Acceptability of a hypothetical dengue vaccine and the potential impact of dengue vaccination on personal vector control behavior: a qualitative study in Fortaleza, Brazil.

BACKGROUND: Dengue is the most rapidly spreading viral vector-borne disease in the world. Promising new dengue vaccines have contributed to a growing consensus that effective dengue control will require integrated strategies of vaccination and vector control. In this qualitative study, we explored the perspectives of residents of Fortaleza, Brazil on acceptability of a hypothetical safe and effective dengue vaccine, specific drivers of dengue vaccine acceptance or hesitance, and the expected impact of dengue vaccination on their personal vector control practices. METHODS: A total of 43 in-depth interviews were conducted from April to June 2022 with Fortaleza residents from a diverse range of educational and professional backgrounds, with and without recent personal experiences of symptomatic dengue infections. Data were analyzed using the principles of inductive grounded theory methodology. RESULTS: Our findings indicate that knowledge of dengue transmission, symptoms, and prevention methods was strong across respondents. Respondents described willingness to accept a hypothetical dengue vaccine for themselves and their children, while emphasizing that the vaccine must be demonstrably safe and effective. Respondents expressed diverse perspectives on how receiving a safe and effective dengue vaccine might influence their personal vector control behaviors, relating these behaviors to their perception of risk from other Aedes mosquito-carried infections and beliefs about the role of vector control in maintaining household cleanliness. CONCLUSIONS: Our study findings provide community-level perspectives on dengue vaccination and its potential impact on personal vector control behavior for policymakers and program managers in Fortaleza to consider as new dengue vaccines become available. With the introduction of any new dengue vaccine, community perspectives and emerging concerns that may drive vaccine hesitancy should be continuously sought out. Improved urban infrastructure and efforts to engage individuals and communities in vector control may be needed to optimize the impact of future dengue vaccinations and prevent rising cases of other arboviruses such as Zika and chikungunya.

Effectiveness of reactive focal mass drug administration and reactive focal vector control to reduce malaria transmission in the low malaria-endemic setting of Namibia: a cluster-randomised controlled, open-label, two-by-two factorial design trial.

BACKGROUND: In low malaria-endemic settings, screening and treatment of individuals in close proximity to index cases, also known as reactive case detection (RACD), is practised for surveillance and response. However, other approaches could be more effective for reducing transmission. We aimed to evaluate the effectiveness of reactive focal mass drug administration (rfMDA) and reactive focal vector control (RAVC) in the low malaria-endemic setting of Zambezi (Namibia). METHODS: We did a cluster-randomised controlled, open-label trial using a two-by-two factorial design of 56 enumeration area clusters in the low malaria-endemic setting of Zambezi (Namibia). We randomly assigned these clusters using restricted randomisation to four groups: RACD only, rfMDA only, RAVC plus RACD, or rfMDA plus RAVC. RACD involved rapid diagnostic testing and treatment with artemether-lumefantrine and single-dose primaquine, rfMDA involved presumptive treatment with artemether-lumefantrine, and RAVC involved indoor residual spraying with pirimiphos-methyl. Interventions were administered within 500 m of index cases. To evaluate the effectiveness of interventions targeting the parasite reservoir in humans (rfMDA vs RACD), in mosquitoes (RAVC vs no RAVC), and in both humans and mosquitoes (rfMDA plus RAVC vs RACD only), an intention-to-treat analysis was done. For each of the three comparisons, the primary outcome was the cumulative incidence of locally acquired malaria cases. This trial is registered with ClinicalTrials.gov, number NCT02610400. FINDINGS: Between Jan 1, 2017, and Dec 31, 2017, 55 enumeration area clusters had 1118 eligible index cases that led to 342 interventions covering 8948 individuals. The cumulative incidence of locally acquired malaria was 30·8 per 1000 person-years (95% CI 12·8-48·7) in the clusters that received rfMDA versus 38·3 per 1000 person-years (23·0-53·6) in the clusters that received RACD; 30·2 per 1000 person-years (15·0-45·5) in the clusters that received RAVC versus 38·9 per 1000 person-years (20·7-57·1) in the clusters that did not receive RAVC; and 25·0 per 1000 person-years (5·2-44·7) in the clusters that received rfMDA plus RAVC versus 41·4 per 1000 person-years (21·5-61·2) in the clusters that received RACD only. After adjusting for imbalances in baseline and implementation factors, the incidence of malaria was lower in clusters receiving rfMDA than in those receiving RACD (adjusted incidence rate ratio 0·52 [95% CI 0·16-0·88], p=0·009), lower in clusters receiving RAVC than in those that did not (0·48 [0·16-0·80], p=0·002), and lower in clusters that received rfMDA plus RAVC than in those receiving RACD only (0·26 [0·10-0·68], p=0·006). No serious adverse events were reported. INTERPRETATION: In a low malaria-endemic setting, rfMDA and RAVC, implemented alone and in combination, reduced malaria transmission and should be considered as alternatives to RACD for elimination of malaria. FUNDING: Novartis Foundation, Bill & Melinda Gates Foundation, and Horchow Family Fund.

