Expression of renal cell markers and detection of 3p loss links endolymphatic sac tumor to renal cell carcinoma and warrants careful evaluation to avoid diagnostic pitfalls.
Endolymphatic sac tumor (ELST) is a rare neoplasm arising in the temporal petrous region thought to originate from endolymphatic sac epithelium. It may arise sporadically or in association with Von-Hippel-Lindau syndrome (VHL). The ELST prevalence in VHL ranges from 3 to 16% and may be the initial presentation of the disease. Onset is usually in the 3rd to 5th decade with hearing loss and an indolent course. ELSTs present as locally destructive lesions with characteristic computed tomography imaging features. Histologically, they show papillary, cystic or glandular architectures. Immunohistochemically, they express keratin, EMA, and variably S100 and GFAP. Currently it is recommended that, given its rarity, ELST needs to be differentiated from other entities with similar morphologic patterns, particularly other VHL-associated neoplasms such as metastatic clear cell renal cell carcinoma (ccRCC). Nineteen ELST cases were studied. Immunohistochemistry (18/19) and single nucleotide polymorphism microarray testing was performed (12/19). Comparison with the immunophenotype and copy number profile in RCC is discussed. Patients presented with characteristic bone destructive lesions in the petrous temporal bones. Pathology of tumors showed characteristic ELST morphology with immunoexpression of CK7, GFAP, S100, PAX-8, PAX-2, CA-9 in the tumor cells. Immunostaines for RCC, CD10, CK20, chromogranin A, synaptophysin, TTF-1, thyroglobulin, and transthyretin were negative in the tumor cells. Molecular testing showed loss of 3p and 9q in 66% (8/12) and 58% (7/12) cases, respectively. Immunoreactivity for renal markers in ELST is an important diagnostic caveat and has not been previously reported. In fact, renal markers are currently recommended in order to rule out metastatic RCC although PAX gene complex and CA-9 have been implicated in the development of the inner ear. Importantly copy number assessment of ELST has not been previously reported. Loss of 3p (including the VHL locus) in ELST suggests similar mechanistic origins as ccRCC.


Evidence-based medicine in internal medicine clerkships: a national survey.
Although evidence-based medicine (EBM) has become widely accepted, the extent of its implementation during clinical clerkships is not well described. This study was done to characterize the implementation of formal EBM curricula in internal medicine clerkships. In 1999, the Clerkship Directors in Internal Medicine surveyed its membership from 123 medical schools. The EBM section of the four-part survey addressed implementation, teaching and evaluation techniques, and barriers to implementing EBM. Survey response was 89%. Of 109 respondents, 38.5% reported having a formal EBM curriculum at some time during the third year and/or fourth year. Variability existed in curricular materials and evaluation tools used. The most common barriers to implementing EBM were lack of time and inadequately trained faculty. Evidence-based medicine has been formally incorporated into relatively few internal medicine clerkships. Faculty development programs in conjunction with innovative teaching methods may help overcome these barriers.


[The effect of noise on the voice of preschool institution educators].
To analyze the association between noise levels present in preschool institutions and vocal disorders among educators. Cross-sectional study conducted in 2009 with 28 teachers from three preschool institutions located in the city of São Paulo (Southeastern Brazil). Sound pressure levels were measured according to Brazilian Technical Standards Association, with the use of a sound level meter. The averages were classified according to the levels of comfort, discomfort, and auditory damage proposed by the Pan American Health Organization. The educators underwent voice evaluation: self-assessment with visual analogue scale, auditory perceptual evaluation using the GRBAS scale, and acoustic analysis utilizing the Praat program. To analyze the association between noise and voice evaluation, descriptive statistics and the chi-square test were employed, with significance of 10% due to sample size. The teachers' age ranged between 21 and 56 years. The noise average was 72.7 dB, considered as damage 2. The professionals' vocal self-assessment ranked an average of 5.1 on the scale, being considered as moderate alteration. In the auditory-perceptual assessment, 74% presented vocal alteration, especially hoarseness; of these, 52% were considered mild alterations. In the acoustic assessment the majority presented fundamental frequency below the expected level. Averages for jitter, shimmer and harmonic-noise ratio showed alterations. An association between the presence of noise between the harmonics and vocal disorders was observed. There is an association between presence of noise between the harmonics and vocal alteration, with high noise levels. Although most teachers presented mild voice alteration, the self-evaluation showed moderate alteration, probably due to the difficulty in projection.


[Importance of pharmacovigilance in current medical practice].
Adverse drug reactions (ADRs) are cause of significant morbi-mortality They are between the fourth and sixth cause of mortality in developed countries and cause nearly 12% of hospitalizations. The objective of this publication was to analyze the incidence of ADRs in a tertiary care hospital in Buenos Aires City. The hospital phamacovigilance database for the period June 2008- February 2012, was analyzed. The Naranjo score was applied to assess drug causality. We consider serious an ADRs when it potentially compromised life, induced hospitalization or prolonged it, caused discapacity, teratogenesis or death. In this period, a total of 2420 ADRs were detected: 469 (19.38%; CI 95%: 17.80 - 20.95) were serious, mainly because they induced hospitalization (n = 287). There were 14 ADRs- related deaths. Cardiovascular and neuropsychiatric drugs, antibiotics and corticoids were those most frequently related to toxicity. Endocrine-metabolic disorders, hepatotoxicity, nephrotoxicity and pharmacodermy were the most frequently involved. Among the ADR most frequently associated to hospitalization were Immunosuppressant-associated severe infections and upper gastrointestinal bleeding related to oral anticoagulants and non steroids anti-inflammatory drugs. The ADRs incidence in hospitalized patients and ADRs related hospital admissions were considered relatively high. Drugs involved were similar to those reported in the international bibliography except for the higher incidence of immunosuppressants related admissions here observed.


Aspergillus flavus: human pathogen, allergen and mycotoxin producer.
Aspergillus infections have grown in importance in the last years. However, most of the studies have focused on Aspergillus fumigatus, the most prevalent species in the genus. In certain locales and hospitals, Aspergillus flavus is more common in air than A. fumigatus, for unclear reasons. After A. fumigatus, A. flavus is the second leading cause of invasive aspergillosis and it is the most common cause of superficial infection. Experimental invasive infections in mice show A. flavus to be 100-fold more virulent than A. fumigatus in terms of inoculum required. Particularly common clinical syndromes associated with A. flavus include chronic granulomatous sinusitis, keratitis, cutaneous aspergillosis, wound infections and osteomyelitis following trauma and inoculation. Outbreaks associated with A. flavus appear to be associated with single or closely related strains, in contrast to those associated with A. fumigatus. In addition, A. flavus produces aflatoxins, the most toxic and potent hepatocarcinogenic natural compounds ever characterized. Accurate species identification within Aspergillus flavus complex remains difficult due to overlapping morphological and biochemical characteristics, and much taxonomic and population genetics work is necessary to better understand the species and related species. The flavus complex currently includes 23 species or varieties, including two sexual species, Petromyces alliaceus and P. albertensis. The genome of the highly related Aspergillus oryzae is completed and available; that of A. flavus in the final stages of annotation. Our understanding of A. flavus lags far behind that of A. fumigatus. Studies of the genomics, taxonomy, population genetics, pathogenicity, allergenicity and antifungal susceptibility of A. flavus are all required.


A pan-cancer proteomic perspective on The Cancer Genome Atlas.
Protein levels and function are poorly predicted by genomic and transcriptomic analysis of patient tumours. Therefore, direct study of the functional proteome has the potential to provide a wealth of information that complements and extends genomic, epigenomic and transcriptomic analysis in The Cancer Genome Atlas (TCGA) projects. Here we use reverse-phase protein arrays to analyse 3,467 patient samples from 11 TCGA 'Pan-Cancer' diseases, using 181 high-quality antibodies that target 128 total proteins and 53 post-translationally modified proteins. The resultant proteomic data are integrated with genomic and transcriptomic analyses of the same samples to identify commonalities, differences, emergent pathways and network biology within and across tumour lineages. In addition, tissue-specific signals are reduced computationally to enhance biomarker and target discovery spanning multiple tumour lineages. This integrative analysis, with an emphasis on pathways and potentially actionable proteins, provides a framework for determining the prognostic, predictive and therapeutic relevance of the functional proteome.


[Pemetrexed-induced scleroderma-like changes in the lower legs].
Pemetrexed (Alimta(®)) is a new-generation antifolate used to treat malignant pleural mesothelioma and non-small cell lung cancer (NSCLC). We report two cases of a new toxicity induced by pemetrexed: scleroderma-like induration of the lower extremities. The first case concerned a 66-year-old man diagnosed with pulmonary adenocarcinoma metastatic from the outset and in whom maintenance treatment comprised pemetrexed after first-line therapy comprising six courses of cisplatin-pemetrexed. After the fourth cycle of pemetrexed, he presented an erythematous oedema of the left leg, which was subsequently bilateral. Clinically, there was painful cellulitis associated with areas of bruising. The lesions had an appearance of erysipeloid-like infection, and there was no fever. The second case concerned a 70-year-old woman diagnosed with metastatic NSCLC. From the first course of pemetrexed, given as maintenance therapy, she presented erythematous oedema of both legs, without fever. After the second course, we observed the recurrence of the lesions consisting of erythemato-violaceous plaques on both legs, with severe bilateral indurated and painful oedema, associated with major functional disability. A diagnosis of bilateral erysipelas was made, and antibiotic treatment with cloxacillin was given. In both cases, pemetrexed was discontinued and the local outcome was very slowly favourable, with persistence of scleroderma. This cutaneous adverse effect is unrecognized, resulting in delayed diagnosis. It is often initially confused with bilateral erysipelas, despite absence of fever. According to some studies, the severity of the cutaneous toxicity may be connected with patients' folate status. Thus folate and vitamin B12 supplementation combined with dexamethasone could decrease the incidence of this side effect. There was no recurrence and no worsening with taxanes, chemotherapy agents known to induce scleroderma. We feel that this cutaneous toxicity must be recognised on account of its potential severity.


