Health care providers' knowledge of clinical protocols for postpartum hemorrhage care in Kenya: a cross-sectional study.

BACKGROUND: Postpartum hemorrhage (PPH) remains the leading cause of maternal death worldwide despite its often-preventable nature. Understanding health care providers' knowledge of clinical protocols is imperative for improving quality of care and reducing mortality. This is especially pertinent in referral and teaching hospitals that train nursing and medical students and interns in addition to managing emergency and referral cases. METHODS: This study aimed to (1) measure health care providers' knowledge of clinical protocols for risk assessment, prevention, and management of PPH in 3 referral hospitals in Kenya and (2) examine factors associated with providers' knowledge. We developed a knowledge assessment tool based on past studies and clinical guidelines from the World Health Organization and the Kenyan Ministry of Health. We conducted in-person surveys with health care providers in three high-volume maternity facilities in Nairobi and western Kenya from October 2018-February 2019. We measured gaps in knowledge using a summative index and examined factors associated with knowledge (such as age, gender, qualification, experience, in-service training attendance, and a self-reported measure of peer-closeness) using linear regression. RESULTS: We interviewed 172 providers including consultants, medical officers, clinical officers, nurse-midwives, and students. Overall, knowledge was lowest for prevention-related protocols (an average of 0.71 out of 1.00; 95% CI 0.69-0.73) and highest for assessment-related protocols (0.81; 95% CI 0.79-0.83). Average knowledge scores did not differ significantly between qualified providers and students. Finally, we found that being a qualified nurse, having a specialization, being female, having a bachelor's degree and self-reported closer relationships with colleagues were statistically significantly associated with higher knowledge scores. CONCLUSION: We found gaps in knowledge of PPH care clinical protocols in Kenya. There is a clear need for innovations in clinical training to ensure that providers in teaching referral hospitals are prepared to prevent, assess, and manage PPH. It is possible that training interventions focused on learning by doing and teamwork may be beneficial.

Know-do gaps in obstetric and newborn care quality in Uganda: a cross-sectional study in rural health facilities.

OBJECTIVES: Variable and inadequate quality of maternity care is a critical factor in persistently high rates of maternal and neonatal mortality in Uganda. We investigated whether provider quality of care deviates from knowledge and the factors associated with these 'know-do gaps' in Ugandan maternity facilities. METHODS: Data were collected from 109 providers in 40 facilities. Quality was measured using direct observations of intrapartum care, and scores were based on the percentage of essential care actions provided out of a 20-item validated quality index. Knowledge was measured based on the percentage of items that providers reported knowing to do using vignette surveys. The know-do gap was the difference between knowledge and quality. Multivariable models were used to assess the association between provider- and facility-level characteristics and knowledge, quality and know-do gaps. RESULTS: The average quality score was 45%, with quality varying widely within and across providers. The mean knowledge score was 70%, yielding a mean know-do gap of 25%. Know-do gaps were largest for practices related to infection control, vitals monitoring, and prevention of postpartum haemorrhage. The association between quality and knowledge scores was positive but small (P = 0.08), so know-do gaps were largest for providers with the highest knowledge scores. Greater provider training was positively associated with knowledge (P = 0.005) but not with quality (P = 0.60). Having 10 or more years of work experience was associated with higher quality scores (5.3, 95%CI: 0.6 to 10.1), while higher patient volumes were associated with lower quality scores (-2.2, 95%CI: -3.7 to - 0.07). None of the factors of provider motivation, cadre, availability of essential medicines and supplies or facility staffing were associated with quality or know-do gaps. CONCLUSIONS: Our results indicate that, in Uganda, gaps between knowledge and quality do not appear to be explained by factors such as lack of motivation, education, training or supplies. Gaps are particularly large for essential practices related to prevention of postpartum haemorrhage, a leading cause of maternal mortality in Uganda and similar settings.

Quality of clinical management of children diagnosed with malaria: A cross-sectional assessment in 9 sub-Saharan African countries between 2007-2018.

