Localized measurements of water potential reveal large loss of conductance in living tissues of maize leaves.

The water status of the living tissue in leaves between the xylem and stomata (outside xylem zone (OXZ) plays a critical role in plant function and global mass and energy balance but has remained largely inaccessible. We resolve the local water relations of OXZ tissue using a nanogel reporter of water potential (ψ), AquaDust, that enables an in situ, nondestructive measurement of both ψ of xylem and highly localized ψ at the terminus of transpiration in the OXZ. Working in maize (Zea mays L.), these localized measurements reveal gradients in the OXZ that are several folds larger than those based on conventional methods and values of ψ in the mesophyll apoplast well below the macroscopic turgor loss potential. We find a strong loss of hydraulic conductance in both the bundle sheath and the mesophyll with decreasing xylem potential but not with evaporative demand. Our measurements suggest the OXZ plays an active role in regulating the transpiration path, and our methods provide the means to study this phenomenon.

Multispectral brain connectivity during visual attention distinguishes controlled from uncontrolled hypertension.

Hypertension-related changes in brain function place individuals at higher risk for cognitive impairment and Alzheimer's disease. The existing functional neuroimaging literature has identified important neural and behavioural differences between normotensive and hypertensive individuals. However, previously-used methods (i.e. magnetic resonance imaging, functional near-infrared spectroscopy) rely on neurovascular coupling, which is a useful but indirect measure of neuronal activity. Furthermore, most studies fail to distinguish between controlled and uncontrolled hypertensive individuals, who exhibit significant behavioural and clinical differences. To partially remedy this gap in the literature, we used magnetoencephalography (MEG) to directly examine neuronal activity that is invariant to neurovascular coupling changes induced by hypertension. Our study included 52 participants (19 healthy controls, 15 controlled hypertensives, 18 uncontrolled hypertensives) who completed a modified flanker attention task during MEG. We identified significant oscillatory neural responses in two frequencies (alpha: 8-14 Hz, gamma: 48-60 Hz) for imaging and used grand-averaged images to determine seeds for whole-brain connectivity analysis. We then conducted Fisher-z tests for each pair of groups, using the relationship between the neural connectivity and behavioural attention effects. This highlighted a distributed network of regions associated with cognitive control and selective attention, including frontal-occipital and interhemispheric occipital connections. Importantly, the inferior frontal cortex exhibited a unique neurobehavioural relationship that distinguished the uncontrolled hypertensive group from the controlled hypertensive and normotensive groups. This is the first investigation of hypertension using MEG and identifies critical whole-brain connectivity differences based on hypertension profiles. KEY POINTS: Structural and functional changes in brain circuitry scale with hypertension severity and increase the risk of cognitive impairment and Alzheimer's disease. We harness the excellent spatiotemporal precision of magnetoencephalography (MEG) to directly quantify dynamic functional connectivity in healthy control, controlled hypertensive and uncontrolled hypertensive groups during a flanker task. In the first MEG study of hypertension, we show that there are neurobehavioural relationships that distinguish the uncontrolled hypertensive group from healthy and controlled hypertensive group in the prefrontal cortex. These results provide novel insights into the differential impact of hypertension on brain dynamics underlying selective attention.

Assessing COVID-19 pandemic policies and behaviours and their economic and educational trade-offs across US states from Jan 1, 2020, to July 31, 2022: an observational analysis.