A connection between stress and development in the multicellular prokaryote Streptomyces coelicolor A3(2).
Morphological changes leading to aerial mycelium formation and sporulation in the mycelial bacterium Streptomyces coelicolor rely on establishing distinct patterns of gene expression in separate regions of the colony. sigmaH was identified previously as one of three paralogous sigma factors associated with stress responses in S. coelicolor. Here, we show that sigH and the upstream gene prsH (encoding a putative antisigma factor of sigmaH) form an operon transcribed from two developmentally regulated promoters, sigHp1 and sigHp2. While sigHp1 activity is confined to the early phase of growth, transcription of sigHp2 is dramatically induced at the time of aerial hyphae formation. Localization of sigHp2 activity using a transcriptional fusion to the green fluorescent protein reporter gene (sigHp2-egfp) showed that sigHp2 transcription is spatially restricted to sporulating aerial hyphae in wild-type S. coelicolor. However, analysis of mutants unable to form aerial hyphae (bld mutants) showed that sigHp2 transcription and sigmaH protein levels are dramatically upregulated in a bldD mutant, and that the sigHp2-egfp fusion was expressed ectopically in the substrate mycelium in the bldD background. Finally, a protein possessing sigHp2 promoter-binding activity was purified to homogeneity from crude mycelial extracts of S. coelicolor and shown to be BldD. The BldD binding site in the sigHp2 promoter was defined by DNase I footprinting. These data show that expression of sigmaH is subject to temporal and spatial regulation during colony development, that this tissue-specific regulation is mediated directly by the developmental transcription factor BldD and suggest that stress and developmental programmes may be intimately connected in Streptomyces morphogenesis.


Nitrate and nitrite concentrations in human saliva for men and women at different ages and times of the day and their consistency over time.
Salivary nitrite arises from nitrate and is the main source of gastric nitrite, a precursor of carcinogenic N-nitroso compounds. We examined nitrate and nitrite levels in unstimulated saliva from subjects consuming low-nitrate low-vitamin C diets. When saliva was collected from six men at nine times of the day (Experiment 1), night time nitrite levels were significantly higher than day time values and nitrite varied more than nitrate. When saliva was collected from 29 subjects aged 19-37 or 60-84 years at four times of the day during 1991-1993 (Experiment 2), all older subjects and older men had significantly higher nitrite levels than the corresponding younger subjects, night time nitrite levels in men were significantly raised, and nitrate and nitrite levels in the same samples were closely correlated. Saliva was collected at 6.00 a.m. on two successive days in 1997 from 16 subjects who had collected saliva in 1991-1993 (Experiment 3). Nitrate and nitrite levels on day 1 of experiment 3 were closely correlated with those on day 2. Nitrate and nitrite levels on days 1 and 2 of Experiment 3 were correlated with the corresponding parameters in Experiment 2 with P = 0.04 and 0.08 for day 1, and 0.10 and 0.28 for day 2, respectively. Hence, saliva nitrite levels rose at night and were higher in older people, especially older men, and saliva nitrate and nitrite levels varied little from day to day, but varied more after 4-6 years.


Outcome of older patients receiving mechanical ventilation.
To determine the threshold of age that best discriminates the survival of mechanically ventilated patients and to estimate the outcome of mechanically ventilated older patients. International prospective cohort study. Three hundred sixty-one intensive care units from 20 countries. PATIENTS AND PARTICIPANTS. Five thousand one hundred eighty-three patients mechanically ventilated for more than 12 h. None. Recursive partitioning and logistic regression were used and an outcome model was derived and validated using independent subgroups of the cohort. Two age thresholds (43 and 70 years) were found, by partitioning recursive analysis, to be associated with outcome. This study focuses on the analysis of patients older than 43 years of age, divided in two subgroups: between 43 and 70 years (middle age group) and older than 70 years (elderly group). Survival in hospital was 45% (95% C.I.: 43-48) for the elderly group and 55% (53-57) for the middle age group ( p<0.001). Advanced age was not associated with prolongation of mechanical ventilation, weaning or length of stay in the ICU and in hospital ( p>0.05). Variables associated with mortality in the elderly were: acute renal failure, shock, Simplified Acute Physiology Score II and a ratio of PaO(2) to FIO(2) more than 150. Older mechanically ventilated patients (age >70 years) had a lower ICU and hospital survival, but the duration of mechanical ventilation, ICU and hospital stay were similar to younger patients. Factors associated with the highest risk of mortality in patients older than 70 were the development of complications during the course of mechanical ventilation, such as acute renal failure and shock.


Computation of highly off-axis diffracted fields using the band-limited angular spectrum method with suppressed Gibbs related artifacts.
The angular spectrum (AS) method is a popular solution to the Helmholtz equation without the use of approximations. Modified band-limited AS methods are of particular interest for the cases of high-off-axis and large distance propagation problems, because conventional AS methods are impractical due to requirements regarding memory and computational effort. However, these techniques make use of rectangular-shaped filters that introduce ringing artifacts in the calculated field that are related to the Gibbs phenomenon. This work proposes AS algorithms based on a smooth band-limiting filter for accurate field computation as well as techniques that evaluate only nonzero components of the field. This enables accurate field calculations with an acceptable level of computational effort that cannot be offered by current AS methods reported in the scientific literature.


Demonstration of local adaptation in maize landraces by reciprocal transplantation.
Populations are locally adapted when they exhibit higher fitness than foreign populations in their native habitat. Maize landrace adaptations to highland and lowland conditions are of interest to researchers and breeders. To determine the prevalence and strength of local adaptation in maize landraces, we performed a reciprocal transplant experiment across an elevational gradient in Mexico. We grew 120 landraces, grouped into four populations (Mexican Highland, Mexican Lowland, South American Highland, South American Lowland), in Mexican highland and lowland common gardens and collected phenotypes relevant to fitness and known highland-adaptive traits such as anthocyanin pigmentation and macrohair density. 67k DArTseq markers were generated from field specimens to allow comparisons between phenotypic patterns and population genetic structure. We found phenotypic patterns consistent with local adaptation, though these patterns differ between the Mexican and South American populations. Quantitative trait differentiation (Q ST) was greater than neutral allele frequency differentiation (F ST) for many traits, signaling directional selection between pairs of populations. All populations exhibited higher fitness metric values when grown at their native elevation, and Mexican landraces had higher fitness than South American landraces when grown in these Mexican sites. As environmental distance between landraces' native collection sites and common garden sites increased, fitness values dropped, suggesting landraces are adapted to environmental conditions at their natal sites. Correlations between fitness and anthocyanin pigmentation and macrohair traits were stronger in the highland site than the lowland site, supporting their status as highland-adaptive. These results give substance to the long-held presumption of local adaptation of New World maize landraces to elevation and other environmental variables across North and South America.


Cloning, sequencing, and analysis of the griseusin polyketide synthase gene cluster from Streptomyces griseus.
A fragment of DNA was cloned from the Streptomyces griseus K-63 genome by using genes (act) for the actinorhodin polyketide synthase (PKS) of Streptomyces coelicolor as a probe. Sequencing of a 5.4-kb segment of the cloned DNA revealed a set of five gris open reading frames (ORFs), corresponding to the act PKS genes, in the following order: ORF1 for a ketosynthase, ORF2 for a chain length-determining factor, ORF3 for an acyl carrier protein, ORF5 for a ketoreductase, and ORF4 for a cyclase-dehydrase. Replacement of the gris genes with a marker gene in the S. griseus genome by using a single-stranded suicide vector propagated in Escherichia coli resulted in loss of the ability to produce griseusins A and B, showing that the five gris genes do indeed encode the type II griseusin PKS. These genes, encoding a PKS that is programmed differently from those for other aromatic PKSs so far available, will provide further valuable material for analysis of the programming mechanism by the construction and analysis of strains carrying hybrid PKS.


Empowering caregivers: impact analysis of FamilyLink Education Programme (FLEP) in Hong Kong, Taipei and Bangkok.
Education and support for caregivers is lacking in Asia and the peer-led FamilyLink Education Programme (FLEP) is one of the few provisions to address this service gap. This study aims to evaluate quantitatively its efficacy in reducing subjective burdens and empowering the participants. One hundred and nine caregiver participants in three Asian cities were successfully surveyed at pre-intervention, post-intervention and six-month intervals with a number of standard inventories. Mixed analysis of variance (ANOVA) procedures showed significant programme impact over time intervals for all sites, and subsequently an empowerment measurement model was tested. FLEP was found effective in reducing worry and displeasure, significantly improving intra-psychic strain, depression and all empowerment measures. The measurement model had an acceptable good fit. Baseline difference showed no interference with the programme efficacy. Apart from the initial support for FLEP, the current study also provides some hindsight on the empowerment practice in mental health for Asia, whose sociocultural political contexts are vastly different from that of the developed countries. It remains to be seen whether qualitative data or more stringent research design will yield consistent results and whether FLEP can also work in rural areas.


Identification by antibody to a synthetic peptide of a protein specified by a diploid gene located in the terminal repeats of the L component of herpes simplex virus genome.
In the course of studies on the a sequences located at the termini of and at the junction between the L and S components of herpes simplex virus 1 DNA, J. Chou and B. Roizman (J. Virol. 57:629-637, 1986) noted that the a sequence acted as a gamma 1 promoter when fused to the structural sequence of the thymidine kinase gene, the b inverted repeat sequences located in the L component next to the a sequences contained an open reading frame predicted to encode the protein of 358 amino acids with a molecular weight of 37,054, and the transcription of an RNA homologous to the open reading frame initiated within the a sequence. The nucleotide sequence of the open reading frame predicted the presence of the triplet Ala-Thr-Pro repeated 10 times. To verify the existence of the predicted gene, designated gamma 134.5, a synthetic peptide consisting of the triplet Ala-Thr-Pro repeated 10 times was synthesized and used to raise antibodies in rabbits. The results were as follows. The antiserum to the peptide reacted with a 43,500-apparent-molecular-weight protein present in lysates of cells infected with herpes simplex virus 1 but not present in mock-infected or herpes simplex virus 2-infected cells. We genetically engineered a recombinant virus containing a single copy of a truncated gene. Concordant with predictions, the antibody reacted with a faster-migrating protein in cells infected with this recombinant. The gamma 134.5 gene product was soluble, and it accumulated primarily in the cytoplasm late in infection. The overlap of the domain of the gamma 134.5 gene with the a sequence raises the possibility that it acts in trans on the a sequence and is associated with one of the functions currently ascribed to the a sequences.


