschung, Fonds National de la Recherche Scientifique, Fonds voor Wetenschappelijk Onderzoek-Vlaanderen, Parents Organization, Danish Medical Research Council, Academy of Finland, Deutsche Forschungsgemeinschaft, Deutsche Krebshilfe, Federal Ministry of Education and Research, Semmelweis Foundation, ZonMw (Council for Medical Research), Research Council of Norway, Scandinavian Sarcoma Group, Swiss Paediatric Oncology Group, Cancer Research UK, National Institute for Health Research, University College London Hospitals, and Biomedical Research Centre

Mechanisms of action of therapeutic exercise for knee and hip OA remain a black box phenomenon: an individual patient data mediation study with the OA Trial Bank

Objectives To evaluate mediating factors for the effect of therapeutic exercise on pain and physical function in people with knee/hip osteoarthritis (OA). Methods For Subgrouping and TargetEd Exercise pRogrammes for knee and hip OsteoArthritis (STEER OA), individual participant data (IPD) were sought from all published randomised controlled trials (RCTs) comparing therapeutic exercise to non-exercise controls in people with knee/hip OA. Using the Counterfactual framework, the effect of the exercise intervention and the percentage mediated through each potential mediator (muscle strength, proprioception and range of motion (ROM)) for knee OA and muscle strength for hip OA were determined. Results Data from 12 of 31 RCTs of STEER OA (1407 participants) were available. Within the IPD data sets, there were generally statistically significant effects from therapeutic exercise for pain and physical function in comparison to non-exercise controls. Of all potential mediators, only the change in knee extension strength was statistically and significantly associated with the change in pain in knee OA (β -0.03 (95% CI -0.05 to -0.01), 2.3% mediated) and with physical function in knee OA (β -0.02 (95% CI -0.04 to -0.00), 2.0% mediated) and hip OA (β -0.03 (95% CI -0.07 to -0.00), no mediation). Conclusions This first IPD mediation analysis of this scale revealed that in people with knee OA, knee extension strength only mediated ±2% of the effect of therapeutic exercise on pain and physical function. ROM and proprioception did not mediate changes in outcomes, nor did knee extension strength in people with hip OA. As 98% of the effectiveness of therapeutic exercise compared with non-exercise controls remains unexplained, more needs to be done to understand the underlying mechanisms of actions