Placental energy metabolism in health and disease-significance of development and implications for preeclampsia.

The placenta is a highly metabolically active organ fulfilling the bioenergetic and biosynthetic needs to support its own rapid growth and that of the fetus. Placental metabolic dysfunction is a common occurrence in preeclampsia although its causal relationship to the pathophysiology is unclear. At the outset, this may simply be seen as an "engine out of fuel." However, placental metabolism plays a vital role beyond energy production and is linked to physiological and developmental processes. In this review, we discuss the metabolic basis for placental dysfunction and propose that the alterations in energy metabolism may explain many of the placental phenotypes of preeclampsia such as reduced placental and fetal growth, redox imbalance, oxidative stress, altered epigenetic and gene expression profiles, and the functional consequences of these aberrations. We propose that placental metabolic reprogramming reflects the dynamic physiological state allowing the tissue to adapt to developmental changes and respond to preeclampsia stress, whereas the inability to reprogram placental metabolism may result in severe preeclampsia phenotypes. Finally, we discuss common tested and novel therapeutic strategies for treating placental dysfunction in preeclampsia and their impact on placental energy metabolism as possible explanations into their potential benefits or harm.I.L.M.H. Aye is funded by a Next Generation Fellowship from the Centre for 20 Trophoblast Research, University of Cambridg

Polymorphisms in Gag spacer peptide 1 confer varying levels of resistance to the HIV- 1maturation inhibitor bevirimat

Background: The maturation inhibitor bevirimat (BVM) potently inhibits human immunodeficiency virus type 1 (HIV-1) replication by blocking capsid-spacer peptide 1 (CA-SP1) cleavage. Recent clinical trials demonstrated that a significant proportion of HIV-1-infected patients do not respond to BVM. A patient’s failure to respond correlated with baseline polymorphisms at SP1 residues 6-8. Results: In this study, we demonstrate that varying levels of BVM resistance are associated with point mutations at these residues. BVM susceptibility was maintained by SP1-Q6A, -Q6H and -T8A mutations. However, an SP1-V7A mutation conferred high-level BVM resistance and SP1-V7M and T8Δ mutations conferred intermediate levels of BVM resistance. Conclusions: Future exploitation of the CA-SP1 cleavage site as an antiretroviral drug target will need to overcome the baseline variability in the SP1 region of Gag.Publisher PDFPeer reviewe

T-SPOT.TB responses during treatment of pulmonary tuberculosis

<p>Abstract</p> <p>Background</p> <p>Immune responses to <it>Mycobacterium tuberculosis </it>antigens could serve as surrogate markers of treatment response.</p> <p>Methods</p> <p>Using the T-SPOT.<it>TB </it>assay and frozen peripheral blood mononuclear cells, we enumerated ESAT-6- and CFP-10-specific IFN-γ-producing T cells over time in pulmonary TB patients receiving directly observed treatment. T cell responses (measured as "spot forming cells" or "SFCs") were assessed prior to treatment and at 16 and 24 weeks of treatment.</p> <p>Results</p> <p>58 patients were evaluated, of whom 57 were HIV seronegative. Mean (SD) ESAT-6, CFP-10, and summed RD1 specific SFCs declined from 42.7 (72.7), 41.2 (66.4), and 83.8 (105.7) at baseline to 23.3 (39.4, p = 0.01), 23.2 (29.4, p = 0.18), and 46.5 (59.5, p = 0.02) at completion of 24 weeks of treatment, respectively. Only 10% of individuals with a baseline reactive test reverted to negative at treatment week 24. For the group that was culture positive at completion of 8 weeks of treatment compared to the culture negative group, the incidence rate ratio (IRR) of ESAT-6, CFP-10, and summed RD1 specific SFC counts were, respectively, 2.23 (p = 0.048), 1.51 (p = 0.20), and 1.83 (p = 0.047). Patients with cavitary disease had mean ESAT-6 specific SFC counts that were higher than those without cavitary disease (IRR 2.08, p = 0.034).</p> <p>Conclusion</p> <p>IFN-γ-producing RD1-specific T cells, as measured in the T-SPOT.<it>TB </it>assay, may be directly related to bacterial load in patients undergoing treatment for pulmonary TB. However, high inter-subject variability in quantitative results coupled with failure of reversion to negative of qualitative results in most subjects at treatment completion may limit the utility of this assay as a surrogate marker for treatment efficacy.</p

Exploring the views of infection consultants in England on a novel delinked funding model for antimicrobials: the SMASH study

