A new, evidence-based estimate of patient harms associated with hospital care.
Based on 1984 data developed from reviews of medical records of patients treated in New York hospitals, the Institute of Medicine estimated that up to 98,000 Americans die each year from medical errors. The basis of this estimate is nearly 3 decades old; herein, an updated estimate is developed from modern studies published from 2008 to 2011. A literature review identified 4 limited studies that used primarily the Global Trigger Tool to flag specific evidence in medical records, such as medication stop orders or abnormal laboratory results, which point to an adverse event that may have harmed a patient. Ultimately, a physician must concur on the findings of an adverse event and then classify the severity of patient harm. Using a weighted average of the 4 studies, a lower limit of 210,000 deaths per year was associated with preventable harm in hospitals. Given limitations in the search capability of the Global Trigger Tool and the incompleteness of medical records on which the Tool depends, the true number of premature deaths associated with preventable harm to patients was estimated at more than 400,000 per year. Serious harm seems to be 10- to 20-fold more common than lethal harm. The epidemic of patient harm in hospitals must be taken more seriously if it is to be curtailed. Fully engaging patients and their advocates during hospital care, systematically seeking the patients' voice in identifying harms, transparent accountability for harm, and intentional correction of root causes of harm will be necessary to accomplish this goal.


Vision screening at two years does not reduce the prevalence of reduced vision at four and a half years of age.
There is currently insufficient evidence to recommend vision screening for children < 36 months of age. This study assessed the effect of comprehensive vision screening, as well as the sensitivity of age-appropriate vision tests, at two years of age on habitual visual acuity at 4.5 years of age. Children born at risk of neonatal hypoglycaemia (n = 477) underwent vision assessment at 54 ± 2 months of age including measurement of monocular and binocular habitual visual acuity, assessment of binocularity and stereopsis. Of these children, 355 (74.4 per cent) had also received vision screening at two years of age (mean age = 24± 1 months), while 122 were not screened. Eighty (16.8 per cent) children were classified as having reduced vision at 4.5 years of age, but the prevalence of reduced vision did not differ between children who had previously been screened at two years of age and those who had not (15.5 per cent versus 20.5 per cent, p = 0.153). However, children with reduced vision at 4.5 years of age were more likely to have had visual abnormalities requiring referral detected at two years of age (p = 0.02). Visual acuity and mean spherical equivalent autorefraction measurements were also worse (higher values) in two-year-old children who were later classified with reduced habitual visual acuity (p = 0.031 and p = 0.001, respectively). Nevertheless, unaided binocular visual acuity, non-cycloplegic refractive error, and stereopsis at two years all showed poor sensitivity and specificity for predicting visual outcomes at 4.5 years of age. Our findings do not support the adoption of early vision screening in children as current vision tests suitable for use with two-year-old children have poor sensitivity for predicting mild-moderate habitual vision impairment at 4.5 years of age.


Control of cell behaviour through nanovibrational stimulation: nanokicking.
Mechanical signals are ubiquitous in our everyday life and the process of converting these mechanical signals into a biological signalling response is known as mechanotransduction. Our understanding of mechanotransduction, and its contribution to vital cellular responses, is a rapidly expanding field of research involving complex processes that are still not clearly understood. The use of mechanical vibration as a stimulus of mechanotransduction, including variation of frequency and amplitude, allows an alternative method to control specific cell behaviour without chemical stimulation (e.g. growth factors). Chemical-independent control of cell behaviour could be highly advantageous for fields including drug discovery and clinical tissue engineering. In this review, a novel technique is described based on nanoscale sinusoidal vibration. Using finite-element analysis in conjunction with laser interferometry, techniques that are used within the field of gravitational wave detection, optimization of apparatus design and calibration of vibration application have been performed. We further discuss the application of nanovibrational stimulation, or 'nanokicking', to eukaryotic and prokaryotic cells including the differentiation of mesenchymal stem cells towards an osteoblast cell lineage. Mechanotransductive mechanisms are discussed including mediation through the Rho-A kinase signalling pathway. Optimization of this technique was first performed in two-dimensional culture using a simple vibration platform with an optimal frequency and amplitude of 1 kHz and 22 nm. A novel bioreactor was developed to scale up cell production, with recent research demonstrating that mesenchymal stem cell differentiation can be efficiently triggered in soft gel constructs. This important step provides first evidence that clinically relevant (three-dimensional) volumes of osteoblasts can be produced for the purpose of bone grafting, without complex scaffolds and/or chemical induction. Initial findings have shown that nanovibrational stimulation can also reduce biofilm formation in a number of clinically relevant bacteria. This demonstrates additional utility of the bioreactor to investigate mechanotransduction in other fields of research.This article is part of a discussion meeting issue 'The promises of gravitational-wave astronomy'.


Hydrogen-Rich Saline Attenuated Subarachnoid Hemorrhage-Induced Early Brain Injury in Rats by Suppressing Inflammatory Response: Possible Involvement of NF-κB Pathway and NLRP3 Inflammasome.
Early brain injury (EBI), highlighted with inflammation and apoptosis, occurring within 72 h after subarachnoid hemorrhage (SAH), is associated with the prognosis of SAH. Recent studies have revealed that hydrogen-rich saline (HS) exerted multiple neuroprotective properties in many neurological diseases including SAH, involved to anti-oxidative and anti-apoptotic effect. We have previously reported that HS could attenuate neuronal apoptosis as well as vasospasm. However, the underlying mechanism of HS on inflammation in SAH-induced EBI remains unclear. In this study, we explored the influence of HS on nuclear factor-κB (NF-κB) pathway and nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome at early stage after SAH, by injecting HS intraperitoneally to SAH rats. One hundred and twenty-nine SD rats were randomly divided into four groups: sham group, SAH group, SAH+vehicle group, and SAH+HS group. SAH model was conducted using endovascular perforation method; all rats were sacrificed at 24 h after SAH. Protein level of pIκBα, cytosolic and nuclear p65, NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), caspase-1, interleukin-1β (IL-1β), and cleaved caspase-3 were measured by western blot. mRNA level of IL-1β, interleukin-6 (IL-6), tumor necrosis factor-c (TNF-α) were evaluated by RT-PCR. Cellular injury and death was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and Nissl staining, respectively. Our results showed that pIκBα, nuclear p65, NLRP3, ASC, caspase-1, IL-1β, cleaved caspase-3 proteins, as well as the mRNA of IL-1β, IL-6, and TNF-ɑ increased at 24 h after SAH, while cytosolic p65 decreased. TUNEL and Nissl staining presented severe cellular injury at 24 h post-SAH. However, after HS administration, the changes mentioned above were reversed. In conclusion, HS may inhibit inflammation in EBI and improve neurobehavioral outcome after SAH, partially via inactivation of NF-κB pathway and NLRP3 inflammasome. Graphical Abstract Schematic representation of the mechanism of HS-mediated anti-inflammatory effect in EBI after SAH. The NF-κB inflammatory pathway and NLRP3 inflammasome are involved in the anti-neuroinflammatory effect of HS post-SAH. SAH-induced oxidative stress enhances the activation of NF-κB, thus promoting the translocation of p65 subunit into nucleus and increasing the mRNA level of its downstream proinflammatory cytokines (IL-1β, IN-6, TNF-α) and NLRP3. Elevated expression of NLRP3 mRNA increases the assembly of NLRP3 inflammasome. In addition, oxidative stress after SAH stimulates the activation of NLRP3 inflammasome, therefore, promoting caspase-1 activation and the cleavage of pro-IL-1β into mature IL-1β. Finally, activation of NF-κB pathway and NLRP3 inflammasome contribute to the inflammation response and cellular injury in EBI after SAH. HS treatment reversed the detrimental effect mentioned above via inactivation of NF-κB pathway and NLRP3 inflammasome. NF-κB nuclear factor-κB, IκB inhibitor of NF-κB, IKK Iκ kinase, NLRP3 nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3, ASC apoptosis-associated speck-like protein containing a caspase recruitment domain.


SymROP: ROP protein with identical helices redesigned by all-atom contact analysis and molecular dynamics.
Experience has shown that protein redesigns (using the backbone from a known protein structure) are far more likely to produce well-ordered, native-like structures than are true de novo designs. Therefore, to design a four-helix bundle made of identical short helices, we here proceed by an extensive redesign of the ROP protein. A fully symmetrical SymROP sequence derived from ROP was chosen by modeling ideal-geometry side chains, including hydrogens, while maintaining the "goodness-of-fit" of side-chain packing by calculating all-atom contact surfaces with the Reduce and Probe programs. To estimate the probable extent of backbone movement and side-chain mobility, restrained molecular dynamics simulations were compared for candidate sequences and controls, including substitution of Abu for all or half the core Ala residues. The resulting 17-residue designed sequence is 41% identical to the relevant regions in ROP. SymROP is intended for construction by the Template Assembled Synthetic Proteins approach, to control the bundle topology, to use short helices, and to allow blocked termini and unnatural amino acids. ROP protein has been a valuable system for studying helical protein structure because of its simplicity and regularity within a structure large enough to have a real hydrophobic core. The SymROP design carries that simplicity and regularity even further.


Tumor necrosis factor increases the rate of lipolysis in primary cultures of adipocytes without altering levels of hormone-sensitive lipase.
To investigate the effects of cytokines on adipocyte lipolysis, a macrophage cell line (RAW 264.7) was treated with Escherichia coli lipopolysaccharide (1 microgram/ml) for 18 h to induce cytokine release. Conditioned medium (5%, vol/vol) from these cells was added to rat epididymal adipocytes isolated and incubated under sterile conditions. After incubation, the adipocytes were washed, and the rate of lipolysis (glycerol release) was determined after a further 1-h incubation. The conditioned medium caused an approximately 2.7-fold increase in lipolysis, detectable after 6-12 h, maximal by 24 h, and reversible by 48 h after washing the cells. The effect of conditioned medium was reversed by a neutralizing antibody to mouse tumor necrosis factor-alpha (TNF alpha), and the direct addition of recombinant human TNF alpha (0.1-50 ng/ml) reproduced the effect, with a half-maximally effective concentration of approximately 3 ng/ml. The effect of TNF on the expression of hormone-sensitive lipase (HSL; the rate-limiting enzyme for lipolysis) was investigated by Western immunoblots using an antibody raised to a bacterially expressed 96-amino acid portion of the HSL enzyme. TNF treatment did not alter the concentration of immunoreactive HSL. From these data we conclude that 1) macrophages release a cytokine(s) in response to lipopolysaccharide that stimulates lipolysis in freshly isolated adipocytes; 2) TNF alpha can account for most, or perhaps all, of this effect; 3) TNF alpha increases the rate of lipolysis by a mechanism that does not involve increased expression of HSL. Based on the time-dependent aspects of TNF alpha stimulation and the lack of change in immunoreactive HSL, the findings suggest a TNF-induced posttranslational modification of the enzyme.


