Distortion of axonal cytoskeleton: an early sign of glaucomatous damage.
Glaucoma damages the retinal nerve fiber layer (RNFL). The purpose of this study was to investigate the distribution of major cytoskeleton components, F-actin, microtubules (MTs), and neurofilaments (NFs), in the RNFL during the development of glaucoma. methods: Intraocular hypertension was induced in a rat model by laser photocoagulation of the trabecular meshwork. Retinas were obtained after 2 to 3.5 weeks of treatment. Multiple fluorescent stains were used to identify F-actin, MTs, NFs, and nuclei simultaneously in the same tissue. Distribution of these components in a whole-mounted retina was examined by confocal microscopy. Fluorescent stain was quantitatively described. In normal RNFL F-actin, MTs, and NFs were intensely stained. Along the bundles, F-actin and MTs were strongly colocalized, but alternating strands of F-actin and NFs were apparent. Normal RNFL lacked nuclei. In glaucomatous retinas, irregular staining of F-actin, MTs, and NFs was found within the bundles. A strong network of F-actin appeared on the RNFL surface and between the bundles. In severely damaged retinal regions total loss of F-actin and MTs was found, whereas residual strands of NFs were evident. Before the decrease in RNFL thickness, irregularity of F-actin stain and density of nuclei in the RNFL significantly increased. The results suggest that F-actin, MTs, and NFs are rich and approximately uniformly distributed in the normal RNFL. Glaucoma causes alteration of the cytoskeleton in the RNFL. F-actin is the most sensitive component in its response to stress on the retina. An increase in the number of nuclei in the RNFL may be an early sign of glaucomatous damage.


Osteopathic Manipulative Treatment for Somatic Dysfunction After Acute Severe Traumatic Brain Injury.
Somatic dysfunction caused by traumatic brain injury (TBI) may be managed by osteopathic manipulative treatment (OMT). In this case report, the authors describe 2 patients with severe TBI who were each treated with OMT in a level-1 regional trauma center. Both patients received OMT beginning in the acute care phase of injury. Somatic dysfunction improved during the course of treatment, and no adverse effects of OMT were noted. More comprehensive research may clarify the efficacy and adverse effects of OMT as part of multimodal acute care of patients with severe TBI.


Corruption in medical sphere of Ukraine: current situation and ways of prevention.
Introduction: All social life spheres in Ukraine are influenced by corruption. Ukrainian citizens were inquired in order to determine corruption rate in various social spheres. It was conditioned by reforming criminal justice and administrative management, which is directed, particularly, for liquidation of corruption in the state. Special emphasize is stressed on corruption rate in the medical sphere. The aim of the article is to determine: 1) population's attitude towards to corruption, in particular, in the medical sphere; 2) the most corruptive social spheres; 3) efficiency of anti-corruption measures; 4) readiness of population to participate into struggle with corruption. Materials and methods: The study is grounded on dialectical, comparative, analytic, synthetic, sociological (special-purpose inquiry form, interview), statistic and comprehensive research methods. The study group consisted of 1 120 citizens and 513 medical and pharmaceutical professionals of Ukraine. Questions were related to: 1) citizens' contact with corruption; 2) corruption expansion rate in state authorities, self-governing authorities, in various infrastructure spheres, particularly, in healthcare; 3) awareness about struggle with corruption in the state and in the region and determination of citizens' readiness to cope with corruption. Results: Corruption contact level of citizens remains steadily high. Corruption in the medical sphere is the most widespread: during the previous year before the inquire 63% respondents were involved into corruptive schemes. Corruption in the medical sphere can be subdivided in the following levels: from patient to doctor; inside the hospital - from a healthcare institution employee to the executive hospital staff; on state level concerning state procurements of medications. A bribe to health care professionals was given for: receipt of a sick leave certificate and various references (for example, about unfitness for military service, fitness for driving a car or fulfillment of particular works); high-quality conduct of an operation, medical servicing rendering; writing out a "necessary" prescription; approval or hiding of any bodily injuries; falsification of a true cause of death. All health care professionals have come across different corruptive practices, among which the following payments are widespread: for employment in a hospital, license for private medical practice or establishment of private clinics, "avoidance" of checks of healthcare institutions' activity. The largest bribes are given state officials for participation in tenders for medical drugs supply by pharmaceutical companies. All health care professionals have come across different corruptive practices, among which the following payments are widespread: for employment in a hospital, license for private medical practice or establishment of private clinics, "avoidance" of checks of healthcare institutions' activity. Conclusion: Corruption on the sphere of medical practice is complex phenomenon. The conducted poll made it possible to structure the corruption problem, to see its various levels and levels. In respondents' opinion, a scrupulous information campaign is a positive tendency: 45% consider this is a guarantee of anticorruption. Nevertheless, only 5% respondents assume personal notification of anticorruption bodies about receipt of a bribe by medical staff.


Pastoral care of mental illness and the accommodation of African Christian beliefs and practices by UK clergy.
Faith-based organisations, especially those related to specific ethnic or migrant groups, are increasingly viewed by secular Western government agencies as potential collaborators in community health and welfare programmes. Although clergy are often called upon to provide mental health pastoral care, their response to such problems remains relatively unexamined. This paper examines how clergy working in multiethnic settings do not always have the answers that people want, or perhaps need, to problems of misfortune and suffering. In the UK these barriers can be attributed, generally, to a lack of training on mental health problems and minimal collaboration with health services. The current paper attempts to highlight the dilemmas of the established churches' involvement in mental health care in the context of diversity. We explore the inability of established churches to accommodate African and other spiritual beliefs and practices related to the etiology and treatment of mental health problems.


Disorders of "taste cognition" are associated with insular involvement in patients with Alzheimer's disease and vascular dementia: "memory of food is impaired in dementia and responsible for poor diet".
In dementia patients, dietary intake problems may occur despite the absence of swallowing problems. We investigated cognitive functions on food and taste in Alzheimer's disease (AD) and vascular dementia (VaD) patients. Participants included 15 healthy controls (HC), 30 AD and 20 VaD patients. Food Cognition Test: Replicas of three popular foods in Japan with no odors were presented visually to each participant, with the instruction to respond with the name of each food. Replicas of food materials were subsequently presented to ask whether they were included in these foods. Taste Cognition Test: Replicas of 12 kinds of foods were presented to describe their expected tastes. The AD/VaD groups exhibited significantly lower scores on Food/Taste Cognition Tests compared with the HC group. These scores correlated inversely with Mini-Mental State Examination (MMSE) scores in the AD group. Decreased dietary intake was observed in 12 of the 50 patients; 8 of the 12 exhibited decreased Taste Cognition Test scores, higher than that of the normal-intake patients. There was no difference in the filter paper taste disc test between HC/AD/VaD groups. To test the hypothesis that the insula is associated with taste cognition, two MMSE-matched AD subgroups (n = 10 vs. 10) underwent positron emission tomography. Glucose metabolism in the right insula was lower in the low taste cognition subgroup. The VaD patients with insular lesions exhibited impaired Taste Cognition Test findings. It is important to consider the cognitive aspect of dietary intake when we care for dementia patients.


The proteome landscape of Giardia lamblia encystation.
Giardia lamblia is an intestinal protozoan parasite required to survive in the environment in order to be transmitted to a new host. To ensure parasite survival, flagellated trophozoites colonizing the small intestine differentiate into non-motile environmentally-resistant cysts which are then shed in the environment. This cell differentiation process called encystation is characterized by significant morphological remodeling which includes secretion of large amounts of cyst wall material. Although much is known about the transcriptional regulation of encystation and the synthesis and trafficking of cyst wall material, the investigation of global changes in protein content and abundance during G. lamblia encystation is still unaddressed. In this study, we report on the quantitative analysis of the G. lamblia proteome during encystation using tandem mass spectrometry. Quantification of more than 1000 proteins revealed major changes in protein abundance in early, mid and late encystation, notably in constitutive secretory protein trafficking. Early stages of encystation were marked by a striking decrease of endoplasmic reticulum-targeted variant-specific surface proteins and significant increases in cytoskeleton regulatory components, NEK protein kinases and proteins involved in protein folding and glycolysis. This was in stark contrast to cells in the later stages of encystation which presented a surprisingly similar proteome composition to non-encysting trophozoites. Altogether these data constitute the first quantitative atlas of the Giardia proteome covering the whole process of encystation and point towards an important role for post-transcriptional control of gene expression in Giardia differentiation. Furthermore, our data provide a valuable resource for the community-based annotation effort of the G. lamblia genome, where almost 70% of all predicted gene models remains "hypothetical".


ACR Appropriateness Criteria® Shoulder Pain-Traumatic.
Traumatic shoulder pain is pain directly attributed to a traumatic event, either acute or chronic. This pain may be the result of either fracture (the clavicle, scapula, or proximal humerus) or soft-tissue injury (most commonly of the rotator cuff, acromioclavicular ligaments, or labroligamentous complex). Imaging assessment of traumatic shoulder pain begins with conventional radiography and, depending on physical examination findings, will require MRI or MR arthrography for assessment of soft-tissue injuries and CT for delineation of fracture planes. Ultrasound excels in assessment of rotator cuff injuries but has limited usefulness for assessment of the deep soft-tissues. CT angiography and conventional arteriography are helpful for assessment of vascular injury, and bone scintigraphy can be used in assessment of complex regional pain syndrome after traumatic shoulder injury. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.


The legacy of Hans Selye and the origins of stress research: a retrospective 75 years after his landmark brief "letter" to the editor# of nature.
Hans Selye's single author short letter to Nature (1936, 138(3479):32) inspired a huge and still growing wave of medical research. His experiments with rats led to recognition of the "general adaptation syndrome", later renamed by Selye "stress response": the triad of enlarged adrenal glands, lymph node and thymic atrophy, and gastric erosions/ulcers. Because of the major role of glucocorticoids (named by Selye), he performed extensive structure-activity studies in the 1930s-1940s, resulting in the first rational classification of steroid hormones, e.g. corticoids, testoids/androgens, and folliculoids/estrogens. During those years, he recognized the respective anti- and pro-inflammatory actions of gluco- and mineralocorticoids in animal models, several years before demonstration of anti-rheumatic actions of cortisone and adrenocorticotrophic hormones in patients. Nevertheless, Selye did not receive a Nobel Prize, which was awarded in 1950 to the clinician Hench and the two chemists who isolated and synthesized some of the glucocorticoids. Nonetheless, Selye was internationally recognized as a world authority in endocrinology, steroid chemistry, experimental surgery, and pathology. He wrote over 1500 original and review articles, singly authored 32 books, and trained 40 PhD students, one of whom (Roger Guillemin) won a Nobel Prize for isolating the hypothalamic releasing factors/hormones. Here, we consider the main implications of his first article launching the biological stress concept and the key ideas and problems that occupied him. Selye considered "Stress in heath and disease is medically, sociologically, and philosophically the most meaningful subject for humanity that I can think of".