BACKGROUND: Appropriate clinical management of malaria in children is critical for preventing progression to severe disease and for reducing the continued high burden of malaria mortality. This study aimed to assess the quality of care provided to children under 5 diagnosed with malaria across 9 sub-Saharan African countries. METHODS AND FINDINGS: We used data from the Service Provision Assessment (SPA) survey. SPAs are nationally representative facility surveys capturing quality of sick-child care, facility readiness, and provider and patient characteristics. The data set contained 24,756 direct clinical observations of outpatient sick-child visits across 9 countries, including Uganda (2007), Rwanda (2007), Namibia (2009), Kenya (2010), Malawi (2013), Senegal (2013-2017), Ethiopia (2014), Tanzania (2015), and Democratic Republic of the Congo (2018). We assessed the proportion of children with a malaria diagnosis who received a blood test diagnosis and an appropriate antimalarial. We used multilevel logistic regression to assess facility and provider and patient characteristics associated with these outcomes. Subgroup analyses with the 2013-2018 country surveys only were conducted for all outcomes. Children observed were on average 20.5 months old and were most commonly diagnosed with respiratory infection (47.7%), malaria (29.7%), and/or gastrointestinal infection (19.7%). Among the 7,340 children with a malaria diagnosis, 32.5% (95% CI: 30.3%-34.7%) received both a blood-test-based diagnosis and an appropriate antimalarial. The proportion of children with a blood test diagnosis and an appropriate antimalarial ranged from 3.4% to 57.1% across countries. In the more recent surveys (2013-2018), 40.7% (95% CI: 37.7%-43.6%) of children with a malaria diagnosis received both a blood test diagnosis and appropriate antimalarial. Roughly 20% of children diagnosed with malaria received no antimalarial at all, and nearly 10% received oral artemisinin monotherapy, which is not recommended because of concerns regarding parasite resistance. Receipt of a blood test diagnosis and appropriate antimalarial was positively correlated with being seen at a facility with diagnostic equipment in stock (adjusted OR 3.67; 95% CI: 2.72-4.95) and, in the 2013-2018 subsample, with being seen at a facility with Artemisinin Combination Therapies (ACTs) in stock (adjusted OR 1.60; 95% CI:1.04-2.46). However, even if all children diagnosed with malaria were seen by a trained provider at a facility with diagnostics and medicines in stock, only a predicted 37.2% (95% CI: 34.2%-40.1%) would have received a blood test and appropriate antimalarial (44.4% for the 2013-2018 subsample). Study limitations include the lack of confirmed malaria test results for most survey years, the inability to distinguish between a diagnosis of uncomplicated or severe malaria, the absence of other relevant indicators of quality of care including dosing and examinations, and that only 9 countries were studied. CONCLUSIONS: In this study, we found that a majority of children diagnosed with malaria across the 9 surveyed sub-Saharan African countries did not receive recommended care. Clinical management is positively correlated with the stocking of essential commodities and is somewhat improved in more recent years, but important quality gaps remain in the countries studied. Continued reductions in malaria mortality will require a bigger push toward quality improvements in clinical care.

CRISPR-delivery particles targeting nuclear receptor-interacting protein 1 (Nrip1) in adipose cells to enhance energy expenditure.

RNA-guided, engineered nucleases derived from the prokaryotic adaptive immune system CRISPR-Cas represent a powerful platform for gene deletion and editing. When used as a therapeutic approach, direct delivery of Cas9 protein and single-guide RNA (sgRNA) could circumvent the safety issues associated with plasmid delivery and therefore represents an attractive tool for precision genome engineering. Gene deletion or editing in adipose tissue to enhance its energy expenditure, fatty acid oxidation, and secretion of bioactive factors through a "browning" process presents a potential therapeutic strategy to alleviate metabolic disease. Here, we developed "CRISPR-delivery particles," denoted CriPs, composed of nano-size complexes of Cas9 protein and sgRNA that are coated with an amphipathic peptide called Endo-Porter that mediates entry into cells. Efficient CRISPR-Cas9-mediated gene deletion of ectopically expressed GFP by CriPs was achieved in multiple cell types, including a macrophage cell line, primary macrophages, and primary pre-adipocytes. Significant GFP loss was also observed in peritoneal exudate cells with minimum systemic toxicity in GFP-expressing mice following intraperitoneal injection of CriPs containing Gfp-targeting sgRNA. Furthermore, disruption of a nuclear co-repressor of catabolism, the Nrip1 gene, in white adipocytes by CriPs enhanced adipocyte browning with a marked increase of uncoupling protein 1 (UCP1) expression. Of note, the CriP-mediated Nrip1 deletion did not produce detectable off-target effects. We conclude that CriPs offer an effective Cas9 and sgRNA delivery system for ablating targeted gene products in cultured cells and in vivo, providing a potential therapeutic strategy for metabolic disease.

Assessment of warfarin algorithms for hospitalized adults: searching for a safe dosing strategy.

