Predicting Post-Disaster Post-Traumatic Stress Disorder Symptom Trajectories: The Role of Pre-Disaster Traumatic Experiences.

The mental health impact of disasters is substantial, with 30-40% of direct disaster victims developing post-traumatic stress disorder (PTSD). It is not yet clear why some people cope well with disaster-related trauma while others experience chronic dysfunction. Prior research on non-disaster trauma suggests that an individual's history of traumatic experiences earlier in the life course, prior to the disaster, may be a key factor in explaining variability in psychological responses to disasters. This study evaluated the extent to which pre-disaster trauma predicts PTSD trajectories in a sample of Hurricane Katrina survivors followed for 12 years after the storm. Four PTSD trajectories were identified using latent class growth analysis: Resistant (49.0%), Recovery (29.3%), Delayed-Onset (8.0%), and Chronic-High (13.7%). After adjusting for covariates, pre-Katrina trauma had only a small, positive impact on the probability of long-term, chronic Katrina-specific PTSD, and little effect on the probability of the Resistant and Delayed-Onset trajectories. Higher pre-Katrina trauma exposure moderately decreased the probability of being in the Recovery trajectory, in which Katrina-specific PTSD symptoms are initially high before declining over time. When covariates were added to the model one at a time, the association between pre-Katrina trauma and Chronic-High PTSD was attenuated most by the addition of Katrina-related trauma. Our findings suggest that while pre-disaster trauma exposure does not have a strong direct effect on chronic Katrina-specific PTSD, pre-Katrina trauma may impact PTSD through other factors that affect Katrina-related PTSD, such as by increasing the severity of Katrina-related trauma. These findings have important implications for the development of disaster preparedness strategies to diminish the long-term burden of disaster-related PTSD.

Kinetic Characterization and Identification of Key Active Site Residues of the L-Aspartate N-Hydroxylase, CreE.

CreE is a flavin-dependent monooxygenase (FMO) that catalyzes three sequential nitrogen oxidation reactions of L-aspartate to produce nitrosuccinate, contributing to the biosynthesis of the antimicrobial and antiproliferative nautral product, cremeomycin. This compound contains a highly reactive diazo functional group for which the reaction of CreE is essential to its formation. Nitro and diazo functional groups can serve as potent electrophiles, important in some challenging nucleophilic addition reactions. Formation of these reactive groups positions CreE as a promising candidate for biomedical and synthetic applications. Here, we present the catalytic mechanism of CreE and the identification of active site residues critical to binding L-aspartate, aiding in future enzyme engineering efforts. Steady-state analysis demonstrated that CreE is very specific for NADPH over NADH and performs a highly coupled reaction with L-aspartate. Analysis of the rapid-reaction kinetics showed that flavin reduction is very fast, along with the formation of the oxygenating species, the C4a-hydroperoxyflavin. The slowest step observed was the dehydration of the flavin. Structural analysis and site-directed mutagenesis implicated T65, R291, and R440 in the binding L-aspartate. The data presented describes the catalytic mechanism and the active site architecture of this unique FMO.

Mechanism of Nitrone Formation by a Flavin-Dependent Monooxygenase.

OxaD is a flavin-dependent monooxygenase (FMO) responsible for catalyzing the oxidation of an indole nitrogen atom, resulting in the formation of a nitrone. Nitrones serve as versatile intermediates in complex syntheses, including challenging reactions like cycloadditions. Traditional organic synthesis methods often yield limited results and involve environmentally harmful chemicals. Therefore, the enzymatic synthesis of nitrone-containing compounds holds promise for more sustainable industrial processes. In this study, we explored the catalytic mechanism of OxaD using a combination of steady-state and rapid-reaction kinetics, site-directed mutagenesis, spectroscopy, and structural modeling. Our investigations showed that OxaD catalyzes two oxidations of the indole nitrogen of roquefortine C, ultimately yielding roquefortine L. The reductive-half reaction analysis indicated that OxaD rapidly undergoes reduction and follows a "cautious" flavin reduction mechanism by requiring substrate binding before reduction can take place. This characteristic places OxaD in class A of the FMO family, a classification supported by a structural model featuring a single Rossmann nucleotide binding domain and a glutathione reductase fold. Furthermore, our spectroscopic analysis unveiled both enzyme-substrate and enzyme-intermediate complexes. Our analysis of the oxidative-half reaction suggests that the flavin dehydration step is the slow step in the catalytic cycle. Finally, through mutagenesis of the conserved D63 residue, we demonstrated its role in flavin motion and product oxygenation. Based on our findings, we propose a catalytic mechanism for OxaD and provide insights into the active site architecture within class A FMOs.