Cognitive prescriptions.
Nonpathological cognitive declines occur with aging and negatively affect everyday functioning and reduce quality of life. Many older adults, aware of such cognitive changes, seek ways to bolster their cognitive functioning. Evidence based on the cognitive aging literature supports a number of factors associated with cognitive functioning. These factors include physical exercise, intellectual exercise, nutrition, sleep hygiene, social interaction, and mood and emotional state. These factors can be manipulated and woven together by nurses and other health professionals to develop an easy-to-use, non-invasive cognitive prescription for improving the cognitive health of older adults. An example and directions for developing and implementing cognitive prescriptions are described.


Substituting prolonged sedentary time and cardiovascular risk in children and youth: a meta-analysis within the International Children's Accelerometry database (ICAD).
Evidence on the association between sitting for extended periods (i.e. prolonged sedentary time (PST)) and cardio-metabolic health is inconsistent in children. We aimed to estimate the differences in cardio-metabolic health associated with substituting PST with non-prolonged sedentary time (non-PST), light (LIPA) or moderate-to-vigorous physical activity (MVPA) in children. Cross-sectional data from 14 studies (7 countries) in the International Children's Accelerometry Database (ICAD, 1998-2009) was included. Accelerometry in 19,502 participants aged 3-18 years, together with covariate and outcome data, was pooled and harmonized. Iso-temporal substitution in linear regression models provided beta coefficients (95%CI) for substitution of 1 h/day PST (sedentary time accumulated in bouts > 15 min) with non-PST, LIPA or MVPA, for each study, which were meta-analysed. Modelling substitution of 1 h/day of PST with non-PST suggested reductions in standardized BMI, but estimates were > 7-fold greater for substitution with MVPA (- 0.44 (- 0.62; - 0.26) SD units). Only reallocation by MVPA was beneficial for waist circumference (- 3.07 (- 4.47; - 1.68) cm), systolic blood pressure (- 1.53 (- 2.42; - 0.65) mmHg) and clustered cardio-metabolic risk (- 0.18 (- 0.3; - 0.1) SD units). For HDL-cholesterol and diastolic blood pressure, substitution with LIPA was beneficial; however, substitution with MVPA showed 5-fold stronger effect estimates (HDL-cholesterol: 0.05 (0.01; 0.10) mmol/l); diastolic blood pressure: - 0.81 (- 1.38; - 0.24) mmHg). Replacement of PST with MVPA may be the preferred scenario for behaviour change, given beneficial associations with a wide range of cardio-metabolic risk factors (including adiposity, HDL-cholesterol, blood pressure and clustered cardio-metabolic risk). Effect estimates are clinically relevant (e.g. an estimated reduction in waist circumference of ≈1.5 cm for 30 min/day replacement). Replacement with LIPA could be beneficial for some of these risk factors, however with substantially lower effect estimates.


The effectiveness of a real life dose reduction strategy for tumour necrosis factor inhibitors in ankylosing spondylitis and psoriatic arthritis.
To determine feasibility of TNF inhibitor (TNFi) dose reduction for severe AS and PsA patients. A retrospective study in a real-world setting. Criteria for dose reduction of TNFi included BASDAI < 4 for ⩾6 months in AS; or DAS28-ESR ⩽ 3.2 for ⩾6 months in PsA. TNFi dose was reduced by one-third. Patients who flared (BASDAI > 4 in AS or DAS28-ESR > 3.2 in PsA) were re-escalated to standard treatment dose. Twenty-six per cent (33/125) of AS and 18% (15/83) of PsA patients fulfilled criteria and underwent TNFi dose reduction. Fifty-eight per cent (19/33) of AS and 60% (9/15) of PsA patients maintained TNFi dose reduction for mean (s.d) of 1.0 (0.8) years. Reinstating standard dose of TNFi recaptured low disease activity in all patients who failed dose reduction within 24 weeks, with no statistically significant difference in mean BASDAI compared with those maintaining TNFi dose reduction in AS at 24 weeks [mean (s.d) BASDAI 2.4 (1.1) vs 1.9 (1.5), respectively (P = 0.229)]; however in PsA, those who failed dose reduction had higher disease activity compared with patients maintained on TNFi dose reduction at 24 weeks [mean (s.d) DAS28-ESR 2.7 (0.6) vs 1.3 (0.5), respectively (P ⩽ 0.001)]. In PsA, a lower DAS28-ESR prior to dose reduction of TNFi was associated with more successful dose reduction. In a real-world setting, 60% of individuals with severe AS and PsA who achieve low disease activity can successfully reduce the dose of TNFi therapy by a third for a mean of 1 year.


Relatedness of chloramphenicol resistance plasmids in epidemiologically unrelated strains of pathogenic Escherichia coli from man and animals.
I have examined 20 plasmids conferring chloramphenicol resistance (Cm) in multiresistant strains of Escherichia coli pathogenic for man and piglets. In Denmark, one plasmid family, exemplar pHG33, is responsible for all chloramphenicol resistance in serotypes of E. coli found in diseased piglets. A closely related plasmid, pHG50, was identified in an enteropathogenic E. coli (EPEC) strain from an infant. The isolate was epidemiologically unrelated to the piglet isolates. The molecular relatedness of the plasmids was established by restriction enzyme analyses and Southern blots. Chloramphenicol resistance plasmids in E. coli from urinary tract infections, or in English EPEC strains, did not show the same close relatedness with the piglet plasmid pHG33. However, many were of the same incompatibility group and their restriction profiles displayed a number of common bands. The close relatedness of pHG50 and pHG33 suggests exchange of plasmids between pathogenic serotypes of E. coli from man and animals. The infant from whom the EPEC strain carrying plasmid pHG50 was isolated might have acquired it from piglets. Disease in human babies caused by EPEC strains is now rare in Denmark and no Cm-resistant strains are found. Possible reasons for the loss of Cm-resistance plasmids from human strains and their retention in piglet strains are discussed.


Legume lectin structure.
The legume lectins are a large family of homologous carbohydrate binding proteins that are found mainly in the seeds of most legume plants. Despite their strong similarity on the level of their amino acid sequences and tertiary structures, their carbohydrate specificities and quaternary structures vary widely. In this review we will focus on the structural features of legume lectins and their complexes with carbohydrates. These will be discussed in the light of recent mutagenesis results when appropriate. Monosaccharide specificity seems to be achieved by the use of a conserved core of residues that hydrogen bond to the sugar, and a variable loop that determines the exact shape of the monosaccharide binding site. The higher affinity for particular oligosaccharides and monosaccharides containing a hydrophobic aglycon results mainly from a few distinct subsites next to the monosaccharide binding site. These subsites consist of a small number of variable residues and are found in both the mannose and galactose specificity groups. The quaternary structures of these proteins form the basis of a higher level of specificity, where the spacing between individual epitopes of multivalent carbohydrates becomes important. This results in homogeneous cross-linked lattices even in mixed precipitation systems, and is of relevance for their effects on the biological activities of cells such as mitogenic responses. Quaternary structure is also thought to play an important role in the high affinity interaction between some legume lectins and adenine and a series of adenine-derived plant hormones. The molecular basis of the variation in quaternary structure in this group of proteins is poorly understood.


FIREWACh: high-throughput functional detection of transcriptional regulatory modules in mammalian cells.
Promoters and enhancers establish precise gene transcription patterns. The development of functional approaches for their identification in mammalian cells has been complicated by the size of these genomes. Here we report a high-throughput functional assay for directly identifying active promoter and enhancer elements called FIREWACh (Functional Identification of Regulatory Elements Within Accessible Chromatin), which we used to simultaneously assess over 80,000 DNA fragments derived from nucleosome-free regions within the chromatin of embryonic stem cells (ESCs) and identify 6,364 active regulatory elements. Many of these represent newly discovered ESC-specific enhancers, showing enriched binding-site motifs for ESC-specific transcription factors including SOX2, POU5F1 (OCT4) and KLF4. The application of FIREWACh to additional cultured cell types will facilitate functional annotation of the genome and expand our view of transcriptional network dynamics.


Patterns of tocilizumab use, effectiveness and safety in patients with rheumatoid arthritis: core data results from a set of multinational observational studies.
To observe patients with rheumatoid arthritis (RA) treated with the interleukin-6 receptor-alpha inhibitor tocilizumab (TCZ) in routine clinical practice. Data on concomitant medications, effectiveness and safety were pooled from independent, multinational studies in patients with RA initiating intravenous TCZ according to local label recommendations observed in routine practice for 6 months. Patients were grouped by TCZ monotherapy or combination therapy with conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs). The primary endpoint was the proportion of patients receiving TCZ after 6 months. Of 1336 patients enrolled, 506 (37.9%) received TCZ monotherapy and 830 (62.1%) received combination therapy. Kaplan-Meier analysis estimated that 80% (95% CI, 76%-83%) of monotherapy and 87% (95% CI, 84%-89%) of combination therapy patients continued to receive TCZ at 6 months (log-rank p<0.001). During the observation period, TCZ was discontinued by 113 (22.3%) monotherapy patients and 116 (14.0%) patients on combination therapy. The mean prednisone-equivalent oral corticosteroid dose was 8.4 mg/day for monotherapy and combination therapy patients at baseline and 7.7 and 7.6 mg/day, respectively, at month 6. Adverse events or laboratory abnormalities requiring TCZ dose modification were reported for 66 (13.0%) monotherapy and 130 (15.7%) combination therapy patients. Effectiveness at 6 months was similar between groups; mean (SD) change from baseline in Clinical Disease Activity Index (CDAI) was -20.3 (14.18) for monotherapy and -22.3 (16.09) for combination therapy (p=0.7347). In routine clinical practice, 38% of patients received TCZ as monotherapy. Persistence on monotherapy or in combination therapy with csDMARDs was high, with a slight trend towards a higher rate with combination therapy, and effectiveness was similar between groups.


