Common mechanisms for calorie restriction and adenylyl cyclase type 5 knockout models of longevity.
Adenylyl cyclase type 5 knockout mice (AC5 KO) live longer and are stress resistant, similar to calorie restriction (CR). AC5 KO mice eat more, but actually weigh less and accumulate less fat compared with WT mice. CR applied to AC5 KO results in rapid decrease in body weight, metabolic deterioration, and death. These data suggest that despite restricted food intake in CR, but augmented food intake in AC5 KO, the two models affect longevity and metabolism similarly. To determine shared molecular mechanisms, mRNA expression was examined genome-wide for brain, heart, skeletal muscle, and liver. Significantly more genes were regulated commonly rather than oppositely in all the tissues in both models, indicating commonality between AC5 KO and CR. Gene ontology analysis identified many significantly regulated, tissue-specific pathways shared by the two models, including sensory perception in heart and brain, muscle function in skeletal muscle, and lipid metabolism in liver. Moreover, when comparing gene expression changes in the heart under stress, the glutathione regulatory pathway was consistently upregulated in the longevity models but downregulated with stress. In addition, AC5 and CR shared changes in genes and proteins involved in the regulation of longevity and stress resistance, including Sirt1, ApoD, and olfactory receptors in both young- and intermediate-age mice. Thus, the similarly regulated genes and pathways in AC5 KO and CR mice, particularly related to the metabolic phenotype, suggest a unified theory for longevity and stress resistance.


Estimating HIV incidence from age-specific prevalence data: comparison with concurrent cohort estimates in a study of male factory workers, Harare, Zimbabwe.
To compare HIV incidence estimates from cross-sectional age-specific prevalence data with concurrent cohort estimates and to examine the sensitivity of the estimates to changes in age-categorization and survivorship assumptions. Two previously described methods of estimating HIV incidence from cross-sectional prevalence data - the cumulative incidence and survival (CIS) and constant prevalence (CP) methods - are applied using data from a study of male factory workers in Harare, Zimbabwe. The methods are applied under two alternative groupings of the HIV prevalence data and under alternative survivorship assumptions: (a) Weibull distribution providing the best fit to the HIV prevalence data using the CIS method; (b) Weibull distribution matching data from an HIV natural history cohort study in Uganda; and (c) survivorship pattern as in (b) with survival periods reducing with increasing age at infection. Age-specific, age-standardized and cumulative HIV incidence estimates are calculated. The results are compared with concurrent longitudinal estimates from 3 years of follow-up of the Harare cohort (1993-1995). Age-standardized HIV incidence was estimated at 2.02 per 100 man years (95% CI, 1.57-2.47) in the cohort study. There was evidence of recent variability in HIV incidence in these data. Estimates from the cross-sectional methods ranged from 1.98 to 2.74 per 100 man years and were sensitive to changes in age-categorization of the HIV prevalence data and changes in survivorship assumptions. The cross-sectional estimates were higher at central ages and lower at older ages than the cohort estimates. The age-specific estimates from the CIS method were less sensitive to changes in age grouping than those from the CP method. HIV incidence remains high in Harare. Incidence estimates broadly consistent with cohort estimates can be obtained from single-round cross-sectional HIV prevalence data in established epidemics - even when the underlying assumption of stable endemic prevalence is not fully met. Estimates based on cross-sectional surveys should therefore be explored when reliable longitudinal estimates cannot be obtained. More data on post-HIV infection survivorship distributions in sub-Saharan Africa would facilitate the improvement of estimates of incidence based on cross-sectional surveys.


Rifampicin decreases neuroinflammation to maintain mitochondrial function and calcium homeostasis in rotenone-treated zebrafish.
Among the mechanisms underlying Parkinson's disease, many pathogenic mechanisms are suggested to be effective such as oxidative stress, mitochondrial dysfunction, disruption of the ubiquitin-proteasome system, and neuroinflammation. Calcium is very important for neuronal and glial cells, neurodegenerative disease mechanisms are closely related to disturbed calcium homeostasis. Recent studies strongly support the role of inflammation in nigrostriatal degeneration in PD. In recent years, Rifampicin, a macrocyclic antibiotic has been shown to have a protective effect on neurons. This study aims to evaluate the effects of rifampicin in the experimental PD model induced by rotenone in zebrafish focusing on the relationship between calcium-dependent mitochondrial dysfunction and inflammation. Adult zebrafish were exposed to rotenone and rifampicin for 3 weeks. Locomotor activity was determined as the total distance that the zebrafish traveled for 5 min. Neuroinflammation and PD-related gene expressions were determined by RT-PCR. Mitochondrial calcium levels were determined using inductively coupled plasma-optical emission spectrometry (ICP-OES). Gamma synuclein, Park 7, Sigma-1 receptor expressions were determined by Western Blot. Our results show that rifampicin may be effective in reducing neuroinflammation, which may be an effective strategy to reduce mitochondrial dysfunction due to impaired calcium homeostasis in PD.


δ-Tocotrienol and quercetin reduce serum levels of nitric oxide and lipid parameters in female chickens.
Chronic, low-grade inflammation provides a link between normal ageing and the pathogenesis of age-related diseases. A series of in vitro tests confirmed the strong anti-inflammatory activities of known inhibitors of NF-κB activation (δ-tocotrienol, quercetin, riboflavin, (-) Corey lactone, amiloride, and dexamethasone). δ-Tocotrienol also suppresses β-hydroxy-β-methylglutaryl coenzyme A (HMG-CoA) reductase activity (the rate-limiting step in de novo cholesterol synthesis), and concomitantly lowers serum total and LDL cholesterol levels. We evaluated these compounds in an avian model anticipating that a dietary additive combining δ-tocotrienol with quercetin, riboflavin, (-) Corey lactone, amiloride, or dexamethasone would yield greater reductions in serum levels of total cholesterol, LDL-cholesterol and inflammatory markers (tumor necrosis factor-α [TNF-α], and nitric oxide [NO]), than that attained with the individual compounds. The present results showed that supplementation of control diets with all compounds tested except riboflavin, (-) Corey lactone, and dexamethasone produced small but significant reductions in body weight gains as compared to control. (-) Corey lactone and riboflavin did not significantly impact body weight gains. Dexamethasone significantly and markedly reduced weight gain (>75%) compared to control. The serum levels of TNF-α and NO were decreased 61% - 84% (P < 0.001), and 14% - 67%, respectively, in chickens fed diets supplemented with δ-tocotrienol, quercetin, riboflavin, (-) Corey lactone, amiloride, or dexamethasone as compared to controls. Significant decreases in the levels of serum total and LDL-cholesterol were attained with δ-tocotrienol, quercetin, riboflavin and (-) Corey lactone (13% - 57%; P < 0.05), whereas, these levels were 2-fold higher in dexamethasone treated chickens as compared to controls. Parallel responses on hepatic lipid infiltration were confirmed by histological analyses. Treatments combining δ-tocotrienol with the other compounds yielded values that were lower than individual values attained with either δ-tocotrienol or the second compound. Exceptions were the significantly lower total and LDL cholesterol and triglyceride values attained with the δ-tocotrienol/(-) Corey lactone treatment and the significantly lower triglyceride value attained with the δ-tocotrienol/riboflavin treatment. δ-Tocotrienol attenuated the lipid-elevating impact of dexamethasone and potentiated the triglyceride lowering impact of riboflavin. Microarray analyses of liver samples identified 62 genes whose expressions were either up-regulated or down-regulated by all compounds suggesting common impact on serum TNF-α and NO levels. The microarray analyses further identified 41 genes whose expression was differentially impacted by the compounds shown to lower serum lipid levels and dexamethasone, associated with markedly elevated serum lipids. This is the first report describing the anti-inflammatory effects of δ-tocotrienol, quercetin, riboflavin, (-) Corey lactone, amiloride, and dexamethasone on serum TNF-δ and NO levels. Serum TNF-δ levels were decreased by >60% by each of the experimental compounds. Additionally, all the treatments except with dexamethasone, resulted in lower serum total cholesterol, LDL-cholesterol and triglyceride levels. The impact of above mentioned compounds on the factors evaluated herein was increased when combined with δ-tocotrienol.


Brief Report: Cutaneous Melanoma Risk Among People With HIV in the United States and Canada.
Cutaneous melanoma incidence may be modestly elevated in people with HIV (PWH) vs. people without HIV. However, little is known about the relationship of immunosuppression, HIV replication, and antiretroviral therapy (ART) with melanoma risk. PWH of white race in the North American AIDS Cohort Collaboration on Research and Design were included. A standardized incidence ratio was calculated comparing risk with the white general population, standardizing by age, sex, and calendar period. Associations between melanoma incidence and current, lagged, and cumulative measures of CD4 count, HIV RNA level, and ART use were estimated with Cox regression, adjusting for established risk factors such as age and annual residential ultraviolet B (UVB) exposure. Eighty melanomas were diagnosed among 33,934 white PWH (incidence = 40.75 per 100,000 person-years). Incidence was not elevated compared with the general population [standardized incidence ratio = 1.15, 95% confidence interval (95% CI) = 0.91 to 1.43]. Higher melanoma incidence was associated with older age [adjusted hazard ratio (aHR) per decade increase = 1.50, 95% CI = 1.20 to 1.89] and higher UVB exposure (aHR for exposure ≥35 vs. <35 mW/m = 1.62, 95% CI = 0.99 to 2.65). Current, lagged, and cumulative CD4 and HIV RNA were not associated with melanoma incidence. Melanoma incidence was higher among people ART-treated for a larger proportion of time in the previous 720 days (aHR per 10% increase = 1.16, 95% CI = 1.03 to 1.30). These results suggest that HIV-induced immune dysfunction does not influence melanoma development. The association between ART and melanoma risk may be due to increased skin surveillance among PWH engaged in clinical care. Associations with age and UVB confirmed those established in the general population.