When Higher Activations Reflect Lower Deactivations: A PET Study in Alzheimer's Disease during Encoding and Retrieval in Episodic Memory.
The aim of the present study was to explore the cerebral substrates of episodic memory disorders in Alzheimer's disease (AD) and investigate patients' hyperactivations frequently reported in the functional imaging literature. It remains unclear whether some of these hyperactivations reflect real increased activity or deactivation disturbances in the default mode network (DMN). Using positron emission tomography ((15)O-H(2)O), cerebral blood flow was measured in 11 AD patients and 12 healthy elderly controls at rest and during encoding and stem-cued recall of verbal items. Subtractions analyses between the target and control conditions were performed and compared between groups. The average signal was extracted in regions showing hyperactivation in AD patients versus controls in both contrasts. To determine whether hyperactivations occurred in regions that were activated or deactivated during the memory tasks, we compared signal intensities between the target conditions versus rest. Our results showed reduced activation in AD patients compared to controls in several core episodic memory regions, including the medial temporal structures, during both encoding and retrieval. Patients also showed hyperactivations compared to controls in a set of brain areas. Further analyses conducted on the signal extracted in these areas indicated that most of these hyperactivations actually reflected a failure of deactivation. Indeed, whereas almost all of these regions were significantly more activated at rest than during the target conditions in controls, only one region presented a similar pattern of deactivation in patients. Altogether, our findings suggest that hyperactivations in AD must be interpreted with caution and may not systematically reflect increased activity. Although there has been evidence supporting the existence of genuine compensatory mechanisms, dysfunction within the DMN may be responsible for part of the apparent hyperactivations reported in the literature on AD.


Deploying triple artemisinin-based combination therapy (TACT) for malaria treatment in Africa: ethical and practical considerations.
Malaria remains a major cause of morbidity and mortality in Africa, particularly in children under five years of age. Availability of effective anti-malarial drug treatment is a cornerstone for malaria control and eventual malaria elimination. Artemisinin-based combination therapy (ACT) is worldwide the first-line treatment for uncomplicated falciparum malaria, but the ACT drugs are starting to fail in Southeast Asia because of drug resistance. Resistance to artemisinins and their partner drugs could spread from Southeast Asia to Africa or emerge locally, jeopardizing the progress made in malaria control with the increasing deployment of ACT in Africa. The development of triple artemisinin-based combination therapy (TACT) could contribute to mitigating the risks of artemisinin and partner drug resistance on the African continent. However, there are pertinent ethical and practical issues that ought to be taken into consideration. In this paper, the most important ethical tensions, some implementation practicalities and preliminary thoughts on addressing them are discussed. The discussion draws upon data from randomized clinical studies using TACT combined with ethical principles, published literature and lessons learned from the introduction of artemisinin-based combinations in African markets.


Natural variation in photosynthetic capacity, growth, and yield in 64 field-grown wheat genotypes.
Increasing photosynthesis in wheat has been identified as an approach to enhance crop yield, with manipulation of key genes involved in electron transport and the Calvin cycle as one avenue currently being explored. However, natural variation in photosynthetic capacity is a currently unexploited genetic resource for potential crop improvement. Using gas-exchange analysis and protein analysis, the existing natural variation in photosynthetic capacity in a diverse panel of 64 elite wheat cultivars grown in the field was examined relative to growth traits, including biomass and harvest index. Significant variations in photosynthetic capacity, biomass, and yield were observed, although no consistent correlation was found between photosynthetic capacity of the flag leaf and grain yield when all cultivars were compared. The majority of the variation in photosynthesis could be explained by components related to maximum capacity and operational rates of CO2 assimilation, and to CO2 diffusion. Cluster analysis revealed that cultivars may have been bred unintentionally for desirable traits at the expense of photosynthetic capacity. These findings suggest that there is significant underutilized photosynthetic capacity among existing wheat varieties. Our observations are discussed in the context of exploiting existing natural variation in physiological processes for the improvement of photosynthesis in wheat.


Rotational diffusion of nondipolar and charged solutes in alkyl-substituted imidazolium triflimides: effect of C2 methylation on solute rotation.
Rotational diffusion of a nondipolar solute 2,5-dimethyl-1,4-dioxo-3,6-diphenylpyrrolo[3,4-c]pyrrole (DMDPP) and a charged solute rhodamine 110 (R110) has been investigated in 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ([BMIM][Tf2N]) and 1-butyl-2,3-dimethylimidazolium bis(trifluoromethylsulfonyl)imide ([BMMIM][Tf2N]) to understand the influence of the C2 methylation on solute rotation. The measured reorientation times of the nondipolar solute DMDPP are similar in both the ionic liquids and follow Stokes-Einstein-Debye hydrodynamic theory with slip hydrodynamics. In contrast, rotational diffusion of the charged solute R110 in [BMIM][Tf2N] obeys stick hydrodynamics due to specific interactions with the anion of the ionic liquid. Nevertheless, the intriguing result of this study is that the reorientation times of R110 in [BMMIM][Tf2N] deviate significantly from the predictions of stick hydrodynamics, especially at ambient temperatures. The solute-solvent boundary condition parameter Cobs, which is defined as the ratio of the measured reorientation time to the one calculated using the SED theory with stick boundary condition, for R110 is lower by a factor of 2 in [BMMIM][Tf2N] compared to [BMIM][Tf2N] at 298 K. Upon increasing the temperature, Cobs gradually increases and eventually matches with that obtained in [BMIM][Tf2N] at 348 K. It has been well established that methylation of the C2 position in [BMMIM][Tf2N] switches off the main hydrogen-bonding interaction between the anion and the cation, but increases the Coulombic interactions. As a consequence of the enhanced interionic interactions between the cation and anion of the ionic liquid, specific interactions between R110 and [Tf2N] diminish leading to the faster rotation of the solute. However, such an influence is not apparent in case of DMDPP as it does not experience specific interactions with either the cation or the anion of these ionic liquids.


Long-term levodopa/carbidopa intestinal gel in advanced Parkinson's disease.
The short-term benefits of levodopa/carbidopa intestinal gel (LCIG) in patients with advanced Parkinson's disease (PD) are well documented, but the long-term benefits are still uncertain. The aim of this study was to investigate the motor and cognitive outcome of LCIG treatment in advanced PD after a follow-up period of at least 24 months. We assessed 29 patients with advanced PD who started LCIG infusion at our centre between 2007 and 2013. Motor fluctuations, parkinsonian symptoms, activities of daily living and impact on quality of life were evaluated. We also investigated the cognitive outcome using a battery of neuropsychological tests. All adverse events were recorded. Of the 29 PD patients who initiated LCIG, 16 patients reached the follow-up evaluation (24 months), after a mean time period of 32.2 ± 12.4 months. Six patients did not fulfil the 24-month follow-up visit and were evaluated after a mean time period of 8.6 ± 5.4 months. Seven patients discontinued the treatment before the scheduled visit. "Off" time and "On" dyskinesia duration were significantly reduced. LCIG improved quality of life and non motor symptoms, despite overall unchanged total levodopa doses prior to LCIG beginning. Motor and cognitive decline were detected. A relatively high number of adverse events occurred during the follow-up, above all, technical problems with the infusion device and mild problems related with gastrostomy. There were four cases of peripheral neuropathy (PN), 2 of which were considered serious. Our data confirm that LCIG is beneficial in the long-term treatment of advanced PD patients despite a decline in cognitive functions in a subgroup of patients, probably due to disease progression. PN in patients with LCIG may be more frequent than the published date suggest.