Feeling an outsider left in uncertainty - a phenomenological study on the experiences of older hospital patients.
This paper starts from a care ethical perspective on care and reports on a phenomenological study into older patients' experiences of hospitalisation. Although hospital care for older patients is at the centre of attention, questions what is at stake and what defines quality of care are rarely discussed with a view to the perspective of older patients themselves. The qualitative observational method of shadowing was used. Ten patients of 75 years old or older were shadowed from admission until discharge. The reflective lifeworld approach, based on phenomenological philosophy, was used to analyse the collected data. For the older patients included in the study, the essential meaning of hospitalisation can be described as feeling an outsider left in uncertainty. The word 'left' reveals how hospitalisation is experienced as a solitary struggle with various uncertainties that are related both to the hospital environment and to the patient's personal situation. The essential meaning is composed of the following three constituents: (i) staying in an inhospitable place, (ii) feeling constrained and (iii) experiencing disruption. The busy walking back and forth of care professionals and the functional character of involvement, restrain older patients from participating and make them feel abandoned. Feeling constrained reveals the feelings brought on by the ageing body which are emphasised by hospitalisation but often neglected by hospital staff. The failure of healthcare professionals to recognise and respond to who older patients are aside from their illness exacerbate the experience of disruptions. To improve care, hospital staff must be more sensitive to older patients' uncertainties. Also, hospital staff should provide older patients with understandable information and explanation which besides offering patients the possibility to feel involved, meets their need for recognition.


Spectral broadening in ultrafast semiconductor optical amplifiers induced by gain dynamics and self-phase modulation.
We investigate experimentally the self-phase modulation (SPM) induced by gain dynamics on picosecond pulses in semiconductor optical amplifiers whose gain recovery is enhanced by amplified spontaneous emission (ASE). The observed pulse spectra are highly asymmetric at low drive currents but become more symmetric with increasing current, owing to the ASE-induced reduction in the gain-recovery time down to 9 ps. Furthermore, the amount of spectral broadening is shown to saturate with drive current. We show that a variety of spectral-lobe strengths is selectable, while maintaining a nearly constant small-signal gain, a feature desirable for all-optical signal processing applications.


Fatigue and perceptual responses of heavier- and lighter-load isolated lumbar extension resistance exercise in males and females.
There is a lack of research considering acute fatigue responses to high- and low-load resistance training as well as the comparison between male and female responses. Furthermore, limited studies have considered fatigue response testing with the inclusion of perceptions of discomfort and exertion. The present study included males (n = 9; 23.8 ± 6.4 years; 176.7 ± 6.2 cm; 73.9 ± 9.3 kg) and females (n = 8; 21.3 ± 0.9 years; 170.5 ± 6.1 cm; 65.5 ± 10.8 kg) who were assessed for differences in fatigue (i.e., loss of torque at maximal voluntary contraction (MVC)) immediately following isolated lumbar extension (ILEX) exercise at heavy- (HL) and light-(LL) loads (80% and 50% MVC, respectively). Participants also reported perceptual measures of effort (RPE-E) and discomfort (RPE-D) between different resistance training protocols. Analysis of variance revealed significantly greater absolute and relative fatigue following LL compared to HL conditions (p < 0.001). Absolute fatigue significantly differed between males and females (p = 0.012), though relative fatigue was not significantly different (p = 0.160). However, effect sizes for absolute fatigue (HL; Males = -1.84, Females = -0.83; LL; Males = -3.11, Females = -2.39) and relative fatigue (HL; Males = -2.17, Females = -0.76; LL; Males = -3.36, Females = -3.08) were larger for males in both HL and LL conditions. RPE-E was maximal for all participants in both conditions, but RPE-D was significantly higher in LL compared to HL (p < 0.001) with no difference between males and females. Our data suggests that females do not incur the same degree of fatigue as males following similar exercise protocols, and indeed that females might be able to sustain longer exercise duration at the same relative loads. As such females should manipulate training variables accordingly, perhaps performing greater repetitions at a relative load, or using heavier relative loads than males. Furthermore, since lighter load exercise is often prescribed in rehabilitation settings (particularly for the lumbar extensors) it seems prudent to know that this might not be necessary to strengthen musculature and indeed might be contraindicated to avoid the increased fatigue and discomfort associated with LL exercise.


Claustrophobia in MRI: the role of cognitions.
This study aimed to investigate the role of cognitive and behavioural factors in the experience of claustrophobia in the context of magnetic resonance imaging (MRI) scanners. One hundred and thirty outpatients attending an MRI unit completed questionnaires before and after their scans. Specific measures of experience in the scanner included subjective anxiety, panic symptoms, strategies used to stay calm and negative cognitions (such as 'I will suffocate' and 'I am going to faint in here'). Other general measures used included anxiety, depression, health anxiety and fears of restriction and suffocation. The amount of anxiety experienced during the scan was related to the perceived amount of time spent having physical symptoms of panic. Cognitions reported concerned the following: suffocation, harm caused by the machine and lack of perceived control. The number of strategies patients used to cope in the machine was also a related factor. Neither position in the scanner, nor head coil use nor previous experience of being in the scanner was related to levels of anxiety. The cognitions identified here may be used to construct a measure to identify those unable to enter the scanner or those most likely to become claustrophobic whilst undergoing the procedure and to further inform future brief, effective interventions.


Abortion Reporting in the United States: An Assessment of Three National Fertility Surveys.
Despite its frequency, abortion remains a highly sensitive, stigmatized, and difficult-to-measure behavior. We present estimates of abortion underreporting for three of the most commonly used national fertility surveys in the United States: the National Survey of Family Growth, the National Longitudinal Survey of Youth 1997, and the National Longitudinal Study of Adolescent to Adult Health. Numbers of abortions reported in each survey were compared with external abortion counts obtained from a census of all U.S. abortion providers, with adjustments for comparable respondent ages and periods of each data source. We examined the influence of survey design factors, including survey mode, sampling frame, and length of recall, on abortion underreporting. We used Monte Carlo simulations to estimate potential measurement biases in relationships between abortion and other variables. Underreporting of abortion in the United States compromises the ability to study abortion-and, consequently, almost any pregnancy-related experience-using national fertility surveys.


Real risks of HIV transmission to physicians and their staffs. American Osteopathic Association Task Force on AIDS.
This series will provide brief clinical updates and perspectives on the human immunodeficiency virus (HIV). It was developed from the AOA Task Force on AIDS Writers' Workshop, held August 16 to 18, 1991, in New York, and sponsored by an education grant from Burroughs Wellcome. A related editorial appears on page 63. Readers may request tear sheets from the AOA editorial offices.


Acupuncture for obesity: a systematic review and meta-analysis.
Acupuncture is widely used in complementary and alternative medicine to reduce body weight. However, a systematic review and meta-analysis to assess an effect of acupuncture has not yet been performed. Aim of this study is to critically assess evidence for reduction of body weight and to evaluate adverse events of acupuncture therapy based on the results of randomized controlled trials (RCTs) that evaluate the effect of various types of acupuncture therapies. A total of 19 electronic databases, including English, Korean, Japanese and Chinese databases, were systematically searched for RCTs of acupuncture for reduction of body weight or improvement in obesity up to March 2008 with no language restrictions. RCTs for acupuncture compared either with placebo controlled or with comparator intervention were considered. Studies' methodological qualities were assessed using the Jadad scale. If no evidence of heterogeneity existed across study results, statistical pooling of data was performed using a fixed effects model; otherwise, a random effects model was used. Publication bias was assessed using funnel plots. Subgroup analyses were performed according to types of acupuncture. A total of 31 studies, which comprised a total of 3013 individual cases, were systematically reviewed. Owing to insufficient data in 2 RCTs, 29 RCTs were used for meta-analysis. About two-thirds of the trials (20 out of 31) showed the lowest score of the Jadad. Compared to control of lifestyle, acupuncture was associated with a significant reduction of average body weight (95% confidence interval, CI) of 1.72 kg (0.50-2.93 kg) and associated with an improvement in obesity (relative risk=2.57; 95% CI, 1.98-3.34). Acupuncture significantly reduced a body weight of 1.56 kg (0.74-2.38 kg), on average, compared to placebo or sham treatments. Acupuncture also showed more improved outcomes for body weight (mean difference=1.90 kg; 1.66-2.13 kg), as well as for obesity (relative risk=1.13; 1.04-1.22), than conventional medication. Only four RCTs reported acupuncture-related adverse events, which were mostly minimal. Our review suggests that acupuncture is an effective treatment for obesity. However, the amount of evidence is not fully convincing because of the poor methodological quality of trials reviewed. In conclusion, there is an urgent need for well-planned, long-term studies to address the effectiveness of acupuncture for treating obesity.


Using institutional ethnography to understand the production of health care disparities.
Questions of health care access and equity are often examined by researchers using quantitative approaches, describing patterns of service utilization. Articles based on such approaches often reveal relatively little about how health care services and resources come to be distributed as they are. Articles about qualitative research with marginalized people, although offering textured accounts of people's experiences of care, often do not systematically link felt troubles to specific features of health systems. Institutional ethnography, a method of inquiry developed over the past 25 years by Canadian sociologist Dorothy Smith and her colleagues, offers a useful resource for researchers exploring and addressing health care disparities. Drawing on previous research and a study in progress on cancer care in Ontario, Canada, I consider the potential of institutional ethnography to make visible how disparities are produced in the routine operation of health services.


Tumorigenesis in the multiple intestinal neoplasia mouse: redundancy of negative regulators and specificity of modifiers.
The interaction between mutations in the tumor-suppressor genes Apc and p53 was studied in congenic mouse strains to minimize the influence of polymorphic modifiers. The multiplicity and invasiveness of intestinal adenomas of Apc(Min/+) (Min) mice was enhanced by deficiency for p53. In addition, the occurrence of desmoid fibromas was strongly enhanced by p53 deficiency. The genetic modifier Mom1 and the pharmacological agents piroxicam and difluoromethylornithine each reduced intestinal adenoma multiplicity in the absence of p53 function. Mom1 showed no influence on the development of desmoid fibromas, whereas the combination of piroxicam and difluoromethylornithine exerted a moderate effect. The ensemble of tumor suppressors and modifiers of a neoplastic process can be usefully analyzed in respect to tissue specificity and synergy.


