Obesity alters pathology and treatment response in inflammatory disease.

Decades of work have elucidated cytokine signalling and transcriptional pathways that control T cell differentiation and have led the way to targeted biologic therapies that are effective in a range of autoimmune, allergic and inflammatory diseases. Recent evidence indicates that obesity and metabolic disease can also influence the immune system1-7, although the mechanisms and effects on immunotherapy outcomes remain largely unknown. Here, using two models of atopic dermatitis, we show that lean and obese mice mount markedly different immune responses. Obesity converted the classical type 2 T helper (TH2)-predominant disease associated with atopic dermatitis to a more severe disease with prominent TH17 inflammation. We also observed divergent responses to biologic therapies targeting TH2 cytokines, which robustly protected lean mice but exacerbated disease in obese mice. Single-cell RNA sequencing coupled with genome-wide binding analyses revealed decreased activity of nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) in TH2 cells from obese mice relative to lean mice. Conditional ablation of PPARγ in T cells revealed that PPARγ is required to focus the in vivo TH response towards a TH2-predominant state and prevent aberrant non-TH2 inflammation. Treatment of obese mice with a small-molecule PPARγ agonist limited development of TH17 pathology and unlocked therapeutic responsiveness to targeted anti-TH2 biologic therapies. These studies reveal the effects of obesity on immunological disease and suggest a precision medicine approach to target the immune dysregulation caused by obesity.

A Novel Air Trapping Segment Score Identifies Opposing Effects of Obesity and Eosinophilia on Air Trapping in Asthma.

Rationale: Density thresholds in computed tomography (CT) lung scans quantify air trapping (AT) at the whole-lung level but are not informative for AT in specific bronchopulmonary segments. Objectives: To apply a segment-based measure of AT in asthma to investigate the clinical determinants of AT in asthma. Methods: In each of 19 bronchopulmonary segments in CT lung scans from 199 patients with asthma, AT was categorized as present if lung attenuation was less than -856 Hounsfield units at expiration in ⩾15% of the lung area. The resulting AT segment score (0-19) was related to patient outcomes. Measurements and Main Results: AT varied at the lung segment level and tended to persist at the patient and lung segment levels over 3 years. Patients with widespread AT (⩾10 segments) had more severe asthma (P < 0.05). The mean (±SD) AT segment score in patients with a body mass index ⩾30 kg/m2 was lower than in patients with a body mass index <30 kg/m2 (3.5 ± 4.6 vs. 5.5 ± 6.3; P = 0.008), and the frequency of AT in lower lobe segments in obese patients was less than in upper and middle lobe segments (35% vs. 46%; P = 0.001). The AT segment score in patients with sputum eosinophils ⩾2% was higher than in patients without sputum eosinophilia (7.0 ± 6.1 vs. 3.3 ± 4.9; P < 0.0001). Lung segments with AT more frequently had airway mucus plugging than lung segments without AT (48% vs. 18%; P ⩽ 0.0001). Conclusions: In patients with asthma, air trapping is more severe in those with airway eosinophilia and mucus plugging, whereas those who are obese have less severe trapping because their lower lobe segments are spared.

Utility of eosinophil peroxidase as a biomarker of eosinophilic inflammation in asthma.

BACKGROUND: The relative utility of eosinophil peroxidase (EPX) and blood and sputum eosinophil counts as disease biomarkers in asthma is uncertain. OBJECTIVE: We sought to determine the utility of EPX as a biomarker of systemic and airway eosinophilic inflammation in asthma. METHODS: EPX protein was measured by immunoassay in serum and sputum in 110 healthy controls to establish a normal reference range and in repeated samples of serum and sputum collected during 3 years of observation in 480 participants in the Severe Asthma Research Program 3. RESULTS: Over 3 years, EPX levels in patients with asthma were higher than normal in 27% to 31% of serum samples and 36% to 53% of sputum samples. Eosinophils and EPX correlated better in blood than in sputum (rs values of 0.74 and 0.43, respectively), and high sputum EPX levels occurred in 27% of participants with blood eosinophil counts less than 150 cells/µL and 42% of participants with blood eosinophil counts between 150 and 299 cells/µL. Patients with persistently high sputum EPX values for 3 years were characterized by severe airflow obstruction, frequent exacerbations, and high mucus plug scores. In 59 patients with asthma who started mepolizumab during observation, serum EPX levels normalized in 96% but sputum EPX normalized in only 49%. Lung function remained abnormal even when sputum EPX normalized. CONCLUSIONS: Serum EPX is a valid protein biomarker of systemic eosinophilic inflammation in asthma, and sputum EPX levels are a more sensitive biomarker of airway eosinophilic inflammation than sputum eosinophil counts. Eosinophil measures in blood frequently miss airway eosinophilic inflammation, and mepolizumab frequently fails to normalize airway eosinophilic inflammation even though it invariably normalizes systemic eosinophilic inflammation.

