The 2015 Nepal earthquake disaster: lessons learned one year on.
The 2015 earthquake in Nepal killed over 8000 people, injured more than 21,000 and displaced a further 2 million. One year later, a national workshop was organized with various Nepali stakeholders involved in the response to the earthquake. The workshop provided participants an opportunity to reflect on their experiences and sought to learn lessons from the disaster. One hundred and thirty-five participants took part and most had been directly involved in the earthquake response. They included representatives from the Ministry of Health, local and national government, the armed forces, non-governmental organizations, health practitioners, academics, and community representatives. Participants were divided into seven focus groups based around the following topics: water, sanitation and hygiene, hospital services, health and nutrition, education, shelter, policy and community. Facilitated group discussions were conducted in Nepalese and the key emerging themes are presented. Participants described a range of issues encountered, some specific to their area of expertize but also more general issues. These included logistics and supply chain challenges, leadership and coordination difficulties, impacts of the media as well as cultural beliefs on population behaviour post-disaster. Lessons identified included the need for community involvement at all stages of disaster response and preparedness, as well as the development of local leadership capabilities and community resilience. A 'disconnect' between disaster management policy and responses was observed, which may result in ineffective, poorly planned disaster response. Finding time and opportunity to reflect on and identify lessons from disaster response can be difficult but are fundamental to improving future disaster preparedness. The Nepal Earthquake National Workshop offered participants the space to do this. It garnered an overwhelming sense of wanting to do things better, of the need for a Nepal-centric approach and the need to learn the lessons of the past to improve disaster management for the future.


Stillbirths: rates, risk factors, and acceleration towards 2030.
An estimated 2.6 million third trimester stillbirths occurred in 2015 (uncertainty range 2.4-3.0 million). The number of stillbirths has reduced more slowly than has maternal mortality or mortality in children younger than 5 years, which were explicitly targeted in the Millennium Development Goals. The Every Newborn Action Plan has the target of 12 or fewer stillbirths per 1000 births in every country by 2030. 94 mainly high-income countries and upper middle-income countries have already met this target, although with noticeable disparities. At least 56 countries, particularly in Africa and in areas affected by conflict, will have to more than double present progress to reach this target. Most (98%) stillbirths are in low-income and middle-income countries. Improved care at birth is essential to prevent 1.3 million (uncertainty range 1.2-1.6 million) intrapartum stillbirths, end preventable maternal and neonatal deaths, and improve child development. Estimates for stillbirth causation are impeded by various classification systems, but for 18 countries with reliable data, congenital abnormalities account for a median of only 7.4% of stillbirths. Many disorders associated with stillbirths are potentially modifiable and often coexist, such as maternal infections (population attributable fraction: malaria 8.0% and syphilis 7.7%), non-communicable diseases, nutrition and lifestyle factors (each about 10%), and maternal age older than 35 years (6.7%). Prolonged pregnancies contribute to 14.0% of stillbirths. Causal pathways for stillbirth frequently involve impaired placental function, either with fetal growth restriction or preterm labour, or both. Two-thirds of newborns have their births registered. However, less than 5% of neonatal deaths and even fewer stillbirths have death registration. Records and registrations of all births, stillbirths, neonatal, and maternal deaths in a health facility would substantially increase data availability. Improved data alone will not save lives but provide a way to target interventions to reach more than 7000 women every day worldwide who experience the reality of stillbirth.


Eosinophilic vasculitis in an isolated central nervous system distribution.
Eosinophilic vasculitis has been described as part of the Churg-Strauss syndrome, but affects the central nervous system (CNS) in <10% of cases; presentation in an isolated CNS distribution is rare. We present a case of eosinophilic vasculitis isolated to the CNS. A 39-year-old woman with a history of migraine without aura presented to an institution (located in the borough of Queens, New York, USA; no academic affiliation) in an acute confusional state with concurrent headache and left-sided weakness and numbness. Laboratory evaluation showed increased cerebrospinal fluid (CSF) protein level, but an otherwise unremarkable serological investigation. Magnetic resonance imaging showed bifrontal polar gyral-enhancing brain lesions. Her symptoms resolved over 2 weeks without residual deficit. After 18 months, later the patient presented with similar symptoms and neuroradiological findings involving territories different from those in her first episode. Again, the CSF protein level was high. She had a raised C reactive protein level and erythrocyte sedimentation rate. Brain biopsy showed transmural, predominantly eosinophilic, inflammatory infiltrates of medium-sized leptomeningeal arteries without granulomas. She improved, without recurrence, when treated with a prolonged course of corticosteroids. To our knowledge, this is the first case of non-granulomatous eosinophilic vasculitis isolated to the CNS. No aetiology for this patient's primary CNS eosinophilic vasculitis has yet been identified. Spontaneous resolution and recurrence of her syndrome is an unusual feature of the typical CNS vasculitis and may suggest an environmental epitope with immune reaction as the cause.


Facile fabrication of efficient organic CMOS circuits.
Organic electronic circuits based on a combination of n- and p-type transistors (so-called CMOS circuits) are attractive, since they promise the realization of a manifold of versatile and low-cost electronic devices. Here, we report a novel photoinduced transformation method, which allows for a particularly straightforward fabrication of highly functional organic CMOS circuits. A solution-deposited single-layer film, comprising a mixture of the n-type semiconductor [6,6]-phenyl-C(61)-butyric acid methyl ester (PCBM) and the p-type semiconductor poly-3-hexylthiophene (P3HT) in a 3:1 mass ratio, was utilized as the common active material in an array of transistors. Selected film areas were exposed to laser light, with the result that the irradiated PCBM monomers were photochemically transformed into a low-solubility and high-mobility dimeric state. Thereafter, the entire film was developed via immersion into a developer solution, which selectively removed the nonexposed, and monomeric, PCBM component. The end result was that the transistors in the exposed film areas are n-type, as dimeric PCBM is the majority component in the active material, while the transistors in the nonexposed film areas are p-type, as P3HT is the sole remaining material. We demonstrate the merit of the method by utilizing the resulting combination of n-type and p-type transistors for the realization of CMOS inverters with a high gain of approximately 35.


The management of acne vulgaris in primary care: a cohort study of consulting and prescribing patterns using the Clinical Practice Research Datalink.
Effective management of acne vulgaris in primary care involves support (usually provided over a number of consultations) and prescription of effective treatments. However, consulting and prescribing patterns for acne in primary care are not well described. To describe the rate of primary-care consultations and follow-up consultations; prescribing patterns, including overall use of acne-related medications (ARMs); and initial and follow-up prescription for acne vulgaris in the U.K. U.K. primary-care acne consultations and prescriptions for ARMs were identified in the Clinical Practice Research Datalink. Annual consultation rates (between 2004 and 2013) by age and sex, new consultations and consultations in the subsequent year were calculated, along with prescribing trends - during a new consultation and over the subsequent 90 days and year - using the number of registered patients as the denominator. Two-thirds (66·1%) of patients who had a new acne consultation had no further acne consultations in the subsequent year. Overall 26·7%, 24·9%, and 23·6% and 2·8% of patients were prescribed no ARM, an oral antibiotic, a topical antibiotic or an oral plus topical antibiotic, respectively, during a new acne consultation. In total 60·1% and 38·6% of patients prescribed an ARM received no further ARM prescriptions in the following 90 days and 1 year, respectively, despite most prescriptions being for 2 months or less. Prescribing rates for lymecycline and topical combined clindamycin and benzoyl peroxide increased substantially between 2004 and 2013. There were no important changes in consultation rates between 2004 and 2013. These data suggest that patients with acne are receiving a suboptimal initial choice of ARMs, longitudinal care and prescribing.


How effective are selection methods in medical education? A systematic review.
Selection methods used by medical schools should reliably identify whether candidates are likely to be successful in medical training and ultimately become competent clinicians. However, there is little consensus regarding methods that reliably evaluate non-academic attributes, and longitudinal studies examining predictors of success after qualification are insufficient. This systematic review synthesises the extant research evidence on the relative strengths of various selection methods. We offer a research agenda and identify key considerations to inform policy and practice in the next 50 years. A formalised literature search was conducted for studies published between 1997 and 2015. A total of 194 articles met the inclusion criteria and were appraised in relation to: (i) selection method used; (ii) research question(s) addressed, and (iii) type of study design. Eight selection methods were identified: (i) aptitude tests; (ii) academic records; (iii) personal statements; (iv) references; (v) situational judgement tests (SJTs); (vi) personality and emotional intelligence assessments; (vii) interviews and multiple mini-interviews (MMIs), and (viii) selection centres (SCs). The evidence relating to each method was reviewed against four evaluation criteria: effectiveness (reliability and validity); procedural issues; acceptability, and cost-effectiveness. Evidence shows clearly that academic records, MMIs, aptitude tests, SJTs and SCs are more effective selection methods and are generally fairer than traditional interviews, references and personal statements. However, achievement in different selection methods may differentially predict performance at the various stages of medical education and clinical practice. Research into selection has been over-reliant on cross-sectional study designs and has tended to focus on reliability estimates rather than validity as an indicator of quality. A comprehensive framework of outcome criteria should be developed to allow researchers to interpret empirical evidence and compare selection methods fairly. This review highlights gaps in evidence for the combination of selection tools that is most effective and the weighting to be given to each tool.