BACKGROUND: The USA struggled in responding to the COVID-19 pandemic, but not all states struggled equally. Identifying the factors associated with cross-state variation in infection and mortality rates could help to improve responses to this and future pandemics. We sought to answer five key policy-relevant questions regarding the following: 1) what roles social, economic, and racial inequities had in interstate variation in COVID-19 outcomes; 2) whether states with greater health-care and public health capacity had better outcomes; 3) how politics influenced the results; 4) whether states that imposed more policy mandates and sustained them longer had better outcomes; and 5) whether there were trade-offs between a state having fewer cumulative SARS-CoV-2 infections and total COVID-19 deaths and its economic and educational outcomes. METHODS: Data disaggregated by US state were extracted from public databases, including COVID-19 infection and mortality estimates from the Institute for Health Metrics and Evaluation's (IHME) COVID-19 database; Bureau of Economic Analysis data on state gross domestic product (GDP); Federal Reserve economic data on employment rates; National Center for Education Statistics data on student standardised test scores; and US Census Bureau data on race and ethnicity by state. We standardised infection rates for population density and death rates for age and the prevalence of major comorbidities to facilitate comparison of states' successes in mitigating the effects of COVID-19. We regressed these health outcomes on prepandemic state characteristics (such as educational attainment and health spending per capita), policies adopted by states during the pandemic (such as mask mandates and business closures), and population-level behavioural responses (such as vaccine coverage and mobility). We explored potential mechanisms connecting state-level factors to individual-level behaviours using linear regression. We quantified reductions in state GDP, employment, and student test scores during the pandemic to identify policy and behavioural responses associated with these outcomes and to assess trade-offs between these outcomes and COVID-19 outcomes. Significance was defined as p<0·05. FINDINGS: Standardised cumulative COVID-19 death rates for the period from Jan 1, 2020, to July 31, 2022 varied across the USA (national rate 372 deaths per 100 000 population [95% uncertainty interval [UI] 364-379]), with the lowest standardised rates in Hawaii (147 deaths per 100 000 [127-196]) and New Hampshire (215 per 100 000 [183-271]) and the highest in Arizona (581 per 100 000 [509-672]) and Washington, DC (526 per 100 000 [425-631]). A lower poverty rate, higher mean number of years of education, and a greater proportion of people expressing interpersonal trust were statistically associated with lower infection and death rates, and states where larger percentages of the population identify as Black (non-Hispanic) or Hispanic were associated with higher cumulative death rates. Access to quality health care (measured by the IHME's Healthcare Access and Quality Index) was associated with fewer total COVID-19 deaths and SARS-CoV-2 infections, but higher public health spending and more public health personnel per capita were not, at the state level. The political affiliation of the state governor was not associated with lower SARS-CoV-2 infection or COVID-19 death rates, but worse COVID-19 outcomes were associated with the proportion of a state's voters who voted for the 2020 Republican presidential candidate. State governments' uses of protective mandates were associated with lower infection rates, as were mask use, lower mobility, and higher vaccination rate, while vaccination rates were associated with lower death rates. State GDP and student reading test scores were not associated with state COVD-19 policy responses, infection rates, or death rates. Employment, however, had a statistically significant relationship with restaurant closures and greater infections and deaths: on average, 1574 (95% UI 884-7107) additional infections per 10 000 population were associated in states with a one percentage point increase in employment rate. Several policy mandates and protective behaviours were associated with lower fourth-grade mathematics test scores, but our study results did not find a link to state-level estimates of school closures. INTERPRETATION: COVID-19 magnified the polarisation and persistent social, economic, and racial inequities that already existed across US society, but the next pandemic threat need not do the same. US states that mitigated those structural inequalities, deployed science-based interventions such as vaccination and targeted vaccine mandates, and promoted their adoption across society were able to match the best-performing nations in minimising COVID-19 death rates. These findings could contribute to the design and targeting of clinical and policy interventions to facilitate better health outcomes in future crises. FUNDING: Bill & Melinda Gates Foundation, J Stanton, T Gillespie, J and E Nordstrom, and Bloomberg Philanthropies.

Effects of endogenous testosterone on oscillatory activity during verbal working memory in youth.

Testosterone levels sharply rise during the transition from childhood to adolescence and these changes are known to be associated with changes in human brain structure. During this same developmental window, there are also robust changes in the neural oscillatory dynamics serving verbal working memory processing. Surprisingly, whereas many studies have investigated the effects of chronological age on the neural oscillations supporting verbal working memory, none have probed the impact of endogenous testosterone levels during this developmental period. Using a sample of 89 youth aged 6-14 years-old, we collected salivary testosterone samples and recorded magnetoencephalography during a modified Sternberg verbal working memory task. Significant oscillatory responses were identified and imaged using a beamforming approach and the resulting maps were subjected to whole-brain ANCOVAs examining the effects of testosterone and sex, controlling for age, during verbal working memory encoding and maintenance. Our primary results indicated robust testosterone-related effects in theta (4-7 Hz) and alpha (8-14 Hz) oscillatory activity, controlling for age. During encoding, females exhibited weaker theta oscillations than males in right cerebellar cortices and stronger alpha oscillations in left temporal cortices. During maintenance, youth with greater testosterone exhibited weaker alpha oscillations in right parahippocampal and cerebellar cortices, as well as regions across the left-lateralized language network. These results extend the existing literature on the development of verbal working memory processing by showing region and sex-specific effects of testosterone, and are the first results to link endogenous testosterone levels to the neural oscillatory activity serving verbal working memory, above and beyond the effects of chronological age.

High-definition transcranial direct current stimulation of the parietal cortices modulates the neural dynamics underlying verbal working memory.