Fibre-infused gel scaffolds guide cardiomyocyte alignment in 3D-printed ventricles.

Hydrogels are attractive materials for tissue engineering, but efforts to date have shown limited ability to produce the microstructural features necessary to promote cellular self-organization into hierarchical three-dimensional (3D) organ models. Here we develop a hydrogel ink containing prefabricated gelatin fibres to print 3D organ-level scaffolds that recapitulate the intra- and intercellular organization of the heart. The addition of prefabricated gelatin fibres to hydrogels enables the tailoring of the ink rheology, allowing for a controlled sol-gel transition to achieve precise printing of free-standing 3D structures without additional supporting materials. Shear-induced alignment of fibres during ink extrusion provides microscale geometric cues that promote the self-organization of cultured human cardiomyocytes into anisotropic muscular tissues in vitro. The resulting 3D-printed ventricle in vitro model exhibited biomimetic anisotropic electrophysiological and contractile properties.

Skeletal Muscle Adiposity and Lung Function Trajectory in the Severe Asthma Research Program.

Rationale: Extrapulmonary manifestations of asthma, including fatty infiltration in tissues, may reflect systemic inflammation and influence lung function and disease severity. Objectives: To determine if skeletal muscle adiposity predicts lung function trajectory in asthma. Methods: Adult SARP III (Severe Asthma Research Program III) participants with baseline computed tomography imaging and longitudinal postbronchodilator FEV1% predicted (median follow-up 5 years [1,132 person-years]) were evaluated. The mean of left and right paraspinous muscle density (PSMD) at the 12th thoracic vertebral body was calculated (Hounsfield units [HU]). Lower PSMD reflects higher muscle adiposity. We derived PSMD reference ranges from healthy control subjects without asthma. A linear multivariable mixed-effects model was constructed to evaluate associations of baseline PSMD and lung function trajectory stratified by sex. Measurements and Main Results: Participants included 219 with asthma (67% women; mean [SD] body mass index, 32.3 [8.8] kg/m2) and 37 control subjects (51% women; mean [SD] body mass index, 26.3 [4.7] kg/m2). Participants with asthma had lower adjusted PSMD than control subjects (42.2 vs. 55.8 HU; P < 0.001). In adjusted models, PSMD predicted lung function trajectory in women with asthma (ß = -0.47 Δ slope per 10-HU decrease; P = 0.03) but not men (ß = 0.11 Δ slope per 10-HU decrease; P = 0.77). The highest PSMD tertile predicted a 2.9% improvement whereas the lowest tertile predicted a 1.8% decline in FEV1% predicted among women with asthma over 5 years. Conclusions: Participants with asthma have lower PSMD, reflecting greater muscle fat infiltration. Baseline PSMD predicted lung function decline among women with asthma but not men. These data support an important role of metabolic dysfunction in lung function decline.

Caspase-cleaved tau is senescence-associated and induces a toxic gain of function by putting a brake on axonal transport.