Caregiver-mediated exercises for improving outcomes after stroke.
Stroke is a major cause of long-term disability in adults. Several systematic reviews have shown that a higher intensity of training can lead to better functional outcomes after stroke. Currently, the resources in inpatient settings are not always sufficient and innovative methods are necessary to meet these recommendations without increasing healthcare costs. A resource efficient method to augment intensity of training could be to involve caregivers in exercise training. A caregiver-mediated exercise programme has the potential to improve outcomes in terms of body function, activities, and participation in people with stroke. In addition, caregivers are more actively involved in the rehabilitation process, which may increase feelings of empowerment with reduced levels of caregiver burden and could facilitate the transition from rehabilitation facility (in hospital, rehabilitation centre, or nursing home) to home setting. As a consequence, length of stay might be reduced and early supported discharge could be enhanced. To determine if caregiver-mediated exercises (CME) improve functional ability and health-related quality of life in people with stroke, and to determine the effect on caregiver burden. We searched the Cochrane Stroke Group Trials Register (October 2015), CENTRAL (the Cochrane Library, 2015, Issue 10), MEDLINE (1946 to October 2015), Embase (1980 to December 2015), CINAHL (1982 to December 2015), SPORTDiscus (1985 to December 2015), three additional databases (two in October 2015, one in December 2015), and six additional trial registers (October 2015). We also screened reference lists of relevant publications and contacted authors in the field. Randomised controlled trials comparing CME to usual care, no intervention, or another intervention as long as it was not caregiver-mediated, aimed at improving motor function in people who have had a stroke. Two review authors independently selected trials. One review author extracted data, and assessed quality and risk of bias, and a second review author cross-checked these data and assessed quality. We determined the quality of the evidence using GRADE. The small number of included studies limited the pre-planned analyses. We included nine trials about CME, of which six trials with 333 patient-caregiver couples were included in the meta-analysis. The small number of studies, participants, and a variety of outcome measures rendered summarising and combining of data in meta-analysis difficult. In addition, in some studies, CME was the only intervention (CME-core), whereas in other studies, caregivers provided another, existing intervention, such as constraint-induced movement therapy. For trials in the latter category, it was difficult to separate the effects of CME from the effects of the other intervention.We found no significant effect of CME on basic ADL when pooling all trial data post intervention (4 studies; standardised mean difference (SMD) 0.21, 95% confidence interval (CI) -0.02 to 0.44; P = 0.07; moderate-quality evidence) or at follow-up (2 studies; mean difference (MD) 2.69, 95% CI -8.18 to 13.55; P = 0.63; low-quality evidence). In addition, we found no significant effects of CME on extended ADL at post intervention (two studies; SMD 0.07, 95% CI -0.21 to 0.35; P = 0.64; low-quality evidence) or at follow-up (2 studies; SMD 0.11, 95% CI -0.17 to 0.39; P = 0.45; low-quality evidence).Caregiver burden did not increase at the end of the intervention (2 studies; SMD -0.04, 95% CI -0.45 to 0.37; P = 0.86; moderate-quality evidence) or at follow-up (1 study; MD 0.60, 95% CI -0.71 to 1.91; P = 0.37; very low-quality evidence).At the end of intervention, CME significantly improved the secondary outcomes of standing balance (3 studies; SMD 0.53, 95% CI 0.19 to 0.87; P = 0.002; low-quality evidence) and quality of life (1 study; physical functioning: MD 12.40, 95% CI 1.67 to 23.13; P = 0.02; mobility: MD 18.20, 95% CI 7.54 to 28.86; P = 0.0008; general recovery: MD 15.10, 95% CI 8.44 to 21.76; P < 0.00001; very low-quality evidence). At follow-up, we found a significant effect in favour of CME for Six-Minute Walking Test distance (1 study; MD 109.50 m, 95% CI 17.12 to 201.88; P = 0.02; very low-quality evidence). We also found a significant effect in favour of the control group at the end of intervention, regarding performance time on the Wolf Motor Function test (2 studies; MD -1.72, 95% CI -2.23 to -1.21; P < 0.00001; low-quality evidence). We found no significant effects for the other secondary outcomes (i.e. motor impairment, upper limb function, mood, fatigue, length of stay and adverse events; caregiver: mood and quality of life).In contrast to the primary analysis, sensitivity analysis of CME-core showed a significant effect of CME on basic ADL post intervention (2 studies; MD 9.45, 95% CI 2.11 to 16.78; P = 0.01; moderate-quality evidence).The methodological quality of the included trials and variability in interventions (e.g. content, timing, and duration), affected the validity and generalisability of these observed results. There is very low- to moderate-quality evidence that CME may be a valuable intervention to augment the pallet of therapeutic options for stroke rehabilitation. Included studies were small, heterogeneous, and some trials had an unclear or high risk of bias. Future high-quality research should determine whether CME interventions are (cost-)effective.


QTLs for shelf life in lettuce co-locate with those for leaf biophysical properties but not with those for leaf developmental traits.
Developmental and biophysical leaf characteristics that influence post-harvest shelf life in lettuce, an important leafy crop, have been examined. The traits were studied using 60 informative F9 recombinant inbed lines (RILs) derived from a cross between cultivated lettuce (Lactuca sativa cv. Salinas) and wild lettuce (L. serriola acc. UC96US23). Quantitative trait loci (QTLs) for shelf life co-located most closely with those for leaf biophysical properties such as plasticity, elasticity, and breakstrength, suggesting that these are appropriate targets for molecular breeding for improved shelf life. Significant correlations were found between shelf life and leaf size, leaf weight, leaf chlorophyll content, leaf stomatal index, and epidermal cell number per leaf, indicating that these pre-harvest leaf development traits confer post-harvest properties. By studying the population in two contrasting environments in northern and southern Europe, the genotype by environment interaction effects of the QTLs relevant to leaf development and shelf life were assessed. In total, 107 QTLs, distributed on all nine linkage groups, were detected from the 29 traits. Only five QTLs were common in both environments. Several areas where many QTLs co-located (hotspots) on the genome were identified, with relatively little overlap between developmental hotspots and those relating to shelf life. However, QTLs for leaf biophysical properties (breakstrength, plasticity, and elasticity) and cell area correlated well with shelf life, confirming that the ideal ideotype lettuce should have small cells with strong cell walls. The identification of QTLs for leaf development, strength, and longevity will lead to a better understanding of processability at a genetic and cellular level, and allow the improvement of salad leaf quality through marker-assisted breeding.


Human papillomavirus testing in primary screening for the detection of high-grade cervical lesions: a study of 7932 women.
High-risk human papillomaviruses (HR-HPV) are the necessary cause of cervical carcinomas. To determine whether HPR-HPV DNA detection in primary routine screening could represent a sensitive and reliable technique for the detection of high-grade squamous intraepithelial lesions (HGSIL), laboratory analysis using 2 cytologic techniques (conventional and liquid-based), HPV testing with Hybrid Capture II assay (HC-II), followed by colposcopic examination of women with abnormal cervical finding and/or persistent HR-HPV infection, was conducted in 7932 women who had routine cervical examination. The sensitivity of HPV testing for detecting a histologically proven HGSIL was 100%, higher than that of conventional (68.1%) and liquid-based (87.8%) cytology. The low specificities of 85.6% and 87.3% of HPV testing slightly increased to 88.4% and 90.1% if HPV testing was reserved for woman >30 years old. The quantitative approach provided by the HC-II assay for the assessment of the viral load was not reliable for predicting HGSIL in normal smears. HR-HPV testing could be proposed in primary screening in association with cytology. With conventional cytology it significantly improves the detection of HGSIL. With the use of the same cervical scrape for HPV testing and liquid-based cytology, HR-HPV testing would allow to select positive samples treated in a second time for cytology which gives a good specificity.


A matter of time: study of circadian clocks and their role in inflammation.
Circadian rhythms regulate changes in physiology, allowing organisms to respond to predictable environmental demands varying over a 24 h period. A growing body of evidence supports a key role for the circadian clock in the regulation of immune functions and inflammatory responses, which influence the understanding of infections and inflammatory diseases and their treatment. A variety of experimental methods have been used to assess the complex bidirectional crosstalk between the circadian clock and inflammation. In this review, we summarize the organization of the molecular clock, experimental methods used to study circadian rhythms, and both the inflammatory and immune consequences of circadian disturbance.


2D versus 3D human induced pluripotent stem cell-derived cultures for neurodegenerative disease modelling.
Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS), affect millions of people every year and so far, there are no therapeutic cures available. Even though animal and histological models have been of great aid in understanding disease mechanisms and identifying possible therapeutic strategies, in order to find disease-modifying solutions there is still a critical need for systems that can provide more predictive and physiologically relevant results. One possible avenue is the development of patient-derived models, e.g. by reprogramming patient somatic cells into human induced pluripotent stem cells (hiPSCs), which can then be differentiated into any cell type for modelling. These systems contain key genetic information from the donors, and therefore have enormous potential as tools in the investigation of pathological mechanisms underlying disease phenotype, and progression, as well as in drug testing platforms. hiPSCs have been widely cultured in 2D systems, but in order to mimic human brain complexity, 3D models have been proposed as a more advanced alternative. This review will focus on the use of patient-derived hiPSCs to model AD, PD, HD and ALS. In brief, we will cover the available stem cells, types of 2D and 3D culture systems, existing models for neurodegenerative diseases, obstacles to model these diseases in vitro, and current perspectives in the field.


Relative analgesic potency of mu, delta and kappa opioids after spinal administration in amphibians.
The analgesic effects of 12 opioid agonists in amphibians were measured using the acetic acid test. Spinal administration of dermorphin, [D-Ala2,NMePhe4,Gly-ol]-enkephalin, fentanyl and morphine (mu opioids); [D-Ser2,Leu5-Thr6]-enkephalin, [D-Ala2,D-Leu5]-enkephalin, [D-Pen2,D-Pen5]-enkephalin and deltorphin (delta opioids); and Cl977 [(5R)-(544 alpha,744 alpha,845 beta)-N-methyl-N-[7-(1-pyrrolidinyl)-1- oxaspiro[4,5]dec-8yl]-4-benzofuranacetamide monohydrochloride, bremazocine), U50488 (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)- cyclohexyl]benzeneacetamide methanesulfonate) and nalorphine (kappa opioids) produced a dose-dependent and long-lasting analgesia in the Northern grass frog, Rana pipiens. With all opioids, time course experiments showed that this analgesic effect lasted for at least 4 hr, with no untoward effects observed within each dosage range used. The analgesic effects of the 12 opioids were blocked by systemic naltrexone pretreatment. Comparison of dose-response curves demonstrated that the rank order of potency was such that, in general, mu opioids > delta opioids > kappa opioids. Dose-response curves obtained in the presence of a fixed dose of naltrexone showed the greatest shift for [D-Ser2,Leu5-Thr6]-enkephalin, less so for [D-Ala2,NMePhe4,Gly-ol]-enkephalin and the least shift for bremazocine. ED50 values for mu and delta opioids in the amphibian acetic acid test were significantly correlated to ED50 values of the same opioids reported in the literature for the rodent TF test. These results show that a spinal site of opioid analgesia is present in amphibians and supports the utility of this alternative, nonmammalian model for studies of opioid analgesia and pain research.


Regulation of the androgen receptor by SET9-mediated methylation.
The androgen receptor (AR) is a member of the nuclear hormone receptor family of transcription factors that plays a critical role in regulating expression of genes involved in prostate development and transformation. Upon hormone binding, the AR associates with numerous co-regulator proteins that regulate the activation status of target genes via flux to the post-translational modification status of histones and the receptor. Here we show that the AR interacts with and is directly methylated by the histone methyltransferase enzyme SET9. Methylation of the AR on lysine 632 is necessary for enhancing transcriptional activity of the receptor by facilitating both inter-domain communication between the N- and C-termini and recruitment to androgen-target genes. We also show that SET9 is pro-proliferative and anti-apoptotic in prostate cancer cells and demonstrates up-regulated nuclear expression in prostate cancer tissue. In all, our date indicate a new mechanism of AR regulation that may be therapeutically exploitable for prostate cancer treatment.