This study evaluates three warfarin dosing algorithms (Kimmel, Dawson, High Dose ≥ 2.5 mg) for hospitalized older adults. A random selection of 250 patients with overshoots (INR ≥ 5 after 48 h of hospitalization) and 250 patients without overshoots were accessed from a database of 12,107 inpatients ≥ 65 years treated with chronic warfarin during hospitalization between January 1, 2014 and June 30, 2016. Algorithms were retrospectively applied to patients 2 days prior to overshoots in the overshoot group, and 2 days prior to the maximum INR reached after 48 h of hospitalization in the non-overshoot group. Patients were categorized as overdosed or not overdosed and compared using descriptive statistics. Logistic regression modeling determined predictors for overshoots. There was no significant difference between overdose and non-overdose groups for progressing to overshoots by the Kimmel (51.0% vs. 48.7%, p = 0.67) or Dawson (48.5 vs. 57.9%, p = 0.19) algorithms. The Low Dose Group (≤ 2.5 mg) was significantly more likely to experience an overshoot than the High Dose Group (56.6% vs. 45.5%, p = 0.04). The Low Dose Group was more likely to be older (81.4% vs. 71.1%, p = 0.02), female (63.5% vs. 49.8%, p = 0.02), weigh less (71.3 ± 21.9 vs. 79 ± 23.1, p = 0.002), and be prescribed amiodarone (16.6% vs. 8.1%, p = 0.01). While none of the algorithms predicted overshoots in logistic regression modeling, weight over 70 kg and black race remained protective. The High Dose Algorithm revealed that providers appropriately gave lower doses to patients at highest risk for warfarin sensitivity. Future studies are needed to investigate tools for inpatient warfarin dosing in older adults.

Shedding light on quality of care: a study protocol for a randomized trial evaluating the impact of the Solar Suitcase in rural health facilities on maternal and newborn care quality in Uganda.

BACKGROUND: Continued progress in reducing maternal and newborn morbidity and mortality in low-income countries requires a renewed focus on quality of delivery care. Reliable electricity and lighting is a cornerstone of a well-equipped health system, but most primary maternity care facilities in sub-Saharan Africa are either not connected to the electrical grid or suffer frequent blackouts. Lack of reliable electricity and light in maternity facilities may contribute to poor quality of both routine and emergency obstetric and newborn care, by hindering infection control, increasing delays in providing care, and reducing health worker morale. The "Solar Suitcase" is a solar electric system designed specifically for maternity care facilities in low-resource environments. The purpose of this trial is to evaluate the impact of the Solar Suitcase on reliability of light, quality of obstetric and newborn care, and health worker satisfaction. METHODS: We are conducting a study with 30 maternity care facilities in rural Uganda that lack access to a reliable, bright light source. The study is a stepped wedge cluster randomized controlled trial. Study facilities are identified according to predefined eligibility criteria, and randomized by blocking on baseline covariates. The intervention is a "Solar Suitcase", a complete solar electric system that provides essential lighting and power for charging phones and small medical devices. The primary outcomes are the reliability and quality of light during intrapartum care, the process quality of obstetric and newborn care, and health worker satisfaction. Outcomes will be assessed via direct clinical observation by trained enumerators (estimated n = 1980 birth observations), as well as interviews with health workers and facility managers. Lighting and blackouts will be captured through direct observation and via light sensors installed in facilities. DISCUSSION: A key feature of a high quality health system is appropriate infrastructure, including reliable, bright lighting and electricity. Rigorous evidence on the role of a reliable light source in maternal and newborn care is needed to accelerate the "electrification" of maternity facilities across sub-Saharan Africa. This study will be the first to rigorously assess the extent to which reliable light is an important driver of the quality of care experienced by women and newborns. TRIAL REGISTRATION: ClinicalTrials.gov : NCT03589625 (July 18, 2018); socialscienceregistry.org : AEARCTR-0003078 (dated June 16, 2018).

Trading Bankruptcy for Health: A Discrete-Choice Experiment.