The optomotor response: a robust first-line visual screening method for mice.
In both scotopic and photopic conditions, the rotation of a grating was found to elicit head movements in mice. The highest spatial frequency eliciting this optomotor response provided an estimate of visual acuity. In male C57BL/6J mice, visual acuity increased from 0.26cpd in scotopic conditions to 0.52cpd in photopic conditions whereas it was 0.52 cpd in both sets of conditions in 129/SvPas mice. No optomotor response was detected in albino CD1 mice and rd1 retinal degeneration mice although light sensitivity in CD1 mice was attested by photophobia and normal electroretinograms. This rapid and cheap method could provide a powerful test of visual performance in genetically modified and pharmacologically treated mice.


[Age-related macular degeneration (AMD)].
Today age-related macular degeneration (AMD) is the most frequent cause for legal blindness in western industrialized countries. The prevalence of this disease rises with increasing age. A multifactorial pathogenesis of AMD is postulated including genetic predisposition and environmental risk factors. The most relevant modifiable risk factor is smoking. Up to today there is no cure of this chronic disease. Prophylaxis, including a healthy diet and antioxidants as nutrional supplements for selected patients, aims to slow down the disease progression. Significant progress has been made in the treatment of the neovascular form of the disease using inhibitors of the vascular endothelial growth factor (VEGF).


Perinatal risk factors interacting with catechol O-methyltransferase and the serotonin transporter gene predict ASD symptoms in children with ADHD.
Symptoms of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) often co-occur. Given the previously found familiality of ASD symptoms in children with ADHD, addressing these symptoms may be useful for genetic association studies, especially for candidate gene findings that have not been consistently replicated for ADHD. We studied the association of the catechol O-methyltransferase (COMT) Val158Met polymorphism and the serotonin transporter (SLC6A4/SERT/5-HTT) 5-HTTLPR insertion/deletion polymorphism with ASD symptoms in children with ADHD, and whether these polymorphisms would interact with pre- and perinatal risk factors, i.e., maternal smoking during pregnancy and low birth weight. Analyses were performed using linear regression in 207 Dutch participants with combined type ADHD of the International Multicenter ADHD Genetics (IMAGE) study, and repeated in an independent ADHD sample (n =439) selected from the TRracking Adolescents' Individual Lives Survey (TRAILS). Dependent variables were the total and subscale scores of the Children's Social Behavior Questionnaire (CSBQ). No significant main effects of COMT Val158Met, 5-HTTLPR, maternal smoking during pregnancy and low birth weight on ASD symptoms were found. However, the COMT Val/Val genotype interacted with maternal smoking during pregnancy in increasing stereotyped behavior in the IMAGE sample (p =.008); this interaction reached significance in the TRAILS sample after correction for confounders (p =.02). In the IMAGE sample, the 5-HTTLPR S/S genotype interacted with maternal smoking during pregnancy, increasing problems in social interaction (p =.02), and also interacted with low birth weight, increasing rigid behavior (p =.03). Findings for 5-HTTLPR in the TRAILS sample were similar, albeit for related CSBQ subscales. These findings suggest gene-environment interaction effects on ASD symptoms in children with ADHD.


Promoter methylation regulates cyclooxygenase expression in breast cancer.
Overexpression of cyclooxygenase (COX-2) is commonly observed in human cancers. In a murine model of metastatic breast cancer, we observed that COX-2 expression and enzyme activity were associated with enhanced tumorigenic and metastatic potential. In contrast to the high COX-2 expression in metastatic tumors, transplantation of poorly tumorigenic tumor cell lines to syngeneic mice results in less COX-2 expression and less COX-2 activity in vivo. Aberrant CpG island methylation, and subsequent silencing of the COX-2 promoter, has been observed in human cancer cell lines and in some human tumors of the gastrointestinal tract. Using bisulfite modification and a methylation-specific PCR, we examined the methylation status of the COX-2 promoter in a series of four closely-related murine mammary tumors differing in COX-2 expression and metastatic potential. We showed that line 410, which does not express COX-2 in vivo, exhibited evidence of promoter methylation. Interestingly, the metastatic counterpart of this cell (line 410.4) displayed only the unmethylated COX-2 promoter, as did two additional cell lines (lines 66.1 and 67). The methylation patterns observed in vitro were maintained when these murine mammary tumor lines were transplanted to syngeneic mice. Treatment with the DNA demethylating agent 5-aza-deoxycytidine increased COX-2 mRNA, increased protein and increased enzyme activity (prostaglandin synthesis). These results indicate that COX-2 promoter methylation may be one mechanism by which tumor cells regulate COX-2 expression. Upregulation of COX-2 expression in closely related metastatic lesions versus nonmetastatic lesions may represent a shift towards the unmethylated phenotype.


Influence of Intensified Supervision by Health Care Inspectorates on Online Patient Ratings of Hospitals: A Multilevel Study of More Than 43,000 Online Ratings.
In the Netherlands, hospitals with quality or safety issues are put under intensified supervision by the Dutch Health Care Inspectorate, which involves frequent announced and unannounced site visits and other measures. Patient rating sites are an upcoming phenomenon in health care. Patient reviews might be influenced by perceived quality including the media coverage of health care providers when the health care inspectorate imposes intensified supervision, but no data are available to show how these are related. The aim of this study was to investigate whether and how being under intensified supervision of the health care inspectorate influences online patient ratings of hospitals. We performed a longitudinal study using data from the patient rating site Zorgkaart Nederland, from January 1, 2010 to December 31, 2015. We compared data of 7 hospitals under intensified supervision with a control group of 28 hospitals. The dataset contained 43,856 ratings. We performed a multilevel logistic regression analysis to account for clustering of ratings within hospitals. Fixed effects in our analysis were hospital type, time, and the period of intensified supervision. Random effect was the hospital. The outcome variable was the dichotomized rating score. The period of intensified supervision was associated with a low rating score for the hospitals compared with control group hospitals; both 1 year before intensified supervision (odds ratio, OR, 1.67, 95% CI 1.06-2.63) and 1 year after (OR 1.79, 95% CI 1.14-2.81) the differences are significant. For all periods, the odds on a low rating score for hospitals under intensified supervision are higher than for the control group hospitals, corrected for time. Time is also associated with low rating scores, with decreasing ORs over time since 2010. Hospitals that are confronted with intensified supervision by the health care inspectorate have lower ratings on patient rating sites. The scores are independent of the period: before, during, or just after the intervention by the health care inspectorate. Health care inspectorates might learn from these results because they indicate that the inspectorate identifies the same hospitals as "at risk" as the patients rate as underperformers.


Safety and efficacy of oral DMSA therapy for children with autism spectrum disorders: Part A--medical results.
This study investigated the effect of oral dimercapto succinic acid (DMSA) therapy for children with autism spectrum disorders ages 3-8 years. Phase 1 involved 65 children who received one round of DMSA (3 days). Participants who had high urinary excretion of toxic metals were selected to continue on to phase 2. In phase 2, 49 participants were randomly assigned in a double-blind design to receive an additional 6 rounds of either DMSA or placebo. DMSA greatly increased the excretion of lead, substantially increased excretion of tin and bismuth, and somewhat increased the excretion of thallium, mercury, antimony, and tungsten. There was some increase in urinary excretion of essential minerals, especially potassium and chromium. The Phase 1 single round of DMSA led to a dramatic normalization of RBC glutathione in almost all cases, and greatly improved abnormal platelet counts, suggesting a significant decrease in inflammation. Overall, DMSA therapy seems to be reasonably safe, effective in removing several toxic metals (especially lead), dramatically effective in normalizing RBC glutathione, and effective in normalizing platelet counts. Only 1 round (3 days) was sufficient to improve glutathione and platelets. Additional rounds increased excretion of toxic metals.


Staphylococcus aureus infections and factors associated with resistance to methicillin in a hospital emergency department.
Assessment of the characteristics of patients with Staphylococcus aureus (SA) infections, and factors associated with resistance to methicillin in a hospital emergency department (ED) in Spain. All adult patients admitted between January 2007 and December 2010 with a SA infection confirmed by a positive culture in a sample obtained in the hospital emergency department were selected for enrolment. Epidemiological, clinical, therapeutic and microbiological variables were retrospectively collected from the patients' medical charts. The variable assessed within the primary outcome of the study was the isolation of methicillin resistant Staphylococcus aureus (MRSA). For the purpose of the analysis, the sample was divided in terms of the presence or not of the resistance to methicillin and a logistic regression analysis was performed to identify the factors associated with isolation and empirical antibiotic coverage of MRSA. A total of 207 patients with a confirmed SA infection were included in the study analysis, with a mean age of 64.7 (SD 20) years. MRSA was isolated in a total of 63 (30.4%) patients, and a linear incremental trend was observed over the course of the study (p=0,047). MRSA was empirically covered in the emergency department on an average rate of one in three patients. Independent factors associated with the isolation of MRSA were: age above 65 years [OR 2.97 (95% CI 1.24 to 7.1), P = 0.014], severe baseline functional dependence [OR 2.41 (95 % 1.02 to 5.69), P = 0.045], chronic obstructive pulmonary disease [OR 4.83 (95% CI 1.88 to 12.42), P = 0.001], history of antibiotic treatment within the previous 2 months [OR 4.94 (95% CI 2.27 to 10.76), P <0.001] and a confirmed urinary infection [OR 5.98 (95% CI 1.65 to 21.69) p = 0.007]. Independent factors associated with empiric coverage of MRSA in the ED were history of antibiotic treatment within the previous 2 months [OR 3.88 (95% CI 1.76 to 8.57), P <0.001] and the presence of a catheter device [OR 6.28 (95% CI 1.64 to 24.07), P = 0.007]. Resistance to methicillin appears to be increasingly frequent in patients infected with SA admitted in our emergency department and there appears to be a need for a more optimal empiric antibiotic treatment in these patients.


The AP-1 transcription factor c-Jun is required for efficient axonal regeneration.
Nerve injury triggers numerous changes in the injured neurons and surrounding nonneuronal cells that ultimately result in successful target reinnervation or cell death. c-Jun is a component of the heterodimeric AP-1 transcription factor, and c-Jun is highly expressed in response to neuronal trauma. Here we have investigated the role of c-jun during axonal regeneration using mice lacking c-jun in the central nervous system. After transection of the facial nerve, the absence of c-Jun caused severe defects in several aspects of the axonal response, including perineuronal sprouting, lymphocyte recruitment, and microglial activation. c-Jun-deficient motorneurons were atrophic, resistant to axotomy-induced cell death, and showed reduced target muscle reinnervation. Expression of CD44, galanin, and alpha7beta1 integrin, molecules known to be involved in regeneration, was greatly impaired, suggesting a mechanism for c-Jun-mediated axonal growth. Taken together, our results identify c-Jun as an important regulator of axonal regeneration in the injured central nervous system.