A G protein-coupled receptor encoded by rhesus rhadinovirus is similar to ORF74 of Kaposi's sarcoma-associated herpesvirus.
Rhesus rhadinovirus (RRV) is a gamma-2 herpesvirus and is the rhesus macaque homologue of human herpesvirus 8 (HHV-8), also known as Kaposi's sarcoma-associated herpesvirus. DNA sequence analysis of RRV indicates that it shares numerous open reading frames (ORFs) with HHV-8, including one (ORF74) encoding a seven-transmembrane-spanning G protein-coupled receptor (GPCR) with similarity to cellular chemokine receptors. Examination of the predicted amino acid sequence of RRV ORF74 reveals that it encodes a seven-transmembrane-spanning GPCR sharing 40.8% amino acid sequence identity with HHV-8 ORF74 and 24.1% amino acid sequence identity with rhesus macaque CXCR2. In addition, immunofluorescence studies indicate that an epitope-tagged version of RRV ORF74 is expressed on the surfaces of transfected cells, suggesting that this protein is in fact a membrane receptor. In in vitro cell culture assays, RRV ORF74 possesses transforming potential, as NIH 3T3 clones stably expressing the receptor demonstrate an increased ability to grow in soft agarose and to induce tumor formation in nude mice. Further analysis of RRV ORF74 indicates that expression of the receptor in NIH 3T3 cells causes an increased secretion of vascular endothelial growth factor and activation of the ERK1/2 (p44/42) mitogen-activated protein kinase signaling pathway. The results of these studies suggest that RRV ORF74 encodes a GPCR with properties similar to those of its homologue in HHV-8 and that this gene may play a role in RRV-associated pathogenesis.


Major differences in the dynamics of primary and secondary progressive multiple sclerosis.
In patients with primary and secondary progressive multiple sclerosis (MS), major differences in the pattern and extent of abnormality on cerebral magnetic resonance imaging (MRI) between the two groups have recently been demonstrated. In the present study, 24 patients, matched for age, sex, duration of disease, and disability, had serial gadolinium diethylenetriaminepentaacetic acid-enhanced MRI over a 6-month period. The 12 patients in the secondary progressive group had a total of 109 new lesions over this time (18.2 lesions per patient per year) and 87% of these enhanced. Enhancement also occurred within and at the edge of preexisting lesions. In contrast, only 20 new lesions were seen in the primary progressive group (3.3 lesions per patient per year) and only one of these enhanced. There was no difference in the degree of clinical deterioration between the two groups over the 6-month period. These findings may indicate a difference in the dynamics of disease activity between the two forms of progressive MS, particularly in relation to the inflammatory component of the lesions, and have important implications for the selection of patients and the monitoring of disease activity in therapeutic trials.


The recent evolution of human L1 retrotransposons.
L1 elements are the most successful retrotransposons in mammals and are responsible for at least 30% of human DNA. Far from being indolent genomic parasites, L1 elements have evolved and amplified rapidly during human evolution. Indeed during just the last 25 million years (MY) five distinct L1 families have emerged and generated tens of thousands of copies. The most recently evolved human specific L1 family is currently active and L1 copies have been accumulating in the human genome at about the same rate per generation as the currently active L1 families in Old World rats and mice. At times during the last 25 MY L1 activity constituted a significant enough genetic load to be subject to negative selection. During these same times, and in apparent response to the host, L1 underwent adaptive evolution. Understanding the molecular basis for these evolutionary changes should help illuminate one of the least understood but most important aspects of L1 biology, namely the extent and nature of the interaction between L1 and its host.


Left ventricular angiography on exercise. A new method of assessing left ventricular function in ischaemic heart disease.
Left ventricular function was studied in 17 patients with ischaemic heart disease and compared with 4 patients with normal left ventricular function. The patients in the homogeneous group of ischaemic heart disease were further subdivided into those 'without angina' (n=5) and those 'with angina' (n=12), depending upon the presence of angina during supine leg exercise at the time of definitive study. At rest there was no significant difference in the heart rate, cardiac output, stroke volume, and left ventricular end-diastolic pressure (LVEDP) in the three groups. During exercise the cardiac output and stroke volume were significantly depressed and LVEDP was significantly raised in the ischaemic heart disease group as a whole but within this group failed to show any significant difference in patients with and without angina. The left ventricular end-diastolic volume (LVEDV) and end-systolic volume (LVESV) measurements showed clear separation of these three groups only on exercise. On exercise, there was decrease in LVEDV and LVESV (P less than 0.05; P less than 0.02) in the group with normal left ventricular function, no change in the group with ischaemic heart disease without angina, and striking increase in LVEDV and LVESV in the group with ischaemic heart disease and angina (P less than 0.01 and P less than 0.02, respectively). This angiographic method of assessing left ventricular function shows clear separation of the three groups and also highlights the significance of angina. Ejection fraction (EF), a commonly measured parameter of left ventricular function, failed to reflect consistent changes on exercise as compared to values at rest which emphasizes the limitations of the measurement of ejection fraction at rest.


Metagonimoides oregonensis (Heterophyidae: Digenea) infection in Pleurocerid snails and Desmognathus quadramaculatus salamander larvae in Southern Appalachian streams.
Metagonimoides oregonensis (Heterophyidae) is a little-known digenetic trematode that uses raccoons and possibly mink as definitive hosts, and stream snails and amphibians as intermediate hosts. Some variation in the life cycle and adult morphology in western and eastern populations has been previously noted. In the southern Appalachians, Pleurocera snails and stream salamanders, e.g., Desmognathus spp., are used as intermediate hosts in the life cycle. We completed a series of studies in this system examining some aspects of larval trematode morphology and first and second intermediate host use. Molecular sequencing of the 28S rDNA of cercariae in our survey placed them clearly within the heterophyid family. However, light and scanning electron microscopy revealed both lateral and dorso-ventral finfolds on the cercariae in our region, whereas original descriptions of M. oregonensis cercariae from the west coast indicate only a dorso-ventral finfold, so further work on the systematics of this group may be warranted. A survey of first intermediate host, Pleurocera proxima, from 7 streams in the region identified only M. oregonensis, virgulate-type cercariae, and cotylomicrocercous-type cercariae in the streams, with M. oregonensis having the highest prevalence, and the only type present that use amphibians as second intermediate hosts. Based on clearing and staining of 6 Desmognathus quadramaculatus salamander larvae, we found that individual salamanders could have over 600 metacercariae, which form between muscle fibers throughout the body. Histological observations suggest that the metacercariae do not cause excessive tissue damage or inflammation, and likely persist through metamorphosis, thereby transmitting potentially large numbers of worms to definitive host raccoons foraging along streams.


Compensating optical systems. Part 1: broadband holographic reconstruction.
The primary chromatic aberrations of a reconstructed holographic image can be compensated by a dispersive lens placed at the quasi-achromatic (QA) point of a hologram. The conditions for obtaining this compensation are derived. Three experimental systems that employ this compensation are discussed. Two of these are in line and use either a zone plate lens or flint glass lens as the dispersive element centered at the QA point. In the third system, an off-axis hologram is followed by an off-axis zone plate lens positioned at the offset QA point.


Health Systems Approach to Ensure Quality and Safety Amid COVID-19 Pandemic in Pakistan.
Ensuring quality and safe care during the coronavirus disease 2019 (COVID-19) pandemic offers a challenge to already strained health systems in low and middle-income countries (LMICs), such as Pakistan with less shock-absorbing capacities. There is a dearth of evidence on mechanisms to provide optimum quality care to COVID-19 patients in the resource-constrained healthcare environment. The lessons learned from the Ebola virus outbreak for the deficient health systems and quality improvement are considered to propose strengthening the health systems response to deliver quality-assured care to patients during the current pandemic. In this regard, the World Health Organization (WHO) health systems framework can serve as a guiding principle towards providing quality-assured and safe healthcare services during the ongoing pandemic in Pakistan by ensuring the availability of an adequate workforce, medical supplies and equipment, strong governance, active information system, and adequate health financing to effectively manage COVID-19. Research evidence is needed to be better prepared for an effective and coordinated health systems response to offer quality and safe care to patients. Key Words: Health systems approach, COVID-19 pandemic, Quality of healthcare, Safe care.


Iodine-doped sumanene and its application for the synthesis of chalcogenasumanenes and silasumanenes.
The synthesis of an iodine-doped sumanene, which represents the first example of halogen-doped buckybowls, is described. Pristine trithiasumanene, trisilasumanene and the hitherto unknown parent triselenasumanene, three interesting heterobuckybowls with significant synthetic challenges, were efficiently prepared from the iodine-doped sumanene through non-pyrolytic conditions. This work demonstrates the high potential of hypervalent iodines embedded in extended π-conjugated systems for the synthesis of novel curved and planar polycyclic aromatic hydrocarbons.


Small duct primary sclerosing cholangitis without inflammatory bowel disease is genetically different from large duct disease.
Small duct primary sclerosing cholangitis (PSC) is phenotypically a mild version of large duct PSC, but it is unknown whether these phenotypes share aetiology. We aimed to characterize their relationship by investigating genetic associations in the human leucocyte antigen (HLA) complex, which represent the strongest genetic risk factors in large duct PSC. Four classical HLA loci (HLA-A, HLA-B, HLA-C and HLA-DRB1) were genotyped in 87 small duct PSC patients, 485 large duct PSC patients and 1117 controls across three geographical regions. HLA-DRB1*13:01 (OR = 2.0, 95% CI 1.2-3.4, P = 0.01) and HLA-B*08 (OR = 1.6, 95% CI 1.1-2.4, P = 0.02) were significantly associated with small duct PSC compared with healthy controls. Based on the observed frequency of HLA-B*08 in small duct PSC, the strongest risk factor in large duct PSC, an estimated 32% (95% CI 4-65%) of this population can be hypothesized to represent early stages or mild variants of large duct PSC. This subgroup may be constituted by small duct PSC patients with inflammatory bowel disease (IBD), which greatly resembled large duct PSC in its HLA association. In contrast, small duct PSC without IBD was only associated with HLA-DRB1*13:01(P = 0.03) and was otherwise distinctly dissimilar from large duct PSC. Small duct PSC with IBD resembles large duct PSC in its HLA association and may represent early stages or mild variants of large duct disease. Different HLA associations in small duct PSC without IBD could indicate that this subgroup is a different entity. HLA-DRB1*13:01 may represent a specific risk factor for inflammatory bile duct disease.