The microtubule-associated protein tau plays a central role in tauopathies such as Alzheimer's disease (AD). The exact molecular mechanisms underlying tau toxicity are unclear, but aging is irrefutably the biggest risk factor. This raises the question of how cellular senescence affects the function of tau as a microtubule regulator. Here we report that the proportion of tau that is proteolytically cleaved at the caspase-3 site (TauC3) doubles in the hippocampus of senescent mice. TauC3 is also elevated in AD patients. Through quantitative live-cell imaging, we show that TauC3 has a drastically reduced dynamics of its microtubule interaction. Single-molecule tracking of tau confirmed that TauC3 has a longer residence time on axonal microtubules. The reduced dynamics of the TauC3-microtubule interaction correlated with a decreased transport of mitochondria, a reduced processivity of APP-vesicle transport and an induction of region-specific dendritic atrophy in CA1 neurons of the hippocampus. The microtubule-targeting drug Epothilone D normalized the interaction of TauC3 with microtubules and modulated the transport of APP-vesicles dependent on the presence of overexpressed human tau. The results indicate a novel toxic gain of function, in which a post-translational modification of tau changes the dynamics of the tau-microtubule interaction and thus leads to axonal transport defects and neuronal degeneration. The data also introduce microtubule-targeting drugs as pharmacological modifiers of the tau-microtubule interaction with the potential to restore the physiological interaction of pathologically altered tau with microtubules.

Development of transgenic composite Stylosanthes plants to study root growth regulated by a ß-expansin gene, SgEXPB1, under phosphorus deficiency.

KEY MESSAGE: A highly efficient transformation procedure to generate transgenic Stylosanthes roots was established. SgEXPB1 is involved in Stylosanthes root growth under phosphorus deficiency. Stylo (Stylosanthes spp.) is an important forage legume widely applied in agricultural systems in the tropics. Due to the recalcitrance of stylo genetic transformation, functional characterization of candidate genes involved in stylo root growth is limited. This study established an efficient procedure for Agrobacterium rhizogenes-mediated transformation for generating transgenic composite plants of S. guianensis cultivar 'Reyan No. 5'. Results showed that composite stylo plants with transgenic hairy roots were efficiently generated by A. rhizogenes strains K599 and Arqual, infecting the residual hypocotyl at 1.0 cm of length below the cotyledon leaves of 9-d-old seedlings, leading to a high transformation efficiency of > 95% based on histochemical ß-glucuronidase (GUS) staining. Notably, 100% of GUS staining-positive hairy roots can be achieved per composite stylo plant. Subsequently, SgEXPB1, a ß-expansin gene up-regulated by phosphorus (P) deficiency in stylo roots, was successfully overexpressed in hairy roots. Analysis of hairy roots showed that root growth and P concentration in the transgenic composite plants were increased by SgEXPB1 overexpression under low-P treatment. Taken together, a highly efficient A. rhizogenes-mediated transformation procedure for generating composite stylo plants was established to study the function of SgEXPB1, revealing that this gene is involved in stylo root growth during P deficiency.

Mucus Plugs Persist in Asthma, and Changes in Mucus Plugs Associate with Changes in Airflow over Time.

Rationale: Cross-sectional analysis of mucus plugs in computed tomography (CT) lung scans in the Severe Asthma Research Program (SARP)-3 showed a high mucus plug phenotype. Objectives: To determine if mucus plugs are a persistent asthma phenotype and if changes in mucus plugs over time associate with changes in lung function. Methods: In a longitudinal analysis of baseline and Year 3 CT lung scans in SARP-3 participants, radiologists generated mucus plug scores to assess mucus plug persistence over time. Changes in mucus plug score were analyzed in relation to changes in lung function and CT air trapping measures. Measurements and Main Results: In 164 participants, the mean (range) mucus plug score was similar at baseline and Year 3 (3.4 [0-20] vs. 3.8 [0-20]). Participants and bronchopulmonary segments with a baseline plug were more likely to have plugs at Year 3 than those without baseline plugs (risk ratio, 2.8; 95% confidence interval [CI], 2.0-4.1; P < 0.001; and risk ratio, 5.0; 95% CI, 4.5-5.6; P < 0.001, respectively). The change in mucus plug score from baseline to Year 3 was significantly negatively correlated with change in FEV1% predicted (rp = -0.35; P < 0.001) and with changes in CT air trapping measures (all P values < 0.05). Conclusions: Mucus plugs identify a persistent asthma phenotype, and susceptibility to mucus plugs occurs at the subject and the bronchopulmonary segment level. The association between change in mucus plug score and change in airflow over time supports a causal role for mucus plugs in mechanisms of airflow obstruction in asthma.