Treating cancer as an infectious disease--viral antigens as novel targets for treatment and potential prevention of tumors of viral etiology.
Nearly 20% of human cancers worldwide have an infectious etiology with the most prominent examples being hepatitis B and C virus-associated hepatocellular carcinoma and human papilloma virus-associated cervical cancer. There is an urgent need to find new approaches to treatment and prevention of virus-associated cancers. Viral antigens have not been previously considered as targets for treatment or prevention of virus-associated cancers. We hypothesized that it was possible to treat experimental HPV16-associated cervical cancer (CC) and Hepatitis B-associated hepatocellular carcinoma (HCC) by targeting viral antigens expressed on cancer cells with radiolabeled antibodies to viral antigens. Treatment of experimental CC and HCC tumors with (188)Re-labeled mAbs to E6 and HBx viral proteins, respectively, resulted in significant and dose-dependent retardation of tumor growth in comparison with untreated mice or mice treated with unlabeled antibodies. This strategy is fundamentally different from the prior uses of radioimmunotherapy in oncology, which targeted tumor-associated human antigens and promises increased specificity and minimal toxicity of treatment. It also raises an exciting possibility to prevent virus-associated cancers in chronically infected patients by eliminating cells infected with oncogenic viruses before they transform into cancer.


Use of baculovirus-expressed glycoprotein H in an enzyme-linked immunosorbent assay developed to assess exposure to chelonid fibropapillomatosis-associated herpesvirus and its relationship to the prevalence of fibropapillomatosis in sea turtles.
Chelonid fibropapillomatosis-associated herpesvirus (CFPHV) is an alphaherpesvirus believed to cause marine turtle fibropapillomatosis (FP). A serodiagnostic assay was developed for monitoring sea turtle populations for CFPHV exposure. CFPHV glycoprotein H (gH) expressed in recombinant baculovirus was used in an enzyme-linked immunosorbent assay (ELISA) to detect virus-specific 7S turtle antibodies. Using captive-reared green turtles (Chelonia mydas) with no history of virus exposure as "known negatives" and others with experimentally induced FP as "known positives," the assay had 100% specificity but low sensitivity, as seroconversion was detected in only half of the turtles bearing experimentally induced tumors. Antibodies were detected only in samples collected after cutaneous fibropapillomas appeared, consistent with observations that tumors are significant sites of virion production and antigen expression and the possibility that prolonged/repeated virus shedding may be required for adequate stimulation of 7S antibody responses to gH. Natural routes of infection, however, may produce higher seroconversion rates. High gH antibody seroprevalences ( approximately 80%) were found among wild green turtles in three Florida localities with different FP prevalences, including one site with no history of FP. In addition, all eight loggerhead turtles (Caretta caretta) tested were seropositive despite FP being uncommon in this species. The possibility that CFPHV infection may be common relative to disease suggests roles for environmental and host factors as modulators of disease expression. Alternatively, the possibility of other antigenically similar herpesviruses present in wild populations cannot be excluded, although antibody cross-reactivity with the lung/eye/trachea disease-associated herpesvirus was ruled out in this study.


Assessment of displacement ventilation systems in airborne infection risk in hospital rooms.
Efficient ventilation in hospital airborne isolation rooms is important vis-à-vis decreasing the risk of cross infection and reducing energy consumption. This paper analyses the suitability of using a displacement ventilation strategy in airborne infection isolation rooms, focusing on health care worker exposure to pathogens exhaled by infected patients. The analysis is mainly based on numerical simulation results obtained with the support of a 3-D transient numerical model validated using experimental data. A thermal breathing manikin lying on a bed represents the source patient and another thermal breathing manikin represents the exposed individual standing beside the bed and facing the patient. A radiant wall represents an external wall exposed to solar radiation. The air change efficiency index and contaminant removal effectiveness indices and inhalation by the health care worker of contaminants exhaled by the patient are considered in a typical airborne infection isolation room set up with three air renewal rates (6 h-1, 9 h-1 and 12 h-1), two exhaust opening positions and two health care worker positions. Results show that the radiant wall significantly affects the air flow pattern and contaminant dispersion. The lockup phenomenon occurs at the inhalation height of the standing manikin. Displacement ventilation renews the air of the airborne isolation room and eliminates the exhaled pollutants efficiently, but is at a disadvantage compared to other ventilation strategies when the risk of exposure is taken into account.


Weak phylogenetic signal in physiological traits of methane-oxidizing bacteria.
The presence of phylogenetic signal is assumed to be ubiquitous. However, for microorganisms, this may not be true given that they display high physiological flexibility and have fast regeneration. This may result in fundamentally different patterns of resemblance, that is, in variable strength of phylogenetic signal. However, in microbiological inferences, trait similarities and therewith microbial interactions with its environment are mostly assumed to follow evolutionary relatedness. Here, we tested whether indeed a straightforward relationship between relatedness and physiological traits exists for aerobic methane-oxidizing bacteria (MOB). We generated a comprehensive data set that included 30 MOB strains with quantitative physiological trait information. Phylogenetic trees were built from the 16S rRNA gene, a common phylogenetic marker, and the pmoA gene which encodes a subunit of the key enzyme involved in the first step of methane oxidation. We used a Blomberg's K from comparative biology to quantify the strength of phylogenetic signal of physiological traits. Phylogenetic signal was strongest for physiological traits associated with optimal growth pH and temperature indicating that adaptations to habitat are very strongly conserved in MOB. However, those physiological traits that are associated with kinetics of methane oxidation had only weak phylogenetic signals and were more pronounced with the pmoA than with the 16S rRNA gene phylogeny. In conclusion, our results give evidence that approaches based solely on taxonomical information will not yield further advancement on microbial eco-evolutionary interactions with its environment. This is a novel insight on the connection between function and phylogeny within microbes and adds new understanding on the evolution of physiological traits across microbes, plants and animals.


Quantum path interferences of electron trajectories in two-center molecules.
We report a new quantum path interference effect of electron trajectories in high-order harmonic generation (HHG) from two-center molecules, in which the interference minima are mainly located in the high-energy portion of HHG spectrum. The quantum calculations of the time-frequency analyses and the classical results of the electron trajectories demonstrate very good agreement and reveal that the positions of the interference minima are associated with the cutoff of various kinds of molecular electron trajectories. The interference fringes within a half optical cycle can be clearly seen in the time-frequency analysis spectrum. Moreover, the characteristics of both the HHG in frequency domain and the corresponding attosecond pulse generation in time domain permit tracing back the interference information of these electron trajectories. These interference phenomena offer new possibilities for getting insight into the attosecond electronic dynamics in molecules.


Single-molecule DNA-mapping and whole-genome sequencing of individual cells.
To elucidate cellular diversity and clonal evolution in tissues and tumors, one must resolve genomic heterogeneity in single cells. To this end, we have developed low-cost, mass-producible micro-/nanofluidic chips for DNA extraction from individual cells. These chips have modules that collect genomic DNA for sequencing or map genomic structure directly, on-chip, with denaturation-renaturation (D-R) optical mapping [Marie R, et al. (2013) Proc Natl Acad Sci USA 110:4893-4898]. Processing of single cells from the LS174T colorectal cancer cell line showed that D-R mapping of single molecules can reveal structural variation (SV) in the genome of single cells. In one experiment, we processed 17 fragments covering 19.8 Mb of the cell's genome. One megabase-large fragment aligned well to chromosome 19 with half its length, while the other half showed variable alignment. Paired-end single-cell sequencing supported this finding, revealing a region of complexity and a 50-kb deletion. Sequencing struggled, however, to detect a 20-kb gap that D-R mapping showed clearly in a megabase fragment that otherwise mapped well to the reference at the pericentromeric region of chromosome 4. Pericentromeric regions are complex and show substantial sequence homology between different chromosomes, making mapping of sequence reads ambiguous. Thus, D-R mapping directly, from a single molecule, revealed characteristics of the single-cell genome that were challenging for short-read sequencing.


Maternal risk indicators for childhood caries in an inner city population.
This study evaluated whether characteristics of mothers, such as high mutans streptococci (MS) level, caries experience, reported sugar consumption and demographic variables, could be important risk indicators of caries for their children. Mothers selected on the basis of the caries status of their 3-5-year-old-children were tested for MS, caries, reported sugar consumption and demographic variables. We found strong associations between children's caries and their mothers' MS levels (high/low adj. OR = 11.3), maternal active caries (yes/no adj. OR = 4.0) and maternal sugar consumption (high/low adj. OR = 4.2). In this small study, mothers' demographic variables were not associated with the status of caries in their children. Our findings suggest that maternal high MS levels, maternal active decay and maternal sugar consumption are strong risk indicators for children's caries. Although further study is needed, these three maternal risk indicators, taken together, may prove useful in predicting children's caries risk.


Host and Parasite Evolution in a Tangled Bank.
Most hosts and parasites exist in diverse communities wherein they interact with other species, spanning the parasite-mutualist continuum. These additional interactions have the potential to impose selection on hosts and parasites and influence the patterns and processes of their evolution. Yet, host-parasite interactions are almost exclusively studied in species pairs. A wave of new research has incorporated a multispecies community context, showing that additional ecological interactions can alter components of host and parasite fitness, as well as interaction specificity and virulence. Here, we synthesize these findings to assess the effects of increased species diversity on the patterns and processes of host and parasite evolution. We argue that our understanding of host-parasite interactions would benefit from a richer biotic perspective.


Ankle syndesmosis injuries: anatomy, biomechanics, mechanism of injury, and clinical guidelines for diagnosis and intervention.
Syndesmosis injuries are rare, but very debilitating and frequently misdiagnosed. The purpose of this clinical commentary is to review the mechanisms of syndesmotic injuries, clinical examination methods, diagnosis, and management of the injuries. Cadaveric studies of the syndesmosis and deltoid ligaments are also reviewed for further understanding of stress transmission and the roles of different structures in stabilizing the distal syndesmosis. External rotation and excessive dorsiflexion of the foot on the leg have been reported as the most common mechanisms of injury. The injury is most often incurred by individuals who participate in skiing, football, soccer, and other sport activities played on turf. The external rotation and squeeze tests are reliable tests to detect this injury. The ability of imaging studies to assist in an accurate diagnosis may depend on the severity of the injury. The results of cadaveric studies indicate the importance of the deltoid ligament in maintaining stability of the distal tibiofibular syndesmosis and the congruency of the ankle mortise. Intervention programs with early rigid immobilization and pain relief strategies, followed by strengthening and balance training are recommended. Heel lift and posterior splint intervention can be used to avoid separation of the distal syndesmosis induced by excessive dorsiflexion of the ankle joint. Application of a rigid external device should be used with caution to prevent medial-lateral compression of the leg superior to the ankle mortise, thereby inducing separation of the distal syndesmosis articulation. Surgical intervention is an option when a complete tear of the syndesmotic ligaments is present or when fractures are observed.


