Higher Dietary Polyphenol Intake Is Associated With Lower Blood Inflammatory Markers.

BACKGROUND: Evidence suggests a link between polyphenol intake and reduced incidence of several chronic diseases. This could arise through associations between polyphenol intake and reduced systemic oxidative stress and subsequent inflammation. However, confirming this association is difficult, as few large cohorts allow for comprehensive assessments of both polyphenol intake and markers of systemic inflammation. OBJECTIVES: To address this, polyphenol intake was assessed in the UK-based Airwave cohort using 7-d diet diaries and data from Phenol-Explorer to test for associations between polyphenol intake and blood biomarkers of inflammation. METHODS: Participants included 9008 males and females aged 17-74 y (median age: 42 y) whose data was included in a cross-sectional analysis. Phenol-Explorer was used to estimate individuals' polyphenol intake from diet data describing the consumption of 4104 unique food items. C-reactive protein (CRP) and fibrinogen were used as blood biomarkers of inflammation. RESULTS: There were 448 polyphenols found in reported diet items. Median total polyphenol intake was 1536 mg/d (1058-2092 mg/d). Phenolic acids and flavonoids were the main types of polyphenols, and nonalcoholic beverages, vegetables, and fruit were the primary sources. Variation in energy-adjusted polyphenol intake was explained by age, sex, salary, body mass index, education level, smoking, and alcohol consumption. Linear regressions showed inverse associations between total daily intake and both CRP (ß: -0.00702; P < 0.001) and fibrinogen (ß: -0.00221; P = 0.038). Associations with specific polyphenol compound groups were also found. Logistic regressions using total polyphenol intake quartiles showed stepwise reductions in the odds of elevated CRP with higher intake (6%, 23%, and 24% compared with quartile 1; P = 0.003), alongside 3% and 7% lower odds per unit of polyphenol consumption equivalent to 1 cup of tea or coffee per day. CONCLUSIONS: This study describes polyphenol intake in a large, contemporary UK cohort. We observed associations between higher intake and lower CRP and fibrinogen. This contributes to evidence supporting the health benefits of dietary polyphenols.

Evidence of gene-nutrient interaction association with waist circumference, cross-sectional analysis.

BACKGROUND AND AIMS: Waist circumference (WC) is a significant indicator of body adiposity and is associated with increased mortality and morbidity of cardiovascular diseases. Although, single nutrient intake and candidate genes were previously associated with WC. Little is known about WC association with overall diet quality, genetic risk score and gene-nutrient interaction. This study aims to investigate the influence of overall diet quality and multiple WC-associated single nucleotide polymorphisms on WC. In addition to investigating gene-nutrient interaction association with WC. METHODS: This study explored cross-sectional data from two large sample-size studies, to provide reproducible results. As a representation of the UK population, the Airwave Health Monitoring Study (n = 6,502) and the UK-Biobank Cohort Study (n = 171,129) were explored for factors associated with WC. Diet quality was evaluated based on the Mellen Index for Dietary Approaches to Stop Hypertension (Mellen-DASH). The genetic risk score for WC (GRS-Waist) was calculated by screening the population genotype for WC-associated single nucleotide polymorphisms. Multivariate linear regression models were built to explore WC association with diet quality and genetic risk score. Gene-nutrient interaction was explored by introducing the interaction term (GRS-Waist X Mellen-DASH score) to multivariate linear regression analysis. RESULTS: The prevalence of high WC (Female > 80 cm, Male > 94 cm) was 46.5% and 51.7% in both populations. Diet quality and genetic risk score of WC were significantly associated with WC. There was no evidence of interaction between GRS-Waist, DASH diet scores and nutrient intake on WC. CONCLUSION: This study's findings provided reproducible results on waist circumference association with diet and genetics and tested the possibility of gene-nutrient interaction. These reproducible results are successful in building the foundation for using diet and genetics for early identification of those at risk of having high WC and WC-associated diseases. In addition, evidence on gene-diet interactions on WC is limited and lacks replication, therefore our findings may guide future research in investigating this interaction and investigating its application in precision nutrition.