Verbal working memory (vWM) is an essential limited-capacity cognitive system that spans the fronto-parietal network and utilizes the subprocesses of encoding, maintenance, and retrieval. With the recent widespread use of noninvasive brain stimulation techniques, multiple recent studies have examined whether such stimulation may enhance cognitive abilities such as vWM, but the findings to date remain unclear in terms of both behavior and critical brain regions. In the current study, we applied high-definition direct current stimulation to the left and right parietal cortices of 39 healthy adults in three separate sessions (left anodal, right anodal, and sham). Following stimulation, participants completed a vWM task during high-density magnetoencephalography (MEG). Significant neural responses at the sensor-level were imaged using a beamformer and whole-brain ANOVAs were used to identify the specific neuromodulatory effects of the stimulation conditions on neural responses serving distinct phases of vWM. We found that right stimulation had a faciliatory effect relative to left stimulation and sham on theta oscillations during encoding in the right inferior frontal, while the opposite pattern was observed for left supramarginal regions. Stimulation also had a faciliatory effect on theta in occipital regions and alpha in temporal regions regardless of the laterality of stimulation. In summary, our data suggest that parietal HD-tDCS both facilitates and interferes with neural responses underlying both the encoding and maintenance phases of vWM. Future studies are warranted to determine whether specific tDCS parameters can be tuned to accentuate the facilitation responses and attenuate the interfering aspects.

New approaches to dissect leaf hydraulics reveal large gradients in living tissues of tomato leaves.

The water status of the living tissue in leaves is critical in determining plant function and global exchange of water and CO2. Despite significant advances in the past two decades, persistent questions remain about the tissue-specific origins of leaf hydraulic properties and their dependence on water status. We use a fluorescent nanoparticle reporter that provides water potential in the mesophyll apoplast adjacent to the epidermis of intact leaves to complement existing methods based on the Scholander Pressure Chamber (SPC). Working in tomato leaves, this approach provides access to the hydraulic conductance of the whole leaf, xylem, and outside-xylem tissues. These measurements show that, as stem water potential decreases, the water potential in the mesophyll apoplast can drop below that assessed with the SPC and can fall significantly below the turgor loss point of the leaf. We find that this drop in potential, dominated by the large loss (10-fold) of hydraulic conductance of the outside-xylem tissue, is not however strong enough to significantly limit transpiration. These observations highlight the need to reassess models of water transfer through the outside-xylem tissues, the potential importance of this tissue in regulating transpiration, and the power of new approaches for probing leaf hydraulics.

Community-Based Health Planning and Services (CHPS) concept and access to healthcare delivery in Sefwi Wiawso Municipal, Ghana.

BACKGROUND: In spite of the successes of the community-based health planning and services (CHPS) policy since its inception in the mid-1990s in Ghana, data pertaining to the implementation and use of CHPS facilities in Sefwi Wiawso Municipal is scant. We assessed access to healthcare delivery and factors influencing the use of CHPS in Sefwi Wiawso Municipal. METHODS: An analytical community-based cross-sectional study was conducted in the Sefwi Wiawo Municipal from September to October 2020. Respondents for the study were recruited through multi-stage sampling. Information was collected on their socio-demographic characteristics, knowledge and use of CHPS facilities through interviews using a structured pre-tested questionnaire. Factors influencing the use of CHPS facilities were assessed using univariable and multivariable logistic regression to generate crude and adjusted odds ratios (ORs) with 95% confidence intervals (CIs). P ≤ 0.05 was considered statistically significant. RESULTS: A total of 483 respondents were recruited for the study. The mean age of the respondents was 43.0 ± 16.3 years, and over 70% were females or married/cohabiting with their partners. Most respondents (88.2%) knew about the CHPS concept and more than half (53.4%) accessed healthcare in the CHPS facilities. Most respondents rated the quality of health services (> 65%) and staff attitude (77.2%) very positively. Significant factors influencing the use of the CHPS facilities were; knowledge of the CHPS concept (AOR 6.57, 95% CI 1.57-27.43; p = 0.01), longer waiting time for a vehicle to the facility, and shorter waiting time at the facility before being provided with care. People who waited for 30-60 min (AOR 2.76, 95% CI 1.08-7.07; p = 0.01) or over an hour (AOR 10.91, 95% CI 3.71-32.06; p = 0.01) before getting a vehicle to the facility, while patients who waited for less than 30 min (AOR 5.74, 95% CI 1.28-25.67; p = 0.03) or 30-60 min (AOR 2.60, 95% CI 0.57-11.78; p = 0.03) at the CHPS facility before receiving care were more likely to access care at the CHPS facilities. CONCLUSION: Knowledge, and use of healthcare services at the CHPS facilities were high in this population. Interventions aimed at reducing waiting time at the CHPS facilities could greatly increase use of healthcare services at these facilities.

Hospital personnel perspectives on factors influencing acute care patient outcomes: a qualitative approach to model refinement.