Possible Signatures of Hominin Hybridization from the Early Holocene of Southwest China.
We have previously described hominin remains with numerous archaic traits from two localities (Maludong and Longlin Cave) in Southwest China dating to the Pleistocene-Holocene transition. If correct, this finding has important implications for understanding the late phases of human evolution. Alternative interpretations have suggested these fossils instead fit within the normal range of variation for early modern humans in East Asia. Here we test this proposition, consider the role of size-shape scaling, and more broadly assess the affinities of the Longlin 1 (LL1) cranium by comparing it to modern human and archaic hominin crania. The shape of LL1 is found to be highly unusual, but on balance shows strongest affinities to early modern humans, lacking obvious similarities to early East Asians specifically. We conclude that a scenario of hybridization with archaic hominins best explains the highly unusual morphology of LL1, possibly even occurring as late as the early Holocene.


The Role of Residential Early Parenting Services in Increasing Parenting Confidence in Mothers with A History of Infertility.
Mothers with a history of infertility may experience parenting difficulties and challenges. This study was conducted to investigate the role of residential early parenting services in increasing parenting confidence in mothers with a history of infertility. This was a retrospective chart review study using the quantitative data from the clients attending the Karitane Residential Units and Parenting Services (known as Karitane RUs) during 2013. Parenting confidence (using Karitane Parenting Confidence Scale-KPCS), depression, demographics, reproductive and medical history, as well as child's information were assessed from a sample of 27 mothers who had a history of infertility and who attended the Karitane RUs for support and assistance. The data were analyzed using SPSS version 19. More than half of the women (59.3%) reported a relatively low level of parenting confidence on the day of admission. The rate of low parenting confidence, however, dropped to 22.2% after receiving 4-5 days support and training in the Karitane RUs. The mean score of the KPCS increased from 36.9 ± 5.6 before the intervention to 41.1 ± 3.4 after the intervention, indicating an improvement in the parenting confidence of the mothers after attending the Karitane RUs (P<0.0001). No statistically significant association was found between maternal low parenting confidence with parental demographics (including age, country of birth, and employment status), a history of help-seeking, symptoms of depression, as well as child's information [including gender, age, siblings, diagnosis of gastroesophageal reflux disease (GORD) and use of medication]. Having a child after a period of infertility can be a stressful experience for some mothers. This can result in low parenting confidence and affect parent-child attachment. Our findings emphasized on the role of the residential early parenting services in promoting the level of parenting confidence and highlighted the need for early recognition and referral of the mothers with a history of infertility to such centers.


Ion channel transcript expression at the rabbit atrioventricular conduction axis.
Little is known about the distribution of gap junctions and ion channels in the atrioventricular node, even though the physiology and pathology of the atrioventricular node is ultimately dependent on them. The abundance of 30 transcripts for markers, gap junctions, ion channels, and Ca(2+)-handling proteins in different regions of the rabbit atrioventricular node (nodal extension and proximal and distal penetrating bundle of His as well as atrial and ventricular muscle) was measured using a novel quantitative polymerase chain reaction technique and in situ hybridization. The expression profile of the nodal extension (slow pathway into penetrating bundle) was similar to that of the sinoatrial node. For example, in the nodal extension, in contrast to the atrial muscle and as expected for a slowly conducting tissue with pacemaker activity, there was no or reduced expression of Cx43, Na(v)1.5, Ca(v)1.2, K(v)1.4, KChIP2, and RYR3 and high expression of Ca(v)1.3 and HCN4. The expression profile of the penetrating bundle was less specialized. In situ hybridization revealed a transitional zone with reduced expression of Cx43, Na(v)1.5, and KChIP2 that may form the fast pathway into the penetrating bundle. At the atrioventricular node, the expression of gap junctions and ion channels in the nodal extension (slow pathway) and a transitional zone (putative fast pathway) as well as the penetrating bundle (output pathway) is specialized and heterogeneous and roughly matches the electrophysiology of the different regions.


Psychosocial burdens negatively impact HIV antiretroviral adherence in gay, bisexual, and other men who have sex with men aged 50 and older.
We sought to characterize HIV antiretroviral therapy (ART) adherence and psychosocial correlates of adherence in a sample of gay, bisexual, and other non-gay or -bisexual identified men who have sex with men aged 50 and over. As part of a cross-sectional study we recruited a community-based sample of 199 men and assessed adherence to current ART medications along four domains: (1) missing doses in the past 4 days, (2) taking doses on the specified schedule in the past 4 days, (3) following instructions about how to take the medications (e.g., to take medications with food), and (4) missing doses in the last weekend. A total adherence score was also computed. Bivariable analyses indicated negative associations between depression, sexual compulsivity, and HIV-related stigma with each of the individual adherence variables and the composite adherence score, while an older age was found to be protective. In multivariable analyses, controlling for age and educational attainment, a higher likelihood of missing doses and failing to follow instructions were related to higher levels of HIV-related stigma, while dosing off-schedule and missing doses on weekends was associated with higher levels of sexual compulsivity. These results indicate that psychosocial burdens undermine the adherence behaviors of older HIV-positive sexual minority men. Programming and services to address this compromising health behavior must embrace a holistic approach to health as informed by syndemics theory, while attending to the developmental and age-specific needs of older men.


Novel insights into the interplay between peripheral reactions encoded by xyl genes and the chlorocatechol pathway encoded by tfd genes for the degradation of chlorobenzoates by Ralstonia eutropha JMP134.
Many bacteria can grow on chloroaromatic pollutants because they can transform them into chlorocatechols, which are further degraded by enzymes of a specialized ortho-cleavage pathway. Ralstonia eutropha JMP134 is able to grow on 3-chlorobenzoate by using two pJP4-encoded, ortho-cleavage chlorocatechol degradation gene clusters (tfdC(I)D(I)E(I)F(I) and tfdD(II)C(II)E(II)F(II)). Very little is known about the acquisition of new catabolic genes encoding enzymes that lead to the formation of chlorocatechols in R. eutropha JMP134. The effect on the catabolic properties of an R. eutropha JMP134 derivative that received the xylS-xylXYZL gene module, encoding the xylS-regulated expression of the broad-substrate-range toluate 1,2-dioxygenase (xylXYZ) and the 1,2-dihydro-1,2-dihydroxytoluate dehydrogenase (xylL) from pWW0, which allows the transformation of 4-chlorobenzoate into 4-chlorocatechol, was studied. Such a derivative could efficiently grow on 4-chlorobenzoate. Unexpectedly, this derivative also grew on 3,5-dichlorobenzoate, a substrate for XylXYZL but not an inducer of the XylS regulatory protein. The ability to grow on 4-chlorobenzoate or 3,5-dichlorobenzoate was also observed in derivatives of strain JMP134 containing the xyl gene module but lacking xylS, indicating the presence of an xylS-like element in R. eutropha with an inducer profile different from that of the pWW0-encoded regulator. Growth on 4-chlorobenzoate was also observed after introduction of the xyl gene module into strain JMP222, a JMP134 derivative lacking pJP4, but only if multiple copies of tfdC(I)D(I)E(I)F(I) or tfdD(II)C(II)E(II)F(II) were present. However, only the derivative containing multiple copies of tfdD(II)C(II)E(II)F(II) was able to grow on 3,5-dichlorobenzoate. These observations indicate that although the acquisition of new catabolic genes actually enhances the catabolic abilities of R. eutropha JMP134, these new properties are strongly influenced by the dosage of the tfd genes, the presence of a chromosomal xylS-like regulatory element and the different contributions of the tfd gene clusters.


Selecting and implementing overview methods: implications from five exemplar overviews.
Overviews of systematic reviews are an increasingly popular method of evidence synthesis; there is a lack of clear guidance for completing overviews and a number of methodological challenges. At the UK Cochrane Symposium 2016, methodological challenges of five overviews were explored. Using data from these five overviews, practical implications to support methodological decision making of authors writing protocols for future overviews are proposed. Methods, and their justification, from the five exemplar overviews were tabulated and compared with areas of debate identified within current literature. Key methodological challenges and implications for development of overview protocols were generated and synthesised into a list, discussed and refined until there was consensus. Methodological features of three Cochrane overviews, one overview of diagnostic test accuracy and one mixed methods overview have been summarised. Methods of selection of reviews and data extraction were similar. Either the AMSTAR or ROBIS tool was used to assess quality of included reviews. The GRADE approach was most commonly used to assess quality of evidence within the reviews. Eight key methodological challenges were identified from the exemplar overviews. There was good agreement between our findings and emerging areas of debate within a recent published synthesis. Implications for development of protocols for future overviews were identified. Overviews are a relatively new methodological innovation, and there are currently substantial variations in the methodological approaches used within different overviews. There are considerable methodological challenges for which optimal solutions are not necessarily yet known. Lessons learnt from five exemplar overviews highlight a number of methodological decisions which may be beneficial to consider during the development of an overview protocol.


Inpatient hospital and post-acute care for vertebral fractures in women.
Approximately 700,000 vertebral fractures occur annually in the United States. Available estimates on hospital costs and length of stay for vertebral fractures do not reflect current practice patterns, nor has post-acute care utilization been reported in sufficient detail. This paper provides new estimates on acute care charges, length-of-stay (LOS), and distribution patterns of post-acute care for osteoporotic vertebral fractures in women aged 50 years and older in the United States. The Nationwide Inpatient Sample (NIS) database (1997) was used to identify admissions with a primary diagnosis of vertebral fracture. Decision rules based on clinical criteria were developed to identify vertebral fracture cases considered to be osteoporosis-related. Charges, LOS and discharge disposition were analyzed according to patient demographics and hospital characteristics. In 1997, there were 53,066 hospital admissions for osteoporotic vertebral fractures in women. Mean charges and LOS were US 9,532 dollars and 6.2 days, respectively, while US totals were US 506 million dollars and 329,000 days. More than 40% were discharged to long-term care (LTC); another 24.3% required other follow-up care. Charges and LOS were inversely related to age. Female patients aged 75 or more were more than five times as likely to be discharged to LTC compared to women between the ages of 50 and 64. Charges and LOS were in general, significantly higher for patients in the Northeast, urban areas, teaching hospitals and in larger hospitals, and for patients transferred from other acute care hospitals. Vertebral fractures are more expensive and resource-intensive than previously reported. Furthermore, total costs may be much greater when the components of post-acute care are fully captured.