Validation of Long-term Recall of Pregnancy-related Weight in the Life-course Experiences And Pregnancy Study.

BACKGROUND: Prepregnancy body mass index (BMI) and gestational weight gain (GWG) are determinants of maternal and child health. However, many studies of these factors rely on error-prone self-reported measures. METHODS: Using data from Life-course Experiences And Pregnancy (LEAP), a US-based cohort, we assessed the validity of prepregnancy BMI and GWG recalled on average 8 years postpartum against medical record data treated as alloyed gold standard ("true") values. We calculated probabilities of being classified into a self-reported prepregnancy BMI or GWG category conditional on one's true category (analogous to sensitivities and specificities) and probabilities of truly being in each prepregnancy BMI or GWG category conditional on one's self-reported category (analogous to positive and negative predictive values). RESULTS: There was a tendency toward under-reporting prepregnancy BMI. Self-report misclassified 32% (95% confidence interval [CI] = 19%, 48%) of those in LEAP with truly overweight and 13% (5%, 27%) with obesity into a lower BMI category. Self-report correctly predicted the truth for 72% (55%, 84%) with self-reported overweight to 100% (90%, 100%) with self-reported obesity. For GWG, both under- and over-reporting were common; self-report misclassified 32% (15%, 55%) with truly low GWG as having moderate GWG and 50% (28%, 72%) with truly high GWG as moderate or low GWG. Self-report correctly predicted the truth for 45% (25%, 67%) with self-reported high GWG to 85% (76%, 91%) with self-reported moderate GWG. Misclassification of BMI and GWG varied across maternal characteristics. CONCLUSION: Findings can be used in quantitative bias analyses to estimate bias-adjusted associations with prepregnancy BMI and GWG.

Cohort profile: Life-course experiences and pregnancy (LEAP)-A retrospective pregnancy cohort for life-course reproductive health research.

BACKGROUND: Life course factors may be associated with pre-pregnancy body mass index and gestational weight gain; however, collecting information on pre-pregnancy exposures and pregnancy health in the same cohort is challenging. OBJECTIVES: The Life-course Experiences And Pregnancy (LEAP) study aims to identify adolescent and young adult risk factors for pre-pregnancy weight and gestational weight gain (GWG). We built upon an existing cohort study to overcome challenges inherent to studying life course determinants of pregnancy health. POPULATION: Participants in an ongoing prospective cohort study of weight-related health who identified as women. DESIGN: Retrospective cohort study. METHODS: In 2019-2020, 1,252 women participating since adolescence in a cohort study of weight-related health were invited to complete an online reproductive history survey. Participants who reported a live birth were invited to release their prenatal, delivery, and postpartum medical records for validation of survey reports. Descriptive analyses were conducted to assess the characteristics of the overall cohort and the medical record validation subsample, and to describe adolescent and young adult characteristics of those with high (>80th percentile), moderate (20th-80th percentile), and low (<20th percentile) GWG z-score for gestational age and pre-pregnancy weight status. PRELIMINARY RESULTS: Nine hundred seventy-seven women (78%) completed the LEAP survey and 656 reported a live birth. Of these, 379 (58%) agreed to release medical records, and 250 records were abstracted (66% of the 379). Of the 977 survey respondents 769 (79%) reported attempting a pregnancy, and 656 (67%) reported at least one live birth. The validation subsample was similar to the overall cohort. Women with a high GWG had a higher adolescent BMI percentile and prevalence of unhealthy weight control behaviors than those with moderate or low GWG. CONCLUSIONS: LEAP offers a valuable resource for identifying life course factors that may influence the health of pregnant people and their offspring.