Wild-type sTREM2 blocks Aß aggregation and neurotoxicity, but the Alzheimer's R47H mutant increases Aß aggregation.

TREM2 is a pattern recognition receptor, expressed on microglia and myeloid cells, detecting lipids and Aß and inducing an innate immune response. Missense mutations (e.g., R47H) of TREM2 increase risk of Alzheimer's disease (AD). The soluble ectodomain of wild-type TREM2 (sTREM2) has been shown to protect against AD in vivo, but the underlying mechanisms are unclear. We show that Aß oligomers bind to cellular TREM2, inducing shedding of the sTREM2 domain. Wild-type sTREM2 bound to Aß oligomers (measured by single-molecule imaging, dot blots, and Bio-Layer Interferometry) inhibited Aß oligomerization and disaggregated preformed Aß oligomers and protofibrils (measured by transmission electron microscopy, dot blots, and size-exclusion chromatography). Wild-type sTREM2 also inhibited Aß fibrillization (measured by imaging and thioflavin T fluorescence) and blocked Aß-induced neurotoxicity (measured by permeabilization of artificial membranes and by loss of neurons in primary neuronal-glial cocultures). In contrast, the R47H AD-risk variant of sTREM2 is less able to bind and disaggregate oligomeric Aß but rather promotes Aß protofibril formation and neurotoxicity. Thus, in addition to inducing an immune response, wild-type TREM2 may protect against amyloid pathology by the Aß-induced release of sTREM2, which blocks Aß aggregation and neurotoxicity. In contrast, R47H sTREM2 promotes Aß aggregation into protofibril that may be toxic to neurons. These findings may explain how wild-type sTREM2 apparently protects against AD in vivo and why a single copy of the R47H variant gene is associated with increased AD risk.

Amyloid-ß toxicity modulates tau phosphorylation through the PAX6 signalling pathway.

The molecular link between amyloid-ß plaques and neurofibrillary tangles, the two pathological hallmarks of Alzheimer's disease, is still unclear. Increasing evidence suggests that amyloid-ß peptide activates multiple regulators of cell cycle pathways, including transcription factors CDKs and E2F1, leading to hyperphosphorylation of tau protein. However, the exact pathways downstream of amyloid-ß-induced cell cycle imbalance are unknown. Here, we show that PAX6, a transcription factor essential for eye and brain development which is quiescent in adults, is increased in the brains of patients with Alzheimer's disease and in APP transgenic mice, and plays a key role between amyloid-ß and tau hyperphosphorylation. Downregulation of PAX6 protects against amyloid-ß peptide-induced neuronal death, suggesting that PAX6 is a key executor of the amyloid-ß toxicity pathway. Mechanistically, amyloid-ß upregulates E2F1, followed by the induction of PAX6 and c-Myb, while Pax6 is a direct target for both E2F1 and its downstream target c-Myb. Furthermore, PAX6 directly regulates transcription of GSK-3ß, a kinase involved in tau hyperphosphorylation and neurofibrillary tangles formation, and its phosphorylation of tau at Ser356, Ser396 and Ser404. In conclusion, we show that signalling pathways that include CDK/pRB/E2F1 modulate neuronal death signals by activating downstream transcription factors c-Myb and PAX6, leading to GSK-3ß activation and tau pathology, providing novel potential targets for pharmaceutical intervention.

SARS-CoV-2 Infections and Hospitalizations Among Persons Aged ≥16 Years, by Vaccination Status - Los Angeles County, California, May 1-July 25, 2021.