Nouns and verbs in the brain: grammatical class and task specific effects as revealed by fMRI.
The wide variety of techniques and tasks used to study the neural correlates of noun and verb processing has resulted in a body of inconsistent evidence. We performed a functional magnetic resonance imaging (fMRI) experiment to detect grammatical class effects that generalize across tasks. A total of 12 participants undertook a grammatical-class switching task (GCST), in which they were presented with a noun (or a verb) and were asked to retrieve the corresponding verb (or noun), and a classical picture naming task (PNT) widely used in the previous aphasiological and imaging literature. The GCST was explicitly designed to ensure control over confounding variables, such as stimulus complexity or imageability. Conjunction analyses of the haemodynamic responses measured in the two tasks indicated a shared verb-related activation of a dorsal premotor and posterior parietal network, pointing to a strong relationship between verb representation and action-oriented (visuo-)spatial knowledge. On the other hand, no brain area was consistently associated with nouns in both tasks. Moreover, there were task-dependent differences between noun and verb retrieval both at behavioural and at physiological level; the grammatical class that elicited the longest reaction times in both tasks (i.e., verbs in the PNT and nouns in the GCST) triggered a greater activation of the left inferior frontal gyrus. Therefore, we suggest that this area reflects a general increase in task demand rather than verb processing per se.


Placebo effect studies are susceptible to response bias and to other types of biases.
Investigations of the effect of placebo are often challenging to conduct and interpret. The history of placebo shows that assessment of its clinical significance has a real potential to be biased. We analyze and discuss typical types of bias in studies on placebo. A methodological analysis and discussion. The inherent nonblinded comparison between placebo and no-treatment is the best research design we have in estimating effects of placebo, both in a clinical and in an experimental setting, but the difference between placebo and no-treatment remains an approximate and fairly crude reflection of the true effect of placebo interventions. A main problem is response bias in trials with outcomes that are based on patients' reports. Other biases involve differential co-intervention and patient dropouts, publication bias, and outcome reporting bias. Furthermore, extrapolation of results to a clinical settings are challenging because of a lack of clear identification of the causal factors in many clinical trials, and the nonclinical setting and short duration of most laboratory experiments. Creative experimental efforts are needed to assess rigorously the clinical significance of placebo interventions and investigate the component elements that may contribute to the therapeutic benefit.


Biotechnologies for critical raw material recovery from primary and secondary sources: R&D priorities and future perspectives.
Europe is confronted with an increasing supply risk of critical raw materials. These can be defined as materials of which the risks of supply shortage and their impacts on the economy are higher compared to most of other raw materials. Within the framework of the EU Innovation Partnership on raw materials Initiative, a list of 14 critical materials was defined, including some bulk metals, industrial minerals, the platinum group metals and rare earth elements. To tackle the supply risk challenge, innovation is required with respect to sustainable primary mining, substitution of critical metals, and urban mining. In these three categories, biometallurgy can play a crucial role. Indeed, microbe-metal interactions have been successfully applied on full scale to win materials from primary sources, but are not sufficiently explored for metal recovery or recycling. On the one hand, this article gives an overview of the microbial strategies that are currently applied on full scale for biomining; on the other hand it identifies technologies, currently developed in the laboratory, which have a perspective for large scale metal recovery and the needs and challenges on which bio-metallurgical research should focus to achieve this ambitious goal.


Fasting and Its Impact on Skin Anatomy, Physiology, and Physiopathology: A Comprehensive Review of the Literature.
Skin serves as the first protective line and barrier of the body. Like many other organs, skin can be affected by several disorders in response to external factors such as pathogens, ultraviolet light, and pollution, as well as endogenous alterations related to aging and/or oxidative stress disturbance. Researchers have reported new insights into how skin cells are altered in response to caloric restriction diets in mammals. One of the most well-known caloric restriction diets is the Ramadan intermittent fasting, which is a radical change in the diet plan of practitioners for the period of one lunar month. Ramadan fasting represents the fourth of the five pillars of the Islamic creed. Even though infirm individuals are waived to take part in this religious duty, patients with various health problems, including those with different skin disorders, might choose to share this event with peers and family members. No standardized protocols or guidelines exist, however, to advise their physicians on the proper management of their patients' condition during fasting. With an increasing Muslim population living in Western countries, this topic has started to draw substantial attention, not only of Middle-Eastern physicians, but also of clinicians in the West. For this purpose, we carried out a comprehensive overview on the topic. Our main findings are that: (1) there is a strong need for evidence-based suggestions and guidance. Literature on the impact of the Ramadan fasting, as well as of other kinds of fasting, on skin diseases is scarce and of poor quality, as well as the information available from the Internet; (2) patients willing to fast should be advised about the importance of taking proper treatments or consider alternative options including administration of trans-dermal/topical drugs, as they are permitted during daylight hours. Further, non-compliance has important, clinical and economic implications for an effective patient management.


Reactions of SO2 and NH3 with epoxy groups on the surface of graphite oxide powder.
Graphite oxide powder was obtained using the modified Hummers' method and characterized using X-ray photoelectron spectroscopy (XPS) and time-of-flight secondary ion mass spectrometry (ToF-SIMS). The XPS results indicated that the epoxy groups were the main functional groups on the graphite oxide powder surface. The graphite oxide powder was then reacted with SO2 and NH3 gases, respectively, at 25 °C. The XPS and ToF-SIMS analyses of the surface of the reacted graphite oxide powder showed that the reactions mainly occurred in the epoxy groups. Bisulfate and amine groups were formed on the surface of the graphite oxide powder after the reactions between the graphite oxide powder and SO2 and NH3 gases. This work demonstrates a new method of removing SO2 and NH3 gases using graphite oxide powder.


Cannabinoid receptor binding and agonist activity of amides and esters of arachidonic acid.
The cannabinoid receptor in brain (CB1) specifically binds delta 9-tetrahydrocannabinol, the predominant central nervous system-active component of marijuana. An eicosanoid found in brain, N-(2-hydroxyethyl)arachidonylamide (anandamide), binds to CB1 with similar affinity. This report considers structure-activity requirements for a series of novel amides and rigid hairpin conformations typified by N-(2-hydroxyethyl)prostaglandin amides, assayed with phenylmethylsulfonyl fluoride inactivation of esterases/amidases. Arachidonyl esters were 30-fold less potent than N-(2-hydroxyethyl)arachidonylamide, showing a rank order of potency of methyl = ethyl > propyl = isopropyl. Within the N-(hydroxyalkyl)arachidonylamide series, a one-carbon increase in chain length increased the potency 2-fold, but continued extension decreased affinity. Substituting the amide for the N-(2-hydroxyethyl)amide function produced a 4-fold loss of affinity. The N-(propyl)-, N-(butyl)-, and N-(benzyl)arachidonylamide derivatives exhibited a 3-fold increase, no change, and a 5-fold decrease, respectively, in affinity, compared with N-(2-hydroxyethyl)arachidonylamide. Both the methoxy ether and the formamide derivatives suffered > 20-fold loss of potency, compared with N-(2-hydroxyethyl)arachidonylamide. N-(2-Aminoethyl)arachidonylamide interacted poorly with CB1. At 100 microM, N-(2-hydroxyethyl)amide analogs of prostaglandin E2, A2, B2, and B1 failed to alter [3H]CP55940 binding to CB1. N-(2-Hydroxyethyl)arachidonylamide inhibited adenylate cyclase with lesser potency but with similar efficacy, compared with desacetyllevonantradol. Extending the length of the hydroxyalkyl moiety by one carbon increased the apparent potency by 1 order of magnitude. The N-(propyl) derivative exhibited a 5-fold greater potency than did the N-(2-hydroxyethyl) analog. It appears that the bulk and length of the moiety appended to arachidonic acid are more important determinants of affinity for CB1 than is hydrogen-bonding capability.


Partial sequencing of recent Portuguese myxoma virus field isolates exhibits a high degree of genetic stability.
To study genetic changes underlying myxoma virus evolution in its new host, the European rabbit (Oryctolagus cuniculus), we sequenced selected genomic regions of nine recent virulent field strains and a live attenuated vaccine strain ("MAV", Germany). DNA was extracted from cell culture passaged myxoma virus. A total of 4863 bp (approximately 3% of the genome) of 10 regions spanning 12 genes of the myxoma viruses was sequenced and compared to the original virulent strain "Lausanne" and its attenuated field derivative strain "6918". The field strains displayed a maximum of three (strains C43, C95) and a minimum of one (strains CD01, CD05) nucleotide substitutions. These were distributed through all analysed coding regions, except gene M022L (major envelope protein), where all strains were identical to "Lausanne" and "6918". Two new single nucleotide insertions were observed in some of the field strains: within the intergenic region M014L/M015L and within gene M009L, where it leads to a frameshift. These insertions were located after homopolymeric regions. The vaccine strain displayed 37 nucleotide substitutions, predominantly (95%) located in genes M022L and M036L. Interestingly, regions M009L and M014L/M015L of the vaccine were not amplified successfully, suggesting major genomic changes that could account for its attenuated phenotype. Our results support a high degree of genetic stability of myxoma virus over the past five decades. None of the analysed genome regions by its own seems sufficient for the genetic characterisation of field strains.