Kinetic characterization of a flavin-dependent monooxygenase from the insect food crop pest, Zonocerus variegatus.

Zonocerus variegatus, or the painted grasshopper, is a food crop pest endemic in Western and Central Africa. Agricultural industries in these regions rely heavily on natural defense mechanisms to control the grasshopper population such as plant-secreted alkaloid compounds. In recent years, the Z. variegatus population has continued to rise due to acquired resistance to alkaloids. Here we focus on the kinetic characterization of a flavin-dependent monooxygenase, ZvFMO, that catalyzes the nitrogen oxidation of many of these alkaloid compounds and confers resistance to the insect. Expression and purification of ZvFMO through a traditional E. coli expression system was successful and provided a unique opportunity to characterize the catalytic properties of an FMO from insects. ZvFMO was found to catalyze oxidation reactions of tertiary nitrogen atoms and the sulfur of cysteamine. Using stopped-flow spectroscopy, we have determined the kinetic mechanism of ZvFMO. We assessed F383 for its involvement in substrate binding, which was previously proposed, and determined that this residue does not play a major role in binding substrates. Through molecular docking, we identified N304 and demonstrated that this residue plays a role in substrate binding. The role of K215 was studied and was shown that it plays a critical role in NAD(P)H binding and cofactor selectivity.

Preliminary Evaluation of 2 Patient-Centered Educational Animations About Kidney Transplant Complications.

BACKGROUND Fear of kidney transplant complications and incomplete information can lower transplant acceptance and preparedness. Our group developed 2 patient-centered educational animated videos on common kidney transplant complications to complement a previously developed video-based curriculum intended to promote kidney transplant access. MATERIAL AND METHODS We preliminarily evaluated the 2 animated educational videos at a single center using mixed methods. We conducted a before-and-after single group study with 22 patients after kidney transplantation to measure the videos' acceptability and feasibility to improve patient knowledge, understanding, and concerns of kidney transplant complications. Concurrently, we individually interviewed 12 patients before kidney transplantation about their perceptions of the 2 videos and analyzed the data thematically. RESULTS Knowledge of kidney transplant complications increased 10% (7.82 to 8.59, P=0.002) from before to after video viewing. Large effect size increases for knowledge were found for different strata of age, race, and health literacy. The mean total score for perceived understanding of kidney transplant complications increased after video exposure by 7% (mean 2.48 to 2.66, P=0.184). There was no change in kidney transplant concern scores from before to after video viewing (mean 1.70 to 1.70, P=1.00). After video viewing, all patients reported positive ratings on comfort watching, understanding, and engaging. Three themes of patient perceptions emerged: (1) messages received as intended, (2) felt informed, and (3) scared but not deterred. CONCLUSIONS Two animated educational videos about kidney transplant complications were well received and promise to positively impact individuals' knowledge and understanding, without raising excessive concerns.

Racial ideology, system justification, and just world belief in African Americans.

Just world belief and system justification have previously been proposed to explain actions and beliefs of disadvantaged groups, but rarely together and never simultaneously in participants of color. A necessary expansion of work in this area is among African-American participants with differing views of race and how those views influence justice perceptions. Racial ideologies, used in African-American racial identity research, were studied as possible predictors of belief in a just world and system justification scores. The four racial ideologies examined in this study are assimilationist, humanist, nationalist, and oppressed minority. The current study examines belief in a just world and system justification as predicted by racial ideology. Participants (n = 261) responded to an online survey containing racial ideology items from the Multidimensional Model of Racial Identity (MMRI), the General and Personal Just World Scales, and the General System Justification Survey. Hierarchical linear regression was conducted, finding that nationalist ideology significantly predicted system justification and general just world belief.

Socioeconomic differences in the impact of prices and taxes on tobacco use in low- and middle-income countries-A systematic review.