Wolffia globosa-Mankai Plant-Based Protein Contains Bioactive Vitamin B12 and Is Well Absorbed in Humans.
Rare plants that contain corrinoid compounds mostly comprise cobalamin analogues, which may compete with cobalamin (vitamin B12 (B12)) metabolism. We examined the presence of B12 in a cultivated strain of an aquatic plant: Wolffia globosa (Mankai), and predicted functional pathways using gut-bioreactor, and the effects of long-term Mankai consumption as a partial meat substitute, on serum B12 concentrations. We used microbiological assay, liquid-chromatography/electrospray-ionization-tandem-mass-spectrometry (LC-MS/MS), and anoxic bioreactors for the B12 experiments. We explored the effect of a green Mediterranean/low-meat diet, containing 100 g of frozen Mankai shake/day, on serum B12 levels during the 18-month DIRECT-PLUS (ID:NCT03020186) weight-loss trial, compared with control and Mediterranean diet groups. The B12 content of Mankai was consistent at different seasons (p = 0.76). Several cobalamin congeners (Hydroxocobalamin(OH-B12); 5-deoxyadenosylcobalamin(Ado-B12); methylcobalamin(Me-B12); cyanocobalamin(CN-B12)) were identified in Mankai extracts, whereas no pseudo B12 was detected. A higher abundance of 16S-rRNA gene amplicon sequences associated with a genome containing a KEGG ortholog involved in microbial B12 metabolism were observed, compared with control bioreactors that lacked Mankai. Following the DIRECT-PLUS intervention (n = 294 participants; retention-rate = 89%; baseline B12 = 420.5 ± 187.8 pg/mL), serum B12 increased by 5.2% in control, 9.9% in Mediterranean, and 15.4% in Mankai-containing green Mediterranean/low-meat diets (p = 0.025 between extreme groups). Mankai plant contains bioactive B12 compounds and could serve as a B12 plant-based food source.


Insight into the potential application of polyphenol-rich dietary intervention in degenerative disease management.
In recent times, a great number of plants have been studied in order to identify new components with nutraceutical properties, among which are polyphenols. Dietary polyphenols represent a large group of bioactive molecules widely found in the food of plant origin and they have been found able to prevent the onset and progression of degenerative diseases, and to reduce and control their symptoms. These health protective effects have been mainly related to their antioxidant and anti-inflammatory properties. However, it must be considered that the application of isolated polyphenols as nutraceuticals is quite limited due to their poor systemic distribution and relative bioavailability. The present review highlights the potential effect of dietary intervention with polyphenol-rich food and plant extracts in patients with cancer, diabetes and neurodegenerative, autoimmune, cardiovascular and ophthalmic diseases, as well as the possible molecular mechanisms of action suggested in numerous studies with animal models.


Photodissociable dimer reduction products of 2-thiopyrimidine derivatives.
Both 4,6-dimethyl-2-thipyrimidine and its 1-methyl derivative undergo polarographic reduction in aqueous medium, via a 1e/1H+ reduction to a free radical which rapidly dimerizes to products isolates and identified as 4,4'-bis-(4,6-dimethyl-3,4-dihydropyrimidin-2-thione) and the corresponding 1-methyl dimer. The dimers may be oxidized electrolytically to regenerate the parent monomers. Both dimers also undergo photodissociation to quantitatively regenerate the parent monomers, in high quantum yield, 0.23 and 0.35 M/Einstein. The correlation between electrochemical and photochemical reductions of 2-thiopyrimidines are discussed, as well as the significance of the dimer photodissociation reactions in relation to nucleic acid photochemistry.


Amitraz Poisoning: The (Un) Common Poisoning.
Pesticide poisoning is always a clinical conundrum for the emergency physician (EP), the complexity of which increases when the pesticide has no antidote! Over the past decade, there has been a sharp increase in cases of Amitraz poisoning, a pesticide routinely used in veterinary medicine, available without a prescription. The usual presentation includes bradycardia, hypotension, poor sensorium, and miosis. In the absence of accurate history, these clinical features can be confused with the cholinergic toxidrome of organophosphorus poisoning. There is a dearth of literature regarding the presentation and protocols for the management of Amitraz poisoning with data mostly based on animal studies and pediatric case reports. Currently, the available medical literature in the form of case reports and case series form an invaluable source of information to the EP to formulate a working diagnosis and methodical approach to this pesticide. Here, we present two case reports highlighting the characteristic clinical features and bringing to light how an organized approach to the toxin can give satisfactory results.


The CRE-binding protein dCREB-A is required for Drosophila embryonic development.
We have previously described the cloning of a cyclic AMP response-element (CRE)-binding protein, dCREB-A, in Drosophila melanogaster that is similar to the mammalian CRE-binding protein CREB. dCREB-A is a member of the bZIP family of transcription factors, shows specific binding to the (CRE), and can activate transcription in cell culture. In this report, we describe the gene structure for dCREB-A, protein expression patterns throughout development and the necessary role for this gene in embryogenesis. The 4.5-kb transcript is encoded in six exons that are distributed over 21 kb of DNA. There are seven start sites and no TATA consensus sequences upstream. The dCREB-A protein is expressed in the nuclei of the embryonic salivary gland, proventriculus and stomadeum. Late in embryogenesis, tracheal cell nuclei and specific nuclei within the segments show staining with anti-dCREB-A antibodies. In adult female ovaries, dCREB-A is expressed in the stage 9 through stage 11 follicle cell nuclei. Null mutations of the dCREB-A gene give rise to animals that no longer express dCREB-A protein and die late in embryogenesis before or at hatching. The absolute requirement of dCREB-A for embryogenesis demonstrates a nonredundant function for a CRE-binding protein that will be useful in studying the role of specific signal transduction cascades in development.


Hierarchical genetic analysis of German cockroach (Blattella germanica) populations from within buildings to across continents.
Understanding the population structure of species that disperse primarily by human transport is essential to predicting and controlling human-mediated spread of invasive species. The German cockroach (Blattella germanica) is a widespread urban invader that can actively disperse within buildings but is spread solely by human-mediated dispersal over longer distances; however, its population structure is poorly understood. Using microsatellite markers we investigated population structure at several spatial scales, from populations within single apartment buildings to populations from several cities across the U.S. and Eurasia. Both traditional measures of genetic differentiation and Bayesian clustering methods revealed increasing levels of genetic differentiation at greater geographic scales. Our results are consistent with active dispersal of cockroaches largely limited to movement within a building. Their low levels of genetic differentiation, yet limited active spread between buildings, suggests a greater likelihood of human-mediated dispersal at more local scales (within a city) than at larger spatial scales (within and between continents). About half the populations from across the U.S. clustered together with other U.S. populations, and isolation by distance was evident across the U.S. Levels of genetic differentiation among Eurasian cities were greater than those in the U.S. and greater than those between the U.S. and Eurasia, but no clear pattern of structure at the continent level was detected. MtDNA sequence variation was low and failed to reveal any geographical structure. The weak genetic structure detected here is likely due to a combination of historical admixture among populations and periodic population bottlenecks and founder events, but more extensive studies are needed to determine whether signatures of global movement may be present in this species.


Initial evaluation of thyroid dysfunction - Are simultaneous TSH and fT4 tests necessary?
Guidelines for thyroid function evaluation recommend testing TSH first, then assessing fT4 only if TSH is out of the reference range (two-step), but many clinicians initially request both TSH and fT4 (one-step). Given limitations of previous studies, we aimed to compare the two-step with the one-step approach in an unselected community-dwelling study population, and develop a prediction score based on clinical parameters that could identify at-risk patients for thyroid dysfunction. Cross-sectional analysis of the population-based Busselton Health Study. We compared the two-step with the one-step approach, focusing on cases that would be missed by the two-step approach, i.e. those with normal TSH, but out-of-range fT4. We used likelihood ratio tests to identify demographic and clinical parameters associated with thyroid dysfunction and developed a clinical prediction score by using a beta-coefficient based scoring method. Following the two-step approach, 93.0% of all 4471 participants had normal TSH and would not need further testing. The two-step approach would have missed 3.8% of all participants (169 of 4471) with a normal TSH, but a fT4 outside the reference range. In 85% (144 of 169) of these cases, fT4 fell within 2 pmol/l of fT4 reference range limits, consistent with healthy outliers. The clinical prediction score that performed best excluded only 22.5% of participants from TSH testing. The two-step approach may avoid measuring fT4 in as many as 93% of individuals with a very small risk of missing thyroid dysfunction. Our findings do not support the simultaneous initial measurement of both TSH and fT4.


Corrective movements in response to displacements in visual feedback are more effective during periods of 13-35 Hz oscillatory synchrony in the human corticospinal system.
Oscillatory synchronization in the beta (approximately 20 Hz) band is a common feature of human motor control, manifest at cortical and muscular levels during tonic contraction. Here we test the hypothesis that the influence of visual feedback on performance in a positional hold task is increased during bursts of beta-band synchrony in the corticospinal motor system. Healthy subjects were instructed to extend their forefinger while receiving high-gain visual feedback of finger position on a PC screen. Small step displacements of the feedback signal were triggered either by bursts of beta oscillations in scalp electroencephalogram or randomly with respect to cortical beta activity, and the resulting positional corrections expressed as a percentage of the step displacement. Corrective responses to beta and randomly triggered step changes in visual feedback were 41.7+/-4.9 and 31.5+/-6.8%, respectively (P<0.05). A marked increase in the coherence in the beta band was also found between muscle activity and cortical activity during the beta-triggered condition. The results suggest that phasic elevations of beta activity in the corticospinal motor system are associated with an increase in the gain of the motor response to visual feedback during a tonic hold task. Beta activity may index a motor state in which processing relevant to the control of positional hold tasks is promoted, with behavioural consequences.