BACKGROUND: Health systems have long been interested in the best practices for staffing in the acute care setting. Studies on staffing often focus on registered nurses and nurse-to-patient staffing ratios. There were fewer studies on the relationship between interprofessional team members or contextual factors such as hospital and community characteristics and patient outcomes. This qualitative study aimed to refine an explanatory model by soliciting hospital personnel feedback on staffing and patient outcomes. METHODS: We conducted a qualitative study using semi-structured interviews and thematic analysis to understand hospital personnel's perspectives and experiences of factors that affect acute care inpatient outcomes. Interviews were conducted in 2022 with 38 hospital personnel representing 19 hospitals across Washington state in the United States of America. RESULTS: Findings support a model of characteristics impacting patient outcomes to include the complex and interconnected relationships between community, hospital, patient, and staffing characteristics. Within the model, patient characteristics were positioned into hospital characteristics, and in turn these were positioned within community characteristics to highlight the importance of setting and context when evaluating outcomes. Together, these factors influenced both staff characteristics and patient outcomes, but these two categories also share a direct relationship. CONCLUSION: Findings can be applied to hospitals and health systems in a variety of contexts to examine how external factors such as community resource availability impact care delivery. Future research should expand on this work with specific attention to how staffing changes and interprofessional team composition can improve patient outcomes.

A minimally disruptive method for measuring water potential in planta using hydrogel nanoreporters.

Leaf water potential is a critical indicator of plant water status, integrating soil moisture status, plant physiology, and environmental conditions. There are few tools for measuring plant water status (water potential) in situ, presenting a critical barrier for developing appropriate phenotyping (measurement) methods for crop development and modeling efforts aimed at understanding water transport in plants. Here, we present the development of an in situ, minimally disruptive hydrogel nanoreporter (AquaDust) for measuring leaf water potential. The gel matrix responds to changes in water potential in its local environment by swelling; the distance between covalently linked dyes changes with the reconfiguration of the polymer, leading to changes in the emission spectrum via Förster Resonance Energy Transfer (FRET). Upon infiltration into leaves, the nanoparticles localize within the apoplastic space in the mesophyll; they do not enter the cytoplasm or the xylem. We characterize the physical basis for AquaDust's response and demonstrate its function in intact maize (Zea mays L.) leaves as a reporter of leaf water potential. We use AquaDust to measure gradients of water potential along intact, actively transpiring leaves as a function of water status; the localized nature of the reporters allows us to define a hydraulic model that distinguishes resistances inside and outside the xylem. We also present field measurements with AquaDust through a full diurnal cycle to confirm the robustness of the technique and of our model. We conclude that AquaDust offers potential opportunities for high-throughput field measurements and spatially resolved studies of water relations within plant tissues.

Regular cannabis use alters the neural dynamics serving complex motor control.

Cannabis is the most widely used recreational drug in the United States and regular use has been linked to deficits in attention and memory. However, the effects of regular use on motor control are less understood, with some studies showing deficits and others indicating normal performance. Eighteen users and 23 nonusers performed a motor sequencing task during high-density magnetoencephalography (MEG). The MEG data was transformed into the time-frequency domain and beta responses (16-24 Hz) during motor planning and execution phases were imaged separately using a beamformer approach. Whole-brain maps were examined for group (cannabis user/nonuser) and time window (planning/execution) effects. As expected, there were no group differences in task performance (e.g., reaction time, accuracy, etc.). Regular cannabis users exhibited stronger beta oscillations in the contralateral primary motor cortex compared to nonusers during the execution phase of the motor sequences, but not during the motor planning phase. Similar group-by-time window interactions were observed in the left superior parietal, right inferior frontal cortices, right posterior insular cortex, and the bilateral motor cortex. We observed differences in the neural dynamics serving motor control in regular cannabis users compared to nonusers, suggesting regular users may employ compensatory processing in both primary motor and higher-order motor cortices to maintain adequate task performance. Future studies will need to examine more complex motor control tasks to ascertain whether this putative compensatory activity eventually becomes exhausted and behavioral differences emerge.

Vital Signs: Progress Toward Eliminating HIV as a Global Public Health Threat Through Scale-Up of Antiretroviral Therapy and Health System Strengthening Supported by the U.S. President's Emergency Plan for AIDS Relief - Worldwide, 2004-2022.