BACKGROUND: Although nearly two-third of bankruptcy in the United States is medical in origin, a common assumption is that individuals facing a potentially lethal disease opt for cure at any cost. This assumption has never been tested, and knowledge of how the American population values a trade-off between cure and bankruptcy is unknown. OBJECTIVES: To determine the relative importance among the general American population of improved health versus improved financial risk protection, and to determine the impact of demographics on these preferences. METHODS: A discrete-choice experiment was performed with 2359 members of the US population. Respondents were asked to value treatments with varying chances of cure and bankruptcy in the presence of a lethal disease. Latent class analysis with concomitant variables was performed, weighted for national representativeness. Sensitivity analyses were undertaken to test the robustness of the results. RESULTS: It was found that 31.3% of the American population values cure at all costs. Nevertheless, for 8.5% of the US population, financial solvency dominates concerns for health in medical decision making. Individuals who value cure at all costs are more likely to have had experience with serious disease and to be women. No demographic characteristics significantly predicted individuals who value solvency over cure. CONCLUSIONS: Although the average American values cure more than financial solvency, a cure-at-all-costs rubric describes the preferences of a minority of the population, and 1 in 12 value financial protection over any chances of cure. This study provides empirical evidence for how the US population values a trade-off between avoiding adverse health outcomes and facing bankruptcy. These findings bring to the fore the decision making that individuals face in balancing the acute financial burden of health care access.

Activated Kupffer cells inhibit insulin sensitivity in obese mice.

Obesity promotes insulin resistance associated with liver inflammation, elevated glucose production, and type 2 diabetes. Although insulin resistance is attenuated in genetic mouse models that suppress systemic inflammation, it is not clear whether local resident macrophages in liver, denoted Kupffer cells (KCs), directly contribute to this syndrome. We addressed this question by selectively silencing the expression of the master regulator of inflammation, NF-κB, in KCs in obese mice. We used glucan-encapsulated small interfering RNA particles (GeRPs) that selectively silence gene expression in macrophages in vivo. Following intravenous injections, GeRPs containing siRNA against p65 of the NF-κB complex caused loss of NF-κB p65 expression in KCs without disrupting NF-κB in hepatocytes or macrophages in other tissues. Silencing of NF-κB expression in KCs in obese mice decreased cytokine secretion and improved insulin sensitivity and glucose tolerance without affecting hepatic lipid accumulation. Importantly, GeRPs had no detectable toxic effect. Thus, KCs are key contributors to hepatic insulin resistance in obesity and a potential therapeutic target for metabolic disease.

Peptide- and Amine-Modified Glucan Particles for the Delivery of Therapeutic siRNA.

Translation of siRNA technology into the clinic is limited by the need for improved delivery systems that target specific cell types. Macrophages are particularly attractive targets for RNAi therapy because they promote pathogenic inflammatory responses in a number of important human diseases. We previously demonstrated that a multicomponent formulation of ß-1,3-d-glucan-encapsulated siRNA particles (GeRPs) can specifically and potently silence genes in mouse macrophages. A major advance would be to simplify the GeRP system by reducing the number of delivery components, thus enabling more facile manufacturing and future commercialization. Here we report the synthesis and evaluation of a simplified glucan-based particle (GP) capable of delivering siRNA in vivo to selectively silence macrophage genes. Covalent attachment of small-molecule amines and short peptides containing weak bases to GPs facilitated electrostatic interaction of the particles with siRNA and aided in the endosomal release of siRNA by the proton-sponge effect. Modified GPs were nontoxic and were efficiently internalized by macrophages in vitro. When injected intraperitoneally (i.p.), several of the new peptide-modified GPs were found to efficiently deliver siRNA to peritoneal macrophages in lean, healthy mice. In an animal model of obesity-induced inflammation, i.p. administration of one of the peptide-modified GPs (GP-EP14) bound to siRNA selectively reduced the expression of target inflammatory cytokines in the visceral adipose tissue macrophages. Decreasing adipose tissue inflammation resulted in an improvement of glucose metabolism in these metabolically challenged animals. Thus, modified GPs represent a promising new simplified system for the efficient delivery of therapeutic siRNAs specifically to phagocytic cells in vivo for modulation of inflammation responses.

Gene silencing in adipose tissue macrophages regulates whole-body metabolism in obese mice.

Adipose tissue (AT) inflammation and infiltration by macrophages is associated with insulin resistance and type 2 diabetes in obese humans, offering a potential target for therapeutics. However, whether AT macrophages (ATMs) directly contribute to systemic glucose intolerance has not been determined. The reason is the lack of methods to ablate inflammatory genes expressed in macrophages specifically localized within AT depots, leaving macrophages in other tissues unaffected. Here we report that i.p. administration of siRNA encapsulated by glucan shells in obese mice selectively silences genes in epididymal ATMs, whereas macrophages within lung, spleen, kidney, heart, skeletal muscle, subcutaneous (SubQ) adipose, and liver are not targeted. Such administration of GeRPs to silence the inflammatory cytokines TNF-α or osteopontin in epididymal ATMs of obese mice caused significant improvement in glucose tolerance. These data are consistent with the hypothesis that cytokines produced by ATMs can exacerbate whole-body glucose intolerance.