Prebiotics may reduce serum concentrations of C-reactive protein and ghrelin in overweight and obese adults: a systematic review and meta-analysis.
Biochemical markers correlate positively with the development and severity of obesity, depression, and anxiety, and can be modulated by changes in intestinal microbiota composition. A systematic review and meta-analysis was conducted to determine the effects of prebiotics or synbiotics on blood biomarkers of obesity, depression, and anxiety (including: ACTH [adrenocorticotropic hormone], cortisol, leptin, ghrelin, TSH [thyroid-stimulating hormone], PTH [parathyroid hormone], vitamin D, BDNF [brain-derived neurotrophic factor], and PCR [polymerase chain reaction]) in individuals with overweight or obesity. MEDLINE, Web of Science, Scopus, and CENTRAL databases were searched, along with the reference lists of included articles. Authors were contacted for unpublished data. RCT in individuals with overweight or obesity, supplemented with prebiotics or synbiotics, assessing any of the outcomes of interest. Data were extracted independently by three researchers. Thirteen studies were identified up to March 7, 2018. Regarding outcomes, 1 study assessed leptin, 4 studies assessed ghrelin, and 10 studies assessed CRP (C-reactive protein). Meta-analysis showed reduction in serum concentrations of ghrelin (-37.17 pg/mL; 95%CI = -69.62, -4.73; P = 0.025) and CRP (SMD [standardized mean difference] = -0.31; 95%CI = -0.58, -0.04; P = 0.027) after supplementation of inulin-type fructans. Prebiotics may help regulate blood concentrations of ghrelin and CRP in overweight or obese individuals.


Clinical interpretation and implications of whole-genome sequencing.
Whole-genome sequencing (WGS) is increasingly applied in clinical medicine and is expected to uncover clinically significant findings regardless of sequencing indication. To examine coverage and concordance of clinically relevant genetic variation provided by WGS technologies; to quantitate inherited disease risk and pharmacogenomic findings in WGS data and resources required for their discovery and interpretation; and to evaluate clinical action prompted by WGS findings. An exploratory study of 12 adult participants recruited at Stanford University Medical Center who underwent WGS between November 2011 and March 2012. A multidisciplinary team reviewed all potentially reportable genetic findings. Five physicians proposed initial clinical follow-up based on the genetic findings. Genome coverage and sequencing platform concordance in different categories of genetic disease risk, person-hours spent curating candidate disease-risk variants, interpretation agreement between trained curators and disease genetics databases, burden of inherited disease risk and pharmacogenomic findings, and burden and interrater agreement of proposed clinical follow-up. Depending on sequencing platform, 10% to 19% of inherited disease genes were not covered to accepted standards for single nucleotide variant discovery. Genotype concordance was high for previously described single nucleotide genetic variants (99%-100%) but low for small insertion/deletion variants (53%-59%). Curation of 90 to 127 genetic variants in each participant required a median of 54 minutes (range, 5-223 minutes) per genetic variant, resulted in moderate classification agreement between professionals (Gross κ, 0.52; 95% CI, 0.40-0.64), and reclassified 69% of genetic variants cataloged as disease causing in mutation databases to variants of uncertain or lesser significance. Two to 6 personal disease-risk findings were discovered in each participant, including 1 frameshift deletion in the BRCA1 gene implicated in hereditary breast and ovarian cancer. Physician review of sequencing findings prompted consideration of a median of 1 to 3 initial diagnostic tests and referrals per participant, with fair interrater agreement about the suitability of WGS findings for clinical follow-up (Fleiss κ, 0.24; P < 001). In this exploratory study of 12 volunteer adults, the use of WGS was associated with incomplete coverage of inherited disease genes, low reproducibility of detection of genetic variation with the highest potential clinical effects, and uncertainty about clinically reportable findings. In certain cases, WGS will identify clinically actionable genetic variants warranting early medical intervention. These issues should be considered when determining the role of WGS in clinical medicine.


Free flap scalp reconstruction in a 91-year-old patient under local-regional anesthesia: case report and review of the literature.
In the elderly population with significant medical comorbidities, the safety of general anesthesia is often in question. In the head and neck, where regional and extradural anesthesia are not options, reconstruction of defects requiring free tissue transfer becomes a particular challenge for patients in whom general anesthesia is contraindicated. We present a case of a scalp reconstruction utilizing a latissimus dorsi free flap in a 91-year-old man performed entirely under local and regional anesthesia. General anesthesia was contraindicated secondary to the patient's multiple medical comorbidities. A paravertebral block was used for the harvest of the latissimus dorsi muscle and skin grafts. The microvascular portion of the procedure and the inset were performed under local anesthesia alone. The patient tolerated the procedure, and the operation was successful. This case is unique in that there are no published reports of head and neck free tissue transfer being performed entirely under local-regional anesthesia. We conclude that despite the medical challenges of performing complex reconstruction in elderly patients, expedient free tissue transfer can offer patients access to successful reconstruction.


Foresight Infectious Diseases China Project--a novel approach to anticipating future trends in risk of infectious diseases in China: methodology and results from an initial application.
The project devised a simple but novel methodology for identifying possible future trends in infectious diseases in animals and humans in China, of priority concern to the Chinese authorities. It used a model of disease drivers (social, economic, biological or environmental factors that affect disease outcomes, by changing the behaviour of diseases, sources or pathways) devised for the Foresight Programme in the United Kingdom. Nine families of drivers were adapted to Chinese circumstances and matrices were constructed to identify the likely relationship of single infectious diseases or families of diseases to the drivers. The likely future trends in those drivers in China were determined by interviews with 36 independent Chinese experts. These trends included not only potentially adverse animal and human movements but also opportunities for innovative surveillance methods, more use of hospitals, antimicrobials and vaccines. Some human behaviours and social trends were expected to increase the risk of infections (in particular sexually transmitted and healthcare-associated infections) while at the same time the experts thought the awareness of risk in the Chinese population would increase. The results suggested a number of areas where the Chinese authorities may experience difficulties in the future, such as rising numbers of healthcare-associated infections, zoonoses and other emerging diseases and sexually transmitted infections (including HIV). Not making firm predictions, this work identifies priority disease groups requiring surveillance and consideration of countermeasures as well as recommending strengthening basic surveillance and response mechanisms for unanticipatable zoonoses and other emerging disease threats.


Investigation of the prevalence and severity of foot pad dermatitis at the slaughterhouse in fattening turkeys reared in organic production systems in Germany.
The present study shows the prevalence and severity of foot pad dermatitis (FPD) in turkeys reared in organic production systems assessed at slaughterhouses in Germany. The investigations of altogether 1,860 turkeys of the strains Kelly Broad Breasted Bronze (Kelly BBB; 540 toms, 540 hens) and British United Turkeys (B.U.T.) 6 and the Test Product 7 (TP 7; 780 hens) showed that 97.7% of the examined turkeys were diagnosed with different degrees of FPD. Only 4.6% of the toms and 1.3% of the hens had feet without lesions. Most frequent were necrotic lesions measuring up to 2 cm in diameter (64.3% of all turkeys). Extensive necrotic lesions of the foot pads (toms: 29.8%; hens: 12.4%) and necrosis of superficial scales (toms: 11.3%; hens: 7.6%) were less frequent. Plantar abscesses were rare findings (1.9%). In general, the feet of the Kelly BBB hens were more affected by foot pad lesions than those of the Kelly BBB toms. There were significant differences between the investigated flocks concerning the occurrence of foot pad lesions. The aim in rearing turkeys must be the reduction of FPD.


7 Themes for guiding situated ergonomic assessments of medical devices: a case study of an inpatient glucometer.
There is relatively little guidance on the situated ergonomic assessment of medical devices, and few case studies that detail this type of evaluation. This paper reports results of a detailed case study that focuses on the design and use of a modern blood glucose meter on an oncology ward. We spent approximately 150 h in-situ, over 11 days and 4 nights, performing observations and interviews with users. This was complemented by interviews with two staff with oversight and management responsibility related to the device. We identified 19 issues with the design and use of this device. These issues were grouped into 7 themes which can help guide the situated study of medical devices: usability, knowledge gaps and mental models, workarounds, wider tasks and equipment, the patient, connection between services, and policy.


Precometary organic matter: A hidden reservoir of water inside the snow line.
The origin and evolution of solar system bodies, including water on the Earth, have been discussed based on the assumption that the relevant ingredients were simply silicates and ices. However, large amounts of organic matter have been found in cometary and interplanetary dust, which are recognized as remnants of interstellar/precometary grains. Precometary organic matter may therefore be a potential source of water; however, to date, there have been no experimental investigations into this possibility. Here, we experimentally demonstrate that abundant water and oil are formed via the heating of a precometary-organic-matter analog under conditions appropriate for the parent bodies of meteorites inside the snow line. This implies that H2O ice is not required as the sole source of water on planetary bodies inside the snow line. Further, we can explain the change in the oxidation state of the Earth from an initially reduced state to a final oxidized state. Our study also suggests that petroleum was present in the asteroids and is present in icy satellites and dwarf planets.


Current evidence for the clinical use of long-chain polyunsaturated n-3 fatty acids to prevent age-related cognitive decline and Alzheimer's disease.
An NIH State of the Science Conference panel concluded in 2010 that insufficient evidence is available to recommend the use of any primary prevention therapy for Alzheimer's disease or cognitive decline with age. Despite the insufficient evidence, candidate therapies with varying levels of evidence for safety and efficacy are taken by the public and discussed in the media. One example is the long-chain n-3 (omega-3) polyunsaturated fatty acids (n-3 LC-PUFA), DHA and EPA, found in some fish and dietary supplements. With this report, we seek to provide a practical overview and rating of the level and type of available evidence that n-3 LC-PUFA supplements are safe and protective against cognitive aging and Alzheimer's disease, with additional discussion of the evidence for effects on quality of life, vascular aging, and the rate of aging. We discuss available sources, dose, bioavailability, and variables that may impact the response to n-3 LC-PUFA treatment such as baseline n-3 LC-PUFA status, APOE ε4 genotype, depression, and background diet. Lastly, we list ongoing clinical trials and propose next research steps to validate these fatty acids for primary prevention of cognitive aging and dementia. Of particular relevance, epidemiology indicates a higher risk of cognitive decline in people in the lower quartile of n-3 LC-PUFA intake or blood levels but these populations have not been specifically targeted by RCTs.