Effect of hypertension on the progress and prognosis of experimental focal glomerular sclerosis.
Effect of hypertension on progressive renal disease was examined in spontaneously hypertensive rats (SHR) with experimental focal glomerular sclerosis, produced by the intravenous administration of adriamycin (ADR). Serial changes of urinary protein, blood pressure and blood chemistry for 22 weeks after ADR-treatment, and renal histology at week 22, were compared between ADR-treated SHR (group ADR-HT) and ADR-treated SHR given antihypertensive drugs (group ADR-AH). Hypertension persisted in group ADR-HT, while blood pressure markedly decreased in group ADR-AH, after oral administration of antihypertensive drugs (guanethidine and hydralazine). Massive proteinuria, hypoalbuminaemia and hypercholesterolaemia were observed throughout the experiment both in group ADR-HT and in group ADR-AH. Urinary protein levels were significantly larger in the former at weeks 12 and 16. Blood urea nitrogen and serum creatinine levels increased progressively from week 16 in the ADR-treated rats. The increase was more rapid in group ADR-HT than in group ADR-AH. In group ADR-HT, 10 of 25 rats died between weeks 20 and 22, whereas all in group ADR-AH survived. Histologically, ADR-treated rats showed focal glomerular sclerosis with tubulointerstitial changes. The lesions were more extensive in group ADR-HT than in group ADR-AH. We conclude that hypertension influences the progress and prognosis of chronic progressive renal disease, as induced by adriamycin.


Investigating the exercise-prescription practices of nurses working in inpatient mental health settings.
Nurses working in mental health are well positioned to prescribe exercise to people with mental illness. However, little is known regarding their exercise-prescription practices. We examined the self-reported physical activity and exercise-prescription practices of nurses working in inpatient mental health facilities. Thirty-four nurses completed the Exercise in Mental Illness Questionnaire - Health Practitioner Version. Non-parametric bivariate statistics revealed no relationship between nurses' self-reported physical activity participation and the frequency of exercise prescription for people with mental illness. Exercise-prescription parameters used by nurses are consistent with those recommended for both the general population and for people with mental illness. A substantial number of barriers to effective exercise prescription, including lack of training, systemic issues (such as prioritization and lack of time), and lack of consumer motivation, impact on the prescription of exercise for people with mental illness. Addressing the barriers to exercise prescription could improve the proportion of nurses who routinely prescribe exercise. Collaboration with exercise professionals, such as accredited exercise physiologists or physiotherapists, might improve knowledge of evidence-based exercise-prescription practices for people with mental illness, thereby improving both physical and mental health outcomes for this vulnerable population.


Enteric infections, diarrhea, and their impact on function and development.
Enteric infections, with or without overt diarrhea, have profound effects on intestinal absorption, nutrition, and childhood development as well as on global mortality. Oral rehydration therapy has reduced the number of deaths from dehydration caused by infection with an enteric pathogen, but it has not changed the morbidity caused by such infections. This Review focuses on the interactions between enteric pathogens and human genetic determinants that alter intestinal function and inflammation and profoundly impair human health and development. We also discuss specific implications for novel approaches to interventions that are now opened by our rapidly growing molecular understanding.


Experimental evaluation of subcarrier modulation in chaotic optical communication systems.
Data streams with bit rates of up to 1 Gbit/s have been applied though the subcarrier modulation technique in an experimentally deployed optical communication system based on chaos data encryption and have been recovered efficiently. By shifting the spectral components of the encrypted data in regions where the chaotic carrier is powerful, a more efficient encryption and final message recovery is recorded with respect to the baseband modulation technique, improving the up-to-date performance of analogous systems.


Evaluation and application of modularly assembled zinc-finger nucleases in zebrafish.
Zinc-finger nucleases (ZFNs) allow targeted gene inactivation in a wide range of model organisms. However, construction of target-specific ZFNs is technically challenging. Here, we evaluate a straightforward modular assembly-based approach for ZFN construction and gene inactivation in zebrafish. From an archive of 27 different zinc-finger modules, we assembled more than 70 different zinc-finger cassettes and evaluated their specificity using a bacterial one-hybrid assay. In parallel, we constructed ZFNs from these cassettes and tested their ability to induce lesions in zebrafish embryos. We found that the majority of zinc-finger proteins assembled from these modules have favorable specificities and nearly one-third of modular ZFNs generated lesions at their targets in the zebrafish genome. To facilitate the application of ZFNs within the zebrafish community we constructed a public database of sites in the zebrafish genome that can be targeted using this archive. Importantly, we generated new germline mutations in eight different genes, confirming that this is a viable platform for heritable gene inactivation in vertebrates. Characterization of one of these mutants, gata2a, revealed an unexpected role for this transcription factor in vascular development. This work provides a resource to allow targeted germline gene inactivation in zebrafish and highlights the benefit of a definitive reverse genetic strategy to reveal gene function.


Doctors' attitudes towards the detection and treatment of hypertension in older people.
Within the former northern region a questionnaire was sent to a one in two random sample of general practitioners and to consultant physicians involved in the treatment of older hypertensive patients, to determine current attitudes of doctors to the management of hypertension in older people. A total of 407 general practitioners and 125 consultant physicians (including 38 consultant geriatricians) completed the questionnaire; response rates of 58% and 73% respectively. The median (range) threshold level for intervention of an otherwise well 75-year-old patient was 180 (140-240)/100 (90-120) mm Hg for general practitioners as against current recommendations of > or = 160/90 mm Hg. Geriatricians adopted significantly lower thresholds than both general practitioners and other specialists. Target blood pressure (BP) and drug therapy were in line with British Hypertension Society recommendations. The majority of general practitioners stated that they would initiate treatment for hypertension later, be less aggressive in their treatment and accept higher levels of BP than with younger patients. Approximately half perceived compliance and lifestyle changes as problematic in older people, while approximately a third were concerned about the problems created by drug treatment and uncertainty about the practicality of treating all older hypertensive patients. A quarter expressed reluctance to initiate hypertensive treatment because of side effects and to treat isolated systolic hypertension. These stated attitudes amongst general practitioners may explain the continuing conservatism in the management of hypertension. This study found considerable variation in diagnostic threshold between doctors, which suggests that current management of hypertension in older people is likely to vary significantly.


Long non-coding antisense RNA controls Uchl1 translation through an embedded SINEB2 repeat.
Most of the mammalian genome is transcribed. This generates a vast repertoire of transcripts that includes protein-coding messenger RNAs, long non-coding RNAs (lncRNAs) and repetitive sequences, such as SINEs (short interspersed nuclear elements). A large percentage of ncRNAs are nuclear-enriched with unknown function. Antisense lncRNAs may form sense-antisense pairs by pairing with a protein-coding gene on the opposite strand to regulate epigenetic silencing, transcription and mRNA stability. Here we identify a nuclear-enriched lncRNA antisense to mouse ubiquitin carboxy-terminal hydrolase L1 (Uchl1), a gene involved in brain function and neurodegenerative diseases. Antisense Uchl1 increases UCHL1 protein synthesis at a post-transcriptional level, hereby identifying a new functional class of lncRNAs. Antisense Uchl1 activity depends on the presence of a 5' overlapping sequence and an embedded inverted SINEB2 element. These features are shared by other natural antisense transcripts and can confer regulatory activity to an artificial antisense to green fluorescent protein. Antisense Uchl1 function is under the control of stress signalling pathways, as mTORC1 inhibition by rapamycin causes an increase in UCHL1 protein that is associated to the shuttling of antisense Uchl1 RNA from the nucleus to the cytoplasm. Antisense Uchl1 RNA is then required for the association of the overlapping sense protein-coding mRNA to active polysomes for translation. These data reveal another layer of gene expression control at the post-transcriptional level.


Discovery of cancer susceptibility genes: study designs, analytic approaches, and trends in technology.
Determining the genetic causes of cancers has immense public health benefits, ranging from prevention to earlier detection and treatment of disease. Although a number of cancer susceptibility genes have been successfully identified, design and analytic issues remain that challenge the current paradigm of gene discovery. Some examples are the definition and measurement of cancer phenotype, the use of intermediate end points, the choice of sample (e.g., affected relative pairs versus large extended pedigrees), the choice of analytic method [e.g., parametric logarithm of the odds (LOD) score method versus model-free methods], and the influence of gene-environment interaction on linkage analysis. Furthermore, association methods, based on either the traditional case-control study design or family-based controls, are popular choices to evaluate candidate genes or screen for linkage disequilibrium. Finally, the study design and analytic methods for gene discovery are determined to some extent by what genomic technology is feasible within the laboratory. Many of the main issues related to gene discovery, as well as trends in genomic technology that will impact on gene discovery, are discussed from the perspective of their strengths and weaknesses, pointing to areas in need of further work.


Late complications of clinical clostridium histolyticum collagenase use in Dupuytren's disease.
While Dupuytren's disease can cause disabling contractures requiring open surgery, a less-invasive option using Clostridium Histolyticum collagenase (CHC) via percutaneous injection was recently reported. A recent prospective, randomized trial demonstrated few complications during 90 days follow-up, however did not assess any longer term follow-up for these patients. Long-term outcomes in this setting have not been adequately reported, and the current manuscript aims to identify late complications from the clinical use of percutaneous CHC. The current manuscript reports an extended 12-month follow-up for a cohort of twelve of patients enrolled in the original prospective, randomized trial, treated at a single institution. An analysis of complications requiring surgical intervention was undertaken. Two of twelve patients reported debilitating pain and triggering requiring surgical intervention. Extensive deep-tissue scarring and adhesions were identified, providing the first visual and qualitative analysis of the pathologic effects of CHC. Late complications from CHC use can and have occurred, outside the follow-up period of the initial phase III trials. Longer term follow-up of such patients is thus essential, and further investigation and characterization of the late effects of CHC use is warranted.


Two-eyed seeing: A useful gaze in Indigenous medical education research.
Medical education has a role in preparing future health care practitioners to have the skills to meaningfully address health disparities while providing effective clinical care considerate of diversity in our societies. This calls for medical education researchers to approach their craft in ways that prioritise and value inputs from a broader range of perspectives and worldviews in an effort to redress the negative impacts of social, political and structural forces on health outcomes. Given the entrenched health inequities experienced by Indigenous populations across the globe, this paper details an approach to medical education research put forward by Canadian Mi'kmaw Elders Murdena and Albert Marshall and named 'two-eyed seeing'. This approach provides the opportunity for medical education researchers to address the ongoing impacts of colonisation, racism and marginalisation on health outcomes by prioritising Indigenous worldviews in medical curricula. The need for researchers and medical academies to critically consider Indigenous governance and processes of respectful knowledge sharing within the wider institutional and societal contexts is addressed. The benefits of two-eyed seeing in the context of better preparing the future workforce to effectively meet the needs of those most vulnerable, and to action change against health inequities, situate it as a promising research approach in medical education.