COVID-19 vaccines fully approved or currently authorized for use through Emergency Use Authorization from the Food and Drug Administration are critical tools for controlling the COVID-19 pandemic; however, even with highly effective vaccines, a proportion of fully vaccinated persons will become infected with SARS-CoV-2, the virus that causes COVID-19 (1). To characterize postvaccination infections, the Los Angeles County Department of Public Health (LACDPH) used COVID-19 surveillance and California Immunization Registry 2 (CAIR2) data to describe age-adjusted infection and hospitalization rates during May 1-July 25, 2021, by vaccination status. Whole genome sequencing (WGS)-based SARS-CoV-2 lineages and cycle threshold (Ct) values from qualitative reverse transcription-polymerase chain reaction (RT-PCR) for two SARS-CoV-2 gene targets, including the nucleocapsid (N) protein gene region and the open reading frame 1 ab (ORF1ab) polyprotein gene region,* were reported for a convenience sample of specimens. Among 43,127 reported SARS-CoV-2 infections in Los Angeles County residents aged ≥16 years, 10,895 (25.3%) were in fully vaccinated persons, 1,431 (3.3%) were in partially vaccinated persons, and 30,801 (71.4%) were in unvaccinated persons. Much lower percentages of fully vaccinated persons infected with SARS-CoV-2 were hospitalized (3.2%), were admitted to an intensive care unit (0.5%), and required mechanical ventilation (0.2%) compared with partially vaccinated persons (6.2%, 1.0%, and 0.3%, respectively) and unvaccinated persons (7.6%, 1.5%, and 0.5%, respectively) (p<0.001 for all comparisons). On July 25, the SARS-CoV-2 infection rate among unvaccinated persons was 4.9 times and the hospitalization rate was 29.2 times the rates among fully vaccinated persons. During May 1-July 25, the percentages of B.1.617.2 (Delta) variant infections estimated from 6,752 samples with lineage data increased among fully vaccinated persons (from 8.6% to 91.2%), partially vaccinated persons (from 0% to 88.1%), and unvaccinated persons (from 8.2% to 87.1%). In May, there were differences in median Ct values by vaccination status; however, by July, no differences were detected among specimens from fully vaccinated, partially vaccinated, and unvaccinated persons by gene targets. These infection and hospitalization rate data indicate that authorized vaccines were protective against SARS-CoV-2 infection and severe COVID-19 during a period when transmission of the Delta variant was increasing. Efforts to increase COVID-19 vaccination, in coordination with other prevention strategies, are critical to preventing COVID-19-related hospitalizations and deaths.

Monitoring Incidence of COVID-19 Cases, Hospitalizations, and Deaths, by Vaccination Status - 13 U.S. Jurisdictions, April 4-July 17, 2021.

COVID-19 vaccine breakthrough infection surveillance helps monitor trends in disease incidence and severe outcomes in fully vaccinated persons, including the impact of the highly transmissible B.1.617.2 (Delta) variant of SARS-CoV-2, the virus that causes COVID-19. Reported COVID-19 cases, hospitalizations, and deaths occurring among persons aged ≥18 years during April 4-July 17, 2021, were analyzed by vaccination status across 13 U.S. jurisdictions that routinely linked case surveillance and immunization registry data. Averaged weekly, age-standardized incidence rate ratios (IRRs) for cases among persons who were not fully vaccinated compared with those among fully vaccinated persons decreased from 11.1 (95% confidence interval [CI] = 7.8-15.8) to 4.6 (95% CI = 2.5-8.5) between two periods when prevalence of the Delta variant was lower (<50% of sequenced isolates; April 4-June 19) and higher (≥50%; June 20-July 17), and IRRs for hospitalizations and deaths decreased between the same two periods, from 13.3 (95% CI = 11.3-15.6) to 10.4 (95% CI = 8.1-13.3) and from 16.6 (95% CI = 13.5-20.4) to 11.3 (95% CI = 9.1-13.9). Findings were consistent with a potential decline in vaccine protection against confirmed SARS-CoV-2 infection and continued strong protection against COVID-19-associated hospitalization and death. Getting vaccinated protects against severe illness from COVID-19, including the Delta variant, and monitoring COVID-19 incidence by vaccination status might provide early signals of changes in vaccine-related protection that can be confirmed through well-controlled vaccine effectiveness (VE) studies.

Reactive or transgenic increase in microglial TYROBP reveals a TREM2-independent TYROBP-APOE link in wild-type and Alzheimer's-related mice.