Antecedent blood pressure, body mass index, and the risk of incident heart failure in later life.
Higher blood pressure and body mass index (BMI) are risk factors for heart failure. It is unknown whether the presence of these risk factors in midadulthood affect the future development of heart failure. In the community-based Framingham Heart Study, we examined the associations of antecedent blood pressure and BMI with heart failure incidence in later life. We studied 3362 participants (57% women; mean age: 62 years) who attended routine examinations between 1969 and 1994 and examined their systolic and diastolic blood pressure, pulse pressure, and BMI at current (baseline), recent (average of readings obtained 1 to 10 years before baseline), and remote (average of readings obtained 11 to 20 years before baseline) time periods. During 67 240 person-years of follow-up, 518 participants (280 women) developed heart failure. Current, recent, and remote systolic pressure; pulse pressure; and BMI were individually associated with incident heart failure (all P<0.001). Recent systolic pressure (hazards ratio [HR] per 1-SD increment: 1.31; 95% CI: 1.11 to 1.55), pulse pressure (HR per 1-SD increment: 1.33; 95% CI: 1.14 to 1.54), and BMI (HR per unit increase: 1.15; 95% CI: 1.08 to 1.23) were associated with heart failure risk even after adjusting for current measures. Similarly, remote systolic pressure (HR per 1 SD: 1.17; 95% CI: 1.04 to 1.31), pulse pressure (HR per 1 SD: 1.17; 95% CI: 1.06 to 1.31), and BMI (HR per unit: 1.09; 95% CI: 1.05 to 1.14) remained associated with incident heart failure after adjusting for current measurements. Higher blood pressure and BMI in midlife are harbingers of increased risk of heart failure in later life. Early risk factor modification may decrease heart failure burden.


Susceptibility to the rubber hand illusion does not tell the whole body-awareness story.
The rubber hand illusion (RHI) is an enigmatic illusion that creates a feeling of owning an artificial limb. Enthusiasts of this paradigm assert that it operationalizes bodily self-awareness, but there are reasons to doubt such a clear link. Because little is known about other functional contributions to the RHI, including effects of context-dependent visual processing and cognitive control or the ability to resolve intermodal conflict, we carried out two complementary experiments. In the first, we examined the relationships between the RHI and (1) body awareness, as assessed by the Body Perception Questionnaire (BPQ); (2) context-dependent visual processing, as assessed by the rod-and-frame test (RFT); and (3) conflict resolution, as assessed by the Stroop test. We found a significant positive correlation between the RHI-associated proprioceptive drift and context-dependent visual processing on the RFT, but not between the RHI and body awareness on the BPQ. In the second experiment, we examined the RHI in advanced yoga practitioners with an embodied lifestyle and a heightened sense of their own body in space. They succumbed to the illusion just as much as did yoga-naïve control participants, despite significantly greater body awareness on the BPQ. These findings suggest that susceptibility to the RHI and awareness of one's own body are at least partially independent processes.


Obese Patients Undergoing Ileal Pouch-Anal Anastomosis: Short-and Long-term Surgical Outcomes.
Ileal pouch-anal anastomosis (IPAA) is the preferred surgical treatment for patients with chronic ulcerative colitis. Little is known about the impact of obesity on operative characteristics, short-term postoperative complications and long-term functional outcomes after IPAA. A retrospective review of all patients undergoing IPAA for chronic ulcerative colitis at a single tertiary referral center between January 2002 and August 2013 was performed. Thirty-day postoperative complications and long-term functional outcomes were analyzed according to body mass index. Nine hundred nine IPAAs (154 obese [body mass index ≥ 30] and 755 not obese [body mass index < 30]) were performed during the study period. For 2-stage IPAA, obese patients were less likely to undergo laparoscopic IPAA (P < 0.0001), had greater estimated blood loss (P = 0.005), and longer operative times (P = 0.02). For 3-stage IPAA, obese patients were less likely to undergo a laparoscopic procedure (P = 0.03), had greater estimated blood loss (P < 0.0001), and longer operative times (P = 0.0002). Postoperatively, obese patients had a longer length of stay after a 2-stage procedure (P = 0.009), an increased rate of superficial surgical site infections (P = 0.003), and an increased rate of urinary tract infections (P = 0.03). Of the 61% (n = 546) of patients with IPAA with long-term (median 5.0 years) follow-up, there were no significant differences in functional outcomes including incontinence, frequency of bowel movements, pad usage, and pouchitis between the groups. Obesity impacts intraoperative complexity and 30-day postoperative outcomes. Long-term functional outcomes are not affected. These findings underscore the need to counsel patients on preoperative weight loss before undergoing elective IPAA.


A qualitative exploration of knowledge of Chagas disease among adolescents in rural Ecuador.
Chagas disease (CD) is a neglected tropical disease that affects 6 to 7 million people worldwide. In South America, CD is a major health problem in several regions, causing more than 12 000 deaths per year. CD is caused by a parasite called Trypanosoma cruzi, mostly transmitted through the contaminated feces of certain species of triatomine bug, commonly known as the 'kissing bug'. CD is endemic in Loja province in the southern region of Ecuador, where triatomines have been found in 68% of communities. Previous promotion of healthy practices in Loja province have included educational programs directed toward youth to affirm cultural and social norms that support health and prevent CD transmission. The present study was designed to evaluate current knowledge related to CD among youth in the three communities of Loja province following previous intervention programs. A descriptive, qualitative approach was applied using individual semi-structured interviews with 14 young people (eight females, six males) from three rural communities in Loja province. Interviews assessed knowledge about CD transmission, knowledge about the parasite-vector-disease pathway, and the role of youth in preventing Chagas disease in their communities. Following a thematic analysis of the data, the study results showed there is cursory knowledge of the triatomine insect that can carry the causative parasite for CD. Participants were able to generally talk about the vector, habitat and prevention practices for triatomine infestation. Nevertheless, limited understanding of transmission dynamics in the parasite-vector-disease pathway itself was found. One major finding was that prevention practices were not correctly applied or followed, increasing the risk of exposure in the community. Youth also articulated that CD is stigmatized in their communities, which may be a barrier for prevention efforts. Gaps in knowledge about the parasite-vector-disease pathway were identified among youth. Overall, youth responses indicated positive regard for prevention practices and a desire to be involved in prevention programs. Developing educational programs focusing on CD transmission may be needed to improve control and prevention of this parasitic disease. The implications of these findings are discussed for developing effective control programs in the region.


Extreme ultraviolet free electron laser seeded with high-order harmonic of Ti:sapphire laser.
The 13th harmonic of a Ti:sapphire (Ti:S) laser in the plateau region was injected as a seeding source to a 250-MeV free-electron-laser (FEL) amplifier. When the amplification conditions were fulfilled, strong enhancement of the radiation intensity by a factor of 650 was observed. The random and uncontrollable spikes, which appeared in the spectra of the Self-Amplified Spontaneous Emission (SASE) based FEL radiation without the seeding source, were found to be suppressed drastically to form to a narrow-band, single peak profile at 61.2 nm. The properties of the seeded FEL radiation were well reproduced by numerical simulations. We discuss the future precept of the seeded FEL scheme to the shorter wavelength region.


The LOREC APE registry: operative technique, oncological outcome and perineal wound healing after abdominoperineal excision.
The Low Rectal Cancer Development programme (LOREC) perineal wound healing registry was developed to record data on abdominoperineal excision (APE) for rectal cancer in colorectal units in England between 2012 and 2014, to understand current practice in operative technique and results. Surgeons wishing to participate received secure Web-based access to the registry. Data were collected on preoperative staging, neoadjuvant treatment, operative details, histopathology, early outcome and follow up at 12 months. Forty-two units entered 266 patients. Of these, 172 (65%) patients underwent extralevator APE (ELAPE) and 94 had non-ELAPE procedures. On preoperative staging, 64% were mrT3/4, and 67% received neoadjuvant treatment. For the ELAPE group the perineal wound was closed primarily with mesh in 55% of patients, without mesh in 15% and with a flap in 21%. For non-ELAPE procedures, 54% of wounds were closed primarily without mesh, 29% primarily with mesh and 5% by a flap. Wound breakdown occurred in 30% and 31% of patients in the ELAPE and non-ELAPE groups, respectively, and was more common after neoadjuvant radiotherapy. Donor-site complications occurred in 17% of patients treated with a flap. Perineal morbidity was recorded in 11% of patients at 12 months. On histopathology, the resection margin was positive in 13% of patients in the ELAPE group and in 4% of patients in the non-ELAPE group. The LOREC registry provides a picture of current APE practice in England. ELAPE was used in two-thirds of patients but does not appear to confer any additional morbidity. Primary closure with mesh appeared as effective as flap reconstruction. The prevalence of an involved resection margin was lower than reported in many historical series but still remains high in the ELAPE group.


Effects of Thresholding on Voxel-Wise Correspondence of Breath-Hold and Resting-State Maps of Cerebrovascular Reactivity.
Functional magnetic resonance imaging for presurgical brain mapping enables neurosurgeons to identify viable tissue near a site of operable pathology which might be at risk of surgery-induced damage. However, focal brain pathology (e.g., tumors) may selectively disrupt neurovascular coupling while leaving the underlying neurons functionally intact. Such neurovascular uncoupling can result in false negatives on brain activation maps thereby compromising their use for surgical planning. One way to detect potential neurovascular uncoupling is to map cerebrovascular reactivity using either an active breath-hold challenge or a passive resting-state scan. The equivalence of these two methods has yet to be fully established, especially at a voxel level of resolution. To quantitatively compare breath-hold and resting-state maps of cerebrovascular reactivity, we first identified threshold settings that optimized coverage of gray matter while minimizing false responses in white matter. When so optimized, the resting-state metric had moderately better gray matter coverage and specificity. We then assessed the spatial correspondence between the two metrics within cortical gray matter, again, across a wide range of thresholds. Optimal spatial correspondence was strongly dependent on threshold settings which if improperly set tended to produce statistically biased maps. When optimized, the two CVR maps did have moderately good correspondence with each other (mean accuracy of 73.6%). Our results show that while the breath-hold and resting-state maps may appear qualitatively similar they are not quantitatively identical at a voxel level of resolution.