The Relationship of Living Environment with Behavioral and Fitness Outcomes by Sex: an Exploratory Study in College-aged Students.
Although physical activity (PA) is associated with several health benefits, there is a marked decline during college years, which is an influential period for the development of health behaviors. This study examined the relationship of neighborhood and living environment with behavioral (PA and sedentary behavior) and fitness outcomes by sex. Participants were college students that participated in a fitness assessment, followed by a survey that measured self-reported exercise and perception of one's environment (sidewalks, crime, traffic, access to PA resources in their neighborhood and/or apartment complex). Pearson correlations examined the relationship between behavioral (moderate and vigorous PA, sedentary behavior, active travel) and fitness outcomes (VO2max, percent body fat, body mass index, push-ups, curl-ups, blood lipids and glucose) with environmental measures separately by sex. Among participants (n=444; female=211, male n=234) environment was significantly related to PA and fitness, with noted differences by sex. For males, seeing others exercising in the neighborhood and in their apartment complex, using neighborhood bike lanes, crime and the number of PA resources at their apartment complex were associated with behavioral and fitness outcomes. Among females, sidewalks in the neighborhood, seeing others exercising, using neighborhood bike lanes and number of PA apartment complex resources were significantly correlated with fitness and behavioral outcomes. These findings suggest a possible relationship between students' objectively measured fitness and their environment for PA. Future implications include the development of policies to create student housing that supports physical activity and expansion of campus wellness initiatives to off-campus locations.


Reproductive behaviour among women on antiretroviral therapy in Botswana: mismatched pregnancy plans and contraceptive use.
Understanding pregnancy planning and contraceptive use is important in preventing unplanned/unwanted pregnancies among women on antiretroviral therapy (ART). Through a cross-sectional survey of 155 women living with HIV on ART in Botswana (mean age = 36), bivariate/multivariate analyses were used to identify and understand pregnancy planning and contraceptive use. Women who did not plan to have a child (n = 85) were older, less educated, had more children and worried about stigmatisation from family and healthcare workers (HCWs). Multivariate analyses found age (OR:3.41; CI:1.57-7.45; p = 0.002); perceived stigmatisation from family and healthcare workers (OR:3.62; CI:1.47-8.96; p = 0.005); and believing it is irresponsible for women living with HIV to want a child (OR:2.40; CI:1.10-5.24; p = 0.028) to be significantly associated with not planning to have a child. Although reported condom use among 85 women who did not plan to have a child was nearly 90%, a total of 26 of these women (34%) believed they did not have control over condom use. Lack of contraception was reported by 6 women who did not plan a child; this, coupled with the lack of control over condom use, puts unmet need for contraception at 38%. Most women reported feeling comfortable talking with HCWs about contraceptives. However, almost a quarter of the women indicated they were infrequently advised about contraceptives at ART clinics. This study found discordance between pregnancy planning and contraceptive use among women on ART. Lack of control over condom use coupled with low hormonal contraceptive use creates unmet need for contraception and increases the risk of unwanted pregnancies. Regular clinic visits for women on ART present excellent opportunities to address contraceptive needs in a considerate and comprehensive manner.


Protocol for a randomized controlled trial evaluating the effect of physical activity on delaying the progression of white matter changes on MRI in older adults with memory complaints and mild cognitive impairment: the AIBL Active trial.
Older adults free of dementia but with subjective memory complaints (SMC) or mild cognitive impairment (MCI) are considered at increased risk of cognitive decline. Vascular risk factors (VRF), including hypertension, heart disease, smoking, hypercholesterolemia and lack of physical activity (PA) have been identified as modifiable risk factors contributing to cognitive decline, and white matter hyperintensities (WMH) are associated with VRF, SMC and cognitive impairment. Findings from a growing number of clinical trials with older adults are providing strong evidence for the benefits of physical activity for maintaining cognitive function, but few studies are investigating these benefits in high-risk populations. The aim of AIBL Active is to determine whether a 24-month physical activity program can delay the progression of white matter changes on magnetic resonance imaging (MRI). This single-blind randomized controlled trial (RCT) is offered to 156 participants, aged 60 and older, in the Melbourne arm of the Australian Imaging Biomarkers and Lifestyle Flagship Study of Aging (AIBL). Participants must have SMC with or without MCI and at least one VRF. The PA intervention is a modification of the intervention previously trialed in older adults with SMC and MCI (Fitness for the Ageing Brain Study). It comprises 24 months of moderate, home-based PA (150 minutes per week) and a behavioral intervention package. The primary outcome measure will be change in WMH after 24 months on MRI. Cognition, quality of life, functional fitness, level of physical activity, plasma biomarkers for cerebrovascular disease and amyloid positron emission tomography (PET) imaging comprise secondary measures. Currently, there is no effective pharmacological treatment available to delay cognitive decline and dementia in older adults at risk. Should our findings show that physical activity can slow down the progression of WMH, this RCT would provide an important proof of concept. Since imbedded in AIBL this RCT will also be able to investigate the interaction between vascular and Alzheimer's disease pathologies. Australia New Zealand Clinical Trials Registry ACTRN12611000612910.


Comparison of Bacillus monooxygenase genes for unique fatty acid production.
This paper reviews Bacillus genes encoding monooxygenase enzymes producing unique fatty acid metabolites. Specifically, it examines standard monooxygenase electron transfer schemes and related domain structures of these fused domain enzymes on route to understanding the observed oxygenase activities. A few crystallographic analyses of the standard bearer enzyme P450(BM-3) are discussed to try to rationalize the common chemistries of this important enzyme family. Detailed P450(BM-3) enzyme activities toward different substrates and the unique substrate-specific primary oxidation products are examined. A few orthologs to the recurring P450(BM-3) enzyme as well as related small single-to-triple nucleotides changed mutants are also discussed. Finally, preliminary data characterizing unique in vivo-based primary and secondary products of a novel ortholog, the ALA2 strain, are presented. This later strain synthesizes several unique multi-oxidized reaction products that require additional study to further understand. It is hoped that a better understanding of these oxygenase reactions, particularly the ALA2 strain, will allow for realistically priced production of target multiple-oxygenated compounds with potential uses as specialty chemicals or as therapeutic agents.


Does exercise prevent major non-communicable diseases and premature mortality? A critical review based on results from randomized controlled trials.
Observational studies show that physical activity is strongly associated with a reduced risk of premature mortality and major non-communicable diseases. We reviewed to which extent these associations have been confirmed in randomized controlled trials (RCTs) for the outcomes of mortality, cardiovascular disease (CVD), type 2 diabetes (T2D), and fracture. The results show that exercise does not reduce all-cause mortality and incident CVD in older adults or in people with chronic conditions, based on RCTs comprising ∼50,000 participants. The results also indicate a lack of effect on cardiovascular mortality in people with chronic conditions, based on RCTs comprising ∼11,000 participants. Furthermore, there is inconsistent evidence regarding the effect of exercise on fractures in older adults, based on RCTs comprising ∼40,000 participants. Finally, based on RCTs comprising ∼17,000 participants, exercise reduces T2D incidence in people with prediabetes when combined with dietary modification, although evidence for the individual effect of exercise is lacking. Identified shortcomings of the current evidence include risks of publication bias, lack of high-quality studies in certain high-risk populations, and inconstant evidence with respect to some outcomes. Thus, additional large trials would be of value, especially with fracture as the primary outcome. In conclusion, according to current RCT evidence, exercise can prevent T2D assuming it is combined with dietary intervention. However, the current evidence shows that exercise does not prevent premature mortality or CVD, with inconsistent evidence for fractures.


Stigma, treatment beliefs, and substance abuse treatment use in historically disadvantaged communities.
Access to substance abuse treatment among historically disadvantaged communities (HDCs) in Cape Town, South Africa is limited, despite a growing demand for services. Although research has reported on structural barriers to treatment access, nonstructural factors remain largely unexplored. The aim of this paper is to describe two nonstructural influences on the use of substance abuse treatment services for people from HDCs: stigma and negative beliefs about treatment. Findings from the qualitative component of a multi-method study are reported. In-depth interviews were conducted with 20 key informants, all of whom worked or lived in HDCs in the greater Cape Town area. Content and thematic techniques were used to analyse data. According to key informants (i) stigma towards individuals with substance use disorders was prevalent in HDCs and negatively impacted on attempts to access services; (ii) negative beliefs about the quality and effectiveness of treatment were commonplace and acted as barriers to the use of existing services; and (iii) several factors contributed to these non-structural barriers including media representations of both individuals with substance use disorders and treatment facilities for these disorders. This paper moves beyond the description of structural barriers to treatment to describe how two nonstructural factors, stigma and negative beliefs about treatment, hinder treatment seeking for substance use disorders. Recommendations for addressing these barriers include efforts to (i) shift discourses about substance abuse treatment, (ii) improve service quality, and (iii) address myths and misconceptions about treatment.


Serum lipidomics meets cardiac magnetic resonance imaging: profiling of subjects at risk of dilated cardiomyopathy.
Dilated cardiomyopathy (DCM), characterized by left ventricular dilatation and systolic dysfunction, constitutes a significant cause for heart failure, sudden cardiac death or need for heart transplantation. Lamin A/C gene (LMNA) on chromosome 1p12 is the most significant disease gene causing DCM and has been reported to cause 7-9% of DCM leading to cardiac transplantation. We have previously performed cardiac magnetic resonance imaging (MRI) to LMNA carriers to describe the early phenotype. Clinically, early recognition of subjects at risk of developing DCM would be important but is often difficult. Thus we have earlier used the MRI findings of these LMNA carriers for creating a model by which LMNA carriers could be identified from the controls at an asymptomatic stage. Some LMNA mutations may cause lipodystrophy. To characterize possible effects of LMNA mutations on lipid profile, we set out to apply global serum lipidomics using Ultra Performance Liquid Chromatography coupled to mass spectrometry in the same LMNA carriers, DCM patients without LMNA mutation and controls. All DCM patients, with or without LMNA mutation, differed from controls in regard to distinct serum lipidomic profile dominated by diminished odd-chain triglycerides and lipid ratios related to desaturation. Furthermore, we introduce a novel approach to identify associations between the molecular lipids from serum and the MR images from the LMNA carriers. The association analysis using dependency network and regression approaches also helped us to obtain novel insights into how the affected lipids might relate to cardiac shape and volume changes. Our study provides a framework for linking serum derived molecular markers not only with clinical endpoints, but also with the more subtle intermediate phenotypes, as derived from medical imaging, of potential pathophysiological relevance.