The Impact of Insulin Resistance on Loss of Lung Function and Response to Treatment in Asthma.

Rationale: The role of obesity-associated insulin resistance (IR) in airflow limitation in asthma is uncertain. Objectives: Using data in the Severe Asthma Research Program 3 (SARP-3), we evaluated relationships between homeostatic measure of IR (HOMA-IR), lung function (cross-sectional and longitudinal analyses), and treatment responses to bronchodilators and corticosteroids. Methods: HOMA-IR values were categorized as without (<3.0), moderate (3.0-5.0), or severe (>5.0). Lung function included FEV1 and FVC measured before and after treatment with inhaled albuterol and intramuscular triamcinolone acetonide and yearly for 5 years. Measurements and Main Results: Among 307 participants in SARP-3, 170 (55%) were obese and 140 (46%) had IR. Compared with patients without IR, those with IR had significantly lower values for FEV1 and FVC, and these lower values were not attributable to obesity effects. Compared with patients without IR, those with IR had lower FEV1 responses to ß-adrenergic agonists and systemic corticosteroids. The annualized decline in FEV1 was significantly greater in patients with moderate IR (-41 ml/year) and severe IR (-32 ml/year,) than in patients without IR (-13 ml/year, P < 0.001 for both comparisons). Conclusions: IR is common in asthma and is associated with lower lung function, accelerated loss of lung function, and suboptimal lung function responses to bronchodilator and corticosteroid treatments. Clinical trials in patients with asthma and IR are needed to determine if improving IR might also improve lung function.

The Precision Interventions for Severe and/or Exacerbation-Prone (PrecISE) Asthma Network: An overview of Network organization, procedures, and interventions.

Asthma is a heterogeneous disease, with multiple underlying inflammatory pathways and structural airway abnormalities that impact disease persistence and severity. Recent progress has been made in developing targeted asthma therapeutics, especially for subjects with eosinophilic asthma. However, there is an unmet need for new approaches to treat patients with severe and exacerbation-prone asthma, who contribute disproportionately to disease burden. Extensive deep phenotyping has revealed the heterogeneous nature of severe asthma and identified distinct disease subtypes. A current challenge in the field is to translate new and emerging knowledge about different pathobiologic mechanisms in asthma into patient-specific therapies, with the ultimate goal of modifying the natural history of disease. Here, we describe the Precision Interventions for Severe and/or Exacerbation-Prone Asthma (PrecISE) Network, a groundbreaking collaborative effort of asthma researchers and biostatisticians from around the United States. The PrecISE Network was designed to conduct phase II/proof-of-concept clinical trials of precision interventions in the population with severe asthma, and is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health. Using an innovative adaptive platform trial design, the PrecISE Network will evaluate up to 6 interventions simultaneously in biomarker-defined subgroups of subjects. We review the development and organizational structure of the PrecISE Network, and choice of interventions being studied. We hope that the PrecISE Network will enhance our understanding of asthma subtypes and accelerate the development of therapeutics for severe asthma.

Healthcare utilization and maternal and child mortality during the COVID-19 pandemic in 18 low- and middle-income countries: An interrupted time-series analysis with mathematical modeling of administrative data.