Allele-Specific Inhibition of Histone Demethylases.

Histone demethylases play a critical role in mammalian gene expression by removing methyl groups from lysine residues in degree- and site-specific manner. To specifically interrogate members and isoforms of this class of enzymes, we have developed demethylase variants with an expanded active site. The mutant enzymes are capable of performing lysine demethylation with wild-type proficiency, but are sensitive to inhibition by cofactor-competitive molecules embellished with a complementary steric "bump". The selected inhibitors show more than 20-fold selectivity over the wild-type demethylase, thus overcoming issues typical to pharmacological and genetic approaches. The mutant-inhibitor pairs are shown to act on a physiologically relevant full-length substrate. By engineering a conserved amino acid to achieve member-specific perturbation, this study provides a general approach for studying histone demethylases in diverse cellular processes.

Randomised placebo-controlled safety and tolerability trial of FK506 (tacrolimus) for pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a devastating disease characterised by occlusive pulmonary vasculopathy. Activation of bone morphogenetic protein receptor 2 (BMPR2) signalling by FK506 (tacrolimus) reverses occlusive vasculopathy in rodent PAH models. Here, we determined the safety and tolerability of low-level FK506 therapy in stable PAH patients.We performed a randomised, double-blind, placebo-controlled, 16-week, single-centre, phase IIa trial in PAH patients with New York Heart Association functional class II/III symptoms using three FK506 target levels (<2, 2-3 and 3-5 ng·mL-1). 23 patients were randomised and 20 patients completed the trial.FK506 was generally well tolerated, with nausea/diarrhoea being the most commonly reported adverse event and no observation of line infections in patients on intravenous prostacyclin therapy. PAH patients had significantly lower BMPR2 expression in peripheral blood mononuclear cells versus healthy controls (n=13; p=0.005), which improved after FK506 treatment. While we observed that some patients responded with a pronounced increase in BMPR2 expression as well as improvement in 6-min walk distance, and serological and echocardiographic parameters of heart failure, these changes were not significant.Low-level FK506 is well tolerated and increases BMPR2 in subsets of PAH patients. These results support the study of FK506 in a phase IIb efficacy trial.

Expanding access to parasite-based malaria diagnosis through retail drug shops in Tanzania: evidence from a randomized trial and implications for treatment.

BACKGROUND: Tanzania has seen a reduction in the fraction of fevers caused by malaria, likely due in part to scale-up of control measures. While national guidelines require parasite-based diagnosis prior to treatment, it is estimated that more than half of suspected malaria treatment-seeking in Tanzania initiates in the private retail sector, where diagnosis by malaria rapid diagnostic test (RDT) or microscopy is illegal. This pilot study investigated whether the introduction of RDTs into Accredited Drug Dispensing Outlets (ADDOs) under realistic market conditions would improve case management practices. METHODS: Dispensers from ADDOs in two intervention districts in Tanzania were trained to stock and perform RDTs and monitored quarterly. Each district was assigned a different recommended retail price to evaluate the need for a subsidy. Malaria RDT and artemisinin-based combination therapy (ACT) uptake and availability were measured pre-intervention and 1 year post-intervention through structured surveys of ADDO owners and exiting customers in both intervention districts and one contiguous control district. Descriptive analysis and logistic regression were used to compare the three districts and identify predictive variables for testing. RESULTS AND DISCUSSION: A total of 310 dispensers from 262 ADDOs were trained to stock and perform RDTs. RDT availability in intervention ADDOs increased from 1% (n = 172) to 73% (n = 163) during the study; ACT medicines were available in 75% of 260 pre-intervention and 68% of 254 post-intervention ADDOs. Pre-treatment testing performed within the ADDO increased from 0 to 65% of suspected malaria patients who visited a shop (95% CI 60.8-69.6%) with no difference between intervention districts. Overall parasite-based diagnosis increased from 19 to 74% in intervention districts and from 3 to 18% in the control district. Prior knowledge of RDT availability (aOR = 1.9, p = 0.03) and RDT experience (aOR = 1.9, p = 0.01) were predictors for testing. Adherence data indicated that 75% of malaria positives received ACT, while 3% of negatives received ACT. CONCLUSIONS: Trained and supervised ADDO dispensers in rural Tanzania performed and sold RDTs under real market conditions to two-thirds of suspected malaria patients during this one-year pilot. These results support the hypothesis that introducing RDTs into regulated private retail sector settings can improve malaria testing and treatment practices without an RDT subsidy. Trial registration ISRCTN ISRCTN14115509.