INTRODUCTION: Microglial TYROBP (DAP12) is a network hub and driver in sporadic late-onset Alzheimer's disease (AD). TYROBP is a cytoplasmic adaptor for TREM2 and other receptors, but little is known about its roles and actions in AD. Herein, we demonstrate that endogenous Tyrobp transcription is specifically increased in recruited microglia. METHODS: Using a novel transgenic mouse overexpressing TYROBP in microglia, we observed a decrease of the amyloid burden and an increase of TAU phosphorylation stoichiometry when crossed with APP/PSEN1 or MAPTP301S mice, respectively. Characterization of these mice revealed Tyrobp-related modulation of apolipoprotein E (Apoe) transcription. We also showed that Tyrobp and Apoe mRNAs were increased in Trem2-null microglia recruited around either amyloid beta deposits or a cortical stab injury. Conversely, microglial Apoe transcription was dramatically diminished when Tyrobp was absent. CONCLUSIONS: Our results provide evidence that TYROBP-APOE signaling does not require TREM2 and could be an initiating step in establishment of the disease-associated microglia (DAM) phenotype.

Pneumococcal Conjugate Vaccines Turning the Tide on Inequity: A Retrospective Cohort Study of New Zealand Children Born 2006-2015.

BACKGROUND: Hospitalization rates for infectious diseases in New Zealand (NZ) children have increased since 1989. The highest burden is among Maori and Pacific children, and the most socioeconomically deprived. New Zealand introduced pneumococcal conjugate vaccine (PCV)7 in June 2008, PCV10 in 2011, and PCV13 in 2014. METHODS: A retrospective cohort study of NZ children aged <6 years between 2006 and 2015 was performed using administrative databases. Demographics and hospitalizations were linked to evaluate the impact of the PCV vaccination program on cases of invasive pneumococcal disease (IPD), all-cause pneumonia (ACP), and otitis media (OM), defined by ICD-10-AM codes, and to explore the effect by ethnicity and deprivation. RESULTS: Between 2006 and 2015, there were 640 children hospitalized with IPD, 26589 for ACP, and 44545 for OM. IPD hospitalizations declined by 73% between 2005 and 2015 for children <6 years of age, whereas ACP and OM declined by 8% and 25%, respectively. The highest rates for all diseases were among Maori and Pacific children and those from high deprivation. However, the declines were highest among Maori and Pacific children and those from socioeconomically deprived areas. IPD hospitalizations declined by 79% and 67% for Maori and Pacific children, respectively, between 2006 and 2015. ACP declined by 12% in Maori and 21% in Pacific children. OM declined by 51% in Maori children. CONCLUSION: In contrast to the increasing trend of hospitalization rates for infectious disease in New Zealand, the use of PCV appears associated with reductions in ethnic and socioeconomic disparities in hospitalization for IPD, ACP, and OM.

Catalytic C(sp3)-H Alkylation via an Iron Carbene Intermediate.

The catalytic transformation of a C(sp3)-H bond to a C(sp3)-C bond via an iron carbene intermediate represents a long-standing challenge. Despite the success of enzymatic and small molecule iron catalysts mediating challenging C(sp3)-H oxidations and aminations via high-valent iron oxos and nitrenes, C(sp3)-H alkylations via isoelectronic iron carbene intermediates have thus far been unsuccessful. Iron carbenes have been inert, or shown to favor olefin cyclopropanation and heteroatom-hydrogen insertion. Herein we report an iron phthalocyanine-catalyzed alkylation of allylic and benzylic C(sp3)-H bonds. Mechanistic investigations support that an electrophilic iron carbene mediates homolytic C-H cleavage and rebounds from the resulting organoiron intermediate to form the C-C bond; both steps are tunable via catalyst modifications. These studies suggest that for iron carbenes, distinct from other late metal carbenes, C-H cleavage is partially rate-determining and must be promoted to effect reactivity.

Label-free Quantitative Proteomics Reveals a Role for the Mycobacterium tuberculosis SecA2 Pathway in Exporting Solute Binding Proteins and Mce Transporters to the Cell Wall.

