Cyclic AMP (cAMP) phosphodiesterase-4 (PDE4) enzymes degrade cAMP and underpin the compartmentalization of cAMP signaling through their targeting to particular protein complexes and intracellular ...locales. We describe the discovery and characterization of a small-molecule compound that allosterically activates PDE4 long isoforms. This PDE4-specific activator displays reversible, noncompetitive kinetics of activation (increased V
max with unchanged K
m), phenocopies the ability of protein kinase A (PKA) to activate PDE4 long isoforms endogenously, and requires a dimeric enzyme assembly, as adopted by long, but not by short (monomeric), PDE4 isoforms. Abnormally elevated levels of cAMP provide a critical driver of the underpinning molecular pathology of autosomal dominant polycystic kidney disease (ADPKD) by promoting cyst formation that, ultimately, culminates in renal failure. Using both animal and human cell models of ADPKD, including ADPKD patient-derived primary cell cultures, we demonstrate that treatment with the prototypical PDE4 activator compound lowers intracellular cAMP levels, restrains cAMP-mediated signaling events, and profoundly inhibits cyst formation. PDE4 activator compounds thus have potential as therapeutics for treating disease driven by elevated cAMP signaling as well as providing a tool for evaluating the action of long PDE4 isoforms in regulating cAMP-mediated cellular processes.
Volumetric prefabricated building construction is growing in most developed countries; for example, in Sweden the market share of prefabricated building systems in the housing industry was more than ...80%. However, in Australia only approximately 3–4% of new building constructions are prefabricated buildings in a year. A major hindrance to the growth of prefab construction in Australia is that systems are developed under commercial and confidential conditions. There are limited publicly-available research and case studies for certifiers, regulators, engineers and academia to provide independent information on the performance, advantages and disadvantages of prefabricated building systems. Independent designers and structural engineers are relying on the strength of the structural and non-structural element, as well as the connections of the prefabricated building systems. This strength is estimated from the “commercial-in-confidence” test of individual components by manufactures, and it might result in undesired outcomes in design. This paper provides an overview of available literature on structural performance, benefits, constraints and challenges of prefabricated building systems. This paper also highlights the research needed on the prefabricated building systems such as full-scale tests, numerical modelling, hybrid simulations, case studies and social and economic assessments. Being supported by sound academic research will increase the market demand for prefabricated building systems in Australia as well as in other countries.
Purpose of review Timely postexposure prophylaxis is important after an occupational exposure. Here we review select organisms, exposure opportunities in the healthcare setting, and postexposure ...prophylaxis regimens. Recent findings Needlestick injuries pose a risk of exposure to bloodborne pathogens, such as HIV, Hepatitis B, and Hepatitis C. Risk mitigation strategies should be reexamined in light of newer vaccines and therapeutics. Increased vaccine hesitancy and vaccine denialisms may foster the re-emergence of some infections that have become extremely uncommon because of effective vaccines. With increasing occurrences of zoonotic infections and the ease of global spread as evidenced by COVID-19 and mpox, healthcare exposures must also consider risks related to emerging and re-emerging infectious diseases. Summary Early recognition and reporting of occupational exposures to pathogens with available postexposure prophylaxis is key to mitigating the risk of transmission. Providers should be able to evaluate the exposure and associated risks to provide prompt and appropriate postexposure prophylaxis.
The launch ofCloudSatandCloud–Aerosol Lidar and Infrared Pathfinder Satellite Observations (CALIPSO)in 2006 provided the first opportunity to incorporate information about the vertical distribution ...of cloud and aerosols directly into global estimates of atmospheric radiative heating. Vertical profiles of radar and lidar backscatter fromCloudSat’s Cloud Profiling Radar (CPR) and the Cloud–Aerosol Lidar with Orthogonal Polarization (CALIOP) aboardCALIPSOnaturally complement Moderate Resolution Imaging Spectroradiometer (MODIS) radiance measurements, providing a nearly complete depiction of the cloud and aerosol properties that are essential for deriving high-vertical-resolution profiles of longwave (LW) and shortwave (SW) radiative fluxes and heating rates throughout the atmosphere. This study describes a new approach for combining vertical cloud and aerosol information fromCloudSatandCALIPSOwith MODIS data to assess impacts of clouds and aerosols on top-of-atmosphere (TOA) and surface radiative fluxes. The resulting multisensor cloud–aerosol product is used to document seasonal and annual mean distributions of cloud and aerosol forcing globally from June 2006 through April 2011. Direct comparisons with Clouds and the Earth’s Radiant Energy System (CERES) TOA fluxes exhibit a close correlation, with improved errors relative toCloudSat-only products. Sensitivity studies suggest that remaining uncertainties in SW fluxes are dominated by uncertainties inCloudSatliquid water content estimates and that the largest sources of LW flux uncertainty are prescribed surface temperature and lower-tropospheric humidity. Globally and annually averaged net TOA cloud radiative effect is found to be −18.1 W m−2. The global, annualmean aerosol direct radiative effect is found to be −1.6 ± 0.5 W m−2(−2.5 ± 0.8 W m−2if only clear skies over the ocean are considered), which, surprisingly, is more consistent with past modeling studies than with observational estimates that were based on passive sensors.