Implicit and explicit processes in category-based induction: is induction best when we don't think?
In category-based induction (CBI), people use category information to predict unknown properties of exemplars. When an item's classification is uncertain, normative principles and Bayesian models suggest that predictions should integrate information across all possible categories. However, researchers previously have found that people often base their predictions on only a single category. In the present studies, we investigated the possible distinction between implicit and explicit processes in CBI. Predictions of an object's motion took the form of either a catching task (implicit) or a verbal answer (explicit). When subjects made predictions implicitly (Experiment 1), they used categories as Bayesian models predict. Explicit predictions (Experiment 2) showed clearly nonnormative use of categories. This distinction between implicit and explicit processes was replicated with a within-subjects design (Experiment 3). When subjects learned categories implicitly (categories were never mentioned) in Experiment 4, their explicit predictions did not reflect integration of information across categories but again showed a nonnormative pattern of category use. These results provide support for a distinction between implicit and explicit processes in CBI and furthermore suggest that the same category knowledge may result in normative or nonnormative responding, depending on the response mode.


Isotopically selective collisional vibrational energy transfer in CF3H.
The authors investigate here the mechanism of collisionally enhanced isotopic selectivity observed in infrared multiple photon dissociation (IRMPD) of vibrationally preexcited CF3H by Boyarkin et al. [J. Chem. Phys. 118, 93 (2003)]. For both the carbon-12 and carbon-13 isotopic species they measure the dependence of the IRMPD yield on the time delay between the preexcitation and the dissociation pulses at different dissociation frequencies as well as its dependence on the initial isotopic composition of the sample. The results reveal that the collisional increase in isotopic selectivity originates not only from that of IRMPD itself but also from the isotopic selectivity of vibrational energy transfer, with the latter making the major contribution under their experimental conditions. They suggest that the observed isotopic selectivity in collisional energy transfer arises from the difference in overlap between the absorption spectra of the nu5 mode in the 12CF3H acceptor molecule with emission spectra of the same mode in the two isotopically different donors. Understanding the origin of this collisional effect has important implications for optimization of laser isotope separation processes.


Decreased pressor reactivity to angiotensin II in cirrhotic rats. Evidence for a post-receptor defect in angiotensin action.
We used a model of cirrhosis in the rat, produced by inhalation of carbon tetrachloride for 6 weeks, to investigate the mechanism of resistance to the pressor effects of angiotensin II. The pressor response to angiotensin II was significantly lower in conscious cirrhotic animals than in controls. On the other hand, cirrhotic animals had normal pressor responses to norepinephrine, indicating that a generalized defect in vascular reactivity does not cause the decreased pressor response to angiotensin II. Enhanced baroreceptor activity was not the cause of the decreased pressor response to angiotensin II, since baroreflex control of heart rate after angiotensin II was similar in cirrhotics and controls. Pretreatment with either the converting enzyme inhibitor captopril to reduce circulating angiotensin II or the prostaglandin synthesis inhibitor meclofenamate failed to normalize the response to angiotensin II. Thus, neither prior occupancy of receptors with endogenous angiotensin II nor the production of vasodilatory prostaglandins was responsible for the decreased angiotensin II response. Studies of angiotensin II binding by mesenteric artery smooth muscle particles showed that, in cirrhotic animals, receptor affinity for angiotensin II, was significantly lower than in controls (kd: cirrhosis 1.11 +/- 0.09 nM, control 0.94 +/- 0.13 nM; P less than 0.02), whereas receptor number was significantly increased (cirrhosis 315 +/- 42 fmol/mg protein, control 277 +/- 43 fmol/mg protein, P less than 0.01). However, total binding of AII by vascular receptors from cirrhotics was no different than in controls, since the decrease in affinity negated the increase in receptor number.(ABSTRACT TRUNCATED AT 250 WORDS)


Can police shootings be reduced by requiring officers to document when they point firearms at citizens?
To examine the impact of a novel firearm 'pointing' policy that requires officers to document when they directly point their guns at citizens. Sixteen years (2003-2018) of narrative officer-involved shooting (OIS) reports from the Dallas Police Department were qualitatively coded to explore both the total frequency and specific characteristics of OIS before and after the policy change in 2013. χ2 tests found that the firearm pointing policy was associated with a reduction in the proportion of 'threat perception failure' shootings (ie, those where an officer mistakes an item for a gun). Auto Regressive Integrated Moving Average analysis found that the policy change was associated with a gradual, permanent reduction in total OIS; however, that impact was not immediate. Firearm pointing policies have the potential to alter organisational behaviour, particularly in highly discretionary shootings. It is unclear whether the specific mechanisms for the changes include more accountability through constrained discretion, reduced options to handle situations once officers' guns are drawn and pointed, or an effect on officers' timing and vision during ambiguous scenarios. Although organisational change may be a long and complex process, reductions in OIS can prevent serious injuries and death. The policy change did not lead to an increase in the proportion of officers injured during OIS incidents.


Comparison of the PHQ9 and ImPACT symptom cluster scores in measuring depression among college athletes.
Accurate identification of athletes in need of mental health services is essential. The clinical utility of the Patient Health Questionnaire - 9 (PHQ-9), a stand-alone measure of depression, was explored among Division II college athletes (n = 1,209) completing pre-participation concussion baseline assessments (mean age = 19.28), which also included Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT). ImPACT's symptom inventory can be divided into four clusters: affective, cognitive, physical/somatic, and sleep. Most athletes (81.9%) did not endorse any items on the affective symptom cluster; however, 90 athletes (7.4%) fell above the cutoff of 5 for depression on the PHQ-9, and approximately half of all athletes endorsed one or more PHQ-9 items. Simple linear regressions revealed ImPACT's sleep symptom cluster as the best predictor of PHQ-9 total score; however, affective, cognitive, and physical symptom clusters significantly predicted PHQ-9 total score as well. Due to relative under-endorsement of items on ImPACT's affective symptom cluster compared to the PHQ-9, the clinical utility of incorporating a stand-alone measure of depression such as the PHQ-9 during baseline testing is supported.


A feasibility and tolerability study of lithium in Alzheimer's disease.
To assess the safety and feasibility of prescribing long term lithium to elderly people with mild to moderate Alzheimer's disease (AD). An open label treatment group with low dose lithium for up to 1 year with the Lithium Side Effects Rating Scale as the primary outcome measure. A comparison group matched for cognition and age not receiving lithium therapy. Twenty-two people with AD initiated lithium. Fourteen participants discontinued therapy after a mean of 16 weeks of treatment compared to the 39 weeks for those continuing to take treatment at the end of the study. Three patients discontinued treatment due to possible side effects that abated on ceasing therapy. The reports of side effects on the primary outcome scale did not differ between those discontinuing therapy and those remaining in the study. Two patients died whilst receiving lithium--in neither case was the treatment felt to be related to cause of death. There was no difference in deaths, drop outs or change in MMSE between those receiving lithium and the comparison group. Lithium treatment in elderly people with AD has relatively few side effects and those that were apparently due to treatment were mild and reversible. Nonetheless discontinuation rates are high. The use of lithium as a potential disease modification therapy in AD should be explored further but is not without problems.


Mapping of distributions of a local b-matrix cross-term strength using diffusion tensor MRI in patients with Alzheimer's disease.
Mapping of the distribution of local susceptibility strength could be very important in understanding the mechanisms of progression in neurodegenerative diseases, due to depositions of iron and iron-containing plaques. The goal of this study is to map the voxelwise distribution of local cross-term b-value (b(c)) effect caused by interactions between the external and internal gradients, in subjects with Alzheimer's disease (AD), mild cognitive impairment (MCI), and cognitively normal (CN) elderly, using a diffusion tensor (DT) MRI. Two DT-MRI experiments were conducted with opposite polarities of the external diffusion-sensitizing gradients, and the authors modeled the 3 × 3 tensor matrix of b(c) maps and drove a rotationally independent mean b(c) (i.e., MB(c)) maps. To test whether AD has higher cross-term gradients than MCI and∕or CN, 15 AD patients, 18 MCI patients, and 16 CN controls were acquired from DT-MRI data, with six diffusion encoding directions, five b-values (0, 160, 360, 640, and 1000 s∕mm(2)), and positively and negatively alternating polarities of the external diffusion-sensitizing gradients. The b(c) and MB(c) maps were calculated and were spatially normalized into a study specific template for all subjects. The differences of MB(c) maps across the three subject groups were investigated with voxelwise one-way ANOVA tests for each b-value. The differences of MB(c) maps, among the four b-values, were also investigated with a voxelwise one-way within-subject ANOVA test for each group. The authors successfully mapped the local cross-term strength, using a DT-MRI data in the three groups. The MB(c) differences between the groups were increased with increasing b-values. Compared with the CN group and the MCI group, MB(c) values in the AD group were significantly increased. However, compared with the CN group, MB(c) values in the MCI group were not significantly different for all the b-values. In order to map the b-matrix cross-term effect, the authors developed a rotationally invariant index of MB(c), and the index was applied in AD, MCI, and CN subjects. In the AD group, compared with the MCI and CN groups, MB(c) values were increased. AD patients may have much more local intrinsic gradients in the brain than those MCI or CN subjects. MB(c) maps may be used to detect the intrinsically susceptible materials in the human brain, such as iron-containing plaques in the brain with AD.


Chlamydia screening of at-risk young women in managed health care: characteristics of top-performing primary care offices.
Despite effective approaches for managing chlamydial infection, asymptomatic disease remains highly prevalent. We linked administrative data with physician data from the American Medical Association physician survey to identify characteristics of primary care offices associated with best chlamydia screening practices. Criteria from the National Committee for Quality Assurance provided chlamydia screening rates. We defined top-performing offices as those with rates in the top decile among 978 primary care offices from 26 states. Offices screened an average of 16.2% of at-risk, young women, but top-performing offices screened 42.2%. Top-performing offices on average had more black physicians (12.5%, 5.1%, P = 0.001) and were more often located in zip code areas with median income less than $30,000 (22.6%, 5.5%, P = 0.001). Although chlamydia screening rates are alarmingly low overall, there is substantial variation across offices. Understanding predictors of better office performance may lead to effective interventions to promote screening.