Lipid storage by adipose tissue macrophages regulates systemic glucose tolerance.

Proinflammatory pathways in adipose tissue macrophages (ATMs) can impair glucose tolerance in obesity, but ATMs may also be beneficial as repositories for excess lipid that adipocytes are unable to store. To test this hypothesis, we selectively targeted visceral ATMs in obese mice with siRNA against lipoprotein lipase (LPL), leaving macrophages within other organs unaffected. Selective silencing of ATM LPL decreased foam cell formation in visceral adipose tissue of obese mice, consistent with a reduced supply of fatty acids from VLDL hydrolysis. Unexpectedly, silencing LPL also decreased the expression of genes involved in fatty acid uptake (CD36) and esterification in ATMs. This deficit in fatty acid uptake capacity was associated with increased circulating serum free fatty acids. Importantly, ATM LPL silencing also caused a marked increase in circulating fatty acid-binding protein-4, an adipocyte-derived lipid chaperone previously reported to induce liver insulin resistance and glucose intolerance. Consistent with this concept, obese mice with LPL-depleted ATMs exhibited higher hepatic glucose production from pyruvate and glucose intolerance. Silencing CD36 in ATMs also promoted glucose intolerance. Taken together, the data indicate that LPL secreted by ATMs enhances their ability to sequester excess lipid in obese mice, promoting systemic glucose tolerance.

Postpartum Primary Care Engagement Using Default Scheduling and Tailored Messaging: A Randomized Clinical Trial.

Importance: More than 30% of pregnant people have at least 1 chronic medical condition, and nearly 20% develop gestational diabetes or pregnancy-related hypertension, increasing the risk of future chronic disease. While these individuals are often monitored closely during pregnancy, they face major barriers when transitioning to primary care following delivery, due in part to a lack of health care support for this transition. Objective: To evaluate the impact of an intervention designed to improve postpartum primary care engagement by reducing patient administrative burden and information gaps. Design, Setting, and Participants: An individual-level randomized clinical trial was conducted from November 3, 2022, to October 11, 2023, at 1 hospital-based and 5 community-based outpatient obstetric clinics affiliated with a large academic medical center. Participants included English- and Spanish-speaking pregnant or recently postpartum adults with obesity, anxiety, depression, diabetes, chronic hypertension, gestational diabetes, or pregnancy-related hypertension and a primary care practitioner (PCP) listed in their electronic health record. Intervention: A behavioral economics-informed intervention bundle, including default scheduling of postpartum PCP appointments and tailored messages. Main Outcome and Measures: Completion of a PCP visit for routine or chronic condition care within 4 months of delivery was the primary outcome, ascertained directly by reviewing the patient's electronic health record approximately 5 months after their estimated due date. Intention-to-treat analysis was conducted. Results: A total of 360 patients were randomized (control, 176; intervention, 184). Individuals had a mean (SD) age of 34.1 (4.9) years and median gestational age of 36.3 (IQR, 34.0-38.6) weeks at enrollment. The distribution of self-reported race and ethnicity was 6.8% Asian, 7.4% Black, 68.6% White, and 15.0% multiple races or other. Most participants (75.4%) had anxiety or depression, 16.1% had a chronic or pregnancy-related hypertensive disorder, 19.5% had preexisting or gestational diabetes, and 40.8% had a prepregnancy body mass index of 30 or greater. Medicaid was the primary payer for 21.2% of patients. Primary care practitioner visit completion within 4 months occurred in 22.0% (95% CI, 6.4%-28.8%) of individuals in the control group and 40.0% (95% CI, 33.1%-47.4%) in the intervention group. In regression models accounting for randomization strata, the intervention increased PCP visit completion by 18.7 percentage points (95% CI, 9.1-28.2 percentage points). Intervention participants also had fewer postpartum readmissions (1.7% vs 5.8%) and increased receipt of the following services by a PCP: blood pressure screening (42.8% vs 28.3%), weight assessment (42.8% vs 27.7%), and depression screening (32.8% vs 16.8%). Conclusions and Relevance: The findings of this randomized clinical trial suggest that the current lack of support for postpartum transitions to primary care is a missed opportunity to improve recently pregnant individual's short- and long-term health. Reducing patient administrative burdens may represent relatively low-resource, high-impact approaches to improving postpartum health and well-being. Trial Registration: ClinicalTrials.gov Identifier: NCT05543265.