Robust CNT field emitters: patterning, growth, transfer, and in situ anchoring.

Robust carbon nanotube (CNT)-based cold cathodes were fabricated on titanium (Ti) substrates. Methods to grow vertically aligned CNTs  directly on Ti substrates were developed. These cathodes can be treated post-growth at elevated temperatures under inert atmosphere which causes the surface-grown CNTs to become anchored to the substrate surface. These samples offer improvements in field emission properties over previously studied silicon (Si) substrate-based cathodes with no anchoring, displaying low threshold voltages, high field enhancement factors, and long operating lifetimes. Current densities of 25 mA cm-2 were held for over 24 h with anchored samples at low electric fields (observed thresholds as low as 0.5 V µm-1) and more current stability. Higher current densities of up to 150 mA cm-2 could be reached with anchored samples, limited only by the experimental setup. In efforts to generate even more stable and reproducible field emission, a transfer process of CNTs from polished Si to Ti with copper (Cu) was developed (flipCNTs). These cathodes display extreme improvements over previous results, with observed thresholds as low as 0.2 V µm-1 and γ-factors as high as 30 000. To demonstrate the utility of these robust cathodes, a flipCNT-based cathode was assembled into a fully functioning vacuum triode.

Incremental Cost of Emergency Versus Elective Surgery.

OBJECTIVE: To determine hospital costs and the adjusted risk of death associated with emergent versus elective surgery. BACKGROUND: Emergency surgery has a higher cost and worse outcomes compared with elective surgery. However, no national estimates of the excess burden of emergency surgery exist. METHODS: Nationwide Inpatient Sample (NIS) data from 2001 to 2010 were analyzed. Patients aged 18 years or older who underwent abdominal aortic aneurysm repair, coronary artery bypass graft, or colon resection for neoplasm were included. Using generalized linear models with propensity scores, cost differences for emergent versus elective admission were calculated for each procedure. Multivariable logistic regression was performed to investigate the adjusted odds of mortality comparing elective and emergent cases. Discharge-level weights were applied to analyses. RESULTS: A total of 621,925 patients, representing a weighted population of 3,057,443, were included. The adjusted mean cost difference for emergent versus elective care was $8741.22 (30% increase) for abdominal aortic aneurysm repair, $5309.78 (17% increase) for coronary artery bypass graft, and $7813.53 (53% increase) for colon resection. If 10% of the weighted estimates of emergency procedures had been performed electively, the cost benefit would have been nearly $1 billion, at $996,169,160 (95% confidence interval [CI], $985,505,565-$1,006,834,104). Elective surgery patients had significantly lower adjusted odds of mortality for all procedures. CONCLUSIONS: Even a modest reduction in the proportion of emergent procedures for 3 conditions is estimated to save nearly $1 billion over 10 years. Preventing emergency surgery through improved care coordination and screening offers a tremendous opportunity to save lives and decrease costs.

Association between intentional injury and long-term survival after trauma.