Random Photon Absorption Model Elucidates How Early Gain Control in Fly Photoreceptors Arises from Quantal Sampling.
Many diurnal photoreceptors encode vast real-world light changes effectively, but how this performance originates from photon sampling is unclear. A 4-module biophysically-realistic fly photoreceptor model, in which information capture is limited by the number of its sampling units (microvilli) and their photon-hit recovery time (refractoriness), can accurately simulate real recordings and their information content. However, sublinear summation in quantum bump production (quantum-gain-nonlinearity) may also cause adaptation by reducing the bump/photon gain when multiple photons hit the same microvillus simultaneously. Here, we use a Random Photon Absorption Model (RandPAM), which is the 1st module of the 4-module fly photoreceptor model, to quantify the contribution of quantum-gain-nonlinearity in light adaptation. We show how quantum-gain-nonlinearity already results from photon sampling alone. In the extreme case, when two or more simultaneous photon-hits reduce to a single sublinear value, quantum-gain-nonlinearity is preset before the phototransduction reactions adapt the quantum bump waveform. However, the contribution of quantum-gain-nonlinearity in light adaptation depends upon the likelihood of multi-photon-hits, which is strictly determined by the number of microvilli and light intensity. Specifically, its contribution to light-adaptation is marginal (≤ 1%) in fly photoreceptors with many thousands of microvilli, because the probability of simultaneous multi-photon-hits on any one microvillus is low even during daylight conditions. However, in cells with fewer sampling units, the impact of quantum-gain-nonlinearity increases with brightening light.


Prevalence of hepatitis C genotypes in Indian patients and their clinical significance.
To study the significance of hepatitis C genotypes in relation to severity of liver disease, progression of liver disease and response to treatment. Sixty one consecutive patients with hepatitis C infection were evaluated with detailed history, clinical examination, biochemical, imaging and virological profile, liver histology whenever feasible. Hepatitis C infection was confirmed with AntiHCV third generation ELISA assay. HCVRNA by PCR and HCV genotyping by direct sequencing. Demographic profile of patients was as M:F 36:25, mean age 46.3 +/- 13.6 years (range 10 to 70 years). Clinical presentations of these patients were as cirrhosis 23, cirrhosis with HCC 3, chronic hepatitis 22, acute hepatitis 4, asymptomatic with normal enzymes nine. Distribution of genotypes was as follows; 13/61 (21%) genotype I, 15/61 (25%) genotypes II and 33/61 (54%) genotype III. Cirrhosis was significantly common in genotype I (77%) when compared to genotype II and III (33%); p < 0.001. Mean time of presenting as cirrhosis was much faster in genotype I (8.7 +/- 6.7 years) as compared to other genotypes (type II 12.8 +/- 4.2 years and genotype III 15.8 +/- 6.9 years). Genotype distribution in CRF and renal transplant patient was genotype I 8/23 (35%), genotype II 5/23 (22%) and genotype III 10/23 (43%). Fourteen patients were treated with interferon and ribavarine combination for one year. Sustained response seen in 8/14 (57%). All these patients had genotype non 1. All the four patients with Genotype I were non-responders. Hepatitis C genotype III is common in India, Genotype I runs a more severe course, faster progression and non responders to interferon as compared with genotype II and III.


How is feedback from national clinical audits used? Views from English National Health Service trust audit leads.
To explore how the output of national clinical audits in England is used by professionals and whether and how their impact could be enhanced. A mixed-methods study with the primary recipients of four national clinical audits of cancer care of 607 local audit leads, 274 (45%) completed a questionnaire and 32 participated in an interview. Our questions focused on how the audits were used and whether barriers existed to using the audits for local service improvement. We described variation in questionnaire responses between the audits using chi-squared tests. Results are reported as percentages with their 95% confidence intervals. Qualitative data were analysed using Framework analysis. More than 90% of survey respondents believed that the audit findings were relevant to their clinical work, and interviewees described how they used the audits for a range of purposes. Forty-two percent of survey respondents said they had changed their clinical practice, and 56% had implemented service improvements in response to the audits. The degree of change differed between the four audits, evident in both the questionnaire and the interview data. In the interviews, two recurring barriers emerged: (1) the importance of data quality, which, in turn, influenced the perceived relevance and validity of the audit data and therefore the ability to make changes based on it and (2) the need for clear presentation of benchmarked local performance data. The perceived authority and credibility of the professional bodies supporting the audits was a key factor underpinning the use of the audit findings. National cancer audit and feedback is used to improve services, but their impact could be enhanced by improving the data quality and relevance of feedback.


Integration: the key to implementing the Sustainable Development Goals.
On 25 September, 2015, world leaders met at the United Nations in New York, where they adopted the Sustainable Development Goals. These 17 goals and 169 targets set out an agenda for sustainable development for all nations that embraces economic growth, social inclusion, and environmental protection. Now, the agenda moves from agreeing the goals to implementing and ultimately achieving them. Across the goals, 42 targets focus on means of implementation, and the final goal, Goal 17, is entirely devoted to means of implementation. However, these implementation targets are largely silent about interlinkages and interdependencies among goals. This leaves open the possibility of perverse outcomes and unrealised synergies. We demonstrate that there must be greater attention on interlinkages in three areas: across sectors (e.g., finance, agriculture, energy, and transport), across societal actors (local authorities, government agencies, private sector, and civil society), and between and among low, medium and high income countries. Drawing on a global sustainability science and practice perspective, we provide seven recommendations to improve these interlinkages at both global and national levels, in relation to the UN's categories of means of implementation: finance, technology, capacity building, trade, policy coherence, partnerships, and, finally, data, monitoring and accountability.


Home, sweet home? The impact of working from home on the division of unpaid work during the COVID-19 lockdown.
A lockdown implies a shift from the public to the private sphere, and from market to non-market production, thereby increasing the volume of unpaid work. Already before the pandemic, unpaid work was disproportionately borne by women. This paper studies the effect of working from home for pay (WFH), due to a lockdown, on the change in the division of housework and childcare within couple households. While previous studies on the effect of WFH on the reconciliation of work and family life and the division of labour within the household suffered from selection bias, we are able to identify this effect by drawing upon the shock of the first COVID-19 lockdown in Austria. The corresponding legal measures left little choice over WFH. In any case, WFH is exogenous, conditional on a small set of individual and household characteristics we control for. We employ data from a survey on the gendered aspects of the lockdown. The dataset includes detailed information on time use during the lockdown and on the quality and experience of WFH. Uniquely, this survey data also includes information on the division, and not only magnitude, of unpaid work within households. Austria is an interesting case in this respect as it is characterized by very conservative gender norms. The results reveal that the probability of men taking on a larger share of housework increases if men are WFH alone or together with their female partner. By contrast, the involvement of men in childcare increased only in the event that the female partner was not able to WFH. Overall, the burden of childcare, and particularly homeschooling, was disproportionately borne by women.


Top-down fabrication of hierarchical nanocubes on nanosheets composite for high-rate lithium storage.
A top-down method was developed to synthesize hierarchical composites consisting of NiCo2O4 nanocubes and graphene nanosheets through the electrostatic interaction of negatively charged graphene oxide nanosheets and positively charged NiCo2O4 spheres. Employed as anode materials for lithium-ion batteries, the hierarchical composites exhibit remarkably high electrochemical performance, including large reversible capacity, superior rate capability, and excellent cycling performance. Large reversible capacities of 1024 and 648 mA h g-1 are maintained at a current density of 500 and 3000 mA g-1, respectively, for over 200 cycles. The excellent electrochemical performance of the composite is attributed to the synergistic effect of the hierarchical structure, the well dispersed NiCo2O4 nanocubes and the uniform graphene coating. This work provides an effective and promising strategy for the rational structural design of the metal oxide electrode material.


Family history of diabetes and pancreatic cancer as risk factors for pancreatic cancer: the PACIFIC study.
Genetic association studies have identified more than a dozen genes associated with risk of pancreatic cancer. Given this genetic heterogeneity, family history can be useful for identifying individuals at high risk for this disease. The goal of this analysis was to evaluate associations of family history of diabetes and family history of pancreatic cancer with risk of pancreatic cancer. PACIFIC is a case-control study based on two large health plans. Cases were diagnosed with pancreatic ductal adenocarcinoma (PDA) and controls were selected from the health plan enrollment databases and frequency matched to cases. Family history data were collected using an interviewer-administered questionnaire and were available on 654 cases and 697 controls. Logistic regression was used for the association analyses. First-degree relative history of diabetes was statistically significantly associated with increased risk of PDA [OR, 1.37; 95% confidence interval (CI), 1.10-1.71]. The highest risk of PDA was observed for an offspring with diabetes (OR, 1.95; 95% CI, 1.23-3.09). In addition, history of pancreatic cancer increased risk for PDA with an OR of 2.79 (95% CI, 1.44-4.08) for any first-degree relative history of pancreatic cancer. This population-based analysis showed that family history of diabetes was associated with increased risk of PDA and confirmed previous studies showing that first-degree family history of pancreatic cancer is associated with PDA. These results support the need for ongoing studies of genetic influences on pancreatic cancer in large samples and investigations of possible pleiotropic genetic effects on diabetes and pancreatic cancer.


Evidence for an internal phenylalkylamine action on the voltage-gated potassium channel Kv1.3.
We characterized the action of verapamil and N-methyl-verapamil on current through the delayed-rectifier potassium channel Kv1.3 mouse (mKv1.3). The whole-cell and inside-out configuration of the patch-clamp technique was used to examine the channel properties after injection of in vitro transcribed cRNA into rat basophilic leukemia cells. The action of verapamil on current through mKv1.3 channels could be separated into an acceleration of the rate of current decay during depolarizing pulses and a reduction of steady state peak current when applied either extracellularly or intracellularly. Both effects were greatly reduced when the membrane-impermeable N-methyl-verapamil was applied extracellularly, but it affected current through mKv1.3 channels similar to verapamil if applied to the intracellular side of the membrane. Mutations in the outer vestibule of the mKv1.3 channel did not change the ability of verapamil to accelerate the mKv1.3 current decay during depolarizing pulses, whereas the reduction of the steady state peak current by verapamil applied either extracellularly and intracellularly and by N-methyl-verapamil applied intracellularly was decreased approximately 25-fold in all three cases. Substances known to interact with an extracellular site of the channel (e.g., extracellularly applied tetraethylammonium or kaliotoxin) did not compete with extracellularly applied verapamil on blocking steady state peak current, whereas intracellularly applied tetraethylammonium, which is known to interact with an intracellular site of the channel, was able to reduce the effect of extracellularly applied verapamil on blocking steady state peak current, suggesting competition for a common binding site between verapamil and intracellularly applied tetraethylammonium. The results from the competition experiments as well as from the mutations in the outer vestibule of mKv1.3 are compatible with the idea that verapamil applied extracellularly moves through the membrane to reach its internal binding site on the mKv1.3 channel.