Mycobacterium tuberculosis is an example of a bacterial pathogen with a specialized SecA2-dependent protein export system that contributes to its virulence. Our understanding of the mechanistic basis of SecA2-dependent export and the role(s) of the SecA2 pathway in M. tuberculosis pathogenesis has been hindered by our limited knowledge of the proteins exported by the pathway. Here, we set out to identify M. tuberculosis proteins that use the SecA2 pathway for their export from the bacterial cytoplasm to the cell wall. Using label-free quantitative proteomics involving spectral counting, we compared the cell wall and cytoplasmic proteomes of wild type M. tuberculosis to that of a ΔsecA2 mutant. This work revealed a role for the M. tuberculosis SecA2 pathway in the cell wall localization of solute binding proteins that work with ABC transporters to import solutes. Another discovery was a profound effect of SecA2 on the cell wall localization of the Mce1 and Mce4 lipid transporters, which contribute to M. tuberculosis virulence. In addition to the effects on solute binding proteins and Mce transporter export, our label-free quantitative analysis revealed an unexpected relationship between SecA2 and the hypoxia-induced DosR regulon, which is associated with M. tuberculosis latency. Nearly half of the transcriptionally controlled DosR regulon of cytoplasmic proteins were detected at higher levels in the ΔsecA2 mutant versus wild type M. tuberculosis. By increasing the list of M. tuberculosis proteins known to be affected by the SecA2 pathway, this study expands our appreciation of the types of proteins exported by this pathway and guides our understanding of the mechanism of SecA2-dependent protein export in mycobacteria. At the same time, the newly identified SecA2-dependent proteins are helpful for understanding the significance of this pathway to M. tuberculosis virulence and physiology.

Interventions to reduce neonatal mortality: a mathematical model to evaluate impact of interventions in sub-Saharan Africa.

AIM: To determine which interventions would have the greatest impact on reducing neonatal mortality in sub-Saharan Africa in 2012. METHODS: We used MANDATE, a mathematical model, to evaluate scenarios for the impact of available interventions on neonatal deaths from primary causes, including: (i) for birth asphyxia - obstetric care preventing intrapartum asphyxia, newborn resuscitation and treatment of asphyxiated infants; (ii) for preterm birth - corticosteroids, oxygen, continuous positive air pressure and surfactant; and, (iii) for serious newborn infection - clean delivery, chlorhexidine cord care and antibiotics. RESULTS: Reductions in infection-related mortality have occurred. Between 80 and 90% of deaths currently occurring from infections and asphyxia can be averted from available interventions, as can 58% of mortality from preterm birth. More than 200 000 neonatal deaths can each be averted from asphyxia, preterm birth and infections. Using available interventions, more than 80% of the neonatal deaths occurring today could be prevented in sub-Saharan Africa. CONCLUSION: Reducing neonatal deaths from asphyxia require improvements in infrastructure and obstetric care to manage maternal conditions such as obstructed labour and preeclampsia. Reducing deaths from preterm birth would also necessitate improved infrastructure and training for preterm infant care. Reducing infection-related mortality requires less infrastructure and lower-level providers.

Diagnosis of placental malaria in poorly fixed and processed placental tissue.

BACKGROUND: Placental histopathology has been considered the gold standard for diagnosis of malaria during pregnancy. However, in under-resourced areas placental tissue is often improperly fixed and processed; the resulting formalin pigment is difficult to distinguish from malaria pigment. This study examines two alternative diagnostic methods: polymerase chain reaction (PCR) and a novel immunohistochemistry (IHC)-based method using an antibody against histidine-rich protein 2 (HRP2). METHODS: Placental histopathology from 151 pregnant women in Kinshasa was assessed by two blinded microscopists and compared with peripheral blood PCR and IHC for HRP2. The Cohen's kappa coefficients were calculated to assess the test agreement. The sensitivity and specificity of individual tests were calculated using PCR or IHC as the reference standard as well as latent class analysis (LCA). RESULTS: PCR and IHC correlated fairly well. The correlation between the two blinded microscopists was poor, as there was widespread formalin pigment. Using LCA, all of the tests had high specificities. The most sensitive test was IHC (67.7 %), with PCR as second-best (56.1 %). CONCLUSIONS: PCR and/or IHC are suitable diagnostics when the presence of formalin pigment substantially compromises placental histopathology.

Maternal Mortality from Obstructed Labor: A MANDATE Analysis of the Ability of Technology to Save Lives in Sub-Saharan Africa.