Regional Variation in Antenatal Late Preterm Steroid Use Following the ALPS Trial.

Importance: The publication of the Antenatal Late Preterm Steroids (ALPS) trial in February 2016 demonstrated that antenatal administration of betamethasone in the late preterm period (between 34 to 36 weeks of gestation) for individuals with a high risk of delivery decreased neonatal respiratory morbidity. National estimates have suggested the trial did change obstetric practice, but little is known if the evidence was adopted uniformly or equitably. Objective: To assess regional variation in the use of late preterm steroids after the publication of the Antenatal Late Preterm Steroids (ALPS) Trial and to understand factors associated with a region's pace of adoption. Design, Setting, and Participants: This cross-sectional study used US natality data from February 2015 to October 2017 from hospital referral regions (HRRs) within the US. Inclusion criteria included live-born, nonanomalous, singleton, late preterm (34 to 36 completed weeks of gestation) neonates born to individuals without pregestational diabetes. This study was conducted from November 15, 2022, to January 13, 2023. Main Outcome and Measures: HRRs were categorized as either a slower adopter or faster adopter of antenatal late preterm steroids based on the observed vs expected pace of antenatal steroid adoption in a 1-year period after the trial's dissemination. Patient and regional factors hypothesized a priori to be associated with the uptake of late preterm steroids were compared between faster and slower adopters. Comparisons were made using Student t test or Wilcoxon rank-sum test, as appropriate. A multivariable logistic regression was constructed to identify factors associated with faster adopter status in the postperiod. Results: There were 666 097 late preterm births in 282 HRRs. The mean (SD) maternal age in HRRs was 27.9 (1.2) years. The median (IQR) percentage of births by race categories in HRRs for patients identifying as American Indian or Alaskan Native was 0.5% (0.2%-1.3%); Asian or Pacific Islander, 3.0% (1.7%-5.3%); Black, 12.9% (5.1%-29.1%); and White, 78.6% (66.6%-87.0%). The median percentage of births in HRRs to patients of Hispanic ethnicity was 11.2% (6.3%-27.4%). In this study, 136 HRRs (48.2%) were classified as faster adopters and 146 (51.8%) were classified as slower adopters. Faster adopters increased their steroid use by 12.1 percentage points (from 5.9% to 18.0%) compared with a 5.5 percentage point increase (from 3.7% to 9.2%) among slower adopters (P < .001). Most examined patient and regional factors were not associated with a region's pace of adoption, with the exception of the regional prevalence of prior preterm birth (adjusted odds ratio [aOR], 2.04 [95% CI, 1.48-2.82]) and the percentage of deliveries at 34 to 35 weeks of gestation (aOR, 0.68 [95% CI, 0.47-0.99]) compared with 36 weeks. Conclusions and Relevance: In this cross-sectional study, there was widespread geographic variation in the adoption of antenatal steroid administration for late preterm births that largely remained unexplained by population factors. These findings should prompt further investigations to barriers to timely or equitable access to new evidence-based practices and guide future dissemination strategies with the goal of more uniform adoption.

Health impact and cost-effectiveness of expanding routine immunization coverage in India through Intensified Mission Indradhanush.

Many children do not receive a full schedule of childhood vaccines, yet there is limited evidence on the cost-effectiveness of strategies for improving vaccination coverage. Evidence is even scarcer on the cost-effectiveness of strategies for reaching 'zero-dose children', who have not received any routine vaccines. We evaluated the cost-effectiveness of periodic intensification of routine immunization (PIRI), a widely applied strategy for increasing vaccination coverage. We focused on Intensified Mission Indradhanush (IMI), a large-scale PIRI intervention implemented in India in 2017-2018. In 40 sampled districts, we measured the incremental economic cost of IMI using primary data, and used controlled interrupted time-series regression to estimate the incremental vaccination doses delivered. We estimated deaths and disability-adjusted life years (DALYs) averted using the Lives Saved Tool and reported cost-effectiveness from immunization programme and societal perspectives. We found that, in sampled districts, IMI had an estimated incremental cost of 2021US$13.7 (95% uncertainty interval: 10.6 to 17.4) million from an immunization programme perspective and increased vaccine delivery by an estimated 2.2 (-0.5 to 4.8) million doses over a 12-month period, averting an estimated 1413 (-350 to 3129) deaths. The incremental cost from a programme perspective was $6.21 per dose ($2.80 to dominated), $82.99 per zero-dose child reached ($39.85 to dominated), $327.63 ($147.65 to dominated) per DALY averted, $360.72 ($162.56 to dominated) per life-year saved and $9701.35 ($4372.01 to dominated) per under-5 death averted. At a cost-effectiveness threshold of 1× per-capita GDP per DALY averted, IMI was estimated to be cost-effective with 90% probability. This evidence suggests IMI was both impactful and cost-effective for improving vaccination coverage, though there is a high degree of uncertainty in the results. As vaccination programmes expand coverage, unit costs may increase due to the higher costs of reaching currently unvaccinated children.