Tunable Fano resonance in a single-ring-resonator-based add/drop interferometer.
We theoretically study a single-ring-resonator-based add/drop interferometer to achieve tunable Fano resonance. The Fano resonance results from the interference of two resonant beams propagating in the ring resonator. The line shapes of the Fano resonance are tunable by controlling the coupling coefficients between the waveguide and ring resonator. The spectra of the drop port and through port of the add/drop interferometer are horizontally mirror-symmetric. A box-like spectral response can be produced with the proper coupling coefficient owing to the double resonances. When the phase difference between the two light inputs to the add/drop interferometer is compensated, a doubled free spectral range can be obtained.


Severe Acute Respiratory Syndrome Coronavirus 2 Cumulative Incidence, United States, August 2020-December 2020.
Reported coronavirus disease 2019 (COVID-19) cases underestimate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. We conducted a national probability survey of US households to estimate cumulative incidence adjusted for antibody waning. From August-December 2020 a random sample of US addresses were mailed a survey and self-collected nasal swabs and dried blood spot cards. One adult household member completed the survey and mail specimens for viral detection and total (immunoglobulin [Ig] A, IgM, IgG) nucleocapsid antibody by a commercial, emergency use authorization-approved antigen capture assay. We estimated cumulative incidence of SARS-CoV-2 adjusted for waning antibodies and calculated reported fraction (RF) and infection fatality ratio (IFR). Differences in seropositivity among demographic, geographic, and clinical subgroups were explored. Among 39 500 sampled households, 4654 respondents provided responses. Cumulative incidence adjusted for waning was 11.9% (95% credible interval [CrI], 10.5%-13.5%) as of 30 October 2020. We estimated 30 332 842 (CrI, 26 703 753-34 335 338) total infections in the US adult population by 30 October 2020. RF was 22.3% and IFR was 0.85% among adults. Black non-Hispanics (Prevalence ratio (PR) 2.2) and Hispanics (PR, 3.1) were more likely than White non-Hispanics to be seropositive. One in 8 US adults had been infected with SARS-CoV-2 by October 2020; however, few had been accounted for in public health reporting. The COVID-19 pandemic is likely substantially underestimated by reported cases. Disparities in COVID-19 by race observed among reported cases cannot be attributed to differential diagnosis or reporting of infections in population subgroups.


Characterization of a 5-azacytidine-induced developmental Aspergillus fumigatus variant.
The hypomethylating agent 5-azacytidine (5AC) is widely used in patients at risk of invasive mycoses. We sought to determine whether 5AC affects the developmental competence and virulence of Aspergillus fumigatus. Incubation of A. fumigatus strain 293 with 5AC induced high-frequency conversion to a fluffy-variant (Af293 (FL) ). The conidiation defect was bypassed by exposing Af293 (FL) to light during the initial 18 hours of growth on solid media. Transcriptional profiling revealed differential expression of multiple genes involved in G-protein signaling, including a putative G-protein coupled photoreceptor (opsin), suggesting that impaired signaling through a light-responsive pathway upstream of brlA is responsible for this phenotype. Af293 (FL) was fully virulent in fruit fly and murine models of invasive aspergillosis. Moreover, Af293 (FL) overexpressed aspergillopepsin F, had increased elastase activity and was more angioinvasive than the parental wild-type strain. The 5AC-induced A. fumigatus fluffy variant illustrates the potential effects of chemotherapeutic agents on the developmental and pathobiologic characteristics of opportunistic fungi.


Cost-benefit analysis of enhancing the uptake of long-acting reversible contraception in Australia.
Objective Long-acting reversible contraception (LARC) is the most effective form of reversible contraception, but its use in Australia is low compared with other countries. The aim of this study was to evaluate the economic effect of an increase in LARC uptake to international rates. Methods An economic model was designed to assess two scenarios, namely increasing the current rate of LARC uptake of 12.5% to the international benchmark of 14.8% among: (1) women currently using the oral contraceptive pill (OCP); and (2) women at risk of pregnancy and not using contraception. Model inputs included cost of contraceptive methods, discontinuation rates and abortion and miscarriage costs associated with unintended pregnancies. Results Women who switch from an OCP to LARC would save A$114-157 per year. Those not currently using any contraception who adopt LARC would incur costs of A$36-194 per year, but would reap savings from the reduction in unintended pregnancies. Over 5 years there would be a net saving of A$74.4 million for Scenario 1 and A$2.4 million for Scenario 2. Conclusion Greater use of LARC would result in a net gain in economic benefits to Australia. These benefits are largely driven by women switching from an OCP to LARC who have reduced costs, as well as women wishing to avoid pregnancy who choose to use LARC rather than no method. This evidence will support women making an informed contraceptive choice and policy makers in increasing the accessibility of LARC. What is known about the topic? LARC is the most effective form of reversible contraception, but uptake in Australia is relatively low. What does this paper add? There are economic benefits to society for women who switch from an OCP to LARC, as well as for women who switch from no contraception to LARC. What are the implications for practitioners? The findings of this study will support women in making an informed contraceptive choice and policy makers in increasing the accessibility of LARC.


The metabolic response of marine copepods to environmental warming and ocean acidification in the absence of food.
Marine copepods are central to the productivity and biogeochemistry of marine ecosystems. Nevertheless, the direct and indirect effects of climate change on their metabolic functioning remain poorly understood. Here, we use metabolomics, the unbiased study of multiple low molecular weight organic metabolites, to examine how the physiology of Calanus spp. is affected by end-of-century global warming and ocean acidification scenarios. We report that the physiological stresses associated with incubation without food over a 5-day period greatly exceed those caused directly by seawater temperature or pH perturbations. This highlights the need to contextualise the results of climate change experiments by comparison to other, naturally occurring stressors such as food deprivation, which is being exacerbated by global warming. Protein and lipid metabolism were up-regulated in the food-deprived animals, with a novel class of taurine-containing lipids and the essential polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid and docosahexaenoic acid, changing significantly over the duration of our experiment. Copepods derive these PUFAs by ingesting diatoms and flagellated microplankton respectively. Climate-driven changes in the productivity, phenology and composition of microplankton communities, and hence the availability of these fatty acids, therefore have the potential to influence the ability of copepods to survive starvation and other environmental stressors.


Essential role of GluD1 in dendritic spine development and GluN2B to GluN2A NMDAR subunit switch in the cortex and hippocampus reveals ability of GluN2B inhibition in correcting hyperconnectivity.
The glutamate delta-1 (GluD1) receptor is highly expressed in the forebrain. We have previously shown that loss of GluD1 leads to social and cognitive deficits in mice, however, its role in synaptic development and neurotransmission remains poorly understood. Here we report that GluD1 is enriched in the medial prefrontal cortex (mPFC) and GluD1 knockout mice exhibit a higher dendritic spine number, greater excitatory neurotransmission as well as higher number of synapses in mPFC. In addition abnormalities in the LIMK1-cofilin signaling, which regulates spine dynamics, and a lower ratio of GluN2A/GluN2B expression was observed in the mPFC in GluD1 knockout mice. Analysis of the GluD1 knockout CA1 hippocampus similarly indicated the presence of higher spine number and synapses and altered LIMK1-cofilin signaling. We found that systemic administration of an N-methyl-d-aspartate (NMDA) receptor partial agonist d-cycloserine (DCS) at a high-dose, but not at a low-dose, and a GluN2B-selective inhibitor Ro-25-6981 partially normalized the abnormalities in LIMK1-cofilin signaling and reduced excess spine number in mPFC and hippocampus. The molecular effects of high-dose DCS and GluN2B inhibitor correlated with their ability to reduce the higher stereotyped behavior and depression-like behavior in GluD1 knockout mice. Together these findings demonstrate a critical requirement for GluD1 in normal spine development in the cortex and hippocampus. Moreover, these results identify inhibition of GluN2B-containing receptors as a mechanism for reducing excess dendritic spines and stereotyped behavior which may have therapeutic value in certain neurodevelopmental disorders such as autism.


The inositol trisphosphate (IP3) signal transduction pathway.
This resource provides and describes two animated lessons that illustrate inositol 1,4,5-trisphosphate signal transduction pathways. They are designed for any collegiate-level course that presents the basic steps of the prototypical pathway. Courses that might employ these animations include Introductory Biology, Cell Biology, Physiology, Biochemistry, Molecular Biology, and Pharmacology.


An analysis of connective tissue disease-associated interstitial lung disease at a US Tertiary Care Center: better survival in patients with systemic sclerosis.
To compare survival of patients with connective tissue disease-associated interstitial lung disease (CTD-ILD) versus idiopathic pulmonary fibrosis (IPF) and patients with systemic sclerosis-associated ILD (SSc-ILD) versus other CTD-ILD followed at our center. We used the Stanford ILD database, which contains prospectively collected information on patients with ILD evaluated at our tertiary care center from 2002 to 2009. Survival at last followup from time of ILD diagnosis was calculated using the Kaplan-Meier estimator. Prognostic factors for survival in the overall cohort (IPF and CTD-ILD) and in the CTD-ILD group were identified with univariate and multivariate Cox regression models. Of 427 patients with ILD, 148 (35%) had IPF and 76 (18%) had CTD-ILD at the baseline visit. The cumulative incidence of CTD was 4%. After a median followup of 4 years, 67 patients (36.4%) had died and 4 (2.2%) were lost to followup. Patients with IPF (n = 122) and CTD-ILD (n = 62) experienced similar survival rates (5-year survival about 50%). Patients with SSc-ILD (n = 24) experienced better survival than those with other CTD-ILD (n = 38), with 1-year, 3-year, and 5-year survival rates of 100%, 90%, and 77%, respectively, versus 78%, 42%, and 38% (p = 0.01). The presence of SSc in patients with CTD-ILD decreased the risk of death by > 80% even after correcting for age at ILD diagnosis, sex, and ethnicity (HR = 0.17, 95% CI 0.04-0.83). Survival in patients with SSc-ILD was better than in patients with other CTD-ILD, potentially related to routine screening for and early detection of ILD in patients with SSc at our center.