BACKGROUND: The Coronavirus Disease 2019 (COVID-19) pandemic has had wide-reaching direct and indirect impacts on population health. In low- and middle-income countries, these impacts can halt progress toward reducing maternal and child mortality. This study estimates changes in health services utilization during the pandemic and the associated consequences for maternal, neonatal, and child mortality. METHODS AND FINDINGS: Data on service utilization from January 2018 to June 2021 were extracted from health management information systems of 18 low- and lower-middle-income countries (Afghanistan, Bangladesh, Cameroon, Democratic Republic of the Congo (DRC), Ethiopia, Ghana, Guinea, Haiti, Kenya, Liberia, Madagascar, Malawi, Mali, Nigeria, Senegal, Sierra Leone, Somalia, and Uganda). An interrupted time-series design was used to estimate the percent change in the volumes of outpatient consultations and maternal and child health services delivered during the pandemic compared to projected volumes based on prepandemic trends. The Lives Saved Tool mathematical model was used to project the impact of the service utilization disruptions on child and maternal mortality. In addition, the estimated monthly disruptions were also correlated to the monthly number of COVID-19 deaths officially reported, time since the start of the pandemic, and relative severity of mobility restrictions. Across the 18 countries, we estimate an average decline in OPD volume of 13.1% and average declines of 2.6% to 4.6% for maternal and child services. We projected that decreases in essential health service utilization between March 2020 and June 2021 were associated with 113,962 excess deaths (110,686 children under 5, and 3,276 mothers), representing 3.6% and 1.5% increases in child and maternal mortality, respectively. This excess mortality is associated with the decline in utilization of the essential health services included in the analysis, but the utilization shortfalls vary substantially between countries, health services, and over time. The largest disruptions, associated with 27.5% of the excess deaths, occurred during the second quarter of 2020, regardless of whether countries reported the highest rate of COVID-19-related mortality during the same months. There is a significant relationship between the magnitude of service disruptions and the stringency of mobility restrictions. The study is limited by the extent to which administrative data, which varies in quality across countries, can accurately capture the changes in service coverage in the population. CONCLUSIONS: Declines in healthcare utilization during the COVID-19 pandemic amplified the pandemic's harmful impacts on health outcomes and threaten to reverse gains in reducing maternal and child mortality. As efforts and resource allocation toward prevention and treatment of COVID-19 continue, essential health services must be maintained, particularly in low- and middle-income countries.

Location of eosinophils in the airway wall is critical for specific features of airway hyperresponsiveness and T2 inflammation in asthma.

BACKGROUND: Eosinophils are implicated as effector cells in asthma, but the functional implications of the precise location of eosinophils in the airway wall is poorly understood. We aimed to quantify eosinophils in the different compartments of the airway wall and associate these findings with clinical features of asthma and markers of airway inflammation. METHODS: In this cross-sectional study, we utilised design-based stereology to accurately partition the numerical density of eosinophils in both the epithelial compartment and the subepithelial space (airway wall area below the basal lamina including the submucosa) in individuals with and without asthma and related these findings to airway hyperresponsiveness (AHR) and features of airway inflammation. RESULTS: Intraepithelial eosinophils were linked to the presence of asthma and endogenous AHR, the type that is most specific for asthma. In contrast, both intraepithelial and subepithelial eosinophils were associated with type 2 (T2) inflammation, with the strongest association between IL5 expression and intraepithelial eosinophils. Eosinophil infiltration of the airway wall was linked to a specific mast cell phenotype that has been described in asthma. We found that interleukin (IL)-33 and IL-5 additively increased cysteinyl leukotriene (CysLT) production by eosinophils and that the CysLT LTC4 along with IL-33 increased IL13 expression in mast cells and altered their protease profile. CONCLUSIONS: We conclude that intraepithelial eosinophils are associated with endogenous AHR and T2 inflammation and may interact with intraepithelial mast cells via CysLTs to regulate airway inflammation.

Use of Fractional Exhaled Nitric Oxide to Guide the Treatment of Asthma: An Official American Thoracic Society Clinical Practice Guideline.

Background: The fractional exhaled nitric oxide (FENO) test is a point-of-care test that is used in the assessment of asthma. Objective: To provide evidence-based clinical guidance on whether FENO testing is indicated to optimize asthma treatment in patients with asthma in whom treatment is being considered. Methods: An international, multidisciplinary panel of experts was convened to form a consensus document regarding a single question relevant to the use of FENO. The question was selected from three potential questions based on the greatest perceived impact on clinical practice and the unmet need for evidence-based answers related to this question. The panel performed systematic reviews of published randomized controlled trials between 2004 and 2019 and followed the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) evidence-to-decision framework to develop recommendations. All panel members evaluated and approved the recommendations. Main Results: After considering the overall low quality of the evidence, the panel made a conditional recommendation for FENO-based care. In patients with asthma in whom treatment is being considered, we suggest that FENO is beneficial and should be used in addition to usual care. This judgment is based on a balance of effects that probably favors the intervention; the moderate costs and availability of resources, which probably favors the intervention; and the perceived acceptability and feasibility of the intervention in daily practice. Conclusions: Clinicians should consider this recommendation to measure FENO in patients with asthma in whom treatment is being considered based on current best available evidence.