Betamethasone Exposure and Neonatal Respiratory Morbidity Among Late Preterm Births by Planned Mode of Delivery and Gestational Age.

OBJECTIVE: To estimate the effect of late preterm antenatal steroids on the risk of respiratory morbidity among subgroups of patients on the basis of the planned mode of delivery and gestational age at presentation. METHODS: This was a secondary analysis of the ALPS (Antenatal Late Preterm Steroid) Trial, a multicenter trial conducted within the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network of individuals with singleton gestations and without preexisting diabetes who were at high risk for late preterm delivery (34-36 weeks of gestation). We fit binomial regression models to estimate the risk of respiratory morbidity, with and without steroid administration, by gestational age and planned mode of delivery at the time of presentation. We assumed a homogeneous effect of steroids on the log-odds scale, as was reported in the ALPS trial. The primary outcome was neonatal respiratory morbidity, as defined in the ALPS Trial. RESULTS: The analysis included 2,825 patients at risk for late preterm birth. The risk of respiratory morbidity varied significantly by planned mode of delivery (adjusted risk ratio [RR] 1.90, 95% CI, 1.55-2.33 for cesarean delivery vs vaginal delivery) and week of gestation at presentation (adjusted RR 0.56, 95% CI, 0.50-0.63). For those planning cesarean delivery and presenting in the 34th week of gestation, the risk of neonatal respiratory morbidity was 39.4% (95% CI, 30.8-47.9%) without steroids and 32.0% (95% CI, 24.6-39.4%) with steroids. In contrast, for patients presenting in the 36th week and planning vaginal delivery, the risk of neonatal respiratory morbidity was 6.9% (95% CI, 5.2-8.6%) without steroids and 5.6% (95% CI, 4.2-7.0%) with steroids. CONCLUSION: The absolute risk difference of neonatal respiratory morbidity between those exposed and those unexposed to late preterm antenatal steroids varies considerably by gestational age at presentation and planned mode of delivery. Because only communicating the relative risk reduction of antenatal steroids for respiratory morbidity may lead to an inaccurate perception of benefit, more patient-specific estimates of risk expected with and without treatment may inform shared decision making.

Diffusion of subsidized ACTs in accredited drug shops in Tanzania: determinants of stocking and characteristics of early and late adopters.

BACKGROUND: Many households in sub-Saharan Africa utilize the private sector as a primary source of treatment for malaria episodes. Expanding access to effective treatment in private drug shops may help reduce incidence of severe disease and mortality. This research leveraged a longitudinal survey of stocking of subsidized artemisinin combination therapies (ACTs), an effective anti-malarial, in Accredited Drug Dispensing Outlets (ADDOs) in two regions of Tanzania. This provided a unique opportunity to explore shop and market level determinants of product diffusion in a developing country retail market. METHODS: 356 ADDOs in the Rukwa and Mtwara regions of Tanzania were surveyed at seven points between Feb 2011 and May 2012. Shop level audits were used to measure the availability of subsidized ACTs at each shop. Data on market and shop level factors were collected during the survey and also extracted from GIS layers. Regression and network based methodologies were used. Shops classified as early and late adopters, following Rogers' model of product diffusion, were compared. The Bass model of product diffusion was applied to determine whether shops stocked ACTs out of a need to imitate market competitors or a desire to satisfy customer needs. RESULTS: Following the introduction of a subsidy for ACTs, stocking increased from 12% to nearly 80% over the seven survey rounds. Stocking was influenced by higher numbers of proximal shops and clinics, larger customer traffic and the presence of a licensed pharmacist. Early adopters were characterized by a larger percentage of customers seeking care for malaria, a larger catchment and sourcing from specific wholesalers/suppliers. The Bass model of product diffusion indicated that shops were adopting products in response to competitor behavior, rather than customer demand. CONCLUSIONS: Decisions to stock new pharmaceutical products in Tanzanian ADDOs are influenced by a combination of factors related to both market competition and customer demand, but are particularly influenced by the behavior of competing shops. Efforts to expand access to new pharmaceutical products in developing country markets could benefit from initial targeting of high profile shops in competitive markets and wholesale suppliers to encourage faster product diffusion across all drug retailers.