OBJECTIVE: To determine the risk-adjusted mortality of intentionally injured patients within 7 to 9 years postinjury, compared with unintentionally injured patients. BACKGROUND: Violent injury contributes significantly to trauma mortality in the United States. Homicide is the second leading killer of American youth, aged 15 to 24 years. Long-term survival among intentionally injured patients has not been well studied. It is also unknown whether intentionally injured patients have worse long-term survival compared with unintentionally or accidentally injured patients with equivalent injuries. METHODS: Adult trauma patients admitted for 24 hours or more and discharged alive from the Johns Hopkins Hospital from January 1, 1998, to December 31, 2000, were included. The primary outcome was mortality within 7 to 9 years postinjury. Long-term patient survival was determined using the National Death Index. The association between injury intentionality and mortality was investigated using a Cox proportional hazard regression model, adjusted for confounders such as injury severity and patient race, socioeconomic status, and comorbid conditions. Overall differences in survival between those with intentional versus unintentional injury were also determined by comparing adjusted Kaplan-Meier survival curves. RESULTS: A total of 2062 patients met inclusion criteria. Of these, 56.4% were intentionally injured and 43.6% were unintentionally injured. Compared with unintentionally injured patients, intentionally injured patients were younger and more often male and from a zip code with low median household income. Approximately 15% of all patients had died within 7 to 9 years of follow-up. Older age and presence of comorbidities were associated with this outcome; however, intentional injury was not found to be significantly associated with long-term mortality rates. There was also no significant difference in survival curves between groups; intentionally injured patients were much more likely to die of a subsequent injury, whereas those with unintentional injury commonly died of noninjury causes. CONCLUSIONS: There was no significant difference in mortality between intentionally injured and unintentionally injured patients within 7 to 9 years postinjury. These results confirm the long-term effectiveness of lifesaving trauma care for those with intentional injury. However, given that patients with intentional injuries were more likely to suffer a subsequent violent death, interventions focused on breaking the cycle of violence are needed.

Counting the lives lost: how many black trauma deaths are attributable to disparities?

BACKGROUND: The number of black trauma deaths attributable to racial disparities is unknown. The objective of this study was to quantify the excess mortality experienced by black patients given disparities in the risk of mortality. MATERIALS AND METHODS: We performed a retrospective analysis of patients aged 16-65 y with blunt and penetrating injuries, who were included in the National Trauma Data Bank from 2007-2010. Generalized linear modeling estimated the relative risk of death for black patients versus white patients, adjusting for known confounders. This analysis determined the difference in the observed number of black trauma deaths at Level I and II centers and the expected number of deaths if the risk of mortality for black patients had been equivalent to that of white patients. RESULTS: A total of 1.06 million patients were included. Among patients with blunt and penetrating injuries at Level I trauma centers, white males and females had a relative risk of death of 0.82 (95% confidence interval [CI], 0.80-0.85) and 0.78 (95% CI, 0.74-0.83), respectively, compared with black patients. Similarly, at Level II trauma centers, white males and females had a relative risk of death of 0.84 (95% CI, 0.80-0.88) and 0.82 (95% CI, 0.73-0.91). Overall, of the estimated 41,613 deaths that occurred at Level I and II centers, 2206 (5.3%) were excess deaths among black patients. CONCLUSIONS: Over a 4-y period, approximately 5% of trauma center deaths could be attributed to racial disparities in trauma outcomes. These data underscore the need to better understand and intervene against the mechanisms that lead to trauma outcomes disparities.

Increased risk of pneumonia among ventilated patients with traumatic brain injury: every day counts!

BACKGROUND: Patients with traumatic brain injury (TBI) frequently require mechanical ventilation (MV). The objective of this study was to examine the association between time spent on MV and the development of pneumonia among patients with TBI. MATERIALS AND METHODS: Patients older than 18 y with head abbreviated injury scale (AIS) scores coded 1-6 requiring MV in the National Trauma Data Bank 2007-2010 data set were included. The study was limited to hospitals reporting pneumonia cases. AIS scores were calculated using ICDMAP-90 software. Patients with injuries in any other region with AIS score >3, significant burns, or a hospital length of stay >30 d were excluded. A generalized linear model was used to determine the approximate relative risk of developing all-cause pneumonia (aspiration pneumonia, ventilator-associated pneumonia [VAP], and infectious pneumonia identified by the International Classification of Disease, Ninth Revision, diagnosis code) for each day of MV, controlling for age, gender, Glasgow coma scale motor score, comorbidity (Charlson comorbidity index) score, insurance status, and injury type and severity. RESULTS: Among the 24,525 patients with TBI who required MV included in this study, 1593 (6.5%) developed all-cause pneumonia. After controlling for demographic and injury factors, each additional day on the ventilator was associated with a 7% increase in the risk of pneumonia (risk ratio 1.07, 95% confidence interval 1.07-1.08). CONCLUSIONS: Patients who have sustained TBIs and require MV are at higher risk for VAP than individuals extubated earlier; therefore, shortening MV exposure will likely reduce the risk of VAP. As patients with TBI frequently require MV because of neurologic impairment, it is key to develop aggressive strategies to expedite ventilator independence.