Prenatal Genetic Screening and Diagnostic Testing: Assessing Patients' Knowledge, Clinical Experiences, and Utilized Resources in Comparison to Provider's Perceptions.
Objective This survey study aimed to assess patient knowledge, clinical resources, and utilized resources about genetic screening and diagnostic testing. Study Design A one-time anonymous paper survey was distributed to 500 patients at a major urban obstetrics and gynecology department, and an online survey was sent to 229 providers. Descriptive statistics and chi-squared analyses were performed. Results In all, 466 of 500 patient surveys were completed, and 441 analyzed (88.2% response rate). Among providers, 66 of 229 (29.0% response rate) responded. Patients were on average 32 years old, 27 weeks pregnant, and most often reported a graduate degree level of education (47.4%). Over 75% of patients reported accurate knowledge of basic genetic statements. Patients reported that discussing screening and diagnostic testing with their provider was significantly associated with properly defining screening and diagnostic testing ( p < 0.001). Less than 10% of patients reported providers distributing web/video links, books, or any other resource; however, patients most often independently accessed web links (40.1%). Conclusion Our findings suggest a positive impact from patient and provider discussions in office on patient knowledge and understanding. Discrepancies between educational resources distributed in the clinic and individually accessed resources highlight possible areas of change. Future work should evaluate and implement differing resources to increase patient knowledge.


Daily variability in working memory is coupled with negative affect: the role of attention and motivation.
Across days, individuals experience varying levels of negative affect, control of attention, and motivation. We investigated whether this intraindividual variability was coupled with daily fluctuations in working memory (WM) performance. In 100 days, 101 younger individuals worked on a spatial N-back task and rated negative affect, control of attention, and motivation. Results showed that individuals differed in how reliably WM performance fluctuated across days, and that subjective experiences were primarily linked to performance accuracy. WM performance was lower on days with higher levels of negative affect, reduced control of attention, and reduced task-related motivation. Thus, variables that were found to predict WM in between-subjects designs showed important relationships to WM at the within-person level. In addition, there was shared predictive variance among predictors of WM. Days with increased negative affect and reduced performance were also days with reduced control of attention and reduced motivation to work on tasks. These findings are in line with proposed mechanisms linking negative affect and cognitive performance.


Electroactive polyurethane/siloxane derived from castor oil as a versatile cardiac patch, part II: HL-1 cytocompatibility and electrical characterizations.
In first part of this experiment, biocompatibility of the newly developed electroactive polyurethane/siloxane films containing aniline tetramer moieties was demonstrated with proliferation and differentiation of C2C12 myoblasts. Here we further assessed the cytocompatibility of the prepared samples with HL1-cell line, the electrophysiological properties and the patch clamp recording of the seeded cells over the selected electroactive sample. Presence of electroactive aniline tetramer in the structure of polyurethane/siloxane led to the increased expression of cardiac-specific genes of HL-1 cells involved in muscle contraction and electrical coupling. Our results showed that expression of Cx43, TrpT-2, and SERCA genes was significantly increased in conductive sample compared to tissue culture plate and the corresponding non-conductive analogous. The prepared materials were not only biocompatible in terms of cellular toxicity, but did not alter the intrinsic electrical characteristics of HL-1 cells. Embedding the electroactive moiety into the prepared films improved the properties of these polymeric cardiac construct through the enhanced transmission of electrical signals between the cells. Based on morphological observation, calcium imaging and electrophysiological recordings, we demonstrated the potential applicability of these materials for cardiac tissue engineering. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 1398-1407, 2016.


First record of locally acquired human babesiosis in Canada caused by Babesia duncani: a case report.
The aim of this clinical assessment was to ascertain whether a 70-year-old Canadian patient, who had no history of out-of-country travel, had contracted a Babesia infection. The adult human male developed constitutional symptoms, which included sweats, chills, and immobilizing fatigue, and was screened for human babesiosis. Subsequent testing included a complete Babesia panel that consisted of B. microti immunoflourescent antibody IgM and IgG, B. duncani immunofluorescent antibody IgM and IgG, Babesia PCR, and Babesia fluorescent in situ hybridization (FISH) test. Both the IgM serology and the molecular FISH RNA probe were positive for B. duncani; all tests for B. microti were negative. Based on clinical symptoms and laboratory tests, the patient was diagnosed with human babesiosis. Interestingly, the patient's wife also was confirmed positive using serological and molecular testing. This is the first report of a locally acquired case of human babesiosis in Canada caused by Babesia duncani. The geographical distribution of B. duncani in North America is much greater than previously anticipated, especially north of the Canada-United States border. Since the patient was bitten by a blacklegged tick, Ixodes scapularis, a carrier of multiple zoonotic pathogens, the author suggests that this tick species is a vector of B. duncani. Health-care providers must be aware that B. duncani is present in Canada, and poses a public health risk.


Indibulin, a novel microtubule inhibitor, discriminates between mature neuronal and nonneuronal tubulin.
Microtubule inhibitors interfere with microtubule dynamics, causing cell cycle arrest and apoptosis. These effects are responsible for the chemotherapeutic activities of members of the taxane and Vinca alkaloid families in oncology. Unfortunately, a major side effect of the taxanes and Vinca alkaloids is the development of peripheral neuropathies. Indibulin (N-[pyridin-4-yl]-[1-(4-chlorbenzyl)-indol-3-yl]-glyoxyl-amid; D-24851; ZIO-301), a novel synthetic small molecule microtubule inhibitor, destabilizes microtubules and has antitumor activity but does not exhibit neurotoxicity in preclinical animal studies. In the present study, it has been found that indibulin is able to discriminate between highly posttranslationally modified tubulin present in mature neuronal microtubules, and less-modified tubulin present in immature neuronal or nonneuronal microtubules. Vincristine and colchicine act on either tubulin equally well. The binding site of indibulin on mature neuronal microtubules seems to be inaccessible due to the posttranslational modifications, a theory that is supported by the observation that indibulin did not disrupt the integrity of highly modified microtubules present in neurites of pheochromocytoma (PC12) cells. The specificity of indibulin for unmodified microtubules seems to be dependent on the pyridyl moiety of indibulin because derivatives that have the pyridyl moiety replaced are not able to discriminate between highly and less-modified tubulins. The observed broad antitumor activity of indibulin and the lack of central and peripheral nervous system toxicity in preclinical studies make it a promising candidate for development as a cancer treatment. Indibulin is currently in phase I clinical trials.


Chain Folding Produces a Multilayered Morphology in a Precise Polymer: Simulations and Experiments.
Precise control over polymer architecture unlocks the potential for engineered self-assembled crystal structures with useful features on the nanometer length scale. Here we elucidate the structure of the ordered phase of a semicrystalline, functional polyethylene having a precise linear architecture, namely, pendant carboxylic acid groups precisely every 21st backbone carbon atom. By comparing the results of atomistic molecular dynamics simulations with experimental X-ray scattering and Raman spectroscopy data, we find that the polymer chains are folded in a hairpin manner near each carboxylic acid group, giving rise to multiple embedded layers of functional groups that have an interlayer distance of 2.5 nm. This is in contrast to other precise polyethylenes, where the chains are mostly trans within the crystals. Such layers could act as two-dimensional pathways for ionic or molecular transport given an appropriate choice of functional group.


A Selective FGFR inhibitor AZD4547 suppresses RANKL/M-CSF/OPG-dependent ostoclastogenesis and breast cancer growth in the metastatic bone microenvironment.
Aberrant activation of fibroblast growth factor receptor (FGFR) signalling contributes to progression and metastasis of many types of cancers including breast cancer. Accordingly, FGFR targeted tyrosine kinase inhibitors (TKIs) are currently under development. However, the efficacy of FGFR TKIs in the bone microenvironment where breast cancer cells most frequently metastasize and also where FGFR is biologically active, has not been clearly investigated. We investigated the FGFR-mediated interactions among cancer and the bone microenvironment stromal cells (osteoblasts and osteoclasts), and also the effects of FGFR inhibition in bone metastasis. We showed that addition of culture supernatant from the MDA-MB-134-VI FGFR-amplified breast cancer cells-activated FGFR siganalling in osteoblasts, including increased expression of RANKL, M-CSF, and osteoprotegerin (OPG). Further in vitro analyses showed that AZD4547, an FGFR TKI currently in clinical trials for breast cancer, decreased RANKL and M-CSF, and subsequently RANKL and M-CSF-dependent osteoclastogenesis of murine bone marrow monocytes. Moreover, AZD4547 suppressed osteoclastogenesis and tumor-induced osteolysis in an orthotopic breast cancer bone metastasis mouse model using FGFR non-amplified MDA-MB-231 cells. Collectively, our results support that FGFR inhibitors inhibit the bone microenvironment stromal cells including osteoblasts and osteoclasts, and effectively suppress both tumor and stromal compartments of bone metastasis.


Position of the academy of nutrition and dietetics: dietary fatty acids for healthy adults.
It is the position of the Academy of Nutrition and Dietetics (the Academy) that dietary fat for the healthy adult population should provide 20% to 35% of energy, with an increased consumption of n-3 polyunsaturated fatty acids and limited intake of saturated and trans fats. The Academy recommends a food-based approach through a diet that includes regular consumption of fatty fish, nuts and seeds, lean meats and poultry, low-fat dairy products, vegetables, fruits, whole grains, and legumes. These recommendations are made within the context of rapidly evolving science delineating the influence of dietary fat and specific fatty acids on human health. In addition to fat as a valuable and calorically dense macronutrient with a central role in supplying essential nutrition and supporting healthy body weight, evidence on individual fatty acids and fatty acid groups is emerging as a key factor in nutrition and health. Small variations in the structure of fatty acids within broader categories of fatty acids, such as polyunsaturated and saturated, appear to elicit different physiological functions. The Academy recognizes that scientific knowledge about the effects of dietary fats on human health is young and takes a prudent approach in recommending an increase in fatty acids that benefit health and a reduction in fatty acids shown to increase risk of disease. Registered dietitian nutritionists are uniquely positioned to translate fat and fatty acid research into practical and effective dietary recommendations.