Applied physiology and game analysis of rugby union.
Increased professionalism in rugby has elicited rapid changes in the fitness profile of elite players. Recent research, focusing on the physiological and anthropometrical characteristics of rugby players, and the demands of competition are reviewed. The paucity of research on contemporary elite rugby players is highlighted, along with the need for standardised testing protocols. Recent data reinforce the pronounced differences in the anthropometric and physical characteristics of the forwards and backs. Forwards are typically heavier, taller, and have a greater proportion of body fat than backs. These characteristics are changing, with forwards developing greater total mass and higher muscularity. The forwards demonstrate superior absolute aerobic and anaerobic power, and muscular strength. Results favour the backs when body mass is taken into account. The scaling of results to body mass can be problematic and future investigations should present results using power function ratios. Recommended tests for elite players include body mass and skinfolds, vertical jump, speed, and the multi-stage shuttle run. Repeat sprint testing is a possible avenue for more specific evaluation of players. During competition, high-intensity efforts are often followed by periods of incomplete recovery. The total work over the duration of a game is lower in the backs compared with the forwards; forwards spend greater time in physical contact with the opposition while the backs spend more time in free running, allowing them to cover greater distances. The intense efforts undertaken by rugby players place considerable stress on anaerobic energy sources, while the aerobic system provides energy during repeated efforts and for recovery. Training should focus on repeated brief high-intensity efforts with short rest intervals to condition players to the demands of the game. Training for the forwards should emphasise the higher work rates of the game, while extended rest periods can be provided to the backs. Players should not only be prepared for the demands of competition, but also the stress of travel and extreme environmental conditions. The greater professionalism of rugby union has increased scientific research in the sport; however, there is scope for significant refinement of investigations on the physiological demands of the game, and sports-specific testing procedures.


Long-term lanreotide treatment in six patients with congenital hyperinsulinism.
Medical treatment is a substantial therapeutic measure to achieve glycemic control and prevent hypoglycemic brain damage without surgery in patients with congenital hyperinsulinism (CHI). However, only few drugs are available and even fewer are approved as a medical therapy to maintain normal blood glucose levels. The established therapies are demanding for caregivers and complicated by different side effects such as gastrointestinal symptoms, hypertrichosis, and obesity. Therefore, it is important to develop new strategies to improve blood glucose control. We report the use of the very-long-acting somatostatin analogue lanreotide autogel in 6 patients with CHI over a mean duration of 40.8 months. Blood glucose levels before and after the start and dosage titration of lanreotide in these patients are compared. In 3 of 6 patients, switching to lanreotide raised mean blood glucose levels and reduced individually as well as overall the risk for hypoglycemic episodes (odds ratio 0.38) significantly. Lanreotide autogel can be used as an alternative pharmacological treatment and may be beneficial in conservatively treated patients with CHI.


Network search method in the design of extreme ultraviolet lithographic objectives.
The merit function space of mirror system for extreme ultraviolet (EUV) lithography is studied. Local minima situated in the multidimensional optical merit function space are connected via links that contain saddle points and form a network. We present networks for EUV lithographic objective designs and discuss how these networks change when control parameters, such as aperture and field, are varied, and constraints are used to limit the variation domain of the variables. A good solution in a network, obtained with a limited number of variables, has been locally optimized with all variables to meet practical requirements.


Quantitative assessment of upper limb motion in neurorehabilitation utilizing inertial sensors.
Two inertial sensor systems were developed for 3-D tracking of upper limb movement. One utilizes four sensors and a kinematic model to track the positions of all four upper limb segments/joints and the other uses one sensor and a dead reckoning algorithm to track a single upper limb segment/joint. Initial evaluation indicates that the system using the kinematic model is able to track orientation to 1 degree and position to within 0.1 cm over a distance of 10 cm. The dead reckoning system combined with the "zero velocity update" correction can reduce errors introduced through double integration of errors in the estimate in offsets of the acceleration from several meters to 0.8% of the total movement distance. Preliminary evaluation of the systems has been carried out on ten healthy volunteers and the kinematic system has also been evaluated on one patient undergoing neurorehabilitation over a period of ten weeks. The initial evaluation of the two systems also shows that they can monitor dynamic information of joint rotation and position and assess rehabilitation process in an objective way, providing additional clinical insight into the rehabilitation process.


The spacious active site of a Y-family DNA polymerase facilitates promiscuous nucleotide incorporation opposite a bulky carcinogen-DNA adduct: elucidating the structure-function relationship through experimental and computational approaches.
Y-family DNA polymerases lack some of the mechanisms that replicative DNA polymerases employ to ensure fidelity, resulting in higher error rates during replication of undamaged DNA templates and the ability to bypass certain aberrant bases, such as those produced by exposure to carcinogens, including benzo[a]pyrene (BP). A tumorigenic metabolite of BP, (+)-anti-benzo-[a]pyrene diol epoxide, attacks DNA to form the major 10S (+)-trans-anti-[BP]-N(2)-dG adduct, which has been shown to be mutagenic in a number of prokaryotic and eukaryotic systems. The 10S (+)-trans-anti-[BP]-N(2)-dG adduct can cause all three base substitution mutations, and the SOS response in Escherichia coli increases bypass of bulky adducts, suggesting that Y-family DNA polymerases are involved in the bypass of such lesions. Dpo4 belongs to the DinB branch of the Y-family, which also includes E. coli pol IV and eukaryotic pol kappa. We carried out primer extension assays in conjunction with molecular modeling and molecular dynamics studies in order to elucidate the structure-function relationship involved in nucleotide incorporation opposite the bulky 10S (+)-trans-anti-[BP]-N(2)-dG adduct by Dpo4. Dpo4 is able to bypass the 10S (+)-trans-anti-[BP]-N(2)-dG adduct, albeit to a lesser extent than unmodified guanine, and the V(max) values for insertion of all four nucleotides opposite the adduct by Dpo4 are similar. Computational studies suggest that 10S (+)-trans-anti-[BP]-N(2)-dG can be accommodated in the active site of Dpo4 in either the anti or syn conformation due to the limited protein-DNA contacts and the open nature of both the minor and major groove sides of the nascent base pair, which can contribute to the promiscuous nucleotide incorporation opposite this lesion.


Effect of nutrient intake and Helicobacter pylori infection on gastric cancer in Korea: a case-control study.
To examine the effects of dietary factor and Helicobacter pylori (H. pylori) infection with emphasis on vitamin intake on the risk of gastric cancer (GC), we conducted a case-control study in South Korea, a high-risk area for GC. Trained dietitians interviewed 136 cases histologically diagnosed with GC. An equal number of hospital controls was selected by matching sex and age. High dietary intakes of vegetable fat [odds ratio (OR) = 0.35; 95% confidence interval (CI) = 0.15-0.83], folate (OR = 0.35; 95% CI = 0.13-0.96), and antioxidants, such as vitamin A (OR = 0.34; 95% CI = 0.13-0.83), beta-carotene (OR = 0.33; 95% CI = 0.13-0.82), vitamin C (OR = 0.26; 95% CI = 0.09-0.72), and vitamin E (OR = 0.41; 95% CI = 0.17-1.01), were shown to have a protective effect on GC risk using a multivariate model adjusting for foods significantly related to GC in our previous study (charcoal grilled beef, spinach, garlic, mushroom, and a number of types of kimchi) and supplement use. When stratified according to H. pylori infection, high intakes of vitamin C (OR = 0.10; 95% CI = 0.02-0.63) and vitamin E (OR = 0.16; 95% CI = 0.03-0.83) exhibited highly significant inverse associations with GC among the H. pylori-infected subjects compared with noninfected individuals. GC risk was significantly decreased only when consumption levels for two of these vitamins were high. Our findings suggest that high intake of antioxidant vitamins contribute to the reduction of GC risk and that GC risk in Korea may be decreased by encouraging those with H. pylori infection to increase their intake of antioxidant vitamins.


Proton sensitivity of ASIC1 appeared with the rise of fishes by changes of residues in the region that follows TM1 in the ectodomain of the channel.
The acid-sensitive ion channel 1 (ASIC1) is a neuronal Na+ channel insensitive to changes in membrane potential but is gated by external protons. Proton sensitivity is believed to be essential for the role of ASIC1 in modulating synaptic transmission and nociception in the mammalian nervous system. To examine the structural determinants that confer proton sensitivity, we cloned and functionally characterized ASIC1 from different species of the chordate lineage: lamprey, shark, toadfish and chicken. We observed that ASIC1s from early vertebrates (lamprey and shark) were proton insensitive in spite of a high degree of amino acid conservation (66-67%) with their mammalian counterparts. Sequence analysis showed that proton-sensitive ASIC1s could not be distinguished from proton-insensitive channels by any signature in the protein sequence. Chimeras made with rat ASIC1 (rASIC1) and lamprey or shark indicated that most of the ectodomain of rASIC1 was required to confer proton sensitivity and the distinct kinetics of activation and desensitization of the rat channel. Proton-sensitive chimeras contained the segment D78-E136, together with residues D351, Q358 and E359 of the rat sequence. However, none of the functional chimeras containing only part of the rat extracellular domain retained the kinetics of activation and desensitization of rASIC1, suggesting that residues distributed in several regions of the ectodomain contribute to allosteric changes underlying activation and desensitization. The results also demonstrate that gating by protons is not a feature common to all ASIC1 channels. Proton sensitivity arose recently in evolution, implying that agonists different from protons activate ASIC1 in lower vertebrates.