Objective The aim of the study is to evaluate clinical interventions to significantly reduce maternal mortality from prolonged labor, obstructed labor, and prolonged obstructed labor (PL/OL/POL) in sub-Saharan Africa (SSA). Methods A mathematical model-Maternal and Neonatal Directed Assessment of Technology ("MANDATE")-was created for SSA with estimated prevalence for PL/OL/POL and case fatality rates from hemorrhage, infection, and uterine rupture. Based on a literature review and expert opinion, the model was populated with estimated likelihoods of the current healthcare system ability to diagnose, transfer, and treat women with these conditions. Impact on maternal mortality of improved diagnosis, transfer, and delivery to relieve PL/OL/POL was assessed. Results Without current technologies, the model estimated 8,464 maternal deaths annually in SSA from these conditions. Imputing current diagnosis, transfer, and treatment of PL/OL/POL, an estimated 7,033 maternal deaths occur annually from these complications. With improved PL/OL/POL diagnosis and improved transfer, 1,700 and 740 lives could be saved, respectively. Improved diagnosis, transfer, and treatment for PL/OL/POL reduce the mortality rate to 864 maternal deaths annually, saving 6,169 lives. If improved transfusion and antibiotic use were added, only 507 women per year would die from PL/OL/POL in SSA. Conclusion In SSA, increasing diagnostics, transfer to higher care, and operative delivery could substantially reduce maternal mortality from PL/OL/POL. Synopsis A computerized model of obstructed labor in SSA was created to explore the interventions necessary to reduce maternal mortality from this condition.

Reducing maternal mortality from preeclampsia and eclampsia in low-resource countries--what should work?

OBJECTIVE: Preeclampsia/eclampsia (PE/E) remains a major cause of maternal death in low-income countries. We evaluated interventions to reduce PE/E-related maternal mortality in sub-Saharan Africa. DESIGN: Mathematical model to assess impact of interventions on PE/E-related maternal morbidity and mortality. SETTING: Sub-Saharan Africa countries. POPULATION: Pregnant women in sub-Saharan Africa in 2012. METHODS: A systematic literature review populated a decision-tree mathematical model with interventions to diagnose, prevent, and treat women with PE/E. The impact of increased use of interventions [diagnostics, transfer to a hospital, magnesium sulfate (MgSO4 ) use, cesarean section/labor induction] on PE/E-related maternal mortality was analyzed. MAIN OUTCOME MEASURES: Prevalence of PE/E and PE/E-associated maternal mortality rates in sub-Saharan Africa. RESULTS: Without interventions, an estimated 20 570 PE/E-associated deaths would have occurred in sub-Saharan Africa in 2012. With current low rates of diagnosis, MgSO4 use, transfers and cesarean section/induction rates, about 17 520 maternal deaths were associated with PE/E in 2012. Higher use of MgSO4 would have prevented about 610 deaths. With high diagnostic levels, MgSO4 use, transfer and cesarean section/induction, mortality was reduced to 3750 annual deaths, saving about 13 770 maternal lives. If all MgSO4 use was removed from the model, 4060 maternal deaths would occur, increasing maternal deaths by only 310. CONCLUSIONS: In sub-Saharan Africa, our model suggests that increasing use of PE/E diagnostics, transfer to higher levels of care and increased hospitalization with cesarean section/induction of labor would substantially reduce maternal mortality from PE/E. Increasing use of MgSO4 would have a smaller impact on maternal mortality.

Resuscitation and Obstetrical Care to Reduce Intrapartum-Related Neonatal Deaths: A MANDATE Study.