Current agents for the treatment of patients with heparin-induced thrombocytopenia.
Several counterintuitive treatment paradoxes complicate the management of immune heparin-induced thrombocytopenia (HIT). For example, simple discontinuation of heparin often fails to prevent subsequent HIT-associated thrombosis. Thus, current treatment guidelines recommend substituting heparin with a rapidly acting alternative anticoagulant (eg, danaparoid, lepirudin, or argatroban) even when HIT is suspected on the basis of thrombocytopenia alone ("isolated HIT"). Another paradox-coumarin (warfarin) anticoagulation-can lead to venous limb gangrene in a patient with HIT-associated deep-vein thrombosis. Thus, warfarin is not recommended during acute thrombocytopenia secondary to HIT. However, warfarin can be given as overlapping therapy with an alternative anticoagulant, provided that (1) initiation of warfarin is delayed until substantial platelet count recovery has occurred (to at least above 100 x 10(9)/L); (2) low initial doses of warfarin are used; (3) at least 5 days of overlapping therapy are given; and (4) the alternative agent is maintained until the platelet count has normalized. It has recently been recognized that HIT antibodies are transient and usually do not recur upon subsequent re-exposure to heparin. This leads to a further paradox-patients with previous HIT can be considered for a brief re-exposure to heparin under exceptional circumstances; for example, heart surgery requiring cardiopulmonary bypass, if HIT antibodies are no longer detectable using sensitive assays. For patients with acute or recent HIT who require urgent heart surgery, other approaches include use of alternative anticoagulants (eg, lepirudin or danaparoid) for cardiopulmonary bypass or antiplatelet agents (eg, tirofiban or epoprostenol) to permit intraoperative use of heparin.


Infection of bryozoans by Tetracapsuloides bryosalmonae at sites endemic for salmonid proliferative kidney disease.
Laboratory-reared colonies of the bryozoans Fredericella sultana and Plumatella fungosa were placed upstream of 2 fish farms endemic for salmonid proliferative kidney disease (PKD) to assess rates of infection of bryozoans by Tetracapsuloides bryosalmonae, the causative agent of PKD. Colonies were deployed in the field for 8 trial periods of 2 wk each throughout the summer of 2001. Following each trial, bryozoan colonies were maintained in laboratory culture for 28 d and were regularly monitored for infection by searching for sac stages of T. bryosalmonae. Infections were never identified by observations of sac stages, however positive PCR results and sequencing of cultured material confirmed that cryptic infections were present in colonies of both species deployed at one site. The possibility that PCR results reflected contamination of surfaces of bryozoans can be excluded, given the short period of spore viability of T. bryosalmonae. Highest rates of infection occurred when 4 of 23 colonies of F. sultana and 1 of 12 colonies of P. fungosa were infected during the period 10 to 24 July. No infections were detected from mid-August to late October at this site. None of the colonies at the other site became infected throughout the period of study. Our data provide the first estimates of infection rates of bryozoans by T. bryosalmonae. Additionally, they provide evidence that a cryptic stage can be maintained within bryozoan hosts for a period of 4 to 6 wk.


The Effectiveness of Hollowing and Bracing Strategies With Lumbar Stabilization Exercise in Older Adult Women With Nonspecific Low Back Pain: A Quasi-Experimental Study on a Community-based Rehabilitation.
The purpose of this study was to explore the therapeutic effectiveness of hollowing lumbar stabilization exercise (HLSE) and bracing lumbar stabilization exercise (BLSE) for older adult women with nonspecific low back pain (NSLBP) in community welfare centers. A total of 38 older adult women with NSLBP were allocated to either the HLSE group (n = 17, 70.4 ± 1.7 years) or the BLSE group (n = 21, 66.8 ± 4.4 years). Both groups performed intervention for 12 consecutive weeks, 3 times per week. Each group performed 5 lumbar stabilization exercises, including side plank exercise, bridge exercise, 4-kneeling exercise, prone plank exercise, and prone back extension exercise with hollowing and bracing strategy, respectively. The baseline and post-test values of trunk strength, low back disability (Korean Oswestry Disability Index [K-ODI] and Korean Roland Morris Disability Questionnaire [K-RMDQ]), and static balance (1-leg standing test) were compared by using per-protocol analysis. In trunk strength, the trunk flexor had significant difference (F = 11.10, P = .001) between groups and within groups of BLSE (t = -5.56, P = .001) and HLSE (t = -2.50, P = .024). Trunk back extensor of HLSE (t = -6.00, P = .001) and BLSE (t = -9.19, P = .001) only had significant within-group difference. However, in trunk side flexor, HLSE and BLSE had only significant difference between groups. In low back disability, K-ODI for HLSE (t = 4.50, P = .001) and BLSE (t = 4.60, P = .001) had significant within-group difference but no significant difference between groups (F = 0.28, P = .202). In K-RMDQ, HLSE only had significant within-group difference (t = 3.97, P = .001). In trunk muscle strength, the effect size of HLSE and BLSE groups for trunk flexor was HLSE -0.53 (medium) and BLSE -1.21 (large); trunk side flexor: HLSE 0.27 (small) and BLSE -0.24 (small); and trunk back extensor: HLSE 1.1 (large) and BLSE 2.00 (large), respectively. In low back disability, the effect size of both groups for K-ODI was HLSE 0.88 (large) and BLSE 1.05 (large), and K-RMDQ, HLSE 0.19 (small) and BLSE 0.40 (small), respectively. Our findings suggest that HLSE and BLSE could be recommended for community settings to improve trunk strength and low back disability in older adult women with NSLBP. Especially, HLSE and BLSE could be recommended for elderly women with NSLBP who have lower back disability and weak trunk muscle strength, respectively.


Intimate partner violence experienced by HIV-infected pregnant women in South Africa: a cross-sectional study.
Intimate partner violence (IPV) during pregnancy may be common in settings where HIV is prevalent but there are few data on IPV in populations of HIV-infected pregnant women in Southern Africa. We examined the prevalence and correlates of IPV among HIV-infected pregnant women. A primary care antenatal clinic in Cape Town, South Africa. 623 consecutive HIV-infected pregnant women initiating lifelong antiretroviral therapy. IPV, depression, substance use and psychological distress were assessed using the 13-item WHO Violence Against Women questionnaire, the Edinburgh Postnatal Depression Scale (EPDS), Alcohol and Drug Use Disorders Identification Tests (AUDIT/DUDIT) and the Kessler 10 (K-10) scale, respectively. The median age in the sample was 28 years, 97% of women reported being in a relationship, and 70% of women reported not discussing and/or agreeing on pregnancy intentions before conception. 21% of women (n=132) reported experiencing ≥1 act of IPV in the past 12 months, including emotional (15%), physical (15%) and sexual violence (2%). Of those reporting any IPV (n=132), 48% reported experiencing 2 or more types. Emotional and physical violence was most prevalent among women aged 18-24 years, while sexual violence was most commonly reported among women aged 25-29 years. Reported IPV was less likely among married women, and women who experienced IPV were more likely to score above threshold for substance use, depression and psychological distress. In addition, women who reported not discussing and/or not agreeing on pregnancy intentions with their partner prior to conception were significantly more likely to experience violence. HIV-infected pregnant women in the study reported experiencing multiple forms of IPV. While the impact of IPV on maternal and child health outcomes in the context of HIV infection requires further research attention, IPV screening and support services should be considered within the package of routine care for HIV-infected pregnant women. NCT01933477.


High-Resolution Electron Diffraction of Hydrated Protein Crystals at Room Temperature.
Structural characterization is crucial to understanding protein function. Compared with X-ray diffraction methods, electron crystallography can be performed on nanometer-sized crystals and can provide additional information from the resulting Coulomb potential map. Whereas electron crystallography has successfully resolved three-dimensional structures of vitrified protein crystals, its widespread use as a structural biology tool has been limited. One main reason is the fragility of such crystals. Protein crystals can be easily damaged by mechanical stress, change in temperature, or buffer conditions as well as by electron irradiation. This work demonstrates a methodology to preserve these nanocrystals in their natural environment at room temperature for electron diffraction experiments as an alternative to existing cryogenic techniques. Lysozyme crystals in their crystallization solution are hermetically sealed via graphene-coated grids, and their radiation damage is minimized by employing a low-dose data collection strategy in combination with a hybrid-pixel direct electron detector. Diffraction patterns with reflections of up to 3 Å are obtained and successfully indexed using a template-matching algorithm. These results demonstrate the feasibility of in situ protein electron diffraction. The method described will also be applicable to structural studies of hydrated nanocrystals important in many research and technological developments.


Lenalidomide for the treatment of relapsed and refractory multiple myeloma.
Lenalidomide is an amino-substituted derivative of thalidomide with direct antiproliferative and cytotoxic effects on the myeloma tumor cell, as well as antiangiogenic activity and immunomodulatory effects. Together with the introduction of bortezomib and thalidomide, lenalidomide has significantly improved the survival of patients with relapsed and refractory myeloma. The most common adverse events associated with lenalidomide include fatigue, skin rash, thrombocytopenia, and neutropenia. In addition, when lenalidomide is combined with dexamethasone or other conventional cytotoxic agents, there is an increase in the incidence of venous thromboembolic events. There is now evidence that continued treatment with lenalidomide has a significant impact on survival by improving the depth and duration of response. This highlights the value of adverse event management and appropriate dose adjustments to prevent toxicity, and of allowing continued treatment until disease progression. In this review, we will discuss the different lenalidomide-based treatment regimens for patients with relapsed/refractory myeloma. This is accompanied by recommendations of how to manage and prevent adverse events associated with lenalidomide-based therapy.