Introduction: In 2004, the U.S. President's Emergency Plan for AIDS Relief (PEPFAR), with CDC as a major U.S. government implementing agency, began providing HIV antiretroviral therapy (ART) worldwide. Through suppression of HIV viral load, effective ART reduces morbidity and mortality among persons with HIV infection and prevents vertical and sexual transmission. Methods: To describe program impact, data were analyzed from all PEPFAR programs and from six countries that have conducted nationally representative Population-based HIV Impact Assessment (PHIA) surveys, including PEPFAR programmatic data on the number of persons with HIV infection receiving PEPFAR-supported ART (2004-2022), rates of viral load coverage (the proportion of eligible persons with HIV infection who received a viral load test) and viral load suppression (proportion of persons who received a viral load test with <1,000 HIV copies per mL of blood) (2015-2022), and population viral load suppression rates in six countries that had two PHIA surveys conducted during 2015-2021. To assess health system strengthening, data on workforce and laboratory systems were analyzed. Results: By September 2022, approximately 20 million persons with HIV infection in 54 countries were receiving PEPFAR-supported ART (62% CDC-supported); this number increased 300-fold from the 66,550 reported in September 2004. During 2015-2022, viral load coverage more than tripled, from 24% to 80%, and viral load suppression increased from 80% to 95%. Despite increases in viral load suppression rates and health system strengthening investments, variability exists in viral load coverage among some subpopulations (children aged <10 years, males, pregnant women, men who have sex with men [MSM], persons in prisons and other closed settings [persons in prisons], and transgender persons) and in viral load suppression among other subpopulations (pregnant and breastfeeding women, persons in prisons, and persons aged <20 years). Conclusions and implications for public health practice: Since 2004, PEPFAR has scaled up effective ART to approximately 20 million persons with HIV infection in 54 countries. To eliminate HIV as a global public health threat, achievements must be sustained and expanded to reach all subpopulations. CDC and PEPFAR remain committed to tackling HIV while strengthening public health systems and global health security.

Optimizing high-throughput viral vector characterization with density gradient equilibrium analytical ultracentrifugation.

Viral vector-based gene therapies and vaccines require accurate characterization of capsid species. The current gold standard for assessing capsid loading of adeno-associated virus (AAV) is sedimentation velocity analytical ultracentrifugation (SV-AUC). However, routine SV-AUC analysis is often size-limited, especially without the use of advanced techniques (e.g., gravitational-sweep) or when acquiring the multiwavelength data needed for assessing the loading fraction of viral vectors, and requires analysis by specialized software packages. Density gradient equilibrium AUC (DGE-AUC) is a highly simplified analytical method that provides high-resolution separation of biologics of different densities (e.g., empty and full viral capsids). The analysis required is significantly simpler than SV-AUC, and larger viral particles such as adenovirus (AdV) are amenable to characterization by DGE-AUC using cesium chloride gradients. This method provides high-resolution data with significantly less sample (estimated 56-fold improvement in sensitivity compared to SV-AUC). Multiwavelength analysis can also be used without compromising data quality. Finally, DGE-AUC is serotype-agnostic and amenable to intuitive interpretation and analysis (not requiring specialized AUC software). Here, we present suggestions for optimizing DGE-AUC methods and demonstrate a high-throughput AdV packaging analysis with the AUC, running as many as 21 samples in 80 min.

Frequency of HIV serodifferent couples within TB-affected households in a setting with a high burden of HIV-associated TB.

INTRODUCTION: Strong epidemiological links between human immunodeficiency virus (HIV) and tuberculosis (TB) may make household TB contact investigation an efficient strategy for HIV screening and finding individuals in serodifferent partnerships at risk of HIV and linking them to HIV prevention services. We aimed to compare the proportions of HIV serodifferent couples in TB-affected households and in the general population of Kampala, Uganda. METHODS: We included data from a cross-sectional trial of HIV counselling and testing (HCT) in the context of home-based TB evaluation in Kampala, Uganda in 2016-2017. After obtaining consent, community health workers visited the homes of participants with TB to screen contacts for TB and offer HCT to household members ≥ 15 years. We defined index participants and their spouses or parents as couples. Couples were classified as serodifferent if confirmed by self-reported HIV status or by HIV testing results. We used a two-sample test of proportions to compare the frequency of HIV serodifference among couples in the study to its prevalence among couples in Kampala in the 2011 Uganda AIDS Indicator Survey (UAIS). RESULTS: We included 323 index TB participants and 507 household contacts aged ≥ 18 years. Most index participants (55%) were male, while most (68%) adult contacts were female. There was ≥ 1 couple in 115/323 (35.6%) households, with most couples (98/115, 85.2%) including the index participant and spouse. The proportion of households with HIV-serodifferent couples was 18/323 (5.6%), giving a number-needed-to-screen of 18 households. The proportion of HIV serodifference among couples identified in the trial was significantly higher than among couples in the UAIS (15.7% vs. 8%, p = 0.039). The 18 serodifferent couples included 14 (77.8%) where the index participant was living with HIV and the spouse was HIV-negative, and 4 (22.2%) where the index partner was HIV-negative, while the spouse was living with HIV. CONCLUSIONS: The frequency of HIV serodifference among couples identified in TB-affected households was higher than in the general population. TB household contact investigation may be an efficient strategy for identifying people with substantial exposure to HIV and linking them to HIV prevention services.