To evaluate the impact of neonatal resuscitation and basic obstetric care on intrapartum-related neonatal mortality in low and middle-income countries, using the mathematical model, Maternal and Neonatal Directed Assessment of Technology (MANDATE). Using MANDATE, we evaluated the impact of interventions for intrapartum-related events causing birth asphyxia (basic neonatal resuscitation, advanced neonatal care, increasing facility birth, and emergency obstetric care) when implemented in home, clinic, and hospital settings of sub-Saharan African and India for 2008. Total intrapartum-related neonatal mortality (IRNM) was acute neonatal deaths from intrapartum-related events plus late neonatal deaths from ongoing intrapartum-related injury. Introducing basic neonatal resuscitation in all settings had a large impact on decreasing IRNM. Increasing facility births and scaling up emergency obstetric care in clinics and hospitals also had a large impact on decreasing IRNM. Increasing prevalence and utilization of advanced neonatal care in hospital settings had limited impact on IRNM. The greatest improvement in IRNM was seen with widespread advanced neonatal care and basic neonatal resuscitation, scaled-up emergency obstetric care in clinics and hospitals, and increased facility deliveries, resulting in an estimated decrease in IRNM to 2.0 per 1,000 live births in India and 2.5 per 1,000 live births in sub-Saharan Africa. With more deliveries occurring in clinics and hospitals, the scale-up of obstetric care can have a greater effect than if modeled individually. Use of MANDATE enables health leaders to direct resources towards interventions that could prevent intrapartum-related deaths. A lack of widespread implementation of basic neonatal resuscitation, increased facility births, and emergency obstetric care are missed opportunities to save newborn lives.

Tranexamic acid to reduce postpartum hemorrhage: A MANDATE systematic review and analyses of impact on maternal mortality.

OBJECTIVE: Postpartum hemorrhage (PPH) is a major cause of maternal mortality, with almost 300,000 cases and ~72,000 PPH deaths annually in sub-Saharan Africa. Novel prevention methods practical in community settings are required. Tranexamic acid, a drug to reduce bleeding during surgical cases including postpartum bleeding, is potentially suitable for community settings. Thus, we sought to determine the impact of tranexamic acid on PPH-related maternal mortality in sub-Saharan Africa. STUDY DESIGN: We created a mathematical model to determine the impact of interventions on PPH-related maternal mortality. The model was populated with baseline birth rates and mortality estimates based on a review of current interventions for PPH in sub-Saharan Africa. Based on a systematic review of literature on tranexamic acid, we assumed 30% efficacy of tranexamic acid to reduce PPH; the model assessed prophylactic and treatment tranexamic acid use, for deliveries at homes, clinics, and hospitals. RESULTS: With tranexamic acid only in the hospitals, less than 2% of the PPH mortality would be reduced. However, if tranexamic acid were available in the home and clinic settings for PPH prophylaxis and treatment, a nearly 30% reduction (nearly 22,000 deaths per year) in PPH mortality is possible. CONCLUSION: These analyses point to the importance of preventive and treatment interventions compatible with home and clinic use, especially for sub-Saharan Africa, where the majority of births occur at home or community health clinics. Given its feasibility to be given in the home, tranexamic acid has potential to save many lives.

An immunological epitope selective for pathological monomer-misfolded SOD1 in ALS.

Misfolding of Cu/Zn-superoxide dismutase (SOD1) is emerging as a mechanism underlying motor neuron degeneration in individuals with amyotrophic lateral sclerosis (ALS) who carry a mutant SOD1 gene (SOD1 ALS). Here we describe a structure-guided approach to developing an antibody that specifically recognizes monomer-misfolded forms of SOD1. We raised this antibody to an epitope that is normally buried in the SOD1 native homodimer interface. The SOD1 exposed dimer interface (SEDI) antibody recognizes only those SOD1 conformations in which the native dimer is disrupted or misfolded and thereby exposes the hydrophobic dimer interface. Using the SEDI antibody, we established the presence of monomer-misfolded SOD1 in three ALS mouse models, with G37R, G85R and G93A SOD1 mutations, and in a human individual with an A4V SOD1 mutation. Despite ubiquitous expression, misfolded SOD1 was found primarily within degenerating motor neurons. Misfolded SOD1 appeared before the onset of symptoms and decreased at the end stage of the disease, concomitant with motor neuron loss.

A Virtual Home Preparedness Intervention Centered on Children and Youth With Special Health Care Needs.