Clinical use of Convalescent Plasma in the COVID-19 pandemic: a transfusion-focussed gap analysis with recommendations for future research priorities.
Use of convalescent plasma for coronavirus disease 2019 (COVID-19) treatment has gained interest worldwide. However, there is lack of evidence on its dosing, safety and effectiveness. Until data from clinical studies are available to provide solid evidence for worldwide applicable guidelines, there is a need to provide guidance to the transfusion community and researchers on this emergent therapeutic option. This paper aims to identify existing key gaps in current knowledge in the clinical application of COVID-19 convalescent plasma (CCP). The International Society of Blood Transfusion (ISBT) initiated a multidisciplinary working group with worldwide representation from all six continents with the aim of reviewing existing practices on CCP use from donor, product and patient perspectives. A subgroup of clinical transfusion professionals was formed to draft a document for CCP clinical application to identify the gaps in knowledge in existing literature. Gaps in knowledge were identified in the following main domains: study design, patient eligibility, CCP dose, frequency and timing of CCP administration, parameters to assess response to CCP treatment and long-term outcome, adverse events and CCP application in less-resourced countries as well as in paediatrics and neonates. This paper outlines a framework of gaps in the knowledge of clinical deployment of CPP that were identified as being most relevant. Studies to address the identified gaps are required to provide better evidence on the effectiveness and safety of CCP use.


Estrogen differentially regulates estrogen and nerve growth factor receptor mRNAs in adult sensory neurons.
We have previously shown that neurons in the basal forebrain colocalize the neurotrophin receptor p75NGFR and estrogen receptors. The present study was designed to examine (1) if neural neurotrophin targets respond to estrogen as a general phenotypic feature and (2) if NGF receptor mRNAs are regulated by estrogen, using a prototypical target of NGF, the dorsal root ganglion (DRG) (sensory) neuron. We demonstrate, for the first time, the presence of estrogen receptor mRNA and protein (binding sites) in adult female rat DRG. Moreover, estrogen receptor mRNA expression, while present in DRG neurons from both the ovariectomized (OVX; estrogen deficient) and intact female rat, was downregulated, as in the adult CNS, during proestrus (high estrogen levels) and in OVX animals replaced with proestrus levels of estrogen, as compared to OVX controls. In contrast, although the mRNAs for the NGF receptors p75NGFR and trkA were also expressed in DRG neurons from OVX and intact animals, expression of both NGF receptor mRNAs was upregulated in sensory neurons during proestrus, as compared to the OVX condition. Estrogen replacement, on the other hand, resulted in a transient downregulation of p75NGFR mRNA and a time-dependent upregulation of trkA mRNA. Estrogen regulation of NGF receptor mRNA in adult peripheral neural targets of the neurotrophins supports the hypothesis that estrogen may regulate neuronal sensitivity to neurotrophins such as NGF and may be an important mediator of neurotrophin actions in normal neural function and following neural trauma.


Higher mental stimulation at work is associated with improved cognitive functioning in both young and older workers.
The study examined whether mental stimulation received in the workplace positively affects cognitive functioning and rate of cognitive change. Data taken from the VISAT (ageing, health and work) longitudinal study concerned 3237 workers who were seen three times (in 1996, 2001 and 2006) and who were aged between 32 and 62 years at baseline. Measures of cognitive stimulation both at work and outside work were available at baseline. Cognitive efficiency was assessed on the three occasions through episodic verbal memory, attention and processing speed tests. Greater cognitive stimulation (at work and outside work) was associated with higher levels of cognitive functioning and a more favourable change over the 10-year follow-up. These results were obtained after adjustment for age, education, sex and a variety of medical, physical and psychosocial confounders. The study thus supports the hypothesis that exposure to jobs that are mentally demanding and that offer learning opportunities increases the level of cognitive functioning and possibly attenuates age-related decline. STATEMENT OF RELEVANCE: The effect of occupational activity on cognitive functioning is under-researched. This paper reports results from a substantive longitudinal study, with findings indicating that exposure to jobs that are mentally demanding are beneficial in increasing levels of cognitive functioning and possibly attenuating age-related decline.


Hydrogen evolution from water based on plasmon-induced charge separation at a TiO2/Au/NiO/Pt system.
Metal-semiconductor plasmonic nanostructures are capable of converting light energy through plasmon-induced charge separation (PICS), providing fruitful new strategies to utilize solar energy in various fields, including photocatalysis. Here, we enhance the PICS efficiencies for hydrogen evolution from water at a Pt cathode coupled with a TiO2/Au photoanode by coating the TiO2/Au with a p-type NiO layer on which a Pt co-catalyst is deposited. PICS occurs at the Au-TiO2 interface under visible light. The electrons injected from the Au nanoparticles into TiO2 are transported to the Pt cathode and cause hydrogen evolution from water, the action spectrum of which matches the plasmonic extinction spectrum of the Au nanoparticles. The NiO layer extracts the separated positive charges from the Au nanoparticles, accumulates the charges and drives methanol oxidation at the Pt co-catalyst on NiO with the positive charges. As a result of the introduction of the Pt-modified NiO layer, the rates of methanol oxidation and accompanying hydrogen evolution at zero bias voltage were improved by ∼3.5 times. The NiO layer may also protect the Au nanoparticles from self-oxidation.


Conservation of folding and association within a family of spidroin N-terminal domains.
Web spiders synthesize silk fibres, nature's toughest biomaterial, through the controlled assembly of fibroin proteins, so-called spidroins. The highly conserved spidroin N-terminal domain (NTD) is a pH-driven self-assembly device that connects spidroins to super-molecules in fibres. The degree to which forces of self-assembly is conserved across spider glands and species is currently unknown because quantitative measures are missing. Here, we report the comparative investigation of spidroin NTDs originating from the major ampullate glands of the spider species Euprosthenops australis, Nephila clavipes, Latrodectus hesperus, and Latrodectus geometricus. We characterized equilibrium thermodynamics and kinetics of folding and self-association using dynamic light scattering, stopped-flow fluorescence and circular dichroism spectroscopy in combination with thermal and chemical denaturation experiments. We found cooperative two-state folding on a sub-millisecond time scale through a late transition state of all four domains. Stability was compromised by repulsive electrostatic forces originating from clustering of point charges on the NTD surface required for function. pH-driven dimerization proceeded with characteristic fast kinetics yielding high affinities. Results showed that energetics and kinetics of NTD self-assembly are highly conserved across spider species despite the different silk mechanical properties and web geometries they produce.


Tailoring IGZO Composition for Enhanced Fully Solution-Based Thin Film Transistors.
Solution-processed metal oxides have been investigated as an alternative to vacuum-based oxides to implement low-cost, high-performance electronic devices on flexible transparent substrates. However, their electrical properties need to be enhanced to apply at industrial scale. Amorphous indium-gallium-zinc oxide (a-IGZO) is the most-used transparent semiconductor metal oxide as an active channel layer in thin-film transistors (TFTs), due to its superior electrical properties. The present work evaluates the influence of composition, thickness and ageing on the electrical properties of solution a-IGZO TFTs, using solution combustion synthesis method, with urea as fuel. After optimizing the semiconductor properties, low-voltage TFTs were obtained by implementing a back-surface passivated 3-layer In:Ga:Zn 3:1:1 with a solution-processed high-к dielectric; AlOx. The devices show saturation mobility of 3.2 cm2 V-1 s-1, IOn/IOff of 106, SS of 73 mV dec-1 and VOn of 0.18 V, thus demonstrating promising features for low-cost circuit applications.


Solitary fibrous tumor of the thigh with epithelioid features: a case report.
Extrapleural Solitary Fibrous tumors (SFTs) have been increasingly reported. The retroperitoneum, deep soft tissues of proximal extremities, abdominal cavity, trunk, head and neck are the most common extraserosal locations reported. Microscopically they show a wide range of morphological features, and so the differential diagnosis is extensive. Immunohistochemically, they commonly express CD34, vimentin, bcl-2 and CD99. Epithelial membrane antigen (EMA) and smooth muscle actin (SMA) may occasionally be expressed. Epithelioid morphology in extrapleural SFT has only very occasionally been described (five cases reported), some of them with biphasic pattern and others with malignant characteristics. A SFT of the thigh with epithelioid areas in a 63 year old woman is reported. Microscopically the tumor showed areas hypo and hipercellular. At the periphery of the hipercellular areas there were nodules composed of epithelioid cells. Immunohistochemically both the spindle and epithelioid cells were positive for CD34, vimentin, bcl-2 and CD99. Epithelial, neural and muscular markers were negative. Molecular study was done and ruled out a synovial sarcoma. Ten cases of SFT of the thigh have been reported but to our knowledge this is the first case with epithelioid morphology affecting the extremities. Identification of this pattern of SFT is of importance, to avoid misdiagnosis with other more aggressive conditions in soft tissue.


PESI - a taxonomic backbone for Europe.
Reliable taxonomy underpins communication in all of biology, not least nature conservation and sustainable use of ecosystem resources. The flexibility of taxonomic interpretations, however, presents a serious challenge for end-users of taxonomic concepts. Users need standardised and continuously harmonised taxonomic reference systems, as well as high-quality and complete taxonomic data sets, but these are generally lacking for non-specialists. The solution is in dynamic, expertly curated web-based taxonomic tools. The Pan-European Species-directories Infrastructure (PESI) worked to solve this key issue by providing a taxonomic e-infrastructure for Europe. It strengthened the relevant social (expertise) and information (standards, data and technical) capacities of five major community networks on taxonomic indexing in Europe, which is essential for proper biodiversity assessment and monitoring activities. The key objectives of PESI were: 1) standardisation in taxonomic reference systems, 2) enhancement of the quality and completeness of taxonomic data sets and 3) creation of integrated access to taxonomic information. This paper describes the results of PESI and its future prospects, including the involvement in major European biodiversity informatics initiatives and programs.