There is indisputable evidence that increases in taxes that raise tobacco prices reduce tobacco use. Consumption taxes on manufactured tobacco products, however, can be regressive in socioeconomic status (e.g., when the ratio of tax paid to income is lower for higher-income groups than for lower-income groups). Nevertheless, if the poor or less educated are more price responsive, a change in tobacco tax may be progressive in socioeconomic status. Existing reviews clearly indicate that populations with lower income or education are more responsive to tobacco tax and price changes than higher-income and more educated populations in high-income countries. Research pertaining to low- and middle-income countries was, however, limited and inconclusive. We conducted a review of quantitative studies that examined if socioeconomic status modified the association between prices and taxes and tobacco use in low- and middle-income countries. We searched two electronic databases, two search engines, and two working paper repositories. At least two reviewers independently screened articles for inclusion, extracted detailed characteristics, and assessed the risk of bias of each included study. Thirty-two studies met our inclusion criteria. Overall, we found that the evidence in low- and middle-income countries was too limited and methodologically weak to make any conclusive statements. Our review highlights a number of data and methodological limitations in existing studies. The most important limitation was the lack of formal assessment of socioeconomic differences in price responsiveness. Only seven of 32 studies assessed statistically whether own-price effects were modified by socioeconomic status. Many modelling studies have examined the distributional effect of a tax increase on tobacco use, while assuming a strong own-price elasticity gradient in income. The poor were generally assumed to be more responsive to price by a factor of two to five, relative to the wealthy. Although there are theoretical reasons to expect poorer individuals to be more responsive to monetary prices than wealthy ones in low- and middle-income countries, our review provides little empirical support.

The role of prior trauma exposure and subsequent posttraumatic stress disorder in reactions to the COVID-19 pandemic: A qualitative study.

OBJECTIVE: A growing body of literature suggests that the COVID-19 pandemic is a traumatic stressor capable of causing posttraumatic stress symptoms. People with a history of trauma, particularly those with posttraumatic stress disorder (PTSD), may be particularly vulnerable to the negative mental health impacts of the pandemic. However, qualitative research exploring potential differences in the lived experiences of and reactions to COVID-19 between people with and without PTSD is lacking. METHOD: Semistructured interviews were conducted with 31 women (n = 15 women with probable PTSD, n = 16 women without probable PTSD) recruited from an ongoing U.S.-based cohort study. Themes were identified using inductive thematic analysis. RESULTS: The majority of women with PTSD described their level of fear or perceived safety related to COVID-19 as a major factor influencing their mental health during the pandemic. In contrast, women without PTSD indicated that their level of distress was largely driven by pandemic-related restrictions on normal activities and family events. Many women with PTSD also described feeling anger or frustration toward people they perceived as not taking the COVID-19 pandemic seriously. Only one participant without PTSD expressed similar feelings. CONCLUSIONS: This study found notable differences in reactions to the COVID-19 pandemic between people with and without PTSD, with findings that are likely relevant to future disasters. These findings can inform the development of preparedness policies for future disasters, pandemics, or other collective traumas to prevent distress and improve mental health, particularly for vulnerable populations such as individuals with preexisting PTSD. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Associations of abuse and neglect with young adult health in a population-based longitudinal cohort: Findings from Project EAT.

Childhood maltreatment (abuse and neglect) is associated with a range of negative outcomes, but a gap remains in understanding of how specific maltreatment types, particularly neglect and non-familial sexual abuse, relate to health and behavior. This study examined the association of neglect and sexual abuse (both familial and non-familial), as well as familial physical and emotional abuse, with: depressive mood and eating disorders; tobacco and marijuana use; and BMI ≥ 25 kg/m2 and BMI ≥ 30 kg/m2 in young adults. Data came from Project EAT (Eating and Activity in Teens and Young Adults), a population-based longitudinal study of weight-related health from adolescence into young adulthood. Maltreatment before age 18 was retrospectively reported at ages 26-33. Risk differences (RDs) and 95% confidence intervals (CIs) were estimated for those with a given maltreatment type to those without, and also for the cumulative number of maltreatment types experienced. One in 3 participants reported abuse or neglect. All maltreatment types were associated with at least one adverse health outcome, with physical abuse being least consistently related to the outcomes. Emotional abuse showed the strongest association with depressive mood. All maltreatment types were associated with eating disorder diagnosis, tobacco use, and marijuana use (except physical abuse for eating disorder). There was little evidence of a maltreatment association with BMI ≥ 25 kg/m2; emotional abuse and neglect were associated with BMI ≥ 30 kg/m2. Prevention of maltreatment needs to be a top public health priority.