Trauma moderates the development of the oscillatory dynamics serving working memory in a sex-specific manner.

Working memory, the ability to hold items in memory stores for further manipulation, is a higher order cognitive process that supports many aspects of daily life. Childhood trauma has been associated with altered cognitive development including particular deficits in verbal working memory (VWM), but the neural underpinnings remain poorly understood. Magnetoencephalography (MEG) studies of VWM have reliably shown decreased alpha activity in left-lateralized language regions during encoding, and increased alpha activity in parieto-occipital cortices during the maintenance phase. In this study, we examined whether childhood trauma affects behavioral performance and the oscillatory dynamics serving VWM using MEG in a cohort of 9- to 15-year-old youth. All participants completed a modified version of the UCLA Trauma History Profile and then performed a VWM task during MEG. Our findings indicated a sex-by-age-by-trauma three-way interaction, whereby younger females experiencing higher levels of trauma had the lowest d' accuracy scores and the strongest positive correlations with age (i.e. older performed better). Likewise, females with higher levels of childhood trauma exhibited altered age-related alpha changes during the maintenance phase within the right temporal and parietal cortices. These findings suggest that trauma exposure may alter the developmental trajectory of neural oscillations serving VWM processing in a sex-specific way.

Cost-effectiveness of antenatal multiple micronutrients and balanced energy protein supplementation compared to iron and folic acid supplementation in India, Pakistan, Mali, and Tanzania: A dynamic microsimulation study.

BACKGROUND: Malnutrition among women of childbearing age is especially prevalent in Asia and sub-Saharan Africa and can be harmful to the fetus during pregnancy. In the most recently available Demographic and Health Survey (DHS), approximately 10% to 20% of pregnant women in India, Pakistan, Mali, and Tanzania were undernourished (body mass index [BMI] <18.5 kg/m2), and according to the Global Burden of Disease (GBD) 2017 study, approximately 20% of babies were born with low birth weight (LBW; <2,500 g) in India, Pakistan, and Mali and 8% in Tanzania. Supplementing pregnant women with micro and macronutrients during the antenatal period can improve birth outcomes. Recently, the World Health Organization (WHO) recommended antenatal multiple micronutrient supplementation (MMS) that includes iron and folic acid (IFA) in the context of rigorous research. Additionally, WHO recommends balanced energy protein (BEP) for undernourished populations. However, few studies have compared the cost-effectiveness of different supplementation regimens. We compared the cost-effectiveness of MMS and BEP with IFA to quantify their benefits in 4 countries with considerable prevalence of maternal undernutrition. METHODS AND FINDINGS: Using nationally representative estimates from the 2017 GBD study, we conducted an individual-based dynamic microsimulation of population cohorts from birth to 2 years of age in India, Pakistan, Mali, and Tanzania. We modeled the effect of maternal nutritional supplementation on infant birth weight, stunting and wasting using effect sizes from Cochrane systematic reviews and published literature. We used a payer's perspective and obtained costs of supplementation per pregnancy from the published literature. We compared disability-adjusted life years (DALYs) and incremental cost-effectiveness ratios (ICERs) in a baseline scenario with existing antenatal IFA coverage with scenarios where 90% of antenatal care (ANC) attendees receive either universal MMS, universal BEP, or MMS + targeted BEP (women with prepregnancy BMI <18.5 kg/m2 receive BEP containing MMS while women with BMI ≥18.5 kg/m2 receive MMS). We obtained 95% uncertainty intervals (UIs) for all outputs to represent parameter and stochastic uncertainty across 100 iterations of model runs. ICERs for all scenarios were lowest in Pakistan and greatest in Tanzania, in line with the baseline trend in prevalence of and attributable burden to LBW. MMS + targeted BEP averts more DALYs than universal MMS alone while remaining cost-effective. ICERs for universal MMS compared to baseline IFA were $52 (95% UI: $28 to $78) for Pakistan, $72 (95% UI: $37 to $118) for Mali, $70 (95% UI: $43 to $104) for India, and $253 (95% UI: $112 to $481) for Tanzania. ICERs for MMS + targeted BEP compared to baseline IFA were $54 (95% UI: $32 to $77) for Pakistan, $73 (95% UI: $40 to $104) for Mali, $83 (95% UI: $58 to $111) for India, and $245 (95% UI: $127 to $405) for Tanzania. Study limitations include generalizing experimental findings from the literature to our populations of interest and using population-level input parameters that may not reflect the heterogeneity of subpopulations. Additionally, our microsimulation fuses multiple sources of data and may be limited by data quality and availability. CONCLUSIONS: In this study, we observed that MMS + targeted BEP averts more DALYs and remains cost-effective compared to universal MMS. As countries consider using MMS in alignment with recent WHO guidelines, offering targeted BEP is a cost-effective strategy that can be considered concurrently to maximize benefits and synergize program implementation.