National cost of trauma care by payer status.

BACKGROUND: Several studies have described the burden of trauma care, but few have explored the economic burden of trauma inpatient costs from a payer's perspective or highlighted the differences in the average costs per person by payer status. The present study provides a conservative inpatient national trauma cost estimate and describes the variation in average inpatient trauma cost by payer status. METHODS: A retrospective analysis of patients who had received trauma care at hospitals in the Nationwide Inpatient Sample from 2005-2010 was conducted. Our sample patients were selected using the appropriate "International Classification of Diseases, Ninth Revision, Clinical Modification" codes to identify admissions due to traumatic injury. The data were weighted to provide national population estimates, and all cost and charges were converted to 2010 US dollar equivalents. Generalized linear models were used to describe the costs by payer status, adjusting for patient characteristics, such as age, gender, and race, and hospital characteristics, such as location, teaching status, and patient case mix. RESULTS: A total of 2,542,551 patients were eligible for the present study, with the payer status as follows: 672,960 patients (26.47%) with private insurance, 1,244,817 (48.96%) with Medicare, 262,256 (10.31%) with Medicaid, 195,056 (7.67%) with self-pay, 18,506 (0.73%) with no charge, and 150,956 (5.94%) with other types of insurance. The estimated yearly trauma inpatient cost burden was highest for Medicare at $17,551,393,082 (46.79%), followed by private insurance ($10,772,025,421 [28.72%]), Medicaid ($3,711,686,012 [9.89%], self-pay ($2,831,438,460 [7.55%]), and other payer types ($2,370,187,494 [6.32%]. The estimated yearly trauma inpatient cost burden was $274,598,190 (0.73%) for patients who were not charged for their inpatient trauma treatment. Our adjusted national inpatient trauma yearly costs were estimated at $37,511,328,659 US dollars. Privately insured patients had a significantly higher mean cost per person than did the Medicare, Medicaid, self-pay, or no charge patients. CONCLUSIONS: The results of the present study have demonstrated that the distribution of trauma burden across payers is significantly different from that of the overall healthcare system and suggest that although the burden of trauma is high, the burden of self-pay or nonreimbursed inpatient services is actually lower than that of overall medical care.

A multistep mediation model examining how consultation in prolonged exposure therapy affects PTSD treatment outcomes.

Prolonged exposure therapy (PE) is an evidence-based psychotherapy (EBP) for posttraumatic stress disorder (PTSD) that is underutilized in the military health system. Previous research suggests that postworkshop consultation is important for successful implementation. However, little is known about how consultation may relate to EBP adoption or patient outcomes. The present study addressed these gaps by examining associations between consultation, provider self-efficacy, use of PE, and patient outcomes using a multistep mediation model. This study used data from Foa et al. (2020), a two-armed randomized implementation trial comparing two PE training models: standard training (workshop only) and extended training (workshop + 6-8 months of postworkshop expert consultation) at three U.S. Army sites. Participants were patients with PTSD (N = 242) receiving care from the participating providers (N = 103). Providers who received extended training reported greater PE self-efficacy compared to standard training providers, but self-efficacy was unrelated to their use of PE components or to patient outcomes. Extended training providers used more PE components and had superior patient outcomes than standard training providers, and patient outcomes were mediated by the use of PE components. To our knowledge, this is the first study to demonstrate that EBP consultation leads to improved clinical outcomes for patients through increased use of the EBP. PE adoption (i.e., use of PE components in therapy) was not explained by increases in self-efficacy among providers who received extended training. Therefore, future research should assess how other factors may influence provider behavior in implementing EBPs. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Impact of 1,7-malaria reactive community-based testing and response (1,7-mRCTR) approach on malaria prevalence in Tanzania.