OBJECTIVES: A novel 'subscription-type' funding model was launched in England in July 2022 for ceftazidime/avibactam and cefiderocol. We explored the views of infection consultants on important aspects of the delinked antimicrobial funding model. METHODS: An online survey was sent to all infection consultants in NHS acute hospitals in England. RESULTS: The response rate was 31.2% (235/753). Most consultants agreed the model is a welcome development (69.8%, 164/235), will improve treatment of drug-resistant infections (68.5%, 161/235) and will stimulate research and development of new antimicrobials (57.9%, 136/235). Consultants disagreed that the model would lead to reduced carbapenem use and reported increased use of cefiderocol post-implementation. The presence of an antimicrobial pharmacy team, requirement for preauthorization by infection specialists, antimicrobial stewardship ward rounds and education of infection specialists were considered the most effective antimicrobial stewardship interventions. Under the new model, 42.1% (99/235) of consultants would use these antimicrobials empirically, if risk factors for antimicrobial resistance were present (previous infection, colonization, treatment failure with carbapenems, ward outbreak, recent admission to a high-prevalence setting).Significantly higher insurance and diversity values were given to model antimicrobials compared with established treatments for carbapenem-resistant infections, while meropenem recorded the highest enablement value. Use of both 'subscription-type' model drugs for a wide range of infection sites was reported. Respondents prioritized ceftazidime/avibactam for infections by bacteria producing OXA-48 and KPC and cefiderocol for those producing MBLs and infections with Stenotrophomonas maltophilia, Acinetobacter spp. and Burkholderia cepacia. CONCLUSIONS: The 'subscription-type' model was viewed favourably by infection consultants in England

Exploring the views of infection consultants in England on a novel delinked funding model for antimicrobials: the SMASH study

OBJECTIVES: A novel ‘subscription-type’ funding model was launched in England in July 2022 for ceftazidime/avibactam and cefiderocol. We explored the views of infection consultants on important aspects of the delinked antimicrobial funding model. METHODS: An online survey was sent to all infection consultants in NHS acute hospitals in England. RESULTS: The response rate was 31.2% (235/753). Most consultants agreed the model is a welcome development (69.8%, 164/235), will improve treatment of drug-resistant infections (68.5%, 161/235) and will stimulate research and development of new antimicrobials (57.9%, 136/235). Consultants disagreed that the model would lead to reduced carbapenem use and reported increased use of cefiderocol post-implementation. The presence of an antimicrobial pharmacy team, requirement for preauthorization by infection specialists, antimicrobial stewardship ward rounds and education of infection specialists were considered the most effective antimicrobial stewardship interventions. Under the new model, 42.1% (99/235) of consultants would use these antimicrobials empirically, if risk factors for antimicrobial resistance were present (previous infection, colonization, treatment failure with carbapenems, ward outbreak, recent admission to a high-prevalence setting). Significantly higher insurance and diversity values were given to model antimicrobials compared with established treatments for carbapenem-resistant infections, while meropenem recorded the highest enablement value. Use of both ‘subscription-type’ model drugs for a wide range of infection sites was reported. Respondents prioritized ceftazidime/avibactam for infections by bacteria producing OXA-48 and KPC and cefiderocol for those producing MBLs and infections with Stenotrophomonas maltophilia, Acinetobacter spp. and Burkholderia cepacia. CONCLUSIONS: The ‘subscription-type’ model was viewed favourably by infection consultants in England

Work satisfaction of professional nurses in South Africa: a comparative analysis of the public and private sectors

<p>Abstract</p> <p>Background</p> <p>Work satisfaction of nurses is important, as there is sufficient empirical evidence to show that it tends to affect individual, organizational and greater health and social outcomes. Although there have been several studies of job satisfaction among nurses in South Africa, these are limited because they relate to studies of individual organizations or regions, use small samples or are dated. This paper presents a national study that compares and contrasts satisfaction levels of nurses in both public and private sectors.</p> <p>Methods</p> <p>This was a cross-sectional survey of professional nurses conducted throughout South Africa using a pretested and self-administered questionnaire. Univariate and bivariate statistical models were used to evaluate levels of satisfaction with various facets of work and to elicit the differences in satisfaction levels between different groups of nurses. A total of 569 professional nurses participated in the study.</p> <p>Results</p> <p>Private-sector nurses were generally satisfied, while public-sector nurses were generally dissatisfied. Public-sector nurses were most dissatisfied with their pay, the workload and the resources available to them. They were satisfied only with the social context of the work. Private-sector nurses were dissatisfied only with their pay and career development opportunities. Professional nurses in the more rural provinces, those intending to change sectors and those more likely not to be in their current positions within the next five years were also more likely to be dissatisfied with all facets of their work.</p> <p>Conclusion</p> <p>This study highlighted the overall dissatisfaction among South African nurses and confirmed the disparity between the levels of job satisfaction between the public and private sectors. Health managers should address those factors that affect job satisfaction, and therefore retention, of nurses in South Africa. Improving the work environment so that it provides a context congruent with the aspirations and values systems of nurses is more likely to increase the satisfaction of nurses and consequently have a positive effect on individual, organizational and health outcomes.</p

Achievement motives and emotional processes in children during problem-solving: Two experimental studies of their relation to performance in different achievement goal conditions