OBJECTIVE: Children and youth with special health care needs (CYSHCN) require additional considerations for staying safe in emergencies. Our team of clinicians and preparedness professionals developed and tested a virtual home preparedness intervention (VHPI) in families with CYSHCN receiving care in a statewide medical home network. METHODS: The VHPI comprised 1) a pre/post interview covering fire safety, emergency evacuation, sheltering in place, and informing emergency responders of the child/youth's care needs; 2) a resource packet containing emergency planning templates and information on local supports; and 3) individualized referrals coordinated through the medical home/community partners. Eligible CYSHCN had medical technology reliance, physical/mobility needs, communication/intellectual challenges, and/or vision/hearing loss. Preparedness was measured as pre/post affirmed rates of 19 items from the interview and as mean composite scores of these items; associations were evaluated using generalized estimating equations-based regression for repeated measures. RESULTS: The pre and post-VHPI interviews were completed by 170 and 148 participants, respectively. Significant individual-item gains included having a current Emergency Information Form for the child/youth (31% [pre] to 47% [post] affirmed) and assembling an evacuation kit (50% to 68%). The mean preparedness score was 13.33/19 items affirmed at baseline and increased to 14.96 post-VHPI (P < .01). In the adjusted regression model, the post-intervention preparedness score remained significantly higher than pre-VHPI, with mean increases of 1.22 preparedness steps affirmed for homeowners and 1.85 for renters. CONCLUSIONS: Preparedness scores improved post-VHPI in families with CYSHCN. Future work should address incorporating the VHPI into care visits in the medical home.

High-resolution phenotypic profiling defines genes essential for mycobacterial growth and cholesterol catabolism.

The pathways that comprise cellular metabolism are highly interconnected, and alterations in individual enzymes can have far-reaching effects. As a result, global profiling methods that measure gene expression are of limited value in predicting how the loss of an individual function will affect the cell. In this work, we employed a new method of global phenotypic profiling to directly define the genes required for the growth of Mycobacterium tuberculosis. A combination of high-density mutagenesis and deep-sequencing was used to characterize the composition of complex mutant libraries exposed to different conditions. This allowed the unambiguous identification of the genes that are essential for Mtb to grow in vitro, and proved to be a significant improvement over previous approaches. To further explore functions that are required for persistence in the host, we defined the pathways necessary for the utilization of cholesterol, a critical carbon source during infection. Few of the genes we identified had previously been implicated in this adaptation by transcriptional profiling, and only a fraction were encoded in the chromosomal region known to encode sterol catabolic functions. These genes comprise an unexpectedly large percentage of those previously shown to be required for bacterial growth in mouse tissue. Thus, this single nutritional change accounts for a significant fraction of the adaption to the host. This work provides the most comprehensive genetic characterization of a sterol catabolic pathway to date, suggests putative roles for uncharacterized virulence genes, and precisely maps genes encoding potential drug targets.

Home-Based Emergency Preparedness for Families of Children and Youth With Special Healthcare Needs: A Scoping Review.

Children and youth with special healthcare needs (CYSHCN) are at disproportionate risk of harm from widespread disasters and from life-safety emergencies. These risks may be mitigated by providing preparedness training and support to family caregivers. We conducted a scoping review to identify and map the scholarly literature on home-focused preparedness of families with CYSHCN. Our search strategy yielded 22 relevant articles; 13 pertained to life-safety emergencies, 5 centered on widespread disasters, and 4 addressed preparedness on multiple scales. Approaches to measure or attempt to improve emergency preparedness levels in CYSHCN and their families were diverse and included interviews and focus groups; didactic, video-based, or side-by-side instruction; simulated medical crises; and provisioning of emergency kits. For the studies that involved an intervention (n=15, 68%), several proxy indicators of preparedness were used, including caregiver knowledge, skill, or comfort level with managing emergencies that could affect their CYSHCN; completion of preparedness tasks; and reduction in adverse clinical outcomes. Despite the varied methodologies, prevailing themes in the studies were that family caregivers of CYSHCN felt underprepared for emergencies and disasters, desired training to improve their preparedness at home, and benefited from such trainings, at least in the short term, across domains of self-efficacy, skill, and health outcomes of their CYSHCN. Although more research is needed to compare preparedness interventions and evaluate the durability of these interventions in larger, more diverse samples of CYSHCN and their families, our findings support incorporating preparedness training into preventive care encounters and the hospital-to-home transition.