BACKGROUND: Progress in malaria control has stalled in recent years and innovative surveillance and response approaches are needed to accelerate malaria control and elimination efforts in endemic areas of Africa. Building on a previous China-UK-Tanzania pilot study on malaria control, this study aimed to assess the impact of the 1,7-malaria Reactive Community-Based Testing and Response (1,7-mRCTR) approach implemented over two years in three districts of Tanzania. METHODS: The 1,7-mRCTR approach provides community-based malaria testing via rapid diagnostic tests and treatment in villages with the highest burden of malaria incidence based on surveillance data from health facilities. We used a difference-in-differences quasi-experimental design with linear probability models and two waves of cross-sectional household surveys to assess the impact of 1,7-mRCTR on malaria prevalence. We conducted sensitivity analyses to assess the robustness of our results, examined how intervention effects varied in subgroups, and explored alternative explanations for the observed results. RESULTS: Between October 2019 and September 2021, 244,771 community-based malaria rapid tests were completed in intervention areas, and each intervention village received an average of 3.85 rounds of 1-7mRCTR. Malaria prevalence declined from 27.4% at baseline to 11.7% at endline in the intervention areas and from 26.0% to 16.0% in the control areas. 1,7-mRCTR was associated with a 4.5-percentage-point decrease in malaria prevalence (95% confidence interval: - 0.067, - 0.023), equivalent to a 17% reduction from the baseline. In Rufiji, a district characterized by lower prevalence and where larviciding was additionally provided, 1,7-mRCTR was associated with a 63.9% decline in malaria prevalence. CONCLUSIONS: The 1,7-mRCTR approach reduced malaria prevalence. Despite implementation interruptions due to the COVID-19 pandemic and supply chain challenges, the study provided novel evidence on the effectiveness of community-based reactive approaches in moderate- to high-endemicity areas and demonstrated the potential of South-South cooperation in tackling global health challenges.

Allele-Specific Chemical Rescue of Histone Demethylases Using Abiotic Cofactors.

Closely related protein families evolved from common ancestral genes present a significant hurdle in developing member- and isoform-specific chemical probes, owing to their similarity in fold and function. In this piece of work, we explore an allele-specific chemical rescue strategy to activate a "dead" variant of a wildtype protein using synthetic cofactors and demonstrate its successful application to the members of the alpha-ketoglutarate (αKG)-dependent histone demethylase 4 (KDM4) family. We show that a mutation at a specific residue in the catalytic site renders the variant inactive toward the natural cosubstrate. In contrast, αKG derivatives bearing appropriate stereoelectronic features endowed the mutant with native-like demethylase activity while remaining refractory to a set of wild type dioxygenases. The orthogonal enzyme-cofactor pairs demonstrated site- and degree-specific lysine demethylation on a full-length chromosomal histone in the cellular milieu. Our work offers a strategy to modulate a specific histone demethylase by identifying and engineering a conserved phenylalanine residue, which acts as a gatekeeper in the KDM4 subfamily, to sensitize the enzyme toward a novel set of αKG derivatives. The orthogonal pairs developed herein will serve as probes to study the role of degree-specific lysine demethylation in mammalian gene expression. Furthermore, this approach to overcome active site degeneracy is expected to have general application among all human αKG-dependent dioxygenases.

Cost and cost effectiveness of reactive case detection (RACD), reactive focal mass drug administration (rfMDA) and reactive focal vector control (RAVC) to reduce malaria in the low endemic setting of Namibia: an analysis alongside a 2×2 factorial design cluster randomised controlled trial.

OBJECTIVES: To estimate the cost and cost effectiveness of reactive case detection (RACD), reactive focal mass drug administration (rfMDA) and reactive focal vector control (RAVC) to reduce malaria in a low endemic setting. SETTING: The study was part of a 2×2 factorial design cluster randomised controlled trial within the catchment area of 11 primary health facilities in Zambezi, Namibia. PARTICIPANTS: Cost and outcome data were collected from the trial, which included 8948 community members that received interventions due to their residence within 500 m of malaria index cases. OUTCOME MEASURES: The primary outcome was incremental cost effectiveness ratio (ICER) per in incident case averted. ICER per prevalent case and per disability-adjusted life years (DALY) averted were secondary outcomes, as were per unit interventions costs and personnel time. Outcomes were compared as: (1) rfMDA versus RACD, (2) RAVC versus no RAVC and (3) rfMDA+RAVC versus RACD only. RESULTS: rfMDA cost 1.1× more than RACD, and RAVC cost 1.7× more than no RAVC. Relative to RACD only, the cost of rfMDA+RAVC was double ($3082 vs $1553 per event). The ICERs for rfMDA versus RACD, RAVC versus no RAVC and rfMDA+RAVC versus RACD only were $114, $1472 and $842, per incident case averted, respectively. Using prevalent infections and DALYs as outcomes, trends were similar. The median personnel time to implement rfMDA was 20% lower than for RACD (30 vs 38 min per person). The median personnel time for RAVC was 34 min per structure sprayed. CONCLUSION: Implemented alone or in combination, rfMDA and RAVC were cost effective in reducing malaria incidence and prevalence despite higher implementation costs in the intervention compared with control arms. Compared with RACD, rfMDA was time saving. Cost and time requirements for the combined intervention could be decreased by implementing rfMDA and RAVC simultaneously by a single team. TRIAL REGISTRATION NUMBER: NCT02610400; Post-results.