In two studies, the influence of key emotional and motivational factors on performance in different achievement goal-type situations is examined. In study 1, based on 314 sixth-graders, two types of goal situations were induced; performance and mastery. The goals were examined with respect to important antecedents (e.g., motive dispositions) and several consequences (e.g., performance, satisfaction, pleasant affect, worry, and emotionality). The results showed that the motive to achieve success (Ms) produced positive affects, satisfaction, and increased performance, whereas the motive to avoid failure (Mf) produced worries and performance reduction. In study 2, based on 331 sixth-graders, three types of goal situations were induced; performance–approach, performance–avoidance, and mastery goals. The findings revealed that the most important single factors positively related to performance were Ms and mastery–goal situation. In addition, high Ms pupils performed better under mastery condition than under performance condition. Finally, avoidance-goal situation accentuate the negative effects of high Mf on performance

Mammography stages of change in middle-aged women with schizophrenia: An exploratory analysis

BACKGROUND: Health care providers and educators who seek to create health promotion programs and individualized comprehensive care plans for women with schizophrenia are hindered by the lack of data to guide their efforts. PURPOSE: This study tested the hypothesis that women with schizophrenia adhere to mammography screening guidelines at the same rate as other same-age women. The study also investigated the validity of the Health Belief (HB) and Stages of Change (SOC) models for breast cancer screening among women with schizophrenia. METHODS: Socio-demographic and clinical variables, as well as knowledge, attitudes, and barriers were assessed as a function of stage of change related to breast cancer screening in 46 women with schizophrenia. RESULTS: Women with schizophrenia were statistically less likely to be adherent to the screening recommendations than those without schizophrenia. Some support was found for the validity of the HB and SOC models for breast cancer screening in women with schizophrenia. Women in the Precontemplation stage had significantly higher negative attitude scores compared to Contemplation and Action/Maintenance stages (59.7, 45.7, and 43.2, respectively), and there was a trend for more barriers in the Precontemplation group (4.6, 2.6, 2.7 respectively). CONCLUSION: Given the small sample size, further research on the rates of breast cancer screening in women with schizophrenia is warranted. Nonetheless, these data suggest that providers who care for women with schizophrenia may need to make take additional measures to ensure that this population receives appropriate screening so as to not put them at greater risk for a late-stage diagnosis of breast cancer. Furthermore, these pilot data suggest that HB and SOC theory-based interventions may be valid for increasing mammography rates in women with schizophrenia

Vegetation Type Dominates the Spatial Variability in CH<inf>4</inf> Emissions Across Multiple Arctic Tundra Landscapes

Methane (CH4) emissions from Arctic tundra are an important feedback to global climate. Currently, modelling and predicting CH4 fluxes at broader scales are limited by the challenge of upscaling plot-scale measurements in spatially heterogeneous landscapes, and by uncertainties regarding key controls of CH4 emissions. In this study, CH4 and CO2 fluxes were measured together with a range of environmental variables and detailed vegetation analysis at four sites spanning 300 km latitude from Barrow to Ivotuk (Alaska). We used multiple regression modelling to identify drivers of CH4 flux, and to examine relationships between gross primary productivity (GPP), dissolved organic carbon (DOC) and CH4 fluxes. We found that a highly simplified vegetation classification consisting of just three vegetation types (wet sedge, tussock sedge and other) explained 54% of the variation in CH4 fluxes across the entire transect, performing almost as well as a more complex model including water table, sedge height and soil moisture (explaining 58% of the variation in CH4 fluxes). Substantial CH4 emissions were recorded from tussock sedges in locations even when the water table was lower than 40 cm below the surface, demonstrating the importance of plant-mediated transport. We also found no relationship between instantaneous GPP and CH4 fluxes, suggesting that models should be cautious in assuming a direct relationship between primary production and CH4 emissions. Our findings demonstrate the importance of vegetation as an integrator of processes controlling CH4 emissions in Arctic ecosystems, and provide a simplified framework for upscaling plot scale CH4 flux measurements from Arctic ecosystems

HIV Capsid is a Tractable Target for Small Molecule Therapeutic Intervention

Despite a high current standard of care in antiretroviral therapy for HIV, multidrug-resistant strains continue to emerge, underscoring the need for additional novel mechanism inhibitors that will offer expanded therapeutic options in the clinic. We report a new class of small molecule antiretroviral compounds that directly target HIV-1 capsid (CA) via a novel mechanism of action. The compounds exhibit potent antiviral activity against HIV-1 laboratory strains, clinical isolates, and HIV-2, and inhibit both early and late events in the viral replication cycle. We present mechanistic studies indicating that these early and late activities result from the compound affecting viral uncoating and assembly, respectively. We show that amino acid substitutions in the N-terminal domain of HIV-1 CA are sufficient to confer resistance to this class of compounds, identifying CA as the target in infected cells. A high-resolution co-crystal structure of the compound bound to HIV-1 CA reveals a novel binding pocket in the N-terminal domain of the protein. Our data demonstrate that broad-spectrum antiviral activity can be achieved by targeting this new binding site and reveal HIV CA as a tractable drug target for HIV therapy