COMT Val(158) Met genotype is associated with reward learning: a replication study and meta-analysis.
Identifying mechanisms through which individual differences in reward learning emerge offers an opportunity to understand both a fundamental form of adaptive responding as well as etiological pathways through which aberrant reward learning may contribute to maladaptive behaviors and psychopathology. One candidate mechanism through which individual differences in reward learning may emerge is variability in dopaminergic reinforcement signaling. A common functional polymorphism within the catechol-O-methyl transferase gene (COMT; rs4680, Val(158) Met) has been linked to reward learning, where homozygosity for the Met allele (linked to heightened prefrontal dopamine function and decreased dopamine synthesis in the midbrain) has been associated with relatively increased reward learning. Here, we used a probabilistic reward learning task to asses response bias, a behavioral form of reward learning, across three separate samples that were combined for analyses (age: 21.80 ± 3.95; n = 392; 268 female; European-American: n = 208). We replicate prior reports that COMT rs4680 Met allele homozygosity is associated with increased reward learning in European-American participants (β = 0.20, t = 2.75, P < 0.01; ΔR(2) = 0.04). Moreover, a meta-analysis of 4 studies, including the current one, confirmed the association between COMT rs4680 genotype and reward learning (95% CI -0.11 to -0.03; z = 3.2; P < 0.01). These results suggest that variability in dopamine signaling associated with COMT rs4680 influences individual differences in reward which may potentially contribute to psychopathology characterized by reward dysfunction.


The role of the hippocampus in prediction and imagination.
Traditionally, the hippocampal system has been studied in relation to the goal of retrieving memories about the past. Recent work in humans and rodents suggests that the hippocampal system may be better understood as a system that facilitates predictions about upcoming events. The hippocampus and associated cortical structures are active when people envision future events, and damage that includes the hippocampal region impairs this ability. In rats, hippocampal ensembles preplay and replay event sequences in the absence of overt behavior. If strung together in novel combinations, these sequences could provide the neural building blocks for simulating upcoming events during decision-making, planning, and when imagining novel scenarios. Moreover, in both humans and rodents, the hippocampal system is spontaneously active during task-free epochs and sleep, further suggesting that the system may use idle moments to derive new representations that set the context for future behaviors.


A New Wide-Band Double-Negative Metamaterial for C- and S-Band Applications.
A new design and analysis of a wide-band double-negative metamaterial, considering a frequency range of 0.5 to 7 GHz, is presented in this paper. Four different unit cells with varying design parameters are analyzed to evaluate the effects of the unit-cell size on the resonance frequencies of the metamaterial. Moreover, open and interconnected 2 × 2 array structures of unit cells are analyzed. The finite-difference time-domain (FDTD) method, based on the Computer Simulation Technology (CST) Microwave Studio, is utilized in the majority of this investigation. The experimental portion of the study was performed in a semi-anechoic chamber. Good agreement is observed between the simulated and measured S parameters of the developed unit cell and array. The designed unit cell exhibits negative permittivity and permeability simultaneously at S-band (2.95 GHz to 4.00 GHz) microwave frequencies. In addition, the designed unit cell can also operate as a double-negative medium throughout the C band (4.00 GHz to 4.95 GHz and 5.00 GHz to 5.57 GHz). At a number of other frequencies, it exhibits a single negative value. The two array configurations cause a slight shift in the resonance frequencies of the metamaterial and hence lead to a slight shift of the single- and double-negative frequency ranges of the metamaterial.


Transcranial Doppler Ultrasonographic Evaluation of Cerebrovascular Abnormalities in Children With Acute Bacterial Meningitis.
Introduction: Bacterial meningitis (BM) is a global public health concern that results in significant morbidity and mortality. Cerebral arterial narrowing contributes to stroke in BM and may be amenable to intervention. However, it is difficult to diagnose in resource-limited settings where the disease is common. Methods: This was a prospective observational study from September 2015 to December 2019 in sub-Saharan Africa. Children 1 month-18 years of age with neutrophilic pleocytosis or a bacterial pathogen identified in the cerebrospinal fluid were enrolled. Transcranial Doppler ultrasound (TCD) of the middle cerebral arteries was performed daily with the aim to identify flow abnormalities consistent with vascular narrowing. Results: Forty-seven patients were analyzed. The majority had Streptococcus pneumoniae (36%) or Neisseria meningitides (36%) meningitis. Admission TCD was normal in 10 (21%). High flow with a normal pulsatility index (PI) was seen in 20 (43%) and high flow with a low PI was identified in 7 (15%). Ten (21%) had low flow. All children with a normal TCD had a good outcome. Patients with a high-risk TCD flow pattern (high flow/low PI or low flow) were more likely to have a poor outcome (82 vs. 38%, p = 0.001). Conclusions: Abnormal TCD flow patterns were common in children with BM and identified those at high risk of poor neurological outcome.


The neural cell adhesion molecule regulates cell-surface delivery of G-protein-activated inwardly rectifying potassium channels via lipid rafts.
Mice deficient in the neural cell adhesion molecule (NCAM) exhibit increased anxiety and anxiolytic sensitivity to serotonin 5-HT1A receptor agonists. Here, we investigate the relationship between NCAM and 5-HT1A receptor signaling pathways modulating G-protein-activated inwardly rectifying K+ (Kir3) channels. When studying this relationship in cultured hippocampal neurons, we observed that in cells from NCAM-deficient mice, inwardly rectifying K+ (Kir3) currents were increased compared with wild-type controls. Analysis of this modulatory mechanism in Xenopus oocytes and Chinese hamster ovary (CHO) cells revealed that the recombinantly expressed major transmembrane isoforms NCAM140 and NCAM180 specifically reduced inward currents generated by neuronal Kir3.1/3.2 and Kir3.1/3.3 but not by cardiac Kir3.1/3.4 channels. Using fluorescence measurements and surface biotinylation assays, we show that this effect was caused by a reduced surface localization of Kir3 channels. Furthermore, expression of flag-tagged Kir3 channels in cultured neurons of NCAM-deficient mice resulted in a higher transport of these channels into neurites and a higher cell-surface localization compared with wild-type neurons. Neuronal Kir3 channels and NCAM isoforms are associated with cholesterol-rich microdomains (lipid rafts) in CHO cells and in isolated brain membranes. Mutational and pharmacological disruption of the lipid raft association of NCAM140 normalizes surface delivery of channels. We conclude that the transmembrane isoforms of NCAM reduce the transport of Kir3 channels to the cell surface via lipid rafts. Thus, regulation of Kir3 channel activity by NCAM may represent a novel mechanism controlling long-term excitability of neurons.


Pathway-Specific Asymmetries between ON and OFF Visual Signals.
Visual processing is largely organized into ON and OFF pathways that signal stimulus increments and decrements, respectively. These pathways exhibit natural pairings based on morphological and physiological similarities, such as ON and OFF α-ganglion cells in the mammalian retina. Several studies have noted asymmetries in the properties of ON and OFF pathways. For example, the spatial receptive fields (RFs) of OFF α-cells are systematically smaller than ON α-cells. Analysis of natural scenes suggests that these asymmetries are optimal for visual encoding. To test the generality of ON/OFF asymmetries, we measured the spatiotemporal RF properties of multiple RGC types in rat retina. Through a quantitative and serial classification, we identified three functional pairs of ON and OFF RGCs. We analyzed the structure of their RFs and compared spatial integration, temporal integration, and gain across ON and OFF pairs. Similar to previous results from the cat and primate, RGC types with larger spatial RFs exhibited briefer temporal integration and higher gain. However, each pair of ON and OFF RGC types exhibited distinct asymmetric relationships between RF properties, some of which were opposite to the findings of previous reports. These results reveal the functional organization of six RGC types in the rodent retina and indicate that ON/OFF asymmetries are pathway specific.SIGNIFICANCE STATEMENT Circuits that process sensory input frequently process increments separately from decrements, so-called ON and OFF responses. Theoretical studies indicate that this separation, and associated asymmetries in ON and OFF pathways, may be beneficial for encoding natural stimuli. However, the generality of ON and OFF pathway asymmetries has not been tested. Here we compare the functional properties of three distinct pairs of ON and OFF pathways in the rodent retina and show that their asymmetries are pathway specific. These results provide a new view on the partitioning of vision across diverse ON and OFF signaling pathways.


Alcohol treatment research assessment exposure subject reactivity effects: part I. Alcohol use and related consequences.
There has been increasing recognition among alcohol treatment researchers that research assessment exposure subject reactivity effects can contribute to clinical outcomes, decrease study design sensitivity, and confound research findings. The present study is an experimental investigation of two of the more salient components of the research assessment interview (i.e., frequency and comprehensiveness) and their effects on clinical outcomes (Part I: Alcohol Use and Related Consequences) and treatment participation (Part II: Treatment Engagement and Involvement). The study design was a 2 (Frequency of Assessment) x 2 (Comprehensiveness of Assessment) completely randomized factorial, and study participants were randomly assigned, using an urn randomization procedure, to one of the resulting four experimental research assessment exposure conditions: (1) frequent-comprehensive, (2) frequent-brief, (3) infrequent-comprehensive, and (4) infrequent-brief. Study participants were recruited from one of two hospital-based outpatient alcohol- and other substance-abuse clinics. Two hundred thirty-five subjects were randomly assigned to one of the four research assessment exposure conditions. Research assessment exposure subject reactivity effects were related significantly to alcohol use and related negative consequences, such that subjects assigned to the infrequent-brief research assessment exposure condition reported the poorest outcomes. The research protocols used to study alcohol treatments have clinical efficacy and can alter the outcomes (e.g., alcohol use) under investigation. It is important for researchers to control/account for subject reactivity effects when conducting alcohol treatment outcome trials. Accurate interpretation of data derived from clinical trials of alcohol treatments necessitates taking research assessment exposure subject reactivity effects into consideration.


Interpretations of person-centered dementia care: Same rhetoric, different practices? A comparative study of nursing homes in England and Sweden.
Using ethnographic data collected from nursing homes in England and Sweden, this article analyzes how a person-centered approach to dementia care has been interpreted in two different contexts. Based on typical elements of person-centered care identified in previous research, the analysis examines environmental changes and the way care is performed. A discourse of person-centered care is articulated at both nursing homes, which aim to create a good environment and care practice for people with dementia. Although we found similarities in how good care was understood at the two homes, we also found important differences. The results point by to two types of care atmospheres, such that cheerfulness and activity are underlined at the English home and calmness at the Swedish home. Differences in the environments and practices of a person-centered approach can be related to how ways of giving care in the two homes accentuate two different symptoms of dementia. In the English home, the problem of a shrinking world was stressed and the solution was stimulation. At the Swedish home, problems of agitation and anxiety were stressed and the solution was calm and quiet. These differences are discussed in the light of the role of national policy, resources and the organization of work, which can partly clarify why some aspects of what is good care for persons with dementia are underscored in a specific context and not in others.