Understanding the impact of the COVID-19 pandemic on stress, mood, and substance use among young adults in the greater Minneapolis-St. Paul area: Findings from project EAT.

RATIONALE: There is a need to understand how the ongoing COVID-19 pandemic has affected the mental and behavioral health of young adults in the U.S. OBJECTIVE: This study used quantitative and qualitative survey data to identify young adults at highest risk for psychological distress during the U.S. outbreak of COVID-19 and to further understand how the pandemic has impacted their stress, mood, and substance use. METHODS: Participants were 670 young adult cohort members (ages 21-29) of the population-based longitudinal study EAT 2010-2018 who participated in the C-EAT study (COVID-19 Eating and Activity over Time). RESULTS: Among the sample, 84% (n = 561) reported pandemic-related changes to their mood or stress and 33% (n = 221) reported changes to their substance use. Linear regression analyses identified several meaningful risk factors for higher psychological distress during the pandemic, including female gender, White race, higher pre-pandemic depressive symptoms and perceived stress, and lower pre-pandemic stress management ability. A thematic analysis further identified five major themes related to changes in stress and mood following the COVID-19 outbreak describing specific emotional reactions, stress related to the direct impact of the pandemic as well as interpersonal connectedness and economic factors, and strategies for managing stress. In addition, two major themes were identified related to substance use during the pandemic detailing specific changes in and motivations for substance use. CONCLUSIONS: These findings underscore the need to develop effective, scalable, and rapidly deployable public health resources that target the stressors commonly experienced among young adults to improve their psychological wellbeing during this pandemic.

Clinical trials to assess adjuvant therapeutics for severe malaria.

Despite potent anti-malarial treatment, mortality rates associated with severe falciparum malaria remain high. To attempt to improve outcome, several trials have assessed a variety of potential adjunctive therapeutics, however none to date has been shown to be beneficial. This may be due, at least partly, to the therapeutics chosen and clinical trial design used. Here, we highlight three themes that could facilitate the choice and evaluation of putative adjuvant interventions for severe malaria, paving the way for their assessment in randomized controlled trials. Most clinical trials of adjunctive therapeutics to date have been underpowered due to the large number of participants required to reach mortality endpoints, rendering these study designs challenging and expensive to conduct. These limitations may be mitigated by the use of risk-stratification of participants and application of surrogate endpoints. Appropriate surrogate endpoints include direct measures of pathways causally involved in the pathobiology of severe and fatal malaria, including markers of host immune and endothelial activation and microcirculatory dysfunction. We propose using circulating markers of these pathways to identify high-risk participants that would be most likely to benefit from adjunctive therapy, and further by adopting these biomarkers as surrogate endpoints; moreover, choosing interventions that target deleterious host immune responses that directly contribute to microcirculatory dysfunction, multi-organ dysfunction and death; and, finally, prioritizing where possible, drugs that act on these pathways that are already approved by the FDA, or other regulators, for other indications, and are known to be safe in target populations, including children. An emerging understanding of the critical role of the host response in severe malaria pathogenesis may facilitate both clinical trial design and the search of effective adjunctive therapeutics.

The role of polo-like kinase 3 in the response of BRAF-mutant cells to targeted anticancer therapies.