Responsiveness to Parenteral Corticosteroids and Lung Function Trajectory in Adults with Moderate-to-Severe Asthma.

Rationale: It is unclear why select patients with moderate-to-severe asthma continue to lose lung function despite therapy. We hypothesized that participants with the smallest responses to parenteral corticosteroids have the greatest risk of undergoing a severe decline in lung function.Objectives: To evaluate corticosteroid-response phenotypes as longitudinal predictors of lung decline.Methods: Adults within the NHLBI SARP III (Severe Asthma Research Program III) who had undergone a course of intramuscular triamcinolone at baseline and at ≥2 annual follow-up visits were evaluated. Longitudinal slopes were calculated for each participant's post-bronchodilator FEV1% predicted. Categories of participant FEV1 slope were defined: severe decline, >2% loss/yr; mild decline, >0.5-2.0% loss/yr; no change, 0.5% loss/yr to <1% gain/yr; and improvement, ≥1% gain/yr. Regression models were used to develop predictors of severe decline.Measurements and Main Results: Of 396 participants, 78 had severe decline, 91 had mild decline, 114 had no change, and 113 showed improvement. The triamcinolone-induced difference in the post-bronchodilator FEV1% predicted (derived by baseline subtraction) was related to the 4-year change in lung function or slope category in univariable models (P < 0.001). For each 5% decrement in the triamcinolone-induced difference the FEV1% predicted, there was a 50% increase in the odds of being in the severe decline group (odds ratio, 1.5; 95% confidence interval, 1.3-1.8), when adjusted for baseline FEV1, exacerbation history, blood eosinophils and body mass index.Conclusions: Failure to improve the post-bronchodilator FEV1 after a challenge with parenteral corticosteroids is an evoked biomarker for patients at risk for a severe decline in lung function.

Benefits of Airway Androgen Receptor Expression in Human Asthma.

Rationale: Androgens are potentially beneficial in asthma, but AR (androgen receptor) has not been studied in human airways.Objectives: To measure whether AR and its ligands are associated with human asthma outcomes.Methods: We compared the effects of AR expression on lung function, symptom scores, and fractional exhaled nitric oxide (FeNO) in adults enrolled in SARP (Severe Asthma Research Program). The impact of sex and of androgens on asthma outcomes was also evaluated in the SARP with validation studies in the Cleveland Clinic Health System and the NHANES (U.S. National Health and Nutrition Examination Survey).Measurements and Main Results: In SARP (n = 128), AR gene expression from bronchoscopic epithelial brushings was positively associated with both FEV1/FVC ratio (R2 = 0.135, P = 0.0002) and the total Asthma Quality of Life Questionnaire score (R2 = 0.056, P = 0.016) and was negatively associated with FeNO (R2 = 0.178, P = 9.8 × 10-6) and NOS2 (nitric oxide synthase gene) expression (R2 = 0.281, P = 1.2 × 10-10). In SARP (n = 1,659), the Cleveland Clinic Health System (n = 32,527), and the NHANES (n = 2,629), women had more asthma exacerbations and emergency department visits than men. The levels of the AR ligand precursor dehydroepiandrosterone sulfate correlated positively with the FEV1 in both women and men.Conclusions: Higher bronchial AR expression and higher androgen levels are associated with better lung function, fewer symptoms, and a lower FeNO in human asthma. The role of androgens should be considered in asthma management.

How service delivery implementation strategies can contribute to attaining universal health coverage: lessons from polio eradication using an implementation science approach.