Earliest evidence for cheese making in the sixth millennium BC in northern Europe.
The introduction of dairying was a critical step in early agriculture, with milk products being rapidly adopted as a major component of the diets of prehistoric farmers and pottery-using late hunter-gatherers. The processing of milk, particularly the production of cheese, would have been a critical development because it not only allowed the preservation of milk products in a non-perishable and transportable form, but also it made milk a more digestible commodity for early prehistoric farmers. The finding of abundant milk residues in pottery vessels from seventh millennium sites from north-western Anatolia provided the earliest evidence of milk processing, although the exact practice could not be explicitly defined. Notably, the discovery of potsherds pierced with small holes appear at early Neolithic sites in temperate Europe in the sixth millennium BC and have been interpreted typologically as 'cheese-strainers', although a direct association with milk processing has not yet been demonstrated. Organic residues preserved in pottery vessels have provided direct evidence for early milk use in the Neolithic period in the Near East and south-eastern Europe, north Africa, Denmark and the British Isles, based on the δ(13)C and Δ(13)C values of the major fatty acids in milk. Here we apply the same approach to investigate the function of sieves/strainer vessels, providing direct chemical evidence for their use in milk processing. The presence of abundant milk fat in these specialized vessels, comparable in form to modern cheese strainers, provides compelling evidence for the vessels having being used to separate fat-rich milk curds from the lactose-containing whey. This new evidence emphasizes the importance of pottery vessels in processing dairy products, particularly in the manufacture of reduced-lactose milk products among lactose-intolerant prehistoric farming communities.


Improving the evidence base of Markov models used to estimate the costs of scaling up antiretroviral programmes in resource-limited settings.
Despite concerns about affordability and sustainability, many models of the lifetime costs of antiretroviral therapy (ART) used in resource limited settings are based on data from small research cohorts, together with pragmatic assumptions about life-expectancy. This paper revisits these modelling assumptions in order to provide input to future attempts to model the lifetime costs and the costs of scaling up ART. We analysed the determinants of costs and outcomes in patients receiving ART in line with standard World Health Organization (WHO) guidelines for resource poor settings in a private sector managed ART programme in South Africa. The cohort included over 5,000 patients with up to 4 years (median 19 months) on ART. Generalized linear and Cox proportional hazards regression models were used to establish cost and outcome determinants respectively. The key variables associated with changes in mean monthly costs were: being on the second line regimen; receiving ART from 4 months prior to 4 months post treatment initiation; having a recent or current CD4 count <50 cells/microL or 50-199 cells/microl; having mean ART adherence <75% as determined by monthly pharmacy refill data; and having a current or recent viral load >100,000 copies/mL. In terms of the likelihood of dying, the key variables were: baseline CD4 count<50 cells/microl (particularly during the first 4 months on treatment); current CD4 count <50 cells/microl and 50-199 cells/microl (particularly during later periods on treatment); and being on the second line regimen. Being poorly adherent and having an unsuppressed viral load was also associated with a higher likelihood of dying. While there are many unknowns associated with modelling the resources needed to scale-up ART, our analysis has suggested a number of key variables which can be used to improve the state of the art of modelling ART. While the magnitude of the effects associated with these variables would be likely to differ in other settings, the variables influencing costs and survival are likely to be generalizable. This is of direct relevance to those concerned about assessing the long-term costs and sustainability of expanded access to ART.


Trypanosoma cruzi proline racemases are involved in parasite differentiation and infectivity.
Polyclonal lymphocyte activation is one of the major immunological disturbances observed after microbial infections and among the primary strategies used by the parasite Trypanosoma cruzi to avoid specific immune responses and ensure survival. T. cruzi is the insect-transmitted protozoan responsible for Chagas' disease, the third public health problem in Latin America. During infection of its mammalian host, the parasite secretes a proline racemase that contributes to parasite immune evasion by acting as a B-cell mitogen. This enzyme is the first described eukaryotic amino acid racemase and is encoded by two paralogous genes per parasite haploid genome, TcPRACA and TcPRACB that give rise, respectively, to secreted and intracellular protein isoforms. While TcPRACB encodes an intracellular enzyme, analysis of TcPRACA paralogue revealed putative signals allowing the generation of an additional, non-secreted isoform of proline racemase by an alternative trans-splicing mechanism. Here, we demonstrate that overexpression of TcPRAC leads to an increase in parasite differentiation into infective forms and in its subsequent penetration into host cells. Furthermore, a critical impairment of parasite viability was observed in functional knock-down parasites. These results strongly emphasize that TcPRAC is a potential target for drug design as well as for immunomodulation of parasite-induced B-cell polyclonal activation.


Hippuric acid in urine: reference values.
To establish reference values for hippuric acid (HA) excreted in the urine, and to evaluate the impact of age, gender, alcohol, and tobacco, on these levels in a population nonexposed to toluene. Reference values for hippuric acid in urine were determined in 115 toluene nonexposed healthy volunteers, from Alfenas city, Southeastern Brazil. A questionnaire was applied to each volunteer and data on occupational and personal habits were collected. Biochemical and hematological analyses were used to confirm the volunteers' good health condition. Reference values were expressed in g HA/g urine creatinine, as mean +/- standard deviation (x +/- SD), median, 95% confidence interval (95%CI), 95th percentile, and upper reference value (URV, mean +2 SD). Reference values of hippuric acid in urine were: mean +/- standard deviation =0.18+/-0.10; median =0.15; 95% confidence interval =0.16+/-0.20; 95th percentile = 0.36 and upper reference value (URV, mean +2 SD) =0.38. Statistically significant differences in urinary HA (Wilcoxon - Mann/Whitney, p<0.05) were observed for different genders and age groups. Alcohol ingestion and smoking habit did not significantly affect the results. The reference values of hippuric acid in urine can be used in biomonitoring programs of workers occupationally exposed to toluene, especially in the southern region of the state of Minas Gerais. Age and gender may affect the HA reference values.


Utilization of ambulatory medical care by women: United States, 1997-98.
This report presents national estimates of the volume and characteristics of ambulatory medical care provided to women 15 years of age and over in the United States. Included is information on the characteristics of the patients, providers, and visits. A section on comparative differences in use by sex is also included. This report is based on an analysis of data from the 1997 and 1998 National Ambulatory Medical Care Survey (NAMCS) and National Hospital Ambulatory Medical Care Survey (NHAMCS), national probability sample surveys of visits to office-based physicians (NAMCS) and visits to the outpatient departments and emergency departments of non-Federal, short-stay and general hospitals (NHAMCS) in the United States. Sample data are weighted to produce annual estimates. Approximately 500 million visits were made by women to ambulatory medical care providers annually in 1997 and 1998, representing an age-adjusted rate of 4.6 visits per woman per year. The rate of ambulatory medical care visits increased with age (3.8 per woman 15-44 years of age, 4.7 visits per woman 45-64 years of age, and 7.1 visits per woman 65 years of age and over). Six out of ten visits to office-based physicians and hospital outpatient departments had no mention of therapeutic or preventive services provided. Nonnarcotic analgesics, antidepressant, and estrogen/progestin were the three most common classifications of medications mentioned. Compared with visits by men, visits by women (with nonpregnancy-related diagnoses) were more frequent at younger ages and more likely to be to primary care physicians and outpatient departments.


Dystonia: a surgeon's perspective.
Surgery for dystonia has a history stretching back for centuries including myotomy and other procedures on the musculoskeletal system. In the last century lesional procedures, mainly involving the pallidum became popular. More recently, with the advent of deep brain stimulation, bilateral medial pallidal stimulation has become commonplace. This review describes the issues with patient selection, technical aspects of implantation and effects as well as complications of the technique. Some of the rarer types of dystonia that have also been treated with DBS are also described.


Human keratinocyte growth factor effects in a porcine model of epidermal wound healing.
Keratinocyte growth factor (KGF) is a member of the fibroblast growth factor (FGF) family (hence the alternative designation FGF-7). It is produced by stromal cells, but acts as a mitogen for epithelial cells. We examined the effects of topically applied KGF on healing of wounds in a porcine model. In partial-thickness wounds, KGF stimulated the rate of reepithelialization (p < 0.0002), associated with a thickening of the epidermis (p < 0.0001). Epidermis from KGF-treated full-thickness wound sites was significantly thicker (0.31 +/- 0.22 mm) compared with mirror image control sites (0.18 +/- 0.12 mm) (p < 0.0001). Moreover, the majority (77%) of KGF-treated wounds exhibited epidermis with a deep rete ridge pattern as compared with control sites. These effects were observed as early as 14 d and persisted for at least 4 wk. KGF treatment also increased the number of serrated basal cells associated with increased deposition of collagen fibers in the superficial dermis adjacent to the acanthotic epidermis. Electron microscopy revealed better developed hemidesmosomes associated with thicker bundles of tonofilaments in the serrated cells. The pattern of epidermal thickening observed in KGF-treated wounds resembled psoriasis. Psoriasis is a disease associated with epidermal thickening, parakeratosis as well as hyperproliferation that extends beyond the basal layer. In striking contrast to psoriasis, KGF-treated wounds exhibited normal orthokeratotic maturation, and proliferation was localized to the basal cells. Our present findings have significant implications concerning the role of KGF as a paracrine modulator of epidermal proliferation and differentiation.