Serological evaluation of the effectiveness of reactive focal mass drug administration and reactive vector control to reduce malaria transmission in Zambezi Region, Namibia: Results from a secondary analysis of a cluster randomised trial.

BACKGROUND: Due to challenges in measuring changes in malaria at low transmission, serology is increasingly being used to complement clinical and parasitological surveillance. Longitudinal studies have shown that serological markers, such as Etramp5.Ag1, can reflect spatio-temporal differences in malaria transmission. However, these markers have yet to be used as endpoints in intervention trials. METHODS: Based on data from a 2017 cluster randomised trial conducted in Zambezi Region, Namibia, evaluating the effectiveness of reactive focal mass drug administration (rfMDA) and reactive vector control (RAVC), this study conducted a secondary analysis comparing antibody responses between intervention arms as trial endpoints. Antibody responses were measured on a multiplex immunoassay, using a panel of eight serological markers of Plasmodium falciparum infection - Etramp5.Ag1, GEXP18, HSP40.Ag1, Rh2.2030, EBA175, PfMSP119, PfAMA1, and PfGLURP.R2. FINDINGS: Reductions in sero-prevalence to antigens Etramp.Ag1, PfMSP119, Rh2.2030, and PfAMA1 were observed in study arms combining rfMDA and RAVC, but only effects for Etramp5.Ag1 were statistically significant. Etramp5.Ag1 sero-prevalence was significantly lower in all intervention arms. Compared to the reference arms, adjusted prevalence ratio (aPR) for Etramp5.Ag1 was 0.78 (95%CI 0.65 - 0.91, p = 0.0007) in the rfMDA arms and 0.79 (95%CI 0.67 - 0.92, p = 0.001) in the RAVC arms. For the combined rfMDA plus RAVC intervention, aPR was 0.59 (95%CI 0.46 - 0.76, p < 0.0001). Significant reductions were also observed based on continuous antibody responses. Sero-prevalence as an endpoint was found to achieve higher study power (99.9% power to detect a 50% reduction in prevalence) compared to quantitative polymerase chain reaction (qPCR) prevalence (72.9% power to detect a 50% reduction in prevalence). INTERPRETATION: While the observed relative reduction in qPCR prevalence in the study was greater than serology, the use of serological endpoints to evaluate trial outcomes measured effect size with improved precision and study power. Serology has clear application in cluster randomised trials, particularly in settings where measuring clinical incidence or infection is less reliable due to seasonal fluctuations, limitations in health care seeking, or incomplete testing and reporting. FUNDING: This study was supported by Novartis Foundation (A122666), the Bill & Melinda Gates Foundation (OPP1160129), and the Horchow Family Fund (5,300,375,400).

Fixed dose rivaroxaban can be used in extremes of bodyweight: A population pharmacokinetic analysis.