BACKGROUND: Improving service delivery is a key strategy for achieving service coverage, one of the two components of universal health coverage (UHC). As one of the largest global public health initiatives, individuals involved with the Global Polio Eradication Initiative (GPEI) have learned many important lessons about service delivery. We identified contributors and challenges to delivering health services at national and subnational levels using experiences from the GPEI. We described strategies used to strengthen service delivery and draw lessons that could be applicable to achieving UHC. METHODS: Online cross-sectional surveys based on the Consolidated Framework for Implementation Research (CFIR) domains and socioecological model were conducted from 2018-2019. Data were analyzed using an embedded mixed methods approach. Frequencies of the contributors and challenges to service delivery by levels of involvement were estimated. Chi-square tests of independence were used to assess unadjusted associations among categorical outcome variables. Logistic regressions were used to examine the association between respondent characteristics and contributors to successful implementation or implementation challenges. Horizontal analysis of free text responses by CFIR domain was done to contextualize the quantitative results. RESULTS: Three thousand nine hundred fifty-five people responded to the online survey which generated 3,659 valid responses. Among these, 887 (24.2%) reported involvement in service delivery at the global, national, or subnational level with more than 90% involved at subnational levels. The main internal contributor of strengthened service delivery was the process of conducting activities (48%); working in frontline role had higher odds of identifying the process of conducting activities as the main internal contributor (AOR: 1.22, p = 0.687). The main external contributor was the social environment (42.5%); having 10-14 years of polio program implementation was significantly associated with identifying the social environment as the main external contributor to strengthened service delivery (AOR: 1.61, p = 0.038). The most frequent implementation challenge was the external environment (56%); working in Eastern Mediterranean region was almost 4 times more likely to identify the external environment as the major challenge in service delivery strengthening (AOR:3.59, p < 0.001). CONCLUSION: Priority actions to improve service delivery include: adopt strategies to systematically reach hard-to-reach populations, expand disease-focused programs to support broader primary healthcare priorities, maximize community outreach strategies to reach broader age groups, build community trust in health workers and develop multisectoral leadership for collaboration. Achieving UHC is contingent on strengthened subnational service delivery.

Evidence for an expanded hypertension care cascade in low- and middle-income countries: a scoping review.

BACKGROUND: With nearly 90% of annual hypertension-related deaths occurring in low- and middle-income countries (LMICs), there is an urgent need to measure the coverage of health services that effectively manage hypertension. However, there is little agreement on how to define effective coverage and the existing hypertension care cascade (hypertension prevalence, percent aware, percent treated, and percent controlled) does not account for the quality of care received by patients. This study reviews definitions of effective coverage and service quality for hypertension management services and proposes an expanded hypertension care cascade to improve measurement of health systems performance. METHODS: A systematic scoping review of literature published in six electronic databases between January 2000 and October 2020 identified studies that defined effective coverage of hypertension management services or integrated dimensions of service quality into population-based estimates of hypertension management in LMICs. Findings informed an expanded hypertension care cascade from which quality-adjusted service coverage can be calculated to approximate effective coverage. RESULTS: The review identified 18 relevant studies, including 6 that defined effective coverage for hypertension management services and 12 that reported a measure of service quality in a population-based study. Based on commonly reported barriers to hypertension management, new steps on the proposed expanded care cascade include (i) population screened, (ii) population linked to quality care, and (iii) population adhering to prescribed treatment. CONCLUSION: There is little consensus on the definition of effective coverage of hypertension management services, and most studies do not describe the quality of hypertension management services provided to populations. Incorporating aspects of service quality to the hypertension care cascade allows for the calculation of quality-adjusted coverage of relevant services, enabling an appropriate measurement of health systems performance through effective coverage.

Can Video Assistance Improve the Quality of Pediatric Dispatcher-Assisted Cardiopulmonary Resuscitation?