Left amygdala structure mediates longitudinal associations between exposure to threat and long-term psychiatric symptomatology in youth.

Traumatic experiences during childhood can have profound effects on stress sensitive brain structures (e.g., amygdala and hippocampus) and the emergence of psychiatric symptoms. Recent theoretical and empirical work has delineated dimensions of trauma (i.e., threat and deprivation) as having distinct neural and behavioral effects, although there are few longitudinal examinations. A sample of 243 children and adolescents were followed for three time points, with each assessment approximately 1 year apart (ages 9-15 years at Time 1; 120 males). Participants or their caregiver reported on youths' threat exposure, perceived stress (Time 1), underwent a T1-weighted structural high-resolution MRI scan (Time 2), and documented their subsequent psychiatric symptoms later in development (Time 3). The primary findings indicate that left amygdala volume, in particular, mediated the longitudinal association between threat exposure and subsequent internalizing and externalizing symptomatology. Greater threat exposure related to reduced left amygdala volume, which in turn differentially predicted internalizing and externalizing symptoms. Decreased bilateral hippocampal volume was related to subsequently elevated internalizing symptoms. These findings suggest that the left amygdala is highly threat-sensitive and that stress-related alterations may partially explain elevated psychopathology in stress-exposed adolescents. Uncovering potential subclinical and/or preclinical predictive biomarkers is essential to understanding the emergence, progression, and eventual targeted treatment of psychopathology following trauma exposure.

Extreme undersaturation in the intercellular airspace of leaves: a failure of Gaastra or Ohm?

BACKGROUND: Recent reports of extreme levels of undersaturation in internal leaf air spaces have called into question one of the foundational assumptions of leaf gas exchange analysis, that leaf air spaces are effectively saturated with water vapour at leaf surface temperature. Historically, inferring the biophysical states controlling assimilation and transpiration from the fluxes directly measured by gas exchange systems has presented a number of challenges, including: (1) a mismatch in scales between the area of flux measurement, the biochemical cellular scale and the meso-scale introduced by the localization of the fluxes to stomatal pores; (2) the inaccessibility of the internal states of CO2 and water vapour required to define conductances; and (3) uncertainties about the pathways these internal fluxes travel. In response, plant physiologists have adopted a set of simplifying assumptions that define phenomenological concepts such as stomatal and mesophyll conductances. SCOPE: Investigators have long been concerned that a failure of basic assumptions could be distorting our understanding of these phenomenological conductances, and the biophysical states inside leaves. Here we review these assumptions and historical efforts to test them. We then explore whether artefacts in analysis arising from the averaging of fluxes over macroscopic leaf areas could provide alternative explanations for some part, if not all, of reported extreme states of undersaturation. CONCLUSIONS: Spatial heterogeneities can, in some cases, create the appearance of undersaturation in the internal air spaces of leaves. Further refinement of experimental approaches will be required to separate undersaturation from the effects of spatial variations in fluxes or conductances. Novel combinations of current and emerging technologies hold promise for meeting this challenge.

Aortic Fibrosis in Insulin-Sensitive Mice with Endothelial Cell-Specific Deletion of Ceacam1 Gene.

(1) Background: Mice with global Ceacam1 deletion developed plaque-like aortic lesions even on C57BL/6J background in the presence of increased endothelial cell permeability and insulin resistance. Loss of endothelial Ceacam1 gene caused endothelial dysfunction and reduced vascular integrity without affecting systemic insulin sensitivity. Because endothelial cell injury precedes atherosclerosis, we herein investigated whether the loss of endothelial Ceacam1 initiates atheroma formation in the absence of insulin resistance. (2) Methods: Endothelial cell-specific Ceacam1 null mice on C57BL/6J.Ldlr-/- background (Ldlr-/-VECadCre+Cc1fl/fl) were fed an atherogenic diet for 3-5 months before metabolic, histopathological, and en-face analysis of aortae were compared to their control littermates. Sirius Red stain was also performed on liver sections to analyze hepatic fibrosis. (3) Results: These mice displayed insulin sensitivity without significant fat deposition on aortic walls despite hypercholesterolemia. They also displayed increased inflammation and fibrosis. Deleting Ceacam1 in endothelial cells caused hyperactivation of VEGFR2/Shc/NF-κB pathway with resultant transcriptional induction of NF-κB targets. These include IL-6 that activates STAT3 inflammatory pathways, in addition to endothelin-1 and PDGF-B profibrogenic effectors. It also induced the association between SHP2 phosphatase and VEGFR2, downregulating the Akt/eNOS pathway and reducing nitric oxide production, a characteristic feature of endothelial dysfunction. Similarly, hepatic inflammation and fibrosis developed in Ldlr-/-VECadCre+Cc1fl/fl mice without an increase in hepatic steatosis. (4) Conclusions: Deleting endothelial cell Ceacam1 caused hepatic and aortic inflammation and fibrosis with increased endothelial dysfunction and oxidative stress in the presence of hypercholesterolemia. However, this did not progress into frank atheroma formation. Because these mice remained insulin sensitive, the study provides an in vivo demonstration that insulin resistance plays a critical role in the pathogenesis of frank atherosclerosis.