The activation of oncogenic mitogen-activated protein kinase cascade via mutations in BRAF is often observed in human melanomas. Targeted inhibitors of BRAF (BRAFi), alone or as a part of a combination therapy, offer a significant benefit to such patients. Unfortunately, some cases are initially nonresponsive to these drugs, while others become refractory in the course of treatment, underscoring the need to understand and mitigate the underlying resistance mechanisms. We report that interference with polo-like kinase 3 (PLK3) reduces the tolerance of BRAF-mutant melanoma cells to BRAFi, while increased PLK3 expression has the opposite effect. Accordingly, PLK3 expression correlates with tolerance to BRAFi in a panel of BRAF-mutant cell lines and is elevated in a subset of recurring BRAFi-resistant melanomas. In PLK3-expressing cells, R406, a kinase inhibitor whose targets include PLK3, recapitulates the sensitizing effects of genetic PLK3 inhibitors. The findings support a role for PLK3 as a predictor of BRAFi efficacy and suggest suppression of PLK3 as a way to improve the efficacy of targeted therapy.

Twelve years later: The long-term mental health consequences of Hurricane Katrina.

In August 2005, Hurricane Katrina caused unprecedented damage, widespread population displacement, and exposed Gulf Coast residents to traumatic events. The hurricane's adverse impact on survivors' mental health was apparent shortly after the storm and persisted, but no study has examined the long-term effects now that more than a decade has transpired. Using new data from a panel study of low-income mothers interviewed once before Hurricane Katrina and now three times after, we document changes in mental health, and estimate the sociodemographic and hurricane-related factors associated with long-term trajectories of mental health. We find that post-traumatic stress symptoms (PTSS) declined at each of the three post-Katrina follow-ups, but 12 years after the hurricane, one in six still had symptoms indicative of probable post-traumatic stress disorder. The rate of non-specific psychological distress (PD) remained consistently higher in all three follow-ups, compared to the pre-disaster period. In full covariate-adjusted models, no sociodemographic variables predicted long-run combinations of PTSS and PD. However, 12 years later, exposure to hurricane-related traumatic events and pre-disaster PD significantly predicted co-occurring PTSS and PD. Hurricane-related housing damage predicted PTSS in earlier follow-ups, but no longer predicted PTSS in the long-term. Furthermore, hurricane-related traumatic events significantly differentiated the risk of having persistent PTSS, relative to recovering from PTSS. The results suggest that there is still a non-negligible group of survivors with continued need for recovery resources and that exposure to traumatic events is a primary predictor of adverse mental health more than a decade post-disaster.

Assessing the Usability of the Automated Self-Administered Dietary Assessment Tool (ASA24) among Low-Income Adults.

The Automated Self-Administered Dietary Assessment Tool (ASA24) is a web-based tool that guides participants through completion of a 24-h dietary recall and automatically codes the data. Despite the advantages of automation, eliminating interviewer contact may diminish data quality. Usability testing can assess the extent to which individuals can use the ASA24 to report dietary intake with efficiency, effectiveness, and satisfaction. This mixed-methods study evaluated the usability of the ASA24 to quantify user performance and to examine qualitatively usability issues in a sample of low-income adults (85% female, 48.2 years on average) participating in a nutrition coupon program. Thirty-nine participants completed a 24-h dietary recall using the ASA24. Audio and screen recordings, and survey responses were analyzed to calculate task times, success rates, and usability issue frequency. Qualitative data were analyzed thematically to characterize usability issues. Only one participant was able to complete a dietary recall unassisted. We identified 286 usability issues within 22 general usability categories, including difficulties using the search function, misunderstanding questions, and uncertainty regarding how to proceed to the next step; 71.4% of participants knowingly misentered dietary information at least once. Usability issues may diminish participation rates and compromise the quality of ASA24 dietary intake data. Researchers should provide on-demand technical support and designers should improve the intelligence and flexibility of the ASA24's search functionality.

A Previsit Screening Checklist Improves Teamwork and Access to Preventive Services in a Medical Home Serving Low-Income Adolescent and Young Adult Patients.

Publicly insured adolescents and young adults experience significant obstacles in accessing primary care services. As a result, they often present to their medical appointments with multiple unmet needs, adding time and complexity to the visit. The goal of this project was to optimize team work and access to primary care services among publicly insured adolescents and young adults attending an urban primary care clinic, using a previsit screening checklist to identify patient needs and delegate tasks within a care team to coordinate access to health services at the time of the visit. We conducted an interventional quality improvement initiative in a PDSA (Plan-Do-Study-Act) cycle format; 291 patients, 13 to 25 years old were included in the study over an 8-months period. The majority of patients were receptive to the previsit screening checklist; 85% of services requested were provided; nonclinician staff felt more involved in patient care; and providers' satisfaction increased.