Agricultural soils of the Animas River watershed after the Gold King Mine spill: An elemental spatiotemporal analysis via portable X-ray fluorescence spectroscopy.
In August 2015, 11.3 million L of heavy metal-contaminated water spilled into the Animas River from the Gold King Mine (Colorado, USA). National attention focused on water quality and agricultural production in areas affected by the spill. In response to local concerns, surface soil elemental concentrations were analyzed in three New Mexico agricultural fields to determine potential threats to agronomic production. Irrigated fields in the Animas watershed were scanned using portable X-ray fluorescence (PXRF) spectrometry to monitor the spatiotemporal variability of Pb, As, Cu, and Cr. A total of 175 locations were scanned using PXRF before and after the growing season for 3 yr. The geostatistical model with the lowest RMSE was chosen as the optimal model. The lowest RMSE for the elements ranged from to 0.10 to 0.44 m for As, from 0.50 to 0.98 m for Cr, from 0.15 to 0.91 m for Cu, and from 0.14 to 0.44 m for Pb across the models selected. The spatial dependence between the measured values exhibited strong to moderate autocorrelation for all metals except for As, for which spatial dependence was strong to weak. Some areas in each field exceeded the New Mexico Environment Department soil screening limit of 7.07 mg As kg-1 . All sampling locations were below the screening limit at last sampling time in 2019. Mixed models used for temporal analysis showed a significant decrease only in As below the screening value at the end of the study. Results indicate that the agricultural soils were below the soil screening guideline values.


Study protocol: a dissemination trial of computerized psychological treatment for depression and alcohol/other drug use comorbidity in an Australian clinical service.
The rise of the internet and related technologies has significant implications for the treatment of complex health problems, including the combination of depression and alcohol/other drug (AOD) misuse. To date, no research exists to test the real world uptake of internet and computer-delivered treatment programs in clinical practice. This study is important, as it is the first to examine the adoption of the SHADE treatment program, a DVD-based psychological treatment for depression and AOD use comorbidity, by clinicians working in a publicly-funded AOD clinical service. The study protocol that follows describes the methodology of this dissemination trial. 19 clinicians within an AOD service on the Central Coast of New South Wales, Australia, will be recruited to the trial. Consenting clinicians will participate in a baseline focus group discussion designed to explore their experiences and perceived barriers to adopting innovation in their clinical practice. Computer comfort and openness to innovation will also be assessed. Throughout the trial, current, new and wait-list clients will be referred to the research program via the clinical service, which will involve clients completing a baseline and 15-week follow-up clinical assessment with independent research assistants, comprising a range of mental health and AOD measures. Clinicians will also complete session checklists following each clinical session with a client, outlining the extent to which the SHADE computer program was used. Therapeutic alliance will be measured at intake and discharge from both the clinician and client perspectives. This study will provide comprehensive data on the factors associated with the adoption of an innovative, computer-delivered evidence-based treatment program, SHADE, by clinicians working in an AOD service. The results will contribute to the development of a model of dissemination of SHADE, which could be applied to a range of technological innovations. Australian Clinical Trial Registration Number: ACTRN12611000382976.


Tunable interacting composite fermion phases in a half-filled bilayer-graphene Landau level.
Non-Abelian anyons are a type of quasiparticle with the potential to encode quantum information in topological qubits protected from decoherence. Experimental systems that are predicted to harbour non-Abelian anyons include p-wave superfluids, superconducting systems with strong spin-orbit coupling, and paired states of interacting composite fermions that emerge at even denominators in the fractional quantum Hall (FQH) regime. Although even-denominator FQH states have been observed in several two-dimensional systems, small energy gaps and limited tunability have stymied definitive experimental probes of their non-Abelian nature. Here we report the observation of robust even-denominator FQH phases at half-integer Landau-level filling in van der Waals heterostructures consisting of dual-gated, hexagonal-boron-nitride-encapsulated bilayer graphene. The measured energy gap is three times larger than observed previously. We compare these FQH phases with numerical and theoretical models while simultaneously controlling the carrier density, layer polarization and magnetic field, and find evidence for the paired Pfaffian phase that is predicted to host non-Abelian anyons. Electric-field-controlled level crossings between states with different Landau-level indices reveal a cascade of FQH phase transitions, including a continuous phase transition between the even-denominator FQH state and a compressible composite fermion liquid. Our results establish graphene as a pristine and tunable experimental platform for studying the interplay between topology and quantum criticality, and for detecting non-Abelian qubits.


Decision latitude and workload demand: implications for full and partial absenteeism.
This research examined the relative importance of two components of job stress--decision latitude and workload demand--on employee absenteeism. The analysis was based on confidential self-reported data from employees at two worksites, which were collected in three independent cross-sections beginning in 1995. The negative binomial technique was used to estimate the effects of decision latitude and workload demand on employee attendance, while controlling for employee demographics and other workplace characteristics. Estimation results show that high decision latitude was negatively and significantly related to number of full days absent from work (full absenteeism) and number of days arriving late to work or leaving work early (partial absenteeism). Conversely, the coefficient estimates for low decision latitude were positive in every model and significantly related to partial absenteeism. Low workload demand was negatively and significantly related to partial absenteeism, but not full days absent. The interaction effects of decision latitude and workload demand on absenteeism were not statistically significant. Several recent studies have estimated a significant relationship between decision latitude, workload demand, and medical problems such as cardiovascular disease. The current findings suggest that decision latitude and workload demand are also related to workplace attendance. Employers and occupational hygienists should consider decision latitude and workload demand as a means to improve workplace productivity and employee health.


Targeting of tumour-infiltrating macrophages via CCL2/CCR2 signalling as a therapeutic strategy against hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is an aggressive malignancy with limited effective treatment options. An alternative strategy is to target cells, such as tumour-infiltrating macrophages, in the HCC tumour microenvironment. The CCL2/CCR2 axis is required for recruitment of monocytes/macrophages and is implicated in various aspects of liver pathology, including HCC. We investigated the feasibility of CCL2/CCR2 as a therapeutic target against HCC. CCL2 expression was analysed in two independent HCC cohorts. Growth of three murine HCC cells was evaluated in an orthotopic model, a postsurgical recurrence model and a subcutaneous model in mice after blocking CCL2/CCR2 axis by a novel CCR2 antagonist or knocking out of host CCR2. In vivo macrophage or T cell depletion and in vitro cell coculture were further conducted to investigate CCL2/CCR2-mediated crosstalk between tumour-associated macrophages (TAMs) and tumour cells. CCL2 is overexpressed in human liver cancers and is prognostic for patients with HCC. Blockade of CCL2/CCR2 signalling with knockout of CCR2 or with a CCR2 antagonist inhibits malignant growth and metastasis, reduces postsurgical recurrence, and enhances survival. Further, therapeutic blocking of the CCL2/CCR2 axis inhibits the recruitment of inflammatory monocytes, infiltration and M2-polarisation of TAMs, resulting in reversal of the immunosuppression status of the tumour microenvironment and activation of an antitumorous CD8+ T cell response. In patients with liver cancer, CCL2 is highly expressed and is a prognostic factor. Blockade of CCL2/CCR2 signalling suppresses murine liver tumour growth via activating T cell antitumour immune response. The results demonstrate the translational potential of CCL2/CCR2 blockade for treatment of HCCs.


Color of cultures of Staphylococcus epidermidis determined by spectral reflectance colorimetry.
Brown, Richard W. (National Animal Disease Laboratory, Ames, Iowa). Color of cultures of Staphylococcus epidermidis determined by spectral reflectance colorimetry. J. Bacteriol. 91:911-918. 1966.-A colorimeter with a reflectance attachment was used to study pigment production by Staphylococcus epidermidis strains grown on a medium containing Trypticase Soy Agar (BBL) and cream. The color of each culture was first characterized by reflectance colorimetry for dominant wavelength, purity, and luminous reflectance (Y) and was then classified visually into 1 of 10 color grades. There was not complete agreement in grading colors by the two methods, inasmuch as cultures that were considered more pigmented in relation to other cultures by the reflectance method were sometimes graded visually as less pigmented, and vice versa. Nevertheless, when the cultures were visually graded as being more pigmented, there was a concomitant increase in the average values of dominant wavelength and purity with a decrease in Y for the cultures in each higher grade. Thus, the nonpigmented cultures had the lowest dominant wavelength and purity values but the highest Y (brightness) values, whereas the most pigmented cultures had the highest dominant wavelength and purity values, but the lowest Y values. These results indicated that the cultures did not produce pigments of different hues (greenish-yellow, yellow, yellowish-orange) each with high, medium, and low degrees of purity and brightness. The value (1 - z), where the chromaticity coordinate z = Z/(X + Y + Z), was found to be proportional to the purity value. An inverse relationship between the tristimulus Z and purity values was also demonstrated. All cultures tested by the reflectance method were also classified according to the type of spectral absorption curve obtained with pigments extracted from the cultures with methanol. A comparison of these methods indicated that determining the type of spectral absorption curve would be better for differentiating strains of S. epidermidis, whereas the use of the reflectance method would be better for determining differences of pigment production within strains.


Synthesis of HLA antigens from membrane-associated messenger RNA.
Proteins encoded by genes in the human major histocompatibility region, HLA, are present on the plasma membranes in the cells of most tissues. We have isolated messenger RNA (mRNA) from lymphoblastoid cells and studied its templating activity for HLA polypeptides by using an mRNA-dependent cell-free translation system and immunorecipitation with specific antisera. We estimate the sizes of the mRNA to be 1,700, 1,300, and 900 nucleotides for HLA-A, -B, and -C (HLA-ABC), HLA-DR, and beta 2-microglobulin, respectively. These sizes are consistent with our inability to detect larger polypeptide precursor for more than one HLA-ABC or HLA-DR antigen. Subcellular fractionation into cytosol and membrane fractions indicated that mRNA for the HLA-ABC and HLA-ABC and HLA-DR polypeptides was found predominantly in the membrane fraction. The beta 2-microglobulin mRNA appeared to be divided into roughly equal portions between both fractions. Nevertheless, we believe that in the cell, beta 2-microglobulin is synthesized in the rough endoplasmic reticulum, and that, because the protein is relatively small, the mRNA is released from the polyribosomes during the isolation procedure. We conclude that the properties of the HLA region and the beta 2-microglobulin mRNA are consistent with current models for the synthesis and membrane insertion of eukaryotic cell surface proteins. Our findings do not suggest the existence of multigenic precursor polypeptides for HLA antigens in contrast to those for several viral membrane glycoproteins.