Activity-dependent relocation of the axon initial segment fine-tunes neuronal excitability.
In neurons, the axon initial segment (AIS) is a specialized region near the start of the axon that is the site of action potential initiation. The precise location of the AIS varies across and within different neuronal types, and has been linked to cells' information-processing capabilities; however, the factors determining AIS position in individual neurons remain unknown. Here we show that changes in electrical activity can alter the location of the AIS. In dissociated hippocampal cultures, chronic depolarization with high extracellular potassium moves multiple components of the AIS, including voltage-gated sodium channels, up to 17 mum away from the soma of excitatory neurons. This movement reverses when neurons are returned to non-depolarized conditions, and depends on the activation of T- and/or L-type voltage-gated calcium channels. The AIS also moved distally when we combined long-term LED (light-emitting diode) photostimulation with sparse neuronal expression of the light-activated cation channel channelrhodopsin-2; here, burst patterning of activity was successful where regular stimulation at the same frequency failed. Furthermore, changes in AIS position correlate with alterations in current thresholds for action potential spiking. Our results show that neurons can regulate the position of an entire subcellular structure according to their ongoing levels and patterns of electrical activity. This novel form of activity-dependent plasticity may fine-tune neuronal excitability during development.


Application of the Doylestown algorithm for the early detection of hepatocellular carcinoma.
We previously developed a logistic regression algorithm that uses AFP, age, gender, ALK and ALT levels to improve the detection of hepatocellular carcinoma (HCC). In 3,158 patients from 5 independent sites, this algorithm, referred to as the "Doylestown" algorithm, increased the AUROC of AFP 4% to 12% and had equal benefit regardless of tumor size or the etiology of liver disease. Analysis of the Doylestown algorithm using samples from individuals taken before their diagnosis of HCC. Here, the algorithm was tested using samples at multiple time points from (a) patients with established chronic liver disease, without HCC (120 patients) and (b) 116 patients with HCC diagnosis (85 patients with early stage HCC and 31 patients with recurrent HCC), taken at the time of, and up to 12 months prior to cancer diagnosis. Among patients who developed HCC, comparing the Doylestown algorithm at a fixed cut-off to AFP at 20 ng/mL, the Doylestown algorithm increased the True Positive Rate (TPR) in identification of HCC from 36 to 50%, at a time point of 12 months prior to the conventional HCC detection. Similar results were obtained in those patients with recurrent HCC, where the Doylestown algorithm increased TPR in detection of HCC from 18% to 59%, at 12 months prior to detection of recurrence. This algorithm significantly improves the prediction of HCC by AFP alone and may have value in the early detection of HCC.


Aspherical and Spherical InvA497-Functionalized Nanocarriers for Intracellular Delivery of Anti-Infective Agents.
The objective of this work was to evaluate the potential of polymeric spherical and aspherical invasive nanocarriers, loaded with antibiotic, to access and treat intracellular bacterial infections. Aspherical nanocarriers were prepared by stretching of spherical precursors, and both aspherical and spherical nanocarriers were surface-functionalized with the invasive protein InvA497. The relative uptake of nanocarriers into HEp-2 epithelial cells was then assessed. Nanocarriers were subsequently loaded with a preparation of the non-permeable antibiotic gentamicin, and tested for their ability to treat HEp-2 cells infected with the enteroinvasive bacterium Shigella flexneri. InvA497-functionalized nanocarriers of both spherical and aspherical shape showed a significantly improved rate and extent of uptake into HEp-2 cells in comparison to non-functionalized nanocarriers. Functionalized and antibiotic-loaded nanocarriers demonstrated a dose dependent killing of intracellular S. flexneri. A slight but significant enhancement of intracellular bacterial killing was also observed with aspherical as compared to spherical functionalized nanocarriers at the highest tested concentration. InvA497-functionalized, polymer-based nanocarriers were able to efficiently deliver a non-permeable antibiotic across host cell membranes to affect killing of intracellular bacteria. Functionalized nanocarriers with an aspherical shape showed an interesting future potential for intracellular infection therapy.


Channeling calcium: a shared mechanism for exocytosis-endocytosis coupling.
Cell surface area is maintained in most cells by coupling exocytotic activity to compensatory endocytosis, a process that specifically retrieves membrane inserted by exocytosis. Although such coupling mechanisms seem to be ubiquitous, the mechanisms through which these membrane trafficking events are linked have remained elusive. A mechanism for coupling exocytosis to endocytosis in fruit fly nerve terminals that depends on the exocytotic insertion of vesicular calcium channels into the plasma membrane has recently been identified. This coupling mechanism resembles one previously described in sea urchin eggs. Here, I compare the similarities and differences of the processes involved in linking exocytosis to endocytosis in these two invertebrate systems and speculate on whether the vertebrate coupling mechanism might also depend on vesicular channels.


Combined Use of Circulating miR-133a and NT-proBNP Improves Heart Failure Diagnostic Accuracy in Elderly Patients.
BACKGROUND Circulating microRNAs (miRNAs) are emerging as novel biomarkers for detecting cardiovascular diseases. Here, circulating miR-133a and miR-221 were investigated as potential diagnostic biomarkers for heart failure (HF) patients, particularly in elderly patients. MATERIAL AND METHODS A total of 94 elderly HF patients (mean age=77.4 years old) and 31 healthy controls (age- and sex-matched) participated in this study. Plasma NT-proBNP levels were measured using an electrochemiluminescence immunoassay, and circulating miR-133a and miR-221 levels were examined using real-time quantitative PCR, with diagnostic efficacies determined for each independently and in combination. RESULTS MiR-133a expression increased by 4.6-fold (P<0.001) and miR-221 expression increased by 2.0-fold (P<0.001) in the elderly HF patients relative to the healthy controls. ROC curves were generated and AUC values of 0.863 for miR-133a (CI95%: 0.800-0.927), 0.718 for miR-221 (CI95%: 0.622-0.813), and 0.895 for NT-proBNP (CI95%: 0.841-0.948) were obtained. Unlike NT-proBNP, miR-133a and miR-221 were found to be unaffected by age, BMI, renal function, albumin, or Hb levels. More importantly, the diagnostic value of NT-proBNP was found to be improved when combined with any of the examined miRNA biomarkers alone or in a panel. When combining miR-133a with NT-proBNP, an AUC value of 0.975 (CI95%: 0.950-0.999) was obtained, which was significantly higher than for NT-proBNP alone (z=2.395, P=0.016). CONCLUSIONS miR-133a and miR-221 can serve as potential HF diagnostic biomarkers in elderly patients. Moreover, the diagnostic accuracy of NT-proBNP can be improved by the addition of miR-133a.


Ventricular assist device implantation corrects myocardial lipotoxicity, reverses insulin resistance, and normalizes cardiac metabolism in patients with advanced heart failure.
Heart failure is associated with impaired myocardial metabolism with a shift from fatty acids to glucose use for ATP generation. We hypothesized that cardiac accumulation of toxic lipid intermediates inhibits insulin signaling in advanced heart failure and that mechanical unloading of the failing myocardium corrects impaired cardiac metabolism. We analyzed the myocardium and serum of 61 patients with heart failure (body mass index, 26.5±5.1 kg/m(2); age, 51±12 years) obtained during left ventricular assist device implantation and at explantation (mean duration, 185±156 days) and from 9 control subjects. Systemic insulin resistance in heart failure was accompanied by decreased myocardial triglyceride and overall fatty acid content but increased toxic lipid intermediates, diacylglycerol, and ceramide. Increased membrane localization of protein kinase C isoforms, inhibitors of insulin signaling, and decreased activity of insulin signaling molecules Akt and Foxo were detectable in heart failure compared with control subjects. Left ventricular assist device implantation improved whole-body insulin resistance (homeostatic model of analysis-insulin resistance, 4.5±0.6-3.2±0.5; P<0.05) and decreased myocardial levels of diacylglycerol and ceramide, whereas triglyceride and fatty acid content remained unchanged. Improved activation of the insulin/phosphatidylinositol-3 kinase/Akt signaling cascade after left ventricular assist device implantation was confirmed by increased phosphorylation of Akt and Foxo, which was accompanied by decreased membrane localization of protein kinase C isoforms after left ventricular assist device implantation. Mechanical unloading after left ventricular assist device implantation corrects systemic and local metabolic derangements in advanced heart failure, leading to reduced myocardial levels of toxic lipid intermediates and improved cardiac insulin signaling.


Utilizing critical angles in sensing partially ordered liquid crystal profile.
This paper investigates a new approach for tracking nematic uniaxial liquid crystal (LC) profile in partially ordered LC based sensors. This approach utilizes measuring critical angles for total internal reflection (TIR) at the interface of optically isotropic and partially ordered LC film. The proposed optical transduction requires measuring of the ordinary critical angle and two extraordinary critical angles in orthogonal directions to report the LC degree of ordering and the director axis orientation.


Low-temperature-grown p-n ZnO nanojunction arrays as rapid and self-driven UV photodetectors.
In this study p-type ZnO nanorod (NR) arrays were grown using a low-temperature hydrothermal method in the presence of various concentrations of Sb in the doping solution. X-ray photoelectron spectroscopy revealed the atomic percentages and chemical states of the Sb dopant atoms in the p-type ZnO NR arrays. Photoluminescence and electrical measurements confirmed the p-type characteristics of the Sb-doped ZnO NR arrays. Sequential growth of n- and p-ZnO was then implemented to form p-n ZnO nanojunction arrays. The photovoltaic properties of the p-n ZnO nanojunction devices were investigated under 365 nm UV light; the short-circuit current densities and open-circuit voltages exhibited linear and logarithmic dependence, respectively, on the power density of the UV light. In addition, the p-n ZnO nanojunction devices displayed a rapid response to UV light at zero bias, with a linear correlation between the responsivity and the incident light power. Such low-temperature growth of p-n ZnO nanojunctions appears to be a facile strategy for fabricating junctioned nanostructures with applications in energy-harvesting and self-driven photodetecting optoelectronics.


Fine structure of excitons and electron-hole exchange energy in polymorphic CsPbBr3 single nanocrystals.
All inorganic CsPbX3 (X = Cl, Br, I) nanocrystals (NCs) belong to the novel class of confined metal-halide perovskites which are currently arousing enthusiasm and stimulating huge activity across several fields of optoelectronics due to outstanding properties. A deep knowledge of the band-edge excitonic properties of these materials is thus crucial to further optimize their performances. Here, high-resolution photoluminescence (PL) spectroscopy of single bromide-based NCs reveals the exciton fine structure in the form of sharp peaks that are linearly polarized and grouped in doublets or triplets, which directly mirror the adopted crystalline structure, tetragonal (D4h symmetry) or orthorhombic (D2h symmetry). Intelligible equations are found that show how the fundamental parameters (spin-orbit coupling, ΔSO, crystal field term, T, and electron-hole exchange energy, J) rule the energy spacings in doublets and triplets. From experimental data, fine estimations of each parameter are obtained. The analysis of the absorption spectra of an ensemble of NCs with a "quasi-bulk" behavior leads to ΔSO = 1.20 ± 0.06 eV and T = -0.34 ± 0.05 eV in CsPbBr3. The study of individual luminescence responses of NCs having sizes comparable to the exciton Bohr diameter, 7 nm, allows us to estimate the value of J to be around ≈3 meV in both tetragonal and orthorhombic phases. This value is already enhanced by confinement.