The full benefits of adult pneumococcal vaccination: A systematic review.

BACKGROUND: Pneumococcal disease causes substantial morbidity and mortality, including among adults. Adult pneumococcal vaccines help to prevent these burdens, but they are underused. Accounting for the full benefits of adult pneumococcal vaccination may promote more rational resource allocation decisions with respect to adult pneumococcal vaccines. OBJECTIVES: Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we conducted a systematic review to assess the extent to which the literature has empirically captured (e.g., through measurement or modeling) the full benefits of adult pneumococcal vaccination. METHODS: We systematically searched PubMed and Embase to identify studies published between January 1, 2010 and April 10, 2016 that examine adult pneumococcal vaccination. We included articles if they captured any health or economic benefit of an adult pneumococcal vaccine administered to adults age ≥ 50 or ≥ 18 in risk groups. Finally, we summarized the literature by categorizing the types of benefits captured, the perspective taken, and the strength of the evidence presented. Our protocol is number 42016038335 in the PROSPERO International prospective register of systematic reviews. RESULTS: We identified 5,857 papers and included 150 studies for analysis. While most capture health gains and healthcare cost savings, far fewer studies consider additional benefit categories, such as productivity gains. However, the studies with a broader approach still exhibit significant limitations; for example, many present only abstracts, while others offer no new measurements. Studies that examine the 13-valent pneumococcal conjugate vaccine focus more on broad economic benefits, but still have limitations. CONCLUSIONS: This review highlights the need for more robust empirical accounting of the full benefits of adult pneumococcal vaccination. Literature outside this realm indicates that these broad benefits may be substantial. Failing to investigate the full benefits may lead society to undervalue vaccines' contributions and therefore underinvest in their development and adoption.

The evidence for a microRNA product of human DROSHA gene.

MicroRNAs are short RNA molecules that regulate function and stability of a large subset of eukaryotic mRNAs. In the main pathway of microRNA biogenesis, a short "hairpin" is excised from a primary transcript by ribonuclease DROSHA, followed by additional nucleolytic processing by DICER and inclusion of the mature microRNA into the RNA-induced silencing complex. We report that a microRNA-like molecule is encoded by human DROSHA gene within a predicted stem-loop element of the respective transcript. This putative mature microRNA is complementary to DROSHA transcript variant 1 and can attenuate expression of the corresponding protein. The findings suggest a possibility for a negative feedback loop, wherein DROSHA processes its own transcript and produces an inhibitor of its own biosynthesis.

P21-activated kinase 1 regulates resistance to BRAF inhibition in human cancer cells.

BRAF is a commonly mutated oncogene in various human malignancies and a target of a new class of anti-cancer agents, BRAF-inhibitors (BRAFi). The initial enthusiasm for these agents, based on the early successes in the management of metastatic melanoma, is now challenged by the mounting evidence of intrinsic BRAFi-insensitivity in many BRAF-mutated tumors, by the scarcity of complete responses, and by the inevitable emergence of drug resistance in initially responsive cases. These setbacks put an emphasis on discovering the means to increase the efficacy of BRAFi and to prevent or overcome BRAFi-resistance. We explored the role of p21-activated kinases (PAKs), in particular PAK1, in BRAFi response. BRAFi lowered the levels of active PAK1 in treated cells. An activated form of PAK1 conferred BRAFi-resistance on otherwise sensitive cells, while genetic or pharmacologic suppression of PAK1 had a sensitizing effect. While activation of AKT1 and RAC1 proto-oncogenes increased BRAFi-tolerance, the protective effect was negated in the presence of PAK inhibitors. Furthermore, combining otherwise ineffective doses of PAK- and BRAF-inhibitors synergistically affected intrinsically BRAFi-resistant cells. Considering the high incidence of PAK1 activation in cancers, our findings suggests PAK inhibition as a strategy to augment BRAFi therapy and overcome some of the well-known resistance mechanisms.