Remote village survey for agents causing hepatosplenic disease in the Republic of Yemen.
The objective of this study was to epidemiologically describe potential infectious agents among rural people in the Republic of Yemen. This would aid clinicians in designing empirical therapy and public health officials in planning disease prevention. We sought to examine evidence for the geographical distribution of pathogens causing human hepatic and splenic disease among villagers and domestic animals living in three remote areas with differing altitudes. In June 1992, a cross-sectional survey was conducted at three survey sites of differing altitudes: 3080, 1440 and 250 m above sea level. Questionnaires, parasitic and serological tests were administered to 627 human volunteers. Additionally 317 domestic animals were studied. Malaria, schistosomiasis, and hepatitis B and C infections were found to be likely causes of human hepatic or splenic disease. Additionally, evidence of human and animal infections with the agents of brucellosis and Q fever was found: IgG antibodies against hepatitis E virus were discovered in two (2.0%) of the 100 volunteers. The prevalence of markers for human and animal disease was often lowest at the village of highest elevation, suggesting that increasing altitude, as a surrogate or a true independent risk factor, was protective against infection with the agents studied.


The relationship between suicide and violence in schizophrenia: analysis of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) dataset.
Suicide and violence often co-occur in the general population as well as in mentally ill individuals. Few studies, however, have assessed whether these suicidal behaviors are predictive of violence risk in mental illness. The aim of this study is to investigate whether suicidal behaviors, including suicidal ideation, threats, and attempts, are significantly associated with increased violence risk in individuals with schizophrenia. Data for these analyses were obtained from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) trial, a randomized controlled trial of antipsychotic medication in 1460 adults with schizophrenia. Univariate Cox regression analyses were used to calculate hazard ratios (HRs) for suicidal ideation, threats, and attempts. Multivariate analyses were conducted to adjust for common confounding factors, including: age, alcohol or drug misuse, major depression, antisocial personality disorder, depression, hostility, positive symptom, and poor impulse control scores. Tests of discrimination, calibration, and reclassification assessed the incremental predictive validity of suicidal behaviors for the prediction of violence risk. Suicidal threats and attempts were significantly associated with violence in both males and females with schizophrenia with little change following adjustment for common confounders. Only suicidal threats, however, were associated with a significant increase in incremental validity beyond age, diagnosis with a comorbid substance use disorder, and recent violent behavior. Suicidal threats are independently associated with violence risk in both males and females with schizophrenia, and may improve violence risk prediction.


Diverse Aquatic Adaptations in Nothosaurus spp. (Sauropterygia)-Inferences from Humeral Histology and Microanatomy.
Mid-diaphyseal cortical bone tissue in humeri of Nothosaurus spp. consists of coarse parallel-fibered bone, finer and higher organized parallel-fibered bone, and lamellar bone. Vascular canals are mainly arranged longitudinally and radially in a dominantly radial system. Blood vessels are represented by simple vascular canals, incompletely lined primary osteons, and fully developed primary osteons. Nothosaurus spp. shows a variety of diaphyseal microanatomical patterns, ranging from thick to very thin-walled cortices. In the early Anisian (Lower Muschelkalk), small- and large-bodied Nothosaurus spp. generally exhibit bone mass increase (BMI). In the middle to late Anisian (Middle Muschelkalk) small-bodied nothosaurs retain BMI whereas larger-bodied forms tend to show a decrease in bone mass (BMD). During the latest Anisian to early Ladinian (Upper Muschelkalk), small- and few large-bodied nothosaurs retain BMI, whereas the majority of large-bodied forms exhibit BMD. The stratigraphically youngest nothosaurs document five microanatomical categories, two of which are unique among marine amniotes: One consists of a very heterogeneously distributed spongy periosteal organization, the other of very thin-walled cortices. The functional significance of the two unique microanatomical specializations seen in large-bodied nothosaurs is the reduction of bone mass, which minimizes inertia of the limbs, and thus saves energy during locomotion. Transitions between the various microanatomical categories are rather gradual. Our results suggest that small-bodied Nothosaurus marchicus and other, not further assignable small-bodied nothosaurs seem to have been bound to near-shore, shallow marine environments throughout their evolution. Some large-bodied Nothosaurus spp. followed the same trend but others became more active swimmers and possibly inhabited open marine environments. The variety of microanatomical patterns may be related to taxonomic differences, developmental plasticity, and possibly sexual dimorphism. Humeral microanatomy documents the diversification of nothosaur species into different environments to avoid intraclade competition as well as competition with other marine reptiles. Nothosaur microanatomy indicates that knowledge of processes involved in secondary aquatic adaptation and their interaction are more complex than previously believed.


Synaptic plasticity as a therapeutic target in the treatment of autism-related single-gene disorders.
The term "Autism Spectrum" is often used to describe disorders that are currently classified as Pervasive Developmental Disorders. These disorders are typically characterized by social deficits, communication difficulties, stereotyped or repetitive behaviors and/or cognitive delays or mental retardation; sometimes they present high comorbidity rates with epilepsy. Although these diagnoses share some common features, individuals with these disorders are thought to be "on the spectrum" because of differences in severity across these domains. Recent advances in the genetics of autism spectrum disorders (ASDs) are offering new valuable insights into molecular and cellular mechanisms of pathology. Of particular interest are transgenic technologies that allowed the engineering of several mouse models mimicking different kinds of monogenic heritable forms of ASDs. These transgenic models provide excellent opportunities to explore in detail cellular and molecular mechanisms underlying disease pathology and to identify novel targets for therapeutic intervention. Increasing evidence suggests that the pathophysiological core of the murine model is primarily due to changes in normal synaptic transmission and plasticity. Here, we will extensively review the synaptic alterations across different animal models of ASDs and recapitulate the pharmacological strategies aimed at rescuing hippocampal plasticity phenotypes. We describe how pharmacological modulation of mGlu5 receptor, through the use of positive or negative allosteric modulators (depending on the specific disorder), may represent a promising therapeutic strategy for ASDs treatment.


New high-speed centre of mass method incorporating background subtraction for accurate determination of fluorescence lifetime.
We demonstrate an implementation of a centre-of-mass method (CMM) incorporating background subtraction for use in multifocal fluorescence lifetime imaging microscopy to accurately determine fluorescence lifetime in live cell imaging using the Megaframe camera. The inclusion of background subtraction solves one of the major issues associated with centre-of-mass approaches, namely the sensitivity of the algorithm to background signal. The algorithm, which is predominantly implemented in hardware, provides real-time lifetime output and allows the user to effectively condense large amounts of photon data. Instead of requiring the transfer of thousands of photon arrival times, the lifetime is simply represented by one value which allows the system to collect data up to limit of pulse pile-up without any limitations on data transfer rates. In order to evaluate the performance of this new CMM algorithm with existing techniques (i.e. rapid lifetime determination and Levenburg-Marquardt), we imaged live MCF-7 human breast carcinoma cells transiently transfected with FRET standards. We show that, it offers significant advantages in terms of lifetime accuracy and insensitivity to variability in dark count rate (DCR) between Megaframe camera pixels. Unlike other algorithms no prior knowledge of the expected lifetime is required to perform lifetime determination. The ability of this technique to provide real-time lifetime readout makes it extremely useful for a number of applications.


Detection of antibodies against the four subtypes of ebola virus in sera from any species using a novel antibody-phage indicator assay.
The natural host for Ebola virus, presumed to be an animal, has not yet been identified despite an extensive search following several major outbreaks in Africa. A straightforward approach used to determine animal contact with Ebola virus is by assessing the presence of specific antibodies in serum. This approach however has been made very difficult by the absence of specific reagents required for the detection of antibodies from the majority of wild animal species. In this study, we isolated a human monoclonal antibody Fab fragment, KZ51, that reacts with an immunodominant epitope on Ebola virus nucleoprotein (NP) that is conserved on all four Ebola virus subtypes. The antibody KZ51 represents a major specificity as sera from all convalescent patients tested (10/10) and sera from guinea pigs infected with each of the four Ebola virus subtypes competed strongly with KZ51 for binding to radiation-inactivated Ebola virus. These features allowed us to develop a novel assay for the detection of seroconversion irrespective of Ebola virus subtype or animal species. In this assay, the binding of KZ51 Fab-phage particles is used as an indicator assay and the presence of specific antibodies against Ebola virus in sera is indicated by binding competition. A prominent feature of the assay is that the Fab-phage particles may be prestained with a dye so that detection of binding can be directly determined by visual inspection. The assay is designed to be both simple and economical to enable its use in the field.


Screen-Space Normal Distribution Function Caching for Consistent Multi-Resolution Rendering of Large Particle Data.
Molecular dynamics (MD) simulations are crucial to investigating important processes in physics and thermodynamics. The simulated atoms are usually visualized as hard spheres with Phong shading, where individual particles and their local density can be perceived well in close-up views. However, for large-scale simulations with 10 million particles or more, the visualization of large fields-of-view usually suffers from strong aliasing artifacts, because the mismatch between data size and output resolution leads to severe under-sampling of the geometry. Excessive super-sampling can alleviate this problem, but is prohibitively expensive. This paper presents a novel visualization method for large-scale particle data that addresses aliasing while enabling interactive high-quality rendering. We introduce the novel concept of screen-space normal distribution functions (S-NDFs) for particle data. S-NDFs represent the distribution of surface normals that map to a given pixel in screen space, which enables high-quality re-lighting without re-rendering particles. In order to facilitate interactive zooming, we cache S-NDFs in a screen-space mipmap (S-MIP). Together, these two concepts enable interactive, scale-consistent re-lighting and shading changes, as well as zooming, without having to re-sample the particle data. We show how our method facilitates the interactive exploration of real-world large-scale MD simulation data in different scenarios.