Daily antecedents and consequences of nightly sleep.
Sleep can serve as both cause and consequence of individuals' everyday experiences. We built upon prior studies of the correlates of sleep, which have relied primarily on cross-sectional data, to examine the antecedents and consequences of sleep using a daily diary design. Specifically, we assessed the temporal sequence between nightly sleep and daily psychosocial stressors. Parents employed in a US information technology company (n = 102) completed eight consecutive daily diaries at both baseline and 1 year later. In telephone interviews each evening, participants reported on the previous night's sleep hours, sleep quality and sleep latency. They also reported daily work-to-family conflict and time inadequacy (i.e. perceptions of not having enough time) for their child and for themselves to engage in exercise. Multi-level models testing lagged and non-lagged effects simultaneously revealed that sleep hours and sleep quality were associated with next-day consequences of work-to-family conflict and time inadequacy, whereas psychosocial stressors as antecedents did not predict sleep hours or quality that night. For sleep latency, the opposite temporal order emerged: on days with more work-to-family conflict or time inadequacy for child and self than usual, participants reported longer sleep latencies than usual. An exception to this otherwise consistent pattern was that time inadequacy for child also preceded shorter sleep hours and poorer sleep quality that night. The results highlight the utility of a daily diary design for capturing the temporal sequences linking sleep and psychosocial stressors.


Intense Exercise for Survival among Men with Metastatic Castrate-Resistant Prostate Cancer (INTERVAL-GAP4): a multicentre, randomised, controlled phase III study protocol.
Preliminary evidence supports the beneficial role of physical activity on prostate cancer outcomes. This phase III randomised controlled trial (RCT) is designed to determine if supervised high-intensity aerobic and resistance exercise increases overall survival (OS) in patients with metastatic castrate-resistant prostate cancer (mCRPC). Participants (n=866) must have histologically documented metastatic prostate cancer with evidence of progressive disease on androgen deprivation therapy (defined as mCRPC). Patients can be treatment-naïve for mCRPC or on first-line androgen receptor-targeted therapy for mCRPC (ie, abiraterone or enzalutamide) without evidence of progression at enrolment, and with no prior chemotherapy for mCRPC. Patients will receive psychosocial support and will be randomly assigned (1:1) to either supervised exercise (high-intensity aerobic and resistance training) or self-directed exercise (provision of guidelines), stratified by treatment status and site. Exercise prescriptions will be tailored to each participant's fitness and morbidities. The primary endpoint is OS. Secondary endpoints include time to disease progression, occurrence of a skeletal-related event or progression of pain, and degree of pain, opiate use, physical and emotional quality of life, and changes in metabolic biomarkers. An assessment of whether immune function, inflammation, dysregulation of insulin and energy metabolism, and androgen biomarkers are associated with OS will be performed, and whether they mediate the primary association between exercise and OS will also be investigated. This study will also establish a biobank for future biomarker discovery or validation. Validation of exercise as medicine and its mechanisms of action will create evidence to change clinical practice. Accordingly, outcomes of this RCT will be published in international, peer-reviewed journals, and presented at national and international conferences. Ethics approval was first obtained at Edith Cowan University (ID: 13236 NEWTON), with a further 10 investigator sites since receiving ethics approval, prior to activation. NCT02730338.


Endotracheal tube cuff pressure monitoring during neurosurgery - Manual vs. automatic method.
Inflation and assessment of the endotracheal tube cuff pressure is often not appreciated as a critical aspect of endotracheal intubation. Appropriate endotracheal tube cuff pressure, endotracheal intubation seals the airway to prevent aspiration and provides for positive-pressure ventilation without air leak. Correlations between manual methods of assessing the pressure by an experienced anesthesiologists and assessment with maintenance of the pressure within the normal range by the automated pressure controller device were studied in 100 patients divided into two groups. In Group M, endotracheal tube cuff was inflated manually by a trained anesthesiologist and checked for its pressure hourly by cuff pressure monitor till the end of surgery. In Group C, endotracheal tube cuff was inflated by automated cuff pressure controller and pressure was maintained at 25-cm H(2)O throughout the surgeries. Repeated measure ANOVA was applied. Repeated measure ANOVA results showed that average of endotracheal tube cuff pressure of 50 patients taken at seven different points is significantly different (F-value: 171.102, P-value: 0.000). Bonferroni correction test shows that average of endotracheal tube cuff pressure in all six groups are significantly different from constant group (P = 0.000). No case of laryngomalacia, tracheomalacia, tracheal stenosis, tracheoesophageal fistula or aspiration pneumonitis was observed. Endotracheal tube cuff pressure was significantly high when endotracheal tube cuff was inflated manually. The known complications of high endotracheal tube cuff pressure can be avoided if the cuff pressure controller device is used and manual methods cannot be relied upon for keeping the pressure within the recommended levels.


Fetal and neonatal metabolism in the pup of a canine diabetic mother. Fasting circulating fuels and neonatal glucose turnover.
The metabolic effects of previously induced alloxan diabetes were investigated among fasted newborn dogs during the first day of life. Maternal insulin-dependent diabetes resulted in enhanced maternal and fetal blood glucose and ketone bodies, while postnatal levels of these substrates were not altered. Plasma insulin levels were augmented in the fetus and neonate (3 and 6 h of age) of the diabetic mother, while pancreatic insulin content was also enhanced at fetal and 3 h of age. Circulating free fatty acid levels were diminished among pups born to diabetic mothers (IDM pups) at 3 and 6 h of age, while glycerol levels were unaffected. Nevertheless, plasma triglyceride concentrations were elevated in pups of diabetic mothers during fetal and at 3 and 6 h of newborn fasting. Systemic glucose turnover was not altered in pups of diabetic mothers at 3, 9, or 24 h, while at 6 h, glucose turnover appeared enhanced in IDM pups, which was due in part to a decline of glucose production between 3 and 6 h among controls. Gluconeogenesis was attenuated at 9 h of age among IDM pups, but increased by 24 h of age. Hyperinsulinism in the presence of unaltered glucose turnover with attenuated free fatty acid levels suggest that neonatal canine glucose production from hepatic glycogen is less sensitive to insulin's effect than is the lipolysis-lipid reesterification cycle. Gluconeogenesis from lactate may be unnecessary if glycogenolysis is able to support systemic and hepatic substrate requirements, while insulin mediated lipid synthesis may augment tissue triglyceride deposits.


Imaging cadavers: cold FLAIR and noninvasive brain thermometry using CSF diffusion.
There is increasing interest in imaging cadavers for noninvasive autopsies for research purposes. However, the temperature is well below that of in vivo imaging, and a variety of interesting 'cold brain' effects are observed. At lower temperatures conventional FLAIR sequences no longer produce dark cerebrospinal fluid (CSF); T(1) is reduced from about 4.0 sec in vivo to 1.7 sec at 1 degrees C. The diffusion coefficient (DC) of CSF is much reduced (from 3.1 10(-9) m(2)s(-1) in vivo to 1.1 at 1 degrees C). DC values therefore provide a noninvasive thermometer to measure brain core temperature to within 1.0 degrees C. In three cadavers DC values were 1.1-1.5 10(-9) m(2)s(-1), indicating brain core temperatures of 1-10 degrees C, consistent with external thermocouple measurements. An improved inversion time (TI(0)) can then be found for FLAIR. At 10 degrees C this Cold FLAIR sequence (TI(0) = 1.5 sec) gave black CSF. Expressions for CSF DC and T(1) as a function of temperature were produced. A measurement of CSF DC could be converted directly to temperature and the required TI(0) found. In vitro values of CSF DC were about 1% lower than that of water. Thus, FLAIR imaging can be optimized for cadaveric brains at low and unknown temperatures, thereby improving value for autopsy purposes and facilitating comparisons with in vivo imaging.


Standing balance on inclined surfaces with different friction.
Working and walking environments often involve standing positions on different surfaces with inclination and different friction. In this study, standing balance of thirteen participants during sudden and irregular external perturbation to calf muscles was investigated. The aim of the study was to evaluate the combined effect of surface inclination and friction on standing balance. The main findings when eyes closed revealed that the standing utilised coefficient of friction (μSUCOF) increased when the surface was inclined for both high and low friction materials. The anterior-posterior torque increased more anteriorly when the surface was inclined toes down and when the surface friction was low. The results indicate that the anterior-posterior torque is a sensitive parameter when evaluating standing balance ability and slip risk. On inclined surface, particularly on the surface with lower friction, the potential slip and fall risk is higher due to the increase of standing utilised coefficient of friction and increased forward turning torque.


Middle cerebral artery occlusion without craniectomy in rats. Which method works best?
Our purpose was to assess the effectiveness of middle cerebral artery occlusion in producing acute focal ischemia in the rat by the use of Koizumi's and Longa's methods, in which occlusion is achieved by passing a nylon thread into the internal carotid artery. Cerebral blood flow was measured by using the hydrogen clearance method, and the brains were examined histologically to assess ischemic damage. By Koizumi's method profound reduction in cerebral blood flow was achieved in 28 of 30 rats (93%). The mean cerebral blood flow in the middle cerebral artery territory was 10.7 (95% confidence interval, 9.9-11.5) ml/100 g per minute. By Longa's method reduction in cerebral blood flow was achieved in only 29 of 52 rats (56%), and in these animals mean cerebral blood flow was 33 (95% confidence interval, 28.3-33.7) ml/100 g per minute (p < 0.001 compared with Koizumi's method). Cerebral blood flow was reduced to < 16 ml/100 g per minute in only seven animals (24%). By Koizumi's method the depth of ischemia is more profound, occlusion is achieved in a much higher proportion of cases, and the incidence of perforation of the intracranial internal carotid is much less frequent than by Longa's method.


Perception of Risk for Older Adults: Differences in Evaluations for Self versus Others and across Risk Domains.
Proxy decision-making may be flawed by inaccurate perceptions of risk. This may be particularly true when older adults are the targets of the decisions, given the pervasive negative stereotypes about older adults. In study 1, individuals aged 18- to 87 years (as target persons) as well as one of their close social partners (as informants) reported on the risks they perceived for the target person in various life domains. Study 2 additionally explored potential differences in how people make risky decisions on behalf of younger and older adult targets. Younger (age 18-35 years) and older (age 60-81 years) adults (as target persons of the risk evaluations) as well as informants reported on risk perceptions and the likelihood of risk-taking for health, financial, and social scenarios concerning the target persons. Congruence between self-rated and informant-rated risk perceptions and risk-taking were computed on a dyadic as well as a group level. Informants' risk perceptions were positively associated with the risks their partners perceived for themselves. Informants and their partners agreed that social risks vary little across adulthood, but they disagreed in terms of recreational, financial, and health risks, and in terms of the decisions they would make. Family members, partners, and close friends are sensitive to vulnerabilities of their social partners, but in some domains and according to their partners' age they perceive a greater (or smaller) risk than their partners perceive for themselves. In situations requiring surrogate decision-making, people may decide differently from how their social partners would decide for themselves.


