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Modulation of host cell function is vital for intracellular pathogens to survive and replicate within host cells. Most commonly, these pathogens utilize specialized secretion systems to inject substrates (also called effector proteins) that function as toxins within host cells. Since it would be detrimental for an intracellular pathogen to immediately kill its host cell, it is essential that secreted toxins be inactivated or degraded after they have served their purpose. The pathogen Legionella pneumophila represents an ideal system to study interactions between toxins as it survives within host cells for approximately a day and its Dot/Icm type IVB secretion system (T4SS) injects a vast number of toxins. Previously we reported that the Dot/Icm substrates SidE, SdeA, SdeB, and SdeC (known as the SidE family of effectors) are secreted into host cells, where they localize to the cytoplasmic face of the Legionella containing vacuole (LCV) in the early stages of infection. SidJ, another effector that is unrelated to the SidE family, is also encoded in the sdeC-sdeA locus. Interestingly, while over-expression of SidE family proteins in a wild type Legionella strain has no effect, we found that their over-expression in a ∆sidJ mutant completely inhibits intracellular growth of the strain. In addition, we found expression of SidE proteins is toxic in both yeast and mammalian HEK293 cells, but this toxicity can be suppressed by co-expression of SidJ, suggesting that SidJ may modulate the function of SidE family proteins. Finally, we were able to demonstrate both in vivo and in vitro that SidJ acts on SidE proteins to mediate their disappearance from the LCV, thereby preventing lethal intoxication of host cells. Based on these findings, we propose that SidJ acts as a metaeffector to control the activity of other Legionella effectors.

Moral distress is widespread in health care, and nurses working in high-pressure environments, such as emergency departments, experience stress at high rates. Understanding how moral distress affects pediatric emergency nursing care is essential to moderate its negative impacts. Increased resilience has been promoted as a tool to mitigate moral distress. The purpose of this study, conducted prior to the pandemic, was to examine patterns of moral distress and the impact of moral distress on resilience among pediatric emergency nurses. A cross-sectional exploratory study of pediatric emergency nurses was performed. Moral Distress Scale-Revised (Pediatric) and Connor-Davidson Resilience Scale 25© scores were collected and calculated. Exploratory factor analysis with principal components was used to identify patterns of moral distress that impact resilience. Four distinct patterns of moral distress that impact resilience were identified: (1) incompetent practice, (2) incongruent truth-telling, (3) potentially inappropriate care, and (4) discordant health care teams. Our study was the first to identify 4 patterns of moral distress in pediatric emergency nurses. As a result, actions to promote resilience include: (1) supporting competent practice, (2) upholding appropriate truth-telling, (3) recognizing and addressing potentially inappropriate care, and (4) building concordant health care teams and systems. This pre-pandemic data provides a foundational understanding of the relationship between moral distress and resilience in pediatric emergency nurses. Identifying factors of moral distress that impact resilience has significant implications for pediatric emergency nursing, including the development of future initiatives, education, and research.

Background The metabolism of archaeal methanogens drives methane release into the environment and is critical to understanding global carbon cycling. Methanogenesis operates at a very low reducing potential compared to other forms of respiration and is therefore critical to many anaerobic environments. Harnessing or altering methanogen metabolism has the potential to mitigate global warming and even be utilized for energy applications. Results Here, we report draft genome sequences for the isolated methanogens Methanobacterium bryantii , Methanosarcina spelaei , Methanosphaera cuniculi , and Methanocorpusculum parvum . These anaerobic, methane-producing archaea represent a diverse set of isolates, capable of methylotrophic, acetoclastic, and hydrogenotrophic methanogenesis. Assembly and analysis of the genomes allowed for simple and rapid reconstruction of metabolism in the four methanogens. Comparison of the distribution of Clusters of Orthologous Groups (COG) proteins to a sample of genomes from the RefSeq database revealed a trend towards energy conservation in genome composition of all methanogens sequenced. Further analysis of the predicted membrane proteins and transporters distinguished differing energy conservation methods utilized during methanogenesis, such as chemiosmotic coupling in Msar. spelaei and electron bifurcation linked to chemiosmotic coupling in Mbac. bryantii and Msph. cuniculi . Conclusions Methanogens occupy a unique ecological niche, acting as the terminal electron acceptors in anaerobic environments, and their genomes display a significant shift towards energy conservation. The genome-enabled reconstructed metabolisms reported here have significance to diverse anaerobic communities and have led to proposed substrate utilization not previously reported in isolation, such as formate and methanol metabolism in Mbac. bryantii and CO 2 metabolism in Msph. cuniculi . The newly proposed substrates establish an important foundation with which to decipher how methanogens behave in native communities, as CO 2 and formate are common electron carriers in microbial communities.