Vimentin contributes to changes in chondrocyte stiffness in osteoarthritis.
Actin and tubulin cytoskeletal components are studied extensively in chondrocytes, but less is known about vimentin intermediate filaments. In other cell types, vimentin is a determinant of cell stiffness and disruption of vimentin networks weakens the mechanical integrity of cells. Changes in vimentin organization correlate with osteoarthritis progression, but the functional consequences of these changes remain undetermined in chondrocytes. The objective of this study was to compare the contribution of vimentin to the mechanical stiffness of primary human chondrocytes isolated from normal versus osteoarthritic cartilage. Chondrocytes were embedded in alginate and vimentin networks disrupted with acrylamide. Constructs were imaged while subjected to 20% nominal strain on a confocal microscope stage, and the aspect ratios of approximately 1,900 cells were measured. Cytosolic stiffness was estimated with a finite element model, and live-cell imaging of GFP-vimentin was used to further analyze the nature of vimentin disruption. Vimentin in normal chondrocytes formed an inner cage-like network that was substantially stiffer than the rest of the cytosol and contributed significantly to overall cellular stiffness. Disruption of vimentin reduced stiffness approximately 2.8-fold in normal chondrocytes. In contrast, osteoarthritic chondrocytes were less stiff and less affected by vimentin disruption. This 3D experimental system revealed contributions of vimentin to chondrocyte stiffness previously not apparent, and correlated changes in vimentin-based chondrocyte stiffness with osteoarthritis.


NMR and crystallographic structural studies of the extremely stable monomeric variant of human cystatin C with single amino acid substitution.
Human cystatin C (hCC), a member of the superfamily of papain-like cysteine protease inhibitors, is the most widespread cystatin in human body fluids. This small protein, in addition to its physiological function, is involved in various diseases, including cerebral amyloid angiopathy, cerebral hemorrhage, stroke, and dementia. Physiologically active hCC is a monomer. However, all structural studies based on crystallization led to the dimeric structure formed as a result of a three-dimensional exchange of the protein domains (3D domain swapping). The monomeric structure was obtained only for hCC variant V57N and for the protein stabilized by an additional disulfide bridge. With this study, we extend the number of models of monomeric hCC by an additional hCC variant with a single amino acid substitution in the flexible loop L1. The V57G variant was chosen for the X-ray and NMR structural analysis due to its exceptional conformational stability in solution. In this work, we show for the first time the structural and dynamics studies of human cystatin C variant in solution. We were also able to compare these data with the crystal structure of the hCC V57G and with other cystatins. The overall cystatin fold is retained in the solute form. Additionally, structural information concerning the N terminus was obtained during our studies and presented for the first time. DATABASE: Crystallographic structure: structural data are available in PDB databases under the accession number 6ROA. NMR structure: structural data are available in PDB and BMRB databases under the accession numbers 6RPV and 34399, respectively.


Physiologic characterization of the chronic bronchitis phenotype in GOLD grade IB COPD.
Smokers with persistent cough and sputum production (chronic bronchitis [CB]) represent a distinct clinical phenotype, consistently linked to negative clinical outcomes. However, the mechanistic link between physiologic impairment, dyspnea, and exercise intolerance in CB has not been studied, particularly in those with mild airway obstruction. We, therefore, compared physiologic abnormalities during rest and exercise in CB to those in patients without symptoms of mucus hypersecretion (non-CB) but with similar mild airway obstruction. Twenty patients with CB (≥ 3 months cough/sputum in 2 successive years), 20 patients without CB but with GOLD (Global Initiative for Chronic Obstructive Lung Disease) grade IB COPD, and 20 age- and sex-matched healthy control subjects underwent detailed physiologic testing, including tests of small airway function and a symptom-limited incremental cycle exercise test. Patients with CB (mean ± SD postbronchodilator FEV1, 93% ± 12% predicted) had greater chronic activity-related dyspnea, poorer health-related quality of life, and reduced habitual physical activity compared with patients without CB and control subjects (all P < .05). The degree of peripheral airway dysfunction and pulmonary gas trapping was comparable in both patient groups. Peak oxygen uptake was similarly reduced in patients with CB and those without compared with control subjects (% predicted ± SD, 70 ± 26, 71 ± 29 and 106 ± 43, respectively), but those with CB had higher exertional dyspnea ratings and greater respiratory mechanical constraints at a standardized work rate than patients without CB (P < .05). Patients with CB reported greater chronic dyspnea and activity restriction than patients without CB and with similar mild airway obstruction. The CB group had greater dynamic respiratory mechanical impairment and dyspnea during exercise than patients without CB, which may help explain some differences in important patient-centered outcomes between the groups.


Association of Inadequately Controlled Disease and Disease Severity With Patient-Reported Disease Burden in Adults With Atopic Dermatitis.
Real-world data are limited on the patient-reported burden of adult atopic dermatitis (AD). To characterize the patient-reported burden of AD with regard to impact of disease severity and inadequate control in adults from clinical settings. In this cross-sectional study using data from 6 academic medical centers in the United States collected by a self-administered internet-based questionnaire, 1519 adult patients with AD were stratified by AD severity as mild or moderate/severe using the Patient-Oriented Scoring Atopic Dermatitis (PO-SCORAD). Patients with moderate/severe disease using systemic immunomodulators/phototherapy were further stratified as having adequate or inadequate disease control. Strata were compared for all outcomes. Outcomes included validated measures and stand-alone questions assessing itch (pruritus numerical rating scale; PO-SCORAD itch visual analog scale), pain (numerical rating scale), sleep (PO-SCORAD sleep visual analog scale; sleep interference with function), anxiety and depression (Hospital Anxiety and Depression Scale), and health-related quality of life (Dermatology Life Quality Index). Among the 1519 adult patients with AD, relative to mild AD (n = 689, 64% women; mean [SD] age, 46.5 [18.0] years), patients with moderate/severe AD (n = 830, 66.8% women; mean [SD] age, 45.1 [16.9] years) reported more severe itching and pain, greater adverse effects on sleep, higher prevalence of anxiety and depression (417 [50.2%] vs 188 [27.3%]), and greater health-related quality-of-life impairment. The 103 patients with moderate/severe AD with inadequate disease control despite treatment with systemic immunomodulators or phototherapy (55.7%) reported higher burdens of itch and sleeping symptoms vs patients with controlled disease including more days per week with itchy skin (5.7 vs 2.7) and higher proportions with itch duration greater than half a day (190 [22.8%] vs 20 [2.9%]). Sleep symptoms included trouble sleeping (3.9 vs 1.1 on the PO-SCORAD VAS), longer sleep latency (38.8 vs 21.6 minutes), more frequent sleep disturbances (2.6 vs 0.4 nights in past week), and greater need for over-the-counter sleep medications (324 [39%] vs 145 [21%]). Inadequate disease control was common among patients with moderate/severe AD, and was associated with a higher patient-reported burden than patients with controlled disease. Regardless of disease control, the burden of moderate/severe AD was higher than mild AD, suggesting a need for more effective therapies for moderate/severe disease.


Patient and informal caregivers' knowledge of heart failure: necessary but insufficient for effective self-care.
Self-care of heart failure (HF) is a process that is important, complex, and challenging. Little is understood of the contextual factors influencing self-care. We aimed to examine the individual and contextual factors perceived by patients and their informal caregivers' to influence their willingness and capacity to undertake effective HF self-care. This was a qualitative study using semi-structured interviews with 42 patients with HF (NYHA Class II and III, mean age: 76 years, 64% males) and 30 nominated caregivers (63% spouses). All patients experienced severe and intrusive HF symptoms; a large proportion of patients practiced some of the range of recommended self-care activities. However, links between knowledge of HF and self-care were weak and long delays in seeking professional care were frequent. Factors consistently reported to influence self-care were faith in health professionals, beliefs about the local health system, and values linked to work associated with place, history, and culture. Knowledge of HF and its management is a necessary though not sufficient determinant of HF self-care. Individual and contextual factors influence willingness and capacity to undertake effective HF self-care.


Evaluation of the bioactivity of a mastoparan peptide from wasp venom and of its analogues designed through targeted engineering.
Mastoparan is a typical cationic and amphipathic tetradecapeptide found in wasp venom and exhibits potent biological activities. Yet, compared with other insect-derived peptides, such as melittin from the bee venom, this family have been underrated. Herein, we evaluated the biological activities of mastoparan-C (MP-C), which was identified from the venom of the European Hornet (Vespa crabro), and rationally designed two analogues (a skeleton-based cyclization by two cysteine residues and an N-terminal extension via tat-linked) for enhancing the stability of the biological activity and membrane permeability, respectively. Three peptides possessed broadly efficacious inhibiting capacities towards common pathogens, resistant strains, as well as microbial biofilm. Although, cyclized MP-C showed longer half-life time than the parent peptide, the lower potency of antimicrobial activity and higher degree of haemolysis were observed. The tat-linked MP-C exhibited more potent anticancer activity than the parent peptide, but it also loses the specificity. The study revealed that MP-C is good candidate for developing antimicrobial agents and the targeted-design could improve the stability and transmembrane delivery, but more investigation would be needed to adjust the side effects brought from the design.


Prion amplification and hierarchical Bayesian modeling refine detection of prion infection.
Prions are unique infectious agents that replicate without a genome and cause neurodegenerative diseases that include chronic wasting disease (CWD) of cervids. Immunohistochemistry (IHC) is currently considered the gold standard for diagnosis of a prion infection but may be insensitive to early or sub-clinical CWD that are important to understanding CWD transmission and ecology. We assessed the potential of serial protein misfolding cyclic amplification (sPMCA) to improve detection of CWD prior to the onset of clinical signs. We analyzed tissue samples from free-ranging Rocky Mountain elk (Cervus elaphus nelsoni) and used hierarchical Bayesian analysis to estimate the specificity and sensitivity of IHC and sPMCA conditional on simultaneously estimated disease states. Sensitivity estimates were higher for sPMCA (99.51%, credible interval (CI) 97.15-100%) than IHC of obex (brain stem, 76.56%, CI 57.00-91.46%) or retropharyngeal lymph node (90.06%, CI 74.13-98.70%) tissues, or both (98.99%, CI 90.01-100%). Our hierarchical Bayesian model predicts the prevalence of prion infection in this elk population to be 18.90% (CI 15.50-32.72%), compared to previous estimates of 12.90%. Our data reveal a previously unidentified sub-clinical prion-positive portion of the elk population that could represent silent carriers capable of significantly impacting CWD ecology.