Estimating propulsive forces in swimming from three-dimensional kinematic data.
Propulsive forces are important determinants of swimming performance. The aim of this study was to quantify the measurement error (uncertainty) in propulsive forces calculated from kinematic data. Ten operators digitized underwater video recordings of a breaststroke swimmer's right arm action. Four landmarks on the hand were digitized at 50 Hz and their three-dimensional coordinates obtained using a DLT algorithm. Two angles (alpha and psi) defining the orientation of the hand relative to the fluid flow were calculated following the procedures of Schleihauf et al. (1983). The hydrodynamic force acting on the hand (FR) was calculated using the force coefficients of Schleihauf (1979). Errors in single measurements of hand speed, alpha and psi were estimated for each video field analysed. Errors in alpha and psi led to average errors in the lift and drag coefficients of 27 and 20% respectively, which, when combined with an average hand speed error of 6%, produced an average error in FR of 26%. Each of these errors was reduced by a factor of square root 10 when the mean of 10 measurements was used to calculate FR. Researchers should report both the estimated errors in their hydrodynamic data and the procedures used to reduce them.


C4d-positive interacinar capillaries correlates with donor-specific antibody-mediated rejection in pancreas allografts.
The deposition of the complement split fragment C4d and its association with acute antibody-mediated rejection (AMR) in pancreas transplant (PTx) is not well defined. To characterize the deposition of C4d in PTx, we analyzed 27 PTx biopsies from 18 patients transplanted between 2004 and 2007 at the University of Wisconsin. The presence of C4d was graded in interacinar capillaries (IAC), islets, interstitium, and small- and medium-size vessels. Sera obtained at the time or within 5 days of the biopsy were tested for antidonor-specific antibodies (DSA). 16 biopsies (59.26%) showed at least 5% C4d+ IAC (range 5%-90%). Of those, five biopsies (18.5%) revealed diffuse labeling (>50% C4d+ IAC) and 11 (40.74%) showed focal staining (5%-50% C4d+ IAC). C4d+ IAC (>5%) was significantly associated with the presence of strong DSA for class I or class II (P<0.018). C4d staining of the media or endothelium of small and medium-size vessels was a common finding in all biopsies without any association with DSA. Similarly, staining of islets and parenchymal interstitium was not statistically associated with AMR. The majority of patients received intravenous corticosteroid bolus and taper, with specific cases requiring thymoglobulin, IVIg, rituximab, or plasmapheresis. Forty-six percent of patients who demonstrated AMR returned to insulin therapy because of chronic graft damage and loss of C-peptide. Our findings support the potential role of C4d labeling of PTx biopsies in the diagnosis of AMR and emphasize the staining of IAC as a valuable histologic tool for the diagnosis.


Differential expression and upregulation of interleukin-1alpha, interleukin-1beta and interleukin-6 by freshly isolated human small intestinal epithelial cells.
Small intestinal epithelial cells (SIEC) may contribute to local immune regulation. To examine production of interleukin (IL)-1alpha, IL-1beta and IL-6 by freshly isolated human SIEC. IL-1alpha and IL-1beta mRNA in epithelial layers (EL) prepared from small intestine and in intestinal epithelial cell (EC) lines were examined by reverse transcription-polymerase chain reaction. IL-1alpha, IL-1beta and IL-6 protein expression by SIEC was examined by flow cytometry before and after activation with lipopolysaccharide and epithelial growth factor. IL-1alpha and IL-1beta mRNA was detected in EL and EC lines. Background expression of IL-1alpha and IL-1beta protein by SIEC was observed, which did not increase even following activation. IL-6 protein was expressed by SIEC, in a proportion that increased in two out of three samples following activation. IL-6 expression and the presence of IL-1alpha and IL-1beta mRNA suggest a role for SIEC in the regulation of local inflammation.


Opposing dorsal/ventral stream dynamics during figure-ground segregation.
The visual system has been commonly subdivided into two segregated visual processing streams: The dorsal pathway processes mainly spatial information, and the ventral pathway specializes in object perception. Recent findings, however, indicate that different forms of interaction (cross-talk) exist between the dorsal and the ventral stream. Here, we used TMS and concurrent EEG recordings to explore these interactions between the dorsal and ventral stream during figure-ground segregation. In two separate experiments, we used repetitive TMS and single-pulse TMS to disrupt processing in the dorsal (V5/HMT⁺) and the ventral (lateral occipital area) stream during a motion-defined figure discrimination task. We presented stimuli that made it possible to differentiate between relatively low-level (figure boundary detection) from higher-level (surface segregation) processing steps during figure-ground segregation. Results show that disruption of V5/HMT⁺ impaired performance related to surface segregation; this effect was mainly found when V5/HMT⁺ was perturbed in an early time window (100 msec) after stimulus presentation. Surprisingly, disruption of the lateral occipital area resulted in increased performance scores and enhanced neural correlates of surface segregation. This facilitatory effect was also mainly found in an early time window (100 msec) after stimulus presentation. These results suggest a "push-pull" interaction in which dorsal and ventral extrastriate areas are being recruited or inhibited depending on stimulus category and task demands.


Evaluation of Progress of an ACGME-International Accredited Residency Program in Qatar.
Background: The American College of Physicians' (ACP) Internal Medicine In-Training Examination (IM-ITE) is designed to evaluate the cognitive knowledge of residents to aid them and program directors in evaluating the training experience. Objective: To determine the impact of the curriculum reform accompanied by the Accreditation Council for Graduate Medical Education (ACGME)-I alignment and accreditation on the internal medicine residency program (IMRP) using residents' performance in the ACP's ITE from 2008 to 2016, and where the IMRP stands in comparison to all ACGME and ACGME-I accredited programs. Methods: This is a descriptive study conducted at a hospital-based IMRP in Doha, Qatar from 2008 to 2016. The study population is 1052 residents at all levels of training in IMRP. The ACP-generated ITE results of all the United States and ACGME-I accredited programs were compared with IM-ITE results in Qatar. These results were expressed in the total program average and the ranking percentile. Results: There is a progressive improvement in resident performance in Qatar as shown by the rise in total average program score from 52% in 2008 to 72% in 2016 and the sharp rise in percentile rank from 3rd percentile in 2008 to 93rd percentile in 2016 with a dramatic increase during the period 2013 to 2014 (from 32nd percentile to 73rd percentile), which represents the period of ACGME-I accreditation. None of the factors (ethnicity, USMLE or year of residency) were statistically significant with a p value >0.05 and standard coefficient ( - 0.017-0.495). There was negligible correlation between the USMLE test scores with the residents' ITE scores with a p value = 0.023 and a Pearson correlation r = 0.097. Conclusion: The initial ACGME-I alignment followed by the accreditation, together with whole curriculum redesign to a structured, competency-based program starting from 2008, has led to an improvement in the ITE scores in the IMRP. This was further evidenced by the lack of change in the residency entry selection criteria.


[Analysis of microdeletions in 22q11 in Colombian patients with congenital heart disease].
Cardiac defects are the most frequent congenital malformations, with an incidence estimated between 4 and 12 per 1000 newborns. Their etiology is multifactorial and might be attributed to genetic predispositions and environmental factors. Since 1990 these types of pathologies have been associated with 22q11 microdeletion. In this study, the frequency of microdeletion 22q11 was determined in 61 patients with non-syndromic congenital heart disease. DNA was extracted from peripheral blood and TUPLE1 and STR D10S2198 genes were amplified by multiplex PCR and visualized in agarose gels. Gene content was quantified by densitometry. Three patients were found with microdeletion 22q11, representing a 4.9% frequency. This microdeletion was associated with two cases of Tetralogy of Fallot and a third case with atrial septal defect (ASD). In conclusion, the frequency for microdeletion 22q11 in the population analyzed was 4.9%. The cases that presented Teratology of Fallot had a frequency for this microdeletion of 7.4% and for ASD of 11.1%.


Three-dimensional computation of focused beam propagation through multiple biological cells.
The FDTD method was used to simulate focused Gaussian beam propagation through multiple inhomogeneous biological cells. To our knowledge this is the first three dimensional computational investigation of a focused beam interacting with multiple biological cells using FDTD. A parametric study was performed whereby three simulated cells were varied by organelle density, nuclear type and arrangement of internal cellular structure and the beam focus depth was varied within the cluster of cells. Of the organelle types investigated, it appears that the cell nuclei are responsible for the greatest scattering of the focused beam in the configurations studied. Additional simulations to determine the optical scattering from 27 cells were also run and compared to the three cell case. No significant degradation of two-photon lateral imaging resolution was predicted to occur within the first 40 microm of imaging depth.


The effect of bisphosphonates and titanium particles on osteoblasts: an in vitro study.
In an attempt to increase the life of cementless prostheses, an hydroxyapatite-coated implant which releases a bisphosphonate has been suggested as a drug-delivery system. Our in vitro study was designed to determine the maximum dose to which osteoblasts could be safely exposed. Our findings demonstrated that zoledronate did not impair the proliferation of human osteoblasts when used at concentrations below 1 microm. Murine cells can be exposed to concentrations as high as 10 microm.A concentration of 0.01% of titanium particles did not impair the proliferation of either cell line. Zoledronate affected the alkaline phosphatase activity of murine osteoblasts through a chelation phenomenon. The presence of titanium particles strongly decreased the alkaline phosphatase activity of murine osteoblasts. We did not detect any synergic effect of zoledronate and titanium particles on the behaviour of both human and murine osteoblasts.