Conflict-related intentional injuries in Baghdad, Iraq, 2003-2014: A modeling study and proposed method for calculating burden of injury in conflict.

BACKGROUND: Previous research has focused on the mortality associated with armed conflict as the primary measure of the population health effects of war. However, mortality only demonstrates part of the burden placed on a population by conflict. Injuries and resultant disabilities also have long-term effects on a population and are not accounted for in estimates that focus solely on mortality. Our aim was to demonstrate a new method to describe the effects of both lives lost, and years of disability generated by a given conflict, with data from the US-led 2003 invasion and subsequent occupation of Iraq. METHODS AND FINDINGS: Our data come from interviews conducted in 2014 in 900 Baghdad households containing 5,148 persons. The average household size was 5.72 persons. The majority of the population (55.8%) were between the ages of 19 and 60. Household composition was evenly divided between males and females. Household sample collection was based on methodology previously designed for surveying households in war zones. Survey questions were answered by the head of household or senior adult present. The questions included year the injury occurred, the mechanism of injury, the body parts injured, whether injury resulted in disability and, if so, the length of disability. We present this modeling study to offer an innovative methodology for measuring "years lived with disability" (YLDs) and "years of life lost" (YLLs) attributable to conflict-related intentional injuries, using the Global Burden of Disease (GBD) approach. YLDs were calculated with disability weights, and YLLs were calculated by comparing the age at death to the GBD standard life table to calculate remaining life expectancy. Calculations were also performed using Iraq-specific life expectancy for comparison. We calculated a burden of injury of 5.6 million disability-adjusted life years (DALYs) lost due to conflict-related injuries in Baghdad from 2003 to 2014. The majority of DALYs lost were attributable to YLLs, rather than YLDs, 4.99 million YLLs lost (95% uncertainty interval (UI) 3.87 million to 6.13 million) versus 616,000 YLDs lost (95% UI 399,000 to 894,000). Cause-based analysis demonstrated that more DALYs were lost to due to gunshot wounds (57%) than any other cause. Our study has several limitations. Recall bias regarding the reporting and attribution of injuries is possible. Second, we have no data past the time of the interview, so we assumed individuals with ongoing disability at the end of data collection would not recover, possibly counting more disability for injuries occurring later. Additionally, incomplete data could have led to misclassification of deaths, resulting in an underestimation of the total burden of injury. CONCLUSIONS: In this study, we propose a methodology to perform burden of disease calculations for conflict-related injuries (expressed in DALYs) in Baghdad from 2003 to 2014. We go beyond previous reports of simple mortality to assess long-term population health effects of conflict-related intentional injuries. Ongoing disability is, in cross section, a relatively small 10% of the total burden. Yet, this small proportion creates years of demands on the health system, persistent limitations in earning capacity, and continuing burdens of care provision on family members.

Alcohol use disorder and cannabis use disorder symptomatology in adolescents is associated with dysfunction in neural processing of future events.

Two of the most commonly used substances by adolescents in the United States are cannabis and alcohol. Cannabis use disorder (CUD) and alcohol use disorder (AUD) are associated with impairments in decision-making processes. One mechanism for impaired decision-making in these individuals is thought to be an inability to adequately represent future events during decision-making. In the current study involving 112 adolescents, we used a comparative optimism task to examine the relationship between relative severity of CUD/AUD (as indexed by the CUD/AUD Identification Tests [CUDIT/AUDIT]) and atypical function within neural systems underlying affect-based neural represenation future events. Greater CUDIT scores were negatively related to responses within subgenual anterior and posterior cingulate cortex when processing high-intensity potential future positive and negative events. There was also a particularly marked negative relationship between CUD symptoms and blood oxygen level-dependent (BOLD) responses within visual and premotor cortices to high-intensity, negatively valenced potential future events. However, AUD symptom severity was not associated with dysfunction within these brain regions. These data indicate that relative risk/severity of CUD is associated with reduced responsiveness to future high-intensity events. This may impair decision-making where future significant consequences should guide response choice.