Investigation of the increased incidence of gonorrhoea diagnosed in genitourinary medicine clinics in England, 1994-6.
To determine important risk factors associated with cases of gonorrhoea in England, and whether any particular risk groups were associated with the substantial rise in numbers of cases seen between 1994 and 1996. Two retrospective cross sectional surveys. 70 randomly selected genitourinary medicine (GUM) clinics in England. 10% of all gonorrhoea patients attending GUM clinics in England in 1994 (847 patients) and 1996 (1146 patients). For risk factors in 1996 (study 1), unadjusted rates per 100,000 population aged 14-70 and relative rates (RR) with 95% confidence intervals (CIs). For the change in risk factors between 1994 and 1996 (study 2), adjusted odds ratios (ORs) with 95% CIs, derived from logistic regression analyses of data on patients in 1996, with patients in 1994 as the comparison group. The incidence of gonorrhoea in 1996 was higher in homosexual males (812 per 100,000; RR = 30.2, CI = 25.2 to 36.0) compared with heterosexual males (27 per 100,000); in black Caribbeans (467 per 100,000; 21.4, 17.9 to 25.5) and black Africans (235 per 100,000; 10.8, 7.5 to 15.5) compared with white people (22 per 100,000); and in previous GUM clinic attenders (433 per 100,000; 37.93, 35.46 to 40.56) compared with those who had not attended previously (11 per 100,000). However, most patients were either white or heterosexual. Heterosexual patients in 1996 were significantly more likely to have reduced sensitivity to penicillin (2.55, 1.20 to 5.41) than those in 1994. Male homo/bisexual patients in 1996 were significantly more likely to be from the north west (3.77, 1.45 to 9.80) and to have either reduced sensitivity (2.63, 1.03 to 6.73) or complete resistance (1.98, 1.03 to 3.78) to penicillin, compared with those in 1994. Homo/bisexual men and the black Caribbean population in England experience a disproportionate burden of gonococcal infections, however, the bulk of diagnoses are in white heterosexuals. No single risk group was associated with the rise in numbers of cases between 1994 and 1996. Resistance to penicillin is widespread and has increased in homo/bisexual men, and it is possible that a rise in treatment failures has, to some extent, enhanced transmission of gonorrhoea and contributed to the rise in numbers of diagnoses in this group.


Expression of kallikrein-related peptidase 7 predicts poor prognosis in patients with unresectable pancreatic ductal adenocarcinoma.
Kallikrein-related peptidase 7 (KLK7) is overexpressed in pancreatic ductal adenocarcinomas (PDAC). The aims of this study were to examine the expression of KLK7 during progression of pancreatic intraepithelial neoplasia (PanIN) to invasive PDAC and to assess its prognostic significance for PDAC. Immunohistochemistry was used to assess KLK7 expression using a tissue microarray (TMA) and full sections of pancreatic tissue containing normal tissue, PanIN, and invasive adenocarcinoma, and the association between KLK7 expression and prognosis was examined by a population-based pancreatic cancer TMA. Normal pancreatic epithelium was negative for KLK7 in either TMAs or full sections. Analysis by TMAs showed that 91% of cases showed KLK7 positivity in the adenocarcinoma component, which was significantly higher than PanIN 2/3. In full tissue sections of PDAC, KLK7 expression was detected in less than 1% of cells among PanIN 1A lesions, and increased with grade among PanIN 1B and PanIN2/3 lesions before reaching 69% in the invasive PDAC. In patients with unresected PDAC, KLK7 positivity was significantly associated with shorter overall survival. Aberrant KLK7 expression starts in intermediate-to-late stages of PanIN progression, and KLK7-positive staining is associated with almost a three-fold increase in mortality rate of patients with unresected PDAC. The association of KLK7 expression and poor outcome of patients with unresectable PDAC suggests that inhibiting either KLK7 expression and/or activity could be a therapeutic strategy. Because the vast majority of patients present with unresectable disease, such an intervention could have a significant impact upon the overall survival of this patient population.


Improving the PCR protocol to amplify a repetitive DNA sequence.
Although PCR-based techniques have become an essential tool in the field of molecular and genetic research, the amplification of repetitive DNA sequences is limited. This is due to the truncated nature of the amplified sequences, which are also prone to errors during DNA polymerase-based amplification. The complex structure of repetitive DNA can form hairpin loops, which promote dissociation of the polymerase from the template, impairing complete amplification, and leading to the formation of incomplete fragments that serve as megaprimers. These megaprimers anneal with other sequences, generating unexpected fragments in each PCR cycle. Our gene model, MaSp1, is 1037-bp long, with 68% GC content, and its amino acid sequence is characterized by poly-alanine-glycine motifs, which represent the repetitive codon consensus. We describe the amplification of the MaSp1 gene through minor changes in the PCR program. The results show that a denaturation temperature of 98°C is the key determinant in the amplification of the MaSp1 partial gene sequence.


Value generalization in human avoidance learning.
Generalization during aversive decision-making allows us to avoid a broad range of potential threats following experience with a limited set of exemplars. However, over-generalization, resulting in excessive and inappropriate avoidance, has been implicated in a variety of psychological disorders. Here, we use reinforcement learning modelling to dissect out different contributions to the generalization of instrumental avoidance in two groups of human volunteers (N = 26, N = 482). We found that generalization of avoidance could be parsed into perceptual and value-based processes, and further, that value-based generalization could be subdivided into that relating to aversive and neutral feedback - with corresponding circuits including primary sensory cortex, anterior insula, amygdala and ventromedial prefrontal cortex. Further, generalization from aversive, but not neutral, feedback was associated with self-reported anxiety and intrusive thoughts. These results reveal a set of distinct mechanisms that mediate generalization in avoidance learning, and show how specific individual differences within them can yield anxiety.


Subchronic treatment with St John's wort produces a positive shift in emotional processing in healthy volunteers.
The neurocognitive model of antidepressant treatment in depression states that antidepressants work by producing relatively immediate positive shifts in emotional processing, which translate into clinical improvement with time. St John's Wort has shown antidepressant potential in randomised controlled trials; however, its pharmacological actions are broad and it is unknown whether treatment also produces changes in emotional processing. We investigated whether short-term treatment with St John's wort has similar effects on emotional processing to those reported with other antidepressants such as selective serotonergic reuptake inhibitors. Forty-eight healthy participants were given St John's wort or placebo treatment for seven days. On day 7 they completed a battery of tasks to measure emotional processing and other elements of cognition. St John's wort treatment produced similar changes to other antidepressants, for example reducing recognition of disgusted faces and attention to fearful faces, while increasing memory for positive words. We failed to find evidence for an effect of St John's wort on other aspects of cognition including working memory. These findings lend support to the theory that the production of early positive biases in emotional processing may be a common feature of all clinically effective antidepressants with diverse pharmacological mechanisms.


Hope of rural women caregivers of persons with advanced cancer: guilt, self-efficacy and mental health.
Caring for a person with advanced disease can have a detrimental impact on the quality of life of family caregivers. This is further compounded in rural areas that have few or no palliative care services. Hope has a positive influence on the quality of life of family caregivers of persons with advanced cancer but factors influencing hope specifically in rural women caregivers of persons with advanced cancer have not been examined. The purpose of this study was to determine factors influencing the hope of rural women caring for persons with advanced cancer, by examining the relationship of hope with demographic variables, self-efficacy, guilt, and caregiver physical and mental health. A cross-sectional prospective correlational design was used. Inclusion criteria for the study were: (a) female, (b) 18 years of age or older, (c) caring for a person diagnosed with advanced cancer, (d) home address with a rural postal code, and (e) English-speaking. Using a modified Dillman technique, surveys and an invitation to participate were mailed to 780 persons with advanced cancer living in rural areas using two western Canadian provincial cancer registries. A reminder card was sent 4 weeks later. The persons with advanced cancer were asked to give the survey to their primary caregiver to complete. Surveys included measures of hope (Herth Hope Index (HHI)), general self-efficacy (General Self-Efficacy Scale (GSES)), grief (Non Death Version Revised Grief Experience Inventory (NDRGEI)), mental and physical health (Short Form Health Survey Version 2 (SF-12v2)), and demographic data such as their relationship to the person for whom the caregiver was caring. Data were entered into the Statistical Package for the Social Sciences v19 (SPSS) and analyzed using generalized linear modeling. Significant factors (p ≤ 0.05) influencing HHI scores were GSES ( p ≤ 0.0001), NDRGEI subscale (p=0.001), and SF-12v2 mental health summary scores (p=0.002). Participants with higher GSES, lower NDRGEI, and higher SF-12v2 mental health summary scores had higher HHI scores. The SF-12v2 physical health summary mean score of 43.30 (standard deviation (SD)=4.63) was below the 25th percentile (46.53) of US population norms. The SF-12v2 mental health summary mean score of 45.24 (SD=5.98) was just above the 25th percentile of US population norms (45.13). Participants with higher hope scores had higher mental health scores, lower perceptions of loss and grief scores, and higher scores in their confidence in their ability to deal with difficult situations (self-efficacy). The significant relationships found between hope and mental health, general self-efficacy, and perceptions of guilt provide a foundation for future research and underscore the importance of hope to rural women caregivers. The low physical and mental health scores of rural women caregivers are of concern and highlight the need to support this population.


Brain angiotensinergic mediation of enhanced water consumption in lactating rats.
The mechanism by which lactating rats increase fluid consumption to meet the demands of milk production is unknown. Because ANG II is the most potent dipsogenic stimulus known, this study examined whether angiotensinergic signaling plays a role in enhanced drinking in lactating rats. ANG II administered intracerebroventricularly caused a significantly greater dipsogenic response in lactating rats than in control rats, suggesting that dipsogenic responsivity to ANG II is enhanced in the brains of lactating rats. The angiotensin type 1 (AT1) ANG II receptor subtype antagonist SKF-108566, also given intracerebroventricularly, caused a significant reduction in water consumption in lactating rats, whereas it did not significantly affect water intake in control rats. In contrast, stimulation of drinking by the muscarinic agonist carbachol, also administered intracerebroventricularly, did not differ between lactating and control rats. Inhibition of drinking by the muscarinic antagonist atropine also did not differ significantly between lactating and control rats. These results suggest that the increased drinking in lactating rats involves an increased responsivity to ANG II in neurons that mediate dipsogenesis, as well as an enhancement in the amount of angiotensinergic input to these ANG II-responsive neurons.