Younger age as a prognostic indicator in breast cancer: a cohort study.
The debate continues as to whether younger women who present with breast cancer have a more aggressive form of disease and a worse prognosis. The objectives of this study were to determine the incidence of breast cancer in women under 40 years old and to analyse the clinicopathological characteristics and outcome compared to an older patient cohort. Data was acquired from a review of charts and the prospectively reviewed GUH Department of Surgery database. Included in the study were 276 women diagnosed with breast cancer under the age of forty and 2869 women over forty. For survival analysis each women less than 40 was matched with two women over forty for both disease stage and grade. The proportion of women diagnosed with breast cancer under the age of forty in our cohort was 8.8%. In comparison to their older counterparts, those under forty had a higher tumour grade (p = 0.044) and stage (p = 0.046), a lower incidence of lobular tumours (p < 0.001), higher estrogen receptor negativity (p < 0.001) and higher HER2 over-expression (p = 0.002); there was no statistical difference as regards tumour size (p = 0.477). There was no significant difference in overall survival (OS) for both groups; and factors like tumour size (p = 0.026), invasion (p = 0.026) and histological type (p = 0.027), PR (p = 0.031) and HER2 (p = 0.002) status and treatment received were independent predictors of OS CONCLUSION: Breast cancer in younger women has distinct histopathological characteristics; however, this does not result in a reduced survival in this population.


Characteristics of a pandemic clone of O3 : K6 and O4 : K68 Vibrio parahaemolyticus isolated in Beira, Mozambique.
The genetic characteristics of Vibrio parahaemolyticus strains isolated in 2004 and 2005 in Mozambique were assessed in this study to determine whether the pandemic clone of V. parahaemolyticus O3 : K6 and O4 : K68 serotypes has spread to Mozambique. Fifty-eight V. parahaemolyticus strains isolated from hospitalized diarrhoea patients in Beira, Mozambique, were serotyped for O : K antigens and genotyped for toxR, tdh and trh genes. A group-specific PCR, a PCR that detects the presence of ORF8 of the filamentous phage f237, arbitrarily primed PCR, PFGE and multilocus sequence typing were performed to determine the pandemic status of the strains and their ancestry. All strains of serovars O3 : K6 (n=38) and O4 : K68 (n=4) were identified as a pandemic clonal group by these analyses. These strains are closely related to the pandemic reference strains of O3 : K6 and O4 : K68, which emerged in Asia in 1996 and were later found globally. The pandemic serotypes O3 : K6 and O4 : K68 including reference strains grouped into a single cluster indicating emergence from a common ancestor. The O3 : K58 (n=8), O4 : K13 (n=6), O3 : KUT (n=1) and O8 : K41 (n=1) strains showed unique characteristics different from the pandemic clone.


Misfolded amyloid-β-42 impairs the endosomal-lysosomal pathway.
Misfolding and aggregation of proteins is strongly linked to several neurodegenerative diseases, but how such species bring about their cytotoxic actions remains poorly understood. Here we used specifically-designed optical reporter probes and live fluorescence imaging in primary hippocampal neurons to characterise the mechanism by which prefibrillar, oligomeric forms of the Alzheimer's-associated peptide, Aβ42, exert their detrimental effects. We used a pH-sensitive reporter, Aβ42-CypHer, to track Aβ internalisation in real-time, demonstrating that oligomers are rapidly taken up into cells in a dynamin-dependent manner, and trafficked via the endo-lysosomal pathway resulting in accumulation in lysosomes. In contrast, a non-assembling variant of Aβ42 (vAβ42) assayed in the same way is not internalised. Tracking ovalbumin uptake into cells using CypHer or Alexa Fluor tags shows that preincubation with Aβ42 disrupts protein uptake. Our results identify a potential mechanism by which amyloidogenic aggregates impair cellular function through disruption of the endosomal-lysosomal pathway.


Francisco Varela (1946-2001): filling the mind--brain gap: a life adventure.
One of the most eminent neuroscientists recently passed away in Paris. Professor Francisco Varela was a scholar that approached science with a remarkably broad and integrative perspective, deeply contributing to a diversity of fields, from mathematics to epistemology, from immunology to neuroscience. He was strongly influenced by Buddhism and actively participated in unraveling the relationship between science and spirituality. This article introduces a special edition of Biological Research dedicated to the memory of this great man. It contains a collection of valuable contributions by various authors who collaborated with Varela at different moments of his outstanding scientific career. Their articles cover most of the fields in which he made contributions.


Music and cancer pain management.
When coupled with the often debilitating side-effects of pharmacological interventions, chronic cancer pain may elicit feelings of anxiety and depression and therefore adversely affect patient well-being and quality of life. This review article is a systematic assessment of the published literature related to music and cancer pain management. A comprehensive systematic evaluation of the data based literature was undertaken and analyzed using matrix analysis. As an adjunctive form of pain management, music therapy has been shown to address some of these hardships by providing patients with an alternative effective means by which to reduce their subjective experiences of pain. Studies investigating the efficacy of music therapy during invasive cancer procedures and chemotherapy demonstrated the role that attention states play in distracting patients from, and therefore minimizing their experience of, the pain associated with such treatments. Other studies examining diverse outpatient populations revealed similar findings, illustrating well the cognitive-affective dimensions of pain perception. Although these findings fail to adequately address the ambiguity surrounding music therapy's role in cancer pain management, music therapy has nonetheless been shown to significantly reduce anxiety and, in so doing, indirectly lessen the intensity of pain while improving patient quality of life.


Perceived consequences and worries among youth in Norway during the COVID-19 pandemic lockdown.
Aims: To examine perceived consequences for everyday life, learning outcomes, family relations, sleep problems and worries for infection, for friends and their future, among youth aged 12-19 years during weeks 7 to 9 of the COVID-19 lockdown in Norway. We examine variations by age, gender, socioeconomic status and country of birth. Methods: Youth within the municipality of Bergen were invited via SMS to participate in a 15-minute online survey. A total of 2997 (40%) youths participated. The mean age was 17 years (standard deviation 1.7). Results: Overall, 28% reported feeling somewhat to a lot impacted by schools closing, 63% reported learning less. In total, 62% reported improvement of everyday life. The youth's situation in their family was worse for 13%. Regarding sleep problems, 19% reported difficulties initiating and maintaining sleep, 12% had more nightmares, while 90% reported later bedtime and rise time. Seven per cent worried about getting infected, while 53% worried about infection among family members. A total of 19% worried that the outbreak would lead to a more difficult future, and 32%worried that friends were facing a difficult situation at home. Perceived consequences and worries related to the lockdown varied across sociodemographic groups. Conclusions: The perceived consequences and degree of worries varied by age, gender, socioeconomic status and to a certain degree country of birth. Girls, older youth, youth with lower socioeconomic status and with a migrant background from developing countries seemed to experience the lockdown as more difficult, and thereby possibly accentuating the need for services in these groups.


Patient narratives of surgical site infection: implications for practice.
Exploring patients' experiences has been used widely within healthcare to improve clinical service delivery. To date there has been minimal patient input of this kind into aspects of surgical site infection (SSI), such as surveillance or prevention interventions. To obtain information from patients' experiences of SSIs to improve clinical practice. Narrative interviews with 17 patients with SSIs (four deep, 12 organ space and one superficial) from three hospitals in England were conducted followed by thematic content analysis. Patients lacked overall awareness, concern and understanding of SSIs. Seven patients did not know that they had SSIs and, judging from patients' accounts, staff may have contributed to the lack of awareness by not informing patients of SSIs or downplaying their existence. The use of primary care resources was considerable and six of the patients were absent from work for two to four months. SSIs have a low profile among patients which, if it were raised, could increase compliance with preventive interventions. This study confirms the appropriateness of using patient self-assessment post-discharge surveillance questionnaires to identify SSI symptoms, and highlights the need to identify total costings including to primary care, patients and the economy.


Nitric oxide delays oocyte aging.
Nitric oxide (NO) is a ubiquitous signaling molecule that plays a crucial role in oocyte maturation and embryo development. However, its role in oocyte aging is unclear. To examine how NO affects oocyte aging, we retrieved young and relatively old mouse oocytes and exposed them to increasing concentrations of NO donor S-nitroso acetyl penicillamine (SNAP). Aging related phenomena of ooplasmic microtubule dynamics (OMD), cortical granule (CG) exocytosis, zona pellucida (ZP) hardening, and spindle/chromatin integrity were studied at each SNAP concentration using fluorescence immunocytochemistry and confocal microscopy and compared with respective unexposed controls. Exposure of both young and old oocytes to NO resulted in a significant diminution in OMD and ZP dissolution time, whereas spontaneous CG loss decreased in old NO exposed oocytes compared to controls (P < 0.001 for all). Furthermore, NO exposure decreased the rate of spindle abnormalities in oocytes compared to unexposed controls. Interestingly, in old oocytes, the positive influence of NO was attenuated beyond 0.23 microM/min and disappeared at 0.46 microM/min NO. Overall, a significant dose-response relationship was noted between NO exposure and markers of aging with between 50 and 100 microM SNAP (0.11-0.23 microM/min NO, P < 0.0001). Collectively, our results demonstrate for the first time that exposure to NO delays oocyte aging and improves the integrity of the microtubular spindle apparatus in young and old oocytes.


Conversion disorder: a problematic diagnosis.
The diagnosis of conversion disorder is problematic. Since doctors have conceptually and practically differentiated the symptoms from neurological ('organic') disease it has been presumed to be a psychological disorder, but the psychological mechanism, and how this differs from feigning (conscious simulation), has remained elusive. Although misdiagnosis of neurological disease as conversion disorder is uncommon, it remains a concern for clinicians, particularly for psychiatrists who may be unaware of the positive ways in which neurologists can exclude organic disease. The diagnosis is anomalous in psychiatry in that current diagnostic systems require that feigning is excluded and that the symptoms can be explained psychologically. In practice, feigning is very difficult to either disprove or prove, and a psychological explanation cannot always be found. Studies of childhood and adult psychological precipitants have tended to support the relevance of stressful life events prior to symptom onset at the group level but they are not found in a substantial proportion of cases. These problems highlight serious theoretical and practical issues not just for the current diagnostic systems but for the concept of the disorder itself. Psychology, physiology and functional imaging techniques have been used in attempts to elucidate the neurobiology of conversion disorder and to differentiate it from feigning, but while intriguing results are emerging they can only be considered preliminary. Such work looks to a future that could refine our understanding of the disorder. However, until that time, the formal diagnostic requirement for associated psychological stressors and the exclusion of feigning are of limited clinical value. Simplified criteria are suggested which will also encourage cooperation between neurology and psychiatry in the management of these patients.