OBJECTIVES: This study aimed to evaluate the impact of adding video conferencing to dispatcher-assisted telephone cardiopulmonary resuscitation (CPR) on pediatric bystander CPR quality. METHODS: We conducted a prospective, randomized manikin study among volunteers with no CPR training and among bachelor nurses. Volunteers randomly received either video or audio assistance in a 6-minute pediatric cardiac arrest scenario. The main outcome measures were the results of the Cardiff Test to assess compression and ventilation performance. RESULTS: Of 255 candidates assessed for eligibility, 120 subjects were randomly assigned to 1 of the 4 following groups: untrained telephone-guided (U-T; n = 30) or video-guided (U-V; n = 30) groups and trained telephone-guided (T-T; n = 30) or video-guided (T-V; n = 30) groups. Cardiac arrest was appropriately identified in 86.7% of the U-T group and in 100% in the other groups (P = 0.0061). Hand positioning was adequate in 76.7% of T-T, 80% of T-V, and 60% of U-V, as compared with 23.4% of the U-T group (P = 0.0001). Fewer volunteers managed to deliver 2 rescue breaths/cycle (P = 0.0001) in the U-T (16.7%) compared with the U-V (43.3%), the T-T (56.7%), and the T-V groups (60%).Subjects in the video groups had a lower fraction of minute to ventilate as compared with the telephone groups (P = 0.0005). CONCLUSIONS: In dispatcher-instructed children CPR simulation, using video assistance improves cardiac arrest recognition and CPR quality with more appropriate chest compression technique and ventilation delivering. The long interruptions in chest compression combined with the mixed success rate to deliver proper ventilation raise question about ventilation quality and its effectiveness.

PrecISE: Precision Medicine in Severe Asthma: An adaptive platform trial with biomarker ascertainment.

Severe asthma accounts for almost half the cost associated with asthma. Severe asthma is driven by heterogeneous molecular mechanisms. Conventional clinical trial design often lacks the power and efficiency to target subgroups with specific pathobiological mechanisms. Furthermore, the validation and approval of new asthma therapies is a lengthy process. A large proportion of that time is taken by clinical trials to validate asthma interventions. The National Institutes of Health Precision Medicine in Severe and/or Exacerbation Prone Asthma (PrecISE) program was established with the goal of designing and executing a trial that uses adaptive design techniques to rapidly evaluate novel interventions in biomarker-defined subgroups of severe asthma, while seeking to refine these biomarker subgroups, and to identify early markers of response to therapy. The novel trial design is an adaptive platform trial conducted under a single master protocol that incorporates precision medicine components. Furthermore, it includes innovative applications of futility analysis, cross-over design with use of shared placebo groups, and early futility analysis to permit more rapid identification of effective interventions. The development and rationale behind the study design are described. The interventions chosen for the initial investigation and the criteria used to identify these interventions are enumerated. The biomarker-based adaptive design and analytic scheme are detailed as well as special considerations involved in the final trial design.

Does harvesting Urochloa and Megathyrsus forages at short intervals confer an advantage on cumulative dry matter yields and quality?

BACKGROUND: Due to increasing demand for livestock products in sub-Saharan Africa, increasing livestock productivity is a priority. The core constraint is limited availability of feed of good quality. We assessed optimal harvesting time of three improved grasses, two Urochloa lines (Basilisk a selection from wild population, Cayman - a hybrid, a product of breeding) plus Mombasa, a Megathyrsus selection. All are released in Latin America and Kenya or in the registration in other regional countries. We assessed dry matter (DM) yields and quality at 4, 6, 8 and 12 weeks of age in two sites. RESULTS: DM yields (in t ha-1 ) were of the order Cayman (9.6-14.3) > Mombasa (8.0-11.3) > Basilisk (5.5-10.2) in one site, and Cayman (6.4-9.7) > Basilisk (4.9-7.6) > Mombasa (3.3-5.9) at site two. The harvesting regimes produced DM largely similar for weeks 4 and 6, 6 and 8, 8 and 12. Across the sites quality was of the order Cayman > Mombasa > Basilisk for neutral detergent fiber (NDF), metabolizable energy (ME) and crude protein (CP). With increasing harvesting interval, MJ ME ha-1 and kg CP ha-1 were inconsistent across both sites, but significant differences returned for MJ ME ha-1 unlike kg CP ha-1 . CONCLUSIONS: Harvesting at either 8 or 12 weeks is not recommendable as quality drops without an increase in DM yield that can compensate despite doubling and tripling time respectively, compared to 4 weeks. We recommend harvesting at 4 through 6 weeks for any of the three grasses based on yield against time, and demand at the intensified cut-and-carry smallholder systems. © 2021 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.