This report updates US Public Health Service recommendations for the management of healthcare personnel (HCP) who experience occupational exposure to blood and/or other body fluids that might contain ...human immunodeficiency virus (HIV). Although the principles of exposure management remain unchanged, recommended HIV postexposure prophylaxis (PEP) regimens and the duration of HIV follow-up testing for exposed personnel have been updated. This report emphasizes the importance of primary prevention strategies, the prompt reporting and management of occupational exposures, adherence to recommended HIV PEP regimens when indicated for an exposure, expert consultation in management of exposures, follow-up of exposed HCP to improve adherence to PEP, and careful monitoring for adverse events related to treatment, as well as for virologic, immunologic, and serologic signs of infection. To ensure timely postexposure management and administration of HIV PEP, clinicians should consider occupational exposures as urgent medical concerns, and institutions should take steps to ensure that staff are aware of both the importance of and the institutional mechanisms available for reporting and seeking care for such exposures. The following is a summary of recommendations: (1) PEP is recommended when occupational exposures to HIV occur; (2) the HIV status of the exposure source patient should be determined, if possible, to guide need for HIV PEP; (3) PEP medication regimens should be started as soon as possible after occupational exposure to HIV, and they should be continued for a 4-week duration; (4) new recommendation-PEP medication regimens should contain 3 (or more) antiretroviral drugs (listed in Appendix A ) for all occupational exposures to HIV; (5) expert consultation is recommended for any occupational exposures to HIV and at a minimum for situations described in Box 1 ; (6) close follow-up for exposed personnel ( Box 2 ) should be provided that includes counseling, baseline and follow-up HIV testing, and monitoring for drug toxicity; follow-up appointments should begin within 72 hours of an HIV exposure; and (7) new recommendation-if a newer fourth-generation combination HIV p24 antigen-HIV antibody test is utilized for follow-up HIV testing of exposed HCP, HIV testing may be concluded 4 months after exposure ( Box 2 ); if a newer testing platform is not available, follow-up HIV testing is typically concluded 6 months after an HIV exposure.
Summary Background Pre-eclampsia is a major cause of mortality and morbidity during pregnancy and childbirth. Antiplatelet agents, especially low-dose aspirin, might prevent or delay pre-eclampsia, ...and thereby improve outcome. Our aim was to assess the use of antiplatelet agents for the primary prevention of pre-eclampsia, and to explore which women are likely to benefit most. Methods We did a meta-analysis of individual patient data from 32 217 women, and their 32 819 babies, recruited to 31 randomised trials of pre-eclampsia primary prevention. Findings For women assigned to receive antiplatelet agents rather than control, the relative risk of developing pre-eclampsia was 0·90 (95% CI 0·84–0·97), of delivering before 34 weeks was 0·90 (0·83–0·98), and of having a pregnancy with a serious adverse outcome was 0·90 (0·85–0·96). Antiplatelet agents had no significant effect on the risk of death of the fetus or baby, having a small for gestational age infant, or bleeding events for either the women or their babies. No particular subgroup of women was substantially more or less likely to benefit from antiplatelet agents than any other. Interpretation Antiplatelet agents during pregnancy are associated with moderate but consistent reductions in the relative risk of pre-eclampsia, of birth before 34 weeks' gestation, and of having a pregnancy with a serious adverse outcome.
Noncommunicable diseases are the leading cause of worldwide death and disability and continue to increase in both developed and developing countries. There is a need to address and treat ...neuropsychiatric disorders in low-income countries, especially in the Horn of Africa. Capacity building by training local doctors and health care workers is a laborious endeavor, with challenges piling up along the way. Nevertheless, the rewards are great when brain specialists who are able to address the needs in their country and treat their fellow citizens receive the training needed to do so effectively. The present article describes a coordinated administrative, educational, and clinical effort to develop and implement a dual residency program in psychiatry and neurology at the University of Hargeisa in Somaliland. The authors highlight the foundations of the program and the challenges faced during its development and implementation in an area of regional conflict. The program provides evidence that this aim is achievable and serves as a model for others seeking to replicate it in other low- and middle-income countries.
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