Perioperative Quality Initiative consensus statement on the physiology of arterial blood pressure control in perioperative medicine.
Perioperative arterial blood pressure management is a physiologically complex challenge influenced by multiple factors. A multidisciplinary, international working subgroup of the Third Perioperative Quality Initiative (POQI) consensus meeting reviewed the (patho)physiology and measurement of arterial pressure as applied to perioperative medicine. We addressed predefined questions by undertaking a modified Delphi analysis, in which primary clinical research and review articles were identified using MEDLINE. Strength of recommendations, where applicable, were graded by National Institute for Health and Care Excellence (NICE) guidelines. Multiple physiological factors contribute to the perioperative physiological importance of arterial pressure: (i) arterial pressure is the input pressure to organ blood flow, but is not the sole determinant of perfusion pressure; (ii) blood flow is often independent of changes in perfusion pressure because of autoregulatory changes in vascular resistance; (iii) microvascular dysfunction uncouples microvascular blood flow from arterial pressure (haemodynamic incoherence). From a practical clinical perspective, we identified that: (i) ambulatory measurement is the optimal method to establish baseline arterial pressure; (ii) automated and invasive arterial pressure measurements have inherent physiological and technical limitations; (iii) individualised arterial pressure targets may change over time, especially in the perioperative period. There remains a need for research in non-invasive, continuous arterial pressure measurements, macro- and micro-circulatory control, regional perfusion pressure measurement, and the development of sensitive, specific, and continuous measures of cellular function to evaluate blood pressure management in a physiologically coherent manner. The multivariable, complex physiology contributing to dynamic changes in perioperative arterial pressure may be underappreciated clinically. The frequently unrecognised dissociation between arterial pressure, organ blood flow, and microvascular and cellular function requires further research to develop a more refined, contextualised clinical approach to this routine perioperative measurement.


Asymmetric caging in soft colloidal mixtures.
The long-standing observations that different amorphous materials exhibit a pronounced enhancement of viscosity and eventually vitrify on compression or cooling continue to fascinate and challenge scientists, on the ground of their physical origin and practical implications. Glass formation is a generic phenomenon, observed in physically quite distinct systems that encompass hard and soft particles. It is believed that a common underlying scenario, namely cage formation, drives dynamical arrest, especially at high concentrations. Here, we identify a novel, asymmetric glassy state in soft colloidal mixtures, which is characterized by strongly anisotropically distorted cages, bearing similarities to those of hard-sphere glasses under shear. The anisotropy is induced by the presence of soft additives. This phenomenon seems to be generic to soft colloids and its origins lie in the penetrability of the constituent particles. The resulting phase diagram for mixtures of soft particles is clearly distinct from that of hard-sphere mixtures and brings forward a rich variety of vitrified states that delineate an ergodic lake in the parameter space spanned by the size ratio between the two components and by the concentration of the additives. Thus, a new route opens for the rational design of soft particles with desired tunable rheological properties.


Effectiveness of a repellent containing DEET and EBAAP for preventing tick bites.
Topical repellents can provide effective personal protection from tick-borne diseases by preventing the attachment of ticks. The goal of this study was to assess the effectiveness of a commercially available repellent spray containing both N,N-diethyl-3-methylbenzamide, previously known as N,N-diethyl-m-toluamide (DEET), and ethyl-butylacetylaminopropionate (EBAAP) against tick bites in a population at risk in Switzerland under real-life conditions. The effectiveness of an insect repellent spray containing both DEET and EBAAP was evaluated in a randomized, double-blind, placebo-controlled field study. The study, requiring simple application of the repellent to exposed skin, was carried out on 276 forestry workers and orienteers under everyday conditions in Switzerland from May to September 1999. We measured total effectiveness of the repellent by the following formula: percentage effectiveness = 100 x (T(P) - T(R))/T(P), where T(P) and T(R) were the average number of ticks per hour spent in wooded areas for the repellent and placebo groups, respectively. The average number of tick bites per hour of exposure to wooded areas differed significantly between the placebo (n = 138) and repellent (n = 138) groups, 0.17 vs 0.10 (P < .05). Total repellent effectiveness against tick attachment was 41.1% (95% CI, 2.5-79.6). On the arms, an effectiveness of 66% (95% CI, 17.3-114.7) was observed. No significant difference in the average number of unattached ticks could be found. This study found that an easily applied repellent is moderately effective in reducing the risk of tick bites.


Femtosecond photodissociation dynamics of 1,4-diiodobenzene by gas-phase X-ray scattering and photoelectron spectroscopy.
We present a multifaceted investigation into the initial photodissociation dynamics of 1,4-diiodobenzene (DIB) following absorption of 267 nm radiation. We combine ultrafast time-resolved photoelectron spectroscopy and X-ray scattering experiments performed at the Linac Coherent Light Source (LCLS) to study the initial electronic excitation and subsequent rotational alignment, and interpret the experiments in light of Complete Active Space Self-Consistent Field (CASSCF) calculations of the excited electronic landscape. The initially excited state is found to be a bound 1B1 surface, which undergoes ultrafast population transfer to a nearby state in 35 ± 10 fs. The internal conversion most likely leads to one or more singlet repulsive surfaces that initiate the dissociation. This initial study is an essential and prerequisite component of a comprehensive study of the complete photodissociation pathway(s) of DIB at 267 nm. Assignment of the initially excited electronic state as a bound state identifies the mechanism as predissociative, and measurement of its lifetime establishes the time between excitation and initiation of dissociation, which is crucial for direct comparison of photoelectron and scattering experiments.


Genome-wide shRNA screen revealed integrated mitogenic signaling between dopamine receptor D2 (DRD2) and epidermal growth factor receptor (EGFR) in glioblastoma.
Glioblastoma remains one of the deadliest of human cancers, with most patients succumbing to the disease within two years of diagnosis. The available data suggest that simultaneous inactivation of critical nodes within the glioblastoma molecular circuitry will be required for meaningful clinical efficacy. We conducted parallel genome-wide shRNA screens to identify such nodes and uncovered a number of G-Protein Coupled Receptor (GPCR) neurotransmitter pathways, including the Dopamine Receptor D2 (DRD2) signaling pathway. Supporting the importance of DRD2 in glioblastoma, DRD2 mRNA and protein expression were elevated in clinical glioblastoma specimens relative to matched non-neoplastic cerebrum. Treatment with independent si-/shRNAs against DRD2 or with DRD2 antagonists suppressed the growth of patient-derived glioblastoma lines both in vitro and in vivo. Importantly, glioblastoma lines derived from independent genetically engineered mouse models (GEMMs) were more sensitive to haloperidol, an FDA approved DRD2 antagonist, than the premalignant astrocyte lines by approximately an order of magnitude. The pro-proliferative effect of DRD2 was, in part, mediated through a GNAI2/Rap1/Ras/ERK signaling axis. Combined inhibition of DRD2 and Epidermal Growth Factor Receptor (EGFR) led to synergistic tumoricidal activity as well as ERK suppression in independent in vivo and in vitro glioblastoma models. Our results suggest combined EGFR and DRD2 inhibition as a promising strategy for glioblastoma treatment.


Functional neuroimaging of emotional processing in women with polycystic ovary syndrome: a case-control pilot study.
To evaluate emotional processing in women with insulin-resistant polycystic ovary syndrome (IR-PCOS) and its relationship to glucose regulation and the mu-opioid system. Case-control pilot. Tertiary referring medical center. Seven women with IR-PCOS and five non-insulin-resistant controls, aged 21-40 years, recruited from the general population. Sixteen weeks of metformin (1,500 mg/day) in women with IR-PCOS. Assessment of mood, metabolic function, and neuronal activation during an emotional task using functional magnetic resonance imaging (fMRI), and mu-opioid receptor availability using positive emission tomography (PET). We found that insulin-resistant PCOS patients [1] had greater limbic activation during an emotion task than controls (n = 5); [2] trended toward decreased positive affect and increased trait anxiety; [3] after metformin treatment, had limbic activation that no longer differed from controls; and [4] had positive correlations between fMRI limbic activation during emotional processing and mu-opioid binding potential. Patients with IR-PCOS had greater regional activation during an emotion task than the controls, although this resolved with metformin therapy. Alterations in mu-opioid neurotransmission may underlie limbic system activity and mood disorders in IR-PCOS.


Workload and cross-harvest kidney injury in a Nicaraguan sugarcane worker cohort.
To examine the association between workload and kidney injury in a fieldworker cohort with different levels of physically demanding work over a sugarcane harvest, and to assess whether the existing heat prevention efforts at a leading occupational safety and health programme are sufficient to mitigate kidney injury. Biological and questionnaire data were collected before (n=545) and at the end (n=427) of harvest among field support staff (low workload), drip irrigation workers (moderate), seed cutters (high) and burned sugarcane cutters (very high). Dropouts were contacted (87%) and reported the reason for leaving work. Cross-harvest incident kidney injury (IKI) was defined as serum creatinine increase ≥0.30 mg/dL or ≥1.5 times the baseline value, or among dropouts reporting kidney injury leading to leaving work. Mean cross-harvest estimated glomerular filtration rate change was significantly associated with workload, increasing from 0 mL/min/1.73 m2 in the low-moderate category to -5 mL/min/1.73 m2 in the high and -9 mL/min/1.73 m2 in the very high workload group. A similar pattern occurred with IKI, where low-moderate workload had 2% compared with 27% in the very high workload category. A healthy worker selection effect was detected, with 32% of dropouts reporting kidney injury. Fever and C reactive protein elevation were associated with kidney injury. Workers considered to have the highest workload had more cross-harvest kidney damage than workers with less workload. Work practices preventing heat stress should be strengthened and their role in preventing kidney damage examined further. Future occupational studies on chronic kidney disease of unknown aetiology should account for a healthy worker effect by pursuing those lost to follow-up.