Immediate postpartum care in low- and middle-income countries: A gap in healthcare quality research and practice.

The immediate postpartum period carries significant risks for complications such as postpartum hemorrhage and sepsis. Postpartum monitoring, including taking vital signs and monitoring blood loss, is important for the early identification and management of complications, but many women in low- and middle-income countries receive minimal attention in the period following childbirth to facility discharge. The World Health Organization recently released new guidelines on postnatal care, which include recommendations for immediate postpartum monitoring. In light of the new guidelines, this presented an opportune moment to address the gaps in postpartum monitoring in low- and middle-income countries. In this commentary, we bring attention to the importance of immediate postpartum monitoring. We identified opportunities for strengthening this often overlooked aspect of maternity care through improvements in quality measurement and data availability, research into barriers against high-quality care, and innovations in service delivery design.

The association of a disability-targeted cash transfer programme with disability status and health-care access: a quasi-experimental study using a nationwide cohort of 4·3 million Chinese adults living with severe disabilities.

BACKGROUND: Cash transfer is a crucial policy tool to address inequality. The objective of this study was to investigate the association between China's disability-targeted cash transfer programme and disability status, as well as equitable access to rehabilitation and medical services. METHODS: For this quasi-experimental study, we drew data from the nationwide administrative cohort of individuals with disabilities between Jan 1, 2015, and Dec 31, 2019. Individuals were enrolled in the cohort if they were aged 18 years or older, had severe disabilities as defined by the Chinese Government, and had available cash transfer information for at least 4 consecutive years, without having started receiving cash transfer benefits at the time of enrolment. We used a quasi-experimental design with propensity score matching to estimate the effects of cash transfers on disability status, access to rehabilitation services, and access to medical treatment. The primary outcomes were development of new disability and reduction of existing disabilities. Secondary outcomes were use of rehabilitation services, financial barriers as a major obstacle to accessing rehabilitation services, use of medical services by individuals who had an illness in the previous 2 weeks, and financial barriers as a major obstacle to accessing medical services. FINDINGS: From an initial pool of 51 356 125 individuals with disabilities registered in the administrative system, 2 686 024 individuals were eligible for analysis, of whom 2 165 335 (80·6%) were cash transfer beneficiaries and 520 689 (19·4%) non-beneficiaries. After propensity score matching, the cohort included 4 330 122 adults with severe disabilities. Cash transfer beneficiaries had significantly lower odds of developing new disabilities over time than non-beneficiaries (odds ratio [OR] 0·90, 95% CI 0·86-0·94; p<0·0001) and higher odds of having a reduced number of disabilities over time (1·17, 1·10-1·25; p<0·0001). Compared with non-beneficiaries, cash transfer beneficiaries were more likely to use rehabilitation services (2·12, 2·11-2·13; p<0·0001) and medical services (1·74, 1·69-1·78; p<0·0001), and less likely to report financial hardship to access rehabilitation services (0·53, 0·52-0·54; p<0·0001) and medical services (0·88, 0·84-0·93; p<0·0001) at the study endpoint. INTERPRETATION: The receipt of cash transfers was associated with improved disability status and increased access to disability-related services. The findings suggest that cash transfers could be a potential method for promoting universal health coverage among individuals living with disabilities. FUNDING: China National Natural Science Foundation.

Conjugation chemistry through acetals toward a dextran-based delivery system for controlled release of siRNA.

New conjugation chemistry for polysaccharides, exemplified by dextran, was developed to enable the attachment of therapeutic or other functional moieties to the polysaccharide through cleavable acetal linkages. The acid-lability of the acetal groups allows the release of therapeutics under acidic conditions, such as that of the endocytic compartments of cells, regenerating the original free polysaccharide in the end. The physical and chemical behavior of these acetal groups can be adjusted by modifying their stereoelectronic and steric properties, thereby providing materials with tunable degradation and release rates. We have applied this conjugation chemistry in the development of water-soluble siRNA carriers, namely acetal-linked amino-dextrans, with various amine structures attached through either slow- or fast-degrading acetal linker. The carriers with the best combination of amine moieties and structural composition of acetals showed high in vitro transfection efficiency and low cytotoxicity in the delivery of siRNA.