Background Investigating the causes of stillbirth is crucial for both parents and healthcare providers as it helps explain why the baby died, guides clinical care in future pregnancies, and aids in developing strategies to prevent stillbirth. The usefulness or utility of investigations for stillbirth is poorly defined and unclear. As a result, protocols for investigating the causes of stillbirth are currently based on clinical consensus and fail to prioritise investigative approaches that are most effective at determining a cause of death. Objectives The objectives of this scoping review were to identify the available evidence, key characteristics, and knowledge gaps regarding the utility of stillbirth investigations. Search strategy An a priori protocol was implemented and included a systematic search in MEDLINE, CINAHL, EMBASE, Scopus, and Cochrane from inception until 28 May 2024. Selection criteria Studies examining stillbirth investigations, yield, and value were included. Data collection and analysis Data were collected using a purpose-built data extraction tool and an analysis was undertaken. Results 57 potentially eligible studies were identified, and 34 studies (with 11,410 stillbirths) were included. Three studies examined clinical utility using a comprehensive testing protocol. Definition of utility or value of investigations varied across the studies, classification system for cause of death and investigation protocols varied. Placental pathology was reported as the most useful investigation in 65%–96% of cases, identified a cause of death in 61–71% of cases and impacting the medical management in 36% of cases (13 studies, 5,169 stillbirths). Autopsy can identify the cause of death in 36–77% of cases and provided new information in 17–26% of cases (17 studies, 4,336 stillbirths). Genetic analysis was useful in 29% of cases (seven studies, 1,886 stillbirths). One study (512 stillbirths) examined the value of investigation by presenting clinical scenario. Conclusions This review indicates that Investigation protocols for stillbirth should include placental pathology, autopsy, and genetic testing. Future studies should address the value of tests by presenting clinical scenarios, use of a consistent definition of stillbirth, classification system and measurement of investigation value.

FR171456 is a natural product with cholesterol-lowering properties in animal models, but its molecular target is unknown, which hinders further drug development. Here we show that FR171456 specifically targets the sterol-4-alpha-carboxylate-3-dehydrogenase (S accharomyces cerevisiae —Erg26p, Homo sapiens —NSDHL (NAD(P) dependent steroid dehydrogenase-like)), an essential enzyme in the ergosterol/cholesterol biosynthesis pathway. FR171456 significantly alters the levels of cholesterol pathway intermediates in human and yeast cells. Genome-wide yeast haploinsufficiency profiling experiments highlight the erg26/ERG26 strain, and multiple mutations in ERG26 confer resistance to FR171456 in growth and enzyme assays. Some of these ERG26 mutations likely alter Erg26 binding to FR171456, based on a model of Erg26. Finally, we show that FR171456 inhibits an artificial Hepatitis C viral replicon, and has broad antifungal activity, suggesting potential additional utility as an anti-infective. The discovery of the target and binding site of FR171456 within the target will aid further development of this compound. FR171456 is a bioactive chemical produced by some microorganisms. Here, the authors identify the enzyme NSDHL of the sterol synthesis pathway as the molecular target of FR171456, rendering it the first compound to specifically target this class of enzyme in yeast and mammalian cells.

Background Despite advances in the care of women and their babies in the past century, an estimated 1.7 million babies are born still each year throughout the world. A robust method to estimate a pregnant woman’s individualized risk of late-pregnancy stillbirth is needed to inform decision-making around the timing of birth to reduce the risk of stillbirth from 35 weeks of gestation in Australia, a high-resource setting. Methods This is a protocol for a cross-sectional study of all late-pregnancy births in Australia (2005–2015) from 35 weeks of gestation including 5188 stillbirths among 3.1 million births at an estimated rate of 1.7 stillbirths per 1000 births. A multivariable logistic regression model will be developed in line with current T ransparent R eporting of a multivariable prediction model for I ndividual P rognosis or D iagnosis (TRIPOD) guidelines to estimate the gestation-specific probability of stillbirth with prediction intervals. Candidate predictors were identified from systematic reviews and clinical consultation and will be described through univariable regression analysis. To generate a final model, elimination by backward stepwise multivariable logistic regression will be performed. The model will be internally validated using bootstrapping with 1000 repetitions and externally validated using a temporally unique dataset. Overall model performance will be assessed with R 2 , calibration, and discrimination. Calibration will be reported using a calibration plot with 95% confidence intervals ( α = 0.05). Discrimination will be measured by the C- statistic and area underneath the receiver-operator curves. Clinical usefulness will be reported as positive and negative predictive values, and a decision curve analysis will be considered. Discussion A robust method to predict a pregnant woman’s individualized risk of late-pregnancy stillbirth is needed to inform timely, appropriate care to reduce stillbirth. Among existing prediction models designed for obstetric use, few have been subject to internal and external validation and many fail to meet recommended reporting standards. In developing a risk prediction model for late-gestation stillbirth with both providers and pregnant women in mind, we endeavor to develop a validated model for clinical use in Australia that meets current reporting standards.