Biophysical and computational studies of membrane penetration by the GRP1 pleckstrin homology domain.
The pleckstrin homology (PH) domain of the general receptor for phosphoinositides 1 (GRP1) exhibits specific, high-affinity, reversible binding to phosphatidylinositol (3,4,5)-trisphosphate (PI(3,4,5)P(3)) at the plasma membrane, but the nature and extent of the interaction between this bound complex and the surrounding membrane environment remains unclear. Combining equilibrium and nonequilibrium molecular dynamics (MD) simulations, NMR spectroscopy, and monolayer penetration experiments, we characterize the membrane-associated state of GRP1-PH. MD simulations show loops flanking the binding site supplement the interaction with PI(3,4,5)P(3) through multiple contacts with the lipid bilayer. NMR data show large perturbations in chemical shift for these loop regions on binding to PI(3,4,5)P(3)-containing DPC micelles. Monolayer penetration experiments and further MD simulations demonstrate that mutating hydrophobic residues to polar residues in the flanking loops reduces membrane penetration. This supports a "dual-recognition" model of binding, with specific GRP1-PH-PI(3,4,5)P(3) interactions supplemented by interactions of loop regions with the lipid bilayer.


The prognostic value of 18F-FDG PET/CT prior to liver transplantation for nonresectable colorectal liver metastases.
The main objective of this study was to evaluate the prognostic value of volumetric and metabolic information derivied from F-18 fluorodeoxyglucose positron emission tomography (18F-FDG PET) in combination with computed tomography (CT) prior to liver transplantation (LT) in patients with nonresectable colorectal liver metastases (CLM). Due to scarcity of liver grafts, prognostic information enabling selection of candidates who will gain the highest survival after LT is of vital importance. 18F-FDG PET/CT was a part of the preoperative study protocol. Patients without evidence of extrahepatic malignant disease on 18F-FDG PET/CT who also fulfilled all the other inclusion criteria underwent LT. The preoperative 18F-FDG PET/CT examinations of all patients included in the SECA (secondary cancer) study were retrospectively assessed. Maximum, mean and peak standardized uptake values (SUVmax, SUVmean and SUVpeak), tumor to background (T/B) ratio, metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were measured and calculated for all liver metastases. Total MTV and TLG were calculated for each patient. Cut-off values were determined for each of these parameters by using receiver operating characteristic (ROC) analysis dividing the patients into two groups. One, three and five-year overall survival (OS) and disease free survival (DFS) for patients over and under the cut-off value were compared by using the Kaplan-Meier method and log rank test. Twenty-three patients underwent LT in the SECA study. Total MTV and TLG under the cut-off values were significantly correlated to improved OS at three and five years (p = 0.027 and 0.026) and DFS (p = 0.01). One, three and five-year OS and DFS were not significantly related to SUVmax, SUVmean, SUVpeak or T/B-ratio. Total MTV and TLG from 18F FDG PET/CT prior to LT for nonresectable CLM were significantly correlated to improved three and five-year OS and DFS and can potentially improve the patient selection for LT.


Romosozumab or Alendronate for Fracture Prevention in Women with Osteoporosis.
Romosozumab is a monoclonal antibody that binds to and inhibits sclerostin, increases bone formation, and decreases bone resorption. We enrolled 4093 postmenopausal women with osteoporosis and a fragility fracture and randomly assigned them in a 1:1 ratio to receive monthly subcutaneous romosozumab (210 mg) or weekly oral alendronate (70 mg) in a blinded fashion for 12 months, followed by open-label alendronate in both groups. The primary end points were the cumulative incidence of new vertebral fracture at 24 months and the cumulative incidence of clinical fracture (nonvertebral and symptomatic vertebral fracture) at the time of the primary analysis (after clinical fractures had been confirmed in ≥330 patients). Secondary end points included the incidences of nonvertebral and hip fracture at the time of the primary analysis. Serious cardiovascular adverse events, osteonecrosis of the jaw, and atypical femoral fractures were adjudicated. Over a period of 24 months, a 48% lower risk of new vertebral fractures was observed in the romosozumab-to-alendronate group (6.2% [127 of 2046 patients]) than in the alendronate-to-alendronate group (11.9% [243 of 2047 patients]) (P<0.001). Clinical fractures occurred in 198 of 2046 patients (9.7%) in the romosozumab-to-alendronate group versus 266 of 2047 patients (13.0%) in the alendronate-to-alendronate group, representing a 27% lower risk with romosozumab (P<0.001). The risk of nonvertebral fractures was lower by 19% in the romosozumab-to-alendronate group than in the alendronate-to-alendronate group (178 of 2046 patients [8.7%] vs. 217 of 2047 patients [10.6%]; P=0.04), and the risk of hip fracture was lower by 38% (41 of 2046 patients [2.0%] vs. 66 of 2047 patients [3.2%]; P=0.02). Overall adverse events and serious adverse events were balanced between the two groups. During year 1, positively adjudicated serious cardiovascular adverse events were observed more often with romosozumab than with alendronate (50 of 2040 patients [2.5%] vs. 38 of 2014 patients [1.9%]). During the open-label alendronate period, adjudicated events of osteonecrosis of the jaw (1 event each in the romosozumab-to-alendronate and alendronate-to-alendronate groups) and atypical femoral fracture (2 events and 4 events, respectively) were observed. In postmenopausal women with osteoporosis who were at high risk for fracture, romosozumab treatment for 12 months followed by alendronate resulted in a significantly lower risk of fracture than alendronate alone. (Funded by Amgen and others; ARCH ClinicalTrials.gov number, NCT01631214 .).


Microstructural imaging of the human brain with a 'super-scanner': 10 key advantages of ultra-strong gradients for diffusion MRI.
The key component of a microstructural diffusion MRI 'super-scanner' is a dedicated high-strength gradient system that enables stronger diffusion weightings per unit time compared to conventional gradient designs. This can, in turn, drastically shorten the time needed for diffusion encoding, increase the signal-to-noise ratio, and facilitate measurements at shorter diffusion times. This review, written from the perspective of the UK National Facility for In Vivo MR Imaging of Human Tissue Microstructure, an initiative to establish a shared 300 mT/m-gradient facility amongst the microstructural imaging community, describes ten advantages of ultra-strong gradients for microstructural imaging. Specifically, we will discuss how the increase of the accessible measurement space compared to a lower-gradient systems (in terms of Δ, b-value, and TE) can accelerate developments in the areas of 1) axon diameter distribution mapping; 2) microstructural parameter estimation; 3) mapping micro-vs macroscopic anisotropy features with gradient waveforms beyond a single pair of pulsed-gradients; 4) multi-contrast experiments, e.g. diffusion-relaxometry; 5) tractography and high-resolution imaging in vivo and 6) post mortem; 7) diffusion-weighted spectroscopy of metabolites other than water; 8) tumour characterisation; 9) functional diffusion MRI; and 10) quality enhancement of images acquired on lower-gradient systems. We finally discuss practical barriers in the use of ultra-strong gradients, and provide an outlook on the next generation of 'super-scanners'.


Epileptic discharges specifically affect intrinsic connectivity networks during absence seizures.
Intrinsic connectivity network (ICN) technique provides a feasible way for evaluating cognitive impairments in epilepsy. This EEG-fMRI study aims to comprehensively assess the alterations of ICNs affected by generalized spike-and-wave discharge (GSWD) during absence seizure (AS). Twelve fMRI sessions with GSWD, and individually paired non-GSWD sessions were acquired from 16 patients with AS. Ten ICNs corresponding to seizure origination and cognitive processes were extracted using independent component analysis. Intra- and inter-network connectivity alterations of the ICNs were observed through comparisons between GSWD and non-GSWD sessions. Sequential correlation analysis between GSWD and the ICN time courses addressed the immediate effects of GSWD on ICNs during AS. GSWD-related increase of intra-network connectivity was found only in the thalamus, and extensive decreases were found in the ICNs corresponding to higher-order cognitive processes including the default-mode network, dorsal attention network, central executive network and salience network. The perceptive networks and motor network were less affected by GSWD. Sequential correlation analysis further demonstrated different responses of the ICNs to GSWD. In addition to GSWD-related functional excitation in the thalamus and functional suspension in the default-mode network, this study revealed extensive inhibitions in the other ICNs corresponding to higher-order cognitive processes, and spared perceptive and motor processes in AS. GSWD elevated synchronization of brain network activity and sequentially affected the ICNs.


Five-year survival after pulmonary metastasectomy for adult soft tissue sarcoma.
Determinants of 5-year survival were evaluated after complete resection of pulmonary metastases from adult soft-tissue sarcomas. Fifty-eight patients had complete resection (median survival 25 months, P = 0.0002), with a 25.8% absolute 5-year survival (15 of 58 patients); six patients had unresectable disease (median survival 6 months) and were excluded from additional analysis. Eleven patients remain disease free, with a median follow-up of 76 months. Significant independent prognostic indicators associated with improved survival (P less than 0.05) included metastasis doubling time of 40 days or greater (median survival 37 months versus 15 months if less than 40 days); unilateral disease on preoperative radiography (33 months versus 15 months if bilateral disease); three or fewer nodules on preoperative computed tomography (40 months versus 14 months if 4 or more nodules); two nodules or fewer resected (40 months versus 17 months if 3 or more nodules resected), and tumor histology (33 months for malignant fibrous histiocytoma versus 17 months for all others). Multivariate analysis identified the number of nodules detected by computed tomography preoperatively as having significant prognostic value.


The PROSITE database.
The PROSITE database consists of a large collection of biologically meaningful signatures that are described as patterns or profiles. Each signature is linked to a documentation that provides useful biological information on the protein family, domain or functional site identified by the signature. The PROSITE database is now complemented by a series of rules that can give more precise information about specific residues. During the last 2 years, the documentation and the ScanProsite web pages were redesigned to add more functionalities. The latest version of PROSITE (release 19.11 of September 27, 2005) contains 1329 patterns and 552 profile entries. Over the past 2 years more than 200 domains have been added, and now 52% of UniProtKB/Swiss-Prot entries (release 48.1 of September 27, 2005) have a cross-reference to a PROSITE entry. The database is accessible at http://www.expasy.org/prosite/.


Robot-assisted retroperitoneal lymph node dissection: Feasibility and outcome in postchemotherapy residual mass in testicular cancer.
We aimed to evaluate the surgical feasibility, complication, and oncological outcome of robot-assisted retroperitoneal lymph node dissection (RA-RPLND) in patients of testicular tumor with postchemotherapy residual retroperitoneal mass. A total of 13 patients underwent RA-RPLND between January 2012 and September 2016 at our institute. A study was started on December 2015, so data were collected retrospectively and prospectively regarding patient demography, tumor characteristics, surgical, pathological outcome, and oncological outcome. RA-RPLND was successfully completed in all the 13 patients. Lateral approach was used in initial 12 patients with unilateral dissection in 11 patients and bilateral dissection after in 1 patient after repositioning in bilateral position. Supine robotic approach used in 1 patient. Median operative time was 200 min, median estimated blood loss was 120 ml, and median length of hospital stay was 4 days. The median yield of lymph node was 20. Three patients had positive lymph nodes, all had teratoma germ cell tumor. Ten patients had only necrosis in lymph nodes. After median follow-up 23 months (range 3-58 months), no systemic or retroperitoneal recurrence was found. Four patients developed chyle leak. One patient was managed conservatively with diet modification, one with intranodal lipiodol lymphangiography and two patients were managed surgically. RA-RPLND is safe and feasible for postchemotherapy residual mass with accepted compilation rate, but larger studies are required to establish its diagnostic and therapeutic utility along with safety of the procedure.


PGI2 Is a Novel SGI1-Relative Multidrug-Resistant Genomic Island Characterized in Proteus mirabilis.
A novel 61,578-bp genomic island named Proteus genomic island 2 (PGI2) was characterized in Proteus mirabilis of swine origin in China. The 23.85-kb backbone of PGI2 is related to those of Salmonella genomic island 1 and Acinetobacter genomic island 1. The multidrug resistance (MDR) region of PGI2 is a complex class 1 integron containing 14 different resistance genes. PGI2 was conjugally mobilized in trans to Escherichia coli in the presence of a conjugative IncC helper plasmid.


Diclofenac poisoning is widespread in declining vulture populations across the Indian subcontinent.
Recent declines in the populations of three species of vultures in the Indian subcontinent are among the most rapid ever recorded in any bird species. Evidence from a previous study of one of these species, Gyps bengalensis, in the Punjab province of Pakistan, strongly implicates mortality caused by ingestion of residues of the veterinary non-steroidal anti-inflammatory drug diclofenac as the major cause of the decline. We show that a high proportion of Gyps bengalensis and G. indicus found dead or dying in a much larger area of India and Nepal also have residues of diclofenac and visceral gout, a post-mortem finding that is strongly associated with diclofenac contamination in both species. Hence, veterinary use of diclofenac is likely to have been the major cause of the rapid vulture population declines across the subcontinent.


Stemphylium botryosum Pathogenic on Spinach Seed Crops in Washington.
In September 2000, symptoms typical of leaf spot caused by Cladosporium variabile were observed on a spinach (Spinacea oleracea L.) seed crop in western Washington. Dry, bleached spots (1 to 20 mm) were most abundant on lower leaves. Two isolates of C. variabile and three isolates of Stemphylium were recovered by plating surface-sterilized (0.1% sodium hypochlorite) sections of symptomatic leaf tissue onto water agar and acidified potato dextrose agar (PDA). Transfers of each isolate were made to PDA, and cultures were kept at 24 ± 2°C on a lab bench (natural day/night cycle) for 10 to 14 days. Spore suspensions (105/ml) of the isolates of C. variabile were prepared in a 0.01% solution of Tween 80. Isolates of Stemphylium produced few spores, so mycelial suspensions (105 fragments/ml) were prepared. Five 8-week-old seedlings of each of the cultivars Winter Bloomsdale and Ozarka II were inoculated per fungal isolate by atomizing the inoculum onto each seedling until all leaves were covered with a thin film of droplets (4 to 5 ml of inoculum per seedling). Plants were enclosed in plastic bags on a greenhouse bench (24 ± 3°C) for 72 h (8 h/16 h day/night). Symptoms developed within 80 h of inoculation for both isolates of C. variabile and two isolates of Stemphylium. Small (1 to 2 mm) sunken spots turned white 24 to 48 h later and became dry and bleached. Lesions caused by isolates of Stemphylium enlarged and coalesced more rapidly than lesions caused by C. variabile, and were more irregular and usually not delimited by the thin brown margin typical of lesions caused by C. variabile. The differences in symptoms were consistent on both spinach cultivars. Symptoms were not observed on non-inoculated control plants nor on plants inoculated with the third isolate of Stemphylium. C. variabile and Stemphylium were reisolated from symptomatic leaf tissue. Colony morphology, conidiophores, and conidia of the pathogenic Stemphylium isolates were similar to those of pathogenic isolates of Stemphylium botryosum obtained from spinach plants in California (2). This is the first report of S. botryosum as a foliar pathogen of spinach seed crops in Washington. Although Correll et al. (1) noted Stemphylium to be damaging on mature spinach plants grown for seed production, S. botryosum may not have been diagnosed previously on spinach seed crops in Washington because of the similarity of symptoms caused by S. botryosum and C. variabile. S. botryosum was recently reported as a foliar pathogen of spinach in California (2). References: (1) J. C. Correll et al. Plant Dis. 78:653, 1994. (2) S. T. Koike et al. Plant Dis. 85:126, 2001.


Toward a research and action agenda on urban planning/design and health equity in cities in low and middle-income countries.
The importance of reestablishing the link between urban planning and public health has been recognized in recent decades; this paper focuses on the relationship between urban planning/design and health equity, especially in cities in low and middle-income countries (LMICs). The physical urban environment can be shaped through various planning and design processes including urban planning, urban design, landscape architecture, infrastructure design, architecture, and transport planning. The resultant urban environment has important impacts on the health of the people who live and work there. Urban planning and design processes can also affect health equity through shaping the extent to which the physical urban environments of different parts of cities facilitate the availability of adequate housing and basic infrastructure, equitable access to the other benefits of urban life, a safe living environment, a healthy natural environment, food security and healthy nutrition, and an urban environment conducive to outdoor physical activity. A new research and action agenda for the urban environment and health equity in LMICs should consist of four main components. We need to better understand intra-urban health inequities in LMICs; we need to better understand how changes in the built environment in LMICs affect health equity; we need to explore ways of successfully planning, designing, and implementing improved health/health equity; and we need to develop evidence-based recommendations for healthy urban planning/design in LMICs.


Investigational therapeutics targeting the IL-4/IL-13/STAT-6 pathway for the treatment of asthma.
Asthma is a complex, persistent, inflammatory disease characterised by airway hyperresponsiveness in association with airway inflammation. Studies suggest that regular use of high-dose inhaled corticosteroids and long-acting bronchodilators or omalizumab (a humanised monoclonal antibody that binds to immunoglobulin E and is often used as next-step therapy) may not be sufficient to provide asthma control in all patients, highlighting an important unmet need. Interleukin-4, interleukin-13, and the signal transducer and activator of transcription factor-6 are key components in the development of airway inflammation, mucus production, and airway hyperresponsiveness in asthma. Biological compounds targeting these molecules may provide a new therapeutic modality for patients with uncontrolled severe asthma. The purpose of this review is to summarise current studies of compounds targeting the interleukin-4/interleukin-13 pathway and to provide a rationale for the development of such compounds for this use.


Jumping robots: a biomimetic solution to locomotion across rough terrain.
This paper introduces jumping robots as a means to traverse rough terrain; such terrain can pose problems for traditional wheeled, tracked and legged designs. The diversity of jumping mechanisms found in nature is explored to support the theory that jumping is a desirable ability for a robot locomotion system to incorporate, and then the size-related constraints are determined from first principles. A series of existing jumping robots are presented and their performance summarized. The authors present two new biologically inspired jumping robots, Jollbot and Glumper, both of which incorporate additional locomotion techniques of rolling and gliding respectively. Jollbot consists of metal hoop springs forming a 300 mm diameter sphere, and when jumping it raises its centre of gravity by 0.22 m and clears a height of 0.18 m. Glumper is of octahedral shape, with four 'legs' that each comprise two 500 mm lengths of CFRP tube articulating around torsion spring 'knees'. It is able to raise its centre of gravity by 1.60 m and clears a height of 1.17 m. The jumping performance of the jumping robot designs presented is discussed and compared against some specialized jumping animals. Specific power output is thought to be the performance-limiting factor for a jumping robot, which requires the maximization of the amount of energy that can be stored together with a minimization of mass. It is demonstrated that this can be achieved through optimization and careful materials selection.


Trends in the frequency and predictive value of reporting high grade abnormalities in cervical smears.
The "organized approach" to cervical screening in Australia includes standardized quality assurance measures for laboratories. This study examines changes in the frequency and the positive predictive value of reporting severe abnormalities in cervical smears over a 3-year period as a guide to the effects of implementing these measures. The results of screening in 6-month periods from January 1995 to December 1997 were determined. Biopsy follow-up for results in the high grade epithelial abnormality ("HGEA") and "inconclusive: possible HGEA" categories was obtained from the Western Australian Cervical Cytology Registry (CCR). Approximately 40,000 smears were examined in each 6-month period. The frequencies of reporting HGEA were 0.47%, 0.59%, 0.79%, 0.85%, and 0.84%, and 0.91% for the study periods (P < 0.001). For the inconclusive category, they were 0.24%, 0.18%, 0.24%, 0.31%, 0.38%, and 0.35% (P < 0.001). Biopsy follow-up was available for 83. 9%, 80.5%, 89.9%, 92.4%, 93.1%, and 90.3% of the HGEA results and for 78.6%, 71.7%, 80.5%, 75.0%, 87.1%, and 85.9% of the inconclusive results over the study periods. The yield of high grade lesions for the biopsied cases was 82.6%, 82.3%, 83.1%, 79.5%, 80.9%, and 79% for HGEA cases and 58.2%, 41.9%, 60.6%, 52.8%, 47.5%, and 54.1% for inconclusive cases. There was a doubling in the reporting of HGEA results, whereas the positive predictive value for biopsied cases remained at about 80%. Reporting rates for inconclusive: possible HGEA cases also doubled, but the yield of biopsy-proven, high grade lesions remained at about 50%. These changes occurred in the absence of ancillary testing and with targeted rescreening methods. A high rate of reporting HGEA, in combination with a high positive predictive value, is among the most important indicators of cervical cytology laboratory performance. Large improvements in results may occur using conventional methods of quality assurance. Cancer (Cancer Cytopathol)