We identify and characterize a gene cluster in El Tor Vibrio cholerae that encodes a cytotoxic activity for HEp-2 cells in vitro. This gene cluster contains four genes and is physically linked to the cholera toxin (CTX) element in the V. cholerae genome. We demonstrate by using insertional mutagenesis that this gene cluster is required for the cytotoxic activity. The toxin, RtxA, resembles members of the RTX (repeats in toxin) toxin family in that it contains a GD-rich repeated motif. Like other RTX toxins, its activity depends on an activator, RtxC, and an associated ABC transporter system, RtxB and RtxD. In V. cholerae strains of the classical biotype, a deletion within the gene cluster removes rtxC and eliminates cytotoxic activity. Other strains, including those of the current cholera pandemic, contain a functional gene cluster and display cytotoxic activity. Thus, the RTX gene cluster in El Tor O1 and O139 strains might have contributed significantly to their emergence. Furthermore, the RTX toxin of V. cholerae may be associated with residual adverse properties displayed by certain live, attenuated cholera vaccines.

Background: Preventable adverse events are an unfortunately frequent occurrence of pediatric health care. Disclosure of preventable adverse events to patients is a vital aspect of ethical and just practice. Pediatric nurses’ have a unique role as part of the clinical care team. Despite the prevalence of preventable adverse events and the impact of nurses, best practice for pediatric nurses during disclosure is not specified. In addition, it is unclear how pediatric patient and their family. This work provides a foundation for future nursing research and the development and identification of best practice for pediatric preventable adverse event disclosure.Methods: First, thorough review of existing literature identified gaps and key themes. Secondly, a cross-sectional survey shared via social media provided insight into the current policy, education, and pediatric nurses’ involvement in PAE. Lastly, pediatric nurses’ perspectives were unveiled via narrative interviews, adding the voice of nurses into the dialogue.Results: Pediatric nurses in the U.S. want the option to be present during disclosure to patients and their families. Currently, nurses are seldom present during disclosure and do not routinely receive disclosure training, nor do they have a policy to guide them through the process. While there has been a trend towards the use of interdisciplinary disclosure teams, it is unclear what role a nurse has.Conclusions: This exploratory work is foundational to understanding pediatric nurses and PAE disclosure and future research exploring best practice for policy, education, and practice are needed.

Background Early insights into the timing of the start, peak, and intensity of the influenza season could be useful in planning influenza prevention and control activities. To encourage development and innovation in influenza forecasting, the Centers for Disease Control and Prevention (CDC) organized a challenge to predict the 2013–14 Unites States influenza season. Methods Challenge contestants were asked to forecast the start, peak, and intensity of the 2013–2014 influenza season at the national level and at any or all Health and Human Services (HHS) region level(s). The challenge ran from December 1, 2013–March 27, 2014; contestants were required to submit 9 biweekly forecasts at the national level to be eligible. The selection of the winner was based on expert evaluation of the methodology used to make the prediction and the accuracy of the prediction as judged against the U.S. Outpatient Influenza-like Illness Surveillance Network (ILINet). Results Nine teams submitted 13 forecasts for all required milestones. The first forecast was due on December 2, 2013; 3/13 forecasts received correctly predicted the start of the influenza season within one week, 1/13 predicted the peak within 1 week, 3/13 predicted the peak ILINet percentage within 1 %, and 4/13 predicted the season duration within 1 week. For the prediction due on December 19, 2013, the number of forecasts that correctly forecasted the peak week increased to 2/13, the peak percentage to 6/13, and the duration of the season to 6/13. As the season progressed, the forecasts became more stable and were closer to the season milestones. Conclusion Forecasting has become technically feasible, but further efforts are needed to improve forecast accuracy so that policy makers can reliably use these predictions. CDC and challenge contestants plan to build upon the methods developed during this contest to improve the accuracy of influenza forecasts.

Pediatric emergency care is conducted primarily outside of academic medical centers. This care is variable among and between pediatric based providers and general emergency medicine physicians. As studies have noted these variations, there has been focus on ways to broadly improve this care and decrease variation in the non-academic community hospital setting. Initial successes have been realized in pediatric emergency preparedness, learning collaboratives and telemedicine. Although these initiatives show promise in building improvements of care for the community pediatric population, the focus towards maintaining and increasing quality in this population requires additional attention. We review current successes and offer perspective for possible future directions.