BACKGROUND: Emerging safety and efficacy data for rivaroxaban suggest traditional therapy and rivaroxaban are comparable in the morbidly obese. However, real-world data that indicate pharmacokinetic (PK) parameters are comparable at the extremes of body size are lacking. The International Society of Thrombosis and Haemostasis Scientific and Standardisation Committee (ISTH SSC) suggests avoiding the use of direct oral anticoagulants (DOACs) in patients weighing >120 kg or with a body mass index >40 kg/m2 and gives no recommendation on the use of DOACs in those <50 kg. OBJECTIVES: To generate a population PK model to understand the influence of bodyweight on rivaroxaban exposure from clinical practice data. METHOD: Rivaroxaban plasma concentrations and patient characteristics were collated between 2013 and 2018 at King's College Hospital anticoagulation clinic. A population PK model was developed using a nonlinear mixed effects approach and then used to simulate rivaroxaban concentrations at the extremes of bodyweight. RESULTS: A robust population PK model derived from 913 patients weighing between 39 kg and 172 kg was developed. The model included data from n = 86 >120 kg, n = 74 BMI >40 kg/m2 , and n = 30 <50 kg. A one-compartment model with between-subject variability on clearance and a proportional error model best described the data. Creatinine clearance calculated by Cockcroft-Gault, with lean bodyweight as the weight descriptor in this equation, was the most significant covariate influencing rivaroxaban exposure. CONCLUSIONS: Our work demonstrates rivaroxaban can be used at extremes of bodyweight provided renal function is satisfactory. We recommend that the ISTH SSC revises the current guidance with respect to rivaroxaban at extremes of body size.

The effects of a prolonged exposure workshop with and without consultation on provider and patient outcomes: a randomized implementation trial.

BACKGROUND: Prolonged exposure therapy (PE) is an evidence-based treatment for posttraumatic stress disorder (PTSD) that is underutilized in the military health system. Standard workshop training in PE may not be sufficient to alter provider behavior, but post-workshop consultation requires significant resources. Therefore, it is important to determine the incremental utility of post-workshop consultation. METHODS: This study used a hybrid type III randomized implementation trial at 3 US Army installations. Providers were randomized to receive a 4-day prolonged exposure workshop (Standard training condition, n = 60), or the prolonged exposure workshop followed by 6-8 months of post-workshop expert case consultation (Extended training condition, n = 43). The effects training condition were examined on provider attitudes (self-efficacy in delivering PE, expectations for patient improvement, and beliefs about PE), use of PE and PE components, and clinical outcomes of patients with PTSD (using the Clinician-Administered PTSD Scale (CAPS-5)). RESULTS: Extended condition providers reported greater improvements in self-efficacy, b = .83, 95% CI [.38, 1.27], t(79) = 3.71, p = .001, and d = .63. A greater proportion of patients in the Extended condition (44%) than in the Standard condition (27%) received at least 1 PE session, b = .76, t(233) = 2.53, p = .012, and OR = 2.13. Extended condition providers used more PE components (M = .9/session) than did Standard condition providers (M = .5/session), b = .54, 95% CI [.15, .93], t(68) = 2.70, p = .007, and d = .68. Finally, decrease in patients' PTSD symptoms was faster for patients of Extended condition providers than for patients of Standard condition providers, b = - 1.81, 95% CI [- 3.57, - .04], t(263) = - 2.02, p = .045, and d = .66, and their symptoms were lower at the second assessment, b = - 5.47, 95% CI [- 9.30, - 1.63], t(210) = - 2.81, p = .005, and d = .66. CONCLUSIONS: Post-workshop consultation improved self-efficacy for delivering PE, greater use of PE, faster PTSD reduction, and lower PTSD severity at the second assessment. To our knowledge, this is the first demonstration that post-workshop case consultation for PE improves patient outcomes. TRIAL REGISTRATION: Clinicaltrials.gov , NCT02982538 . Registered December 5, 2016; retrospectively registered.

Probing Ca2+-induced conformational change of calmodulin with gold nanoparticle-decorated single-walled carbon nanotube field-effect transistors.

Nanomaterials are ideal for electrochemical biosensors, with their nanoscale dimensions enabling the sensitive probing of biomolecular interactions. In this study, we compare field-effect transistors (FET) comprised of unsorted (un-) and semiconducting-enriched (sc-) single-walled carbon nanotubes (SWCNTs). un-SWCNTs have both metallic and semiconducting SWCNTs in the ensemble, while sc-SWCNTs have a >99.9% purity of semiconducting nanotubes. Both SWCNT FET devices were decorated with gold nanoparticles (AuNPs) and were then employed in investigating the Ca2+-induced conformational change of calmodulin (CaM) - a vital process in calcium signal transduction in the human body. Different biosensing behavior was observed from FET characteristics of the two types of SWCNTs, with sc-SWCNT FET devices displaying better sensing performance with a dynamic range from 10-15 M to 10-13 M Ca2+, and a lower limit of detection at 10-15 M Ca2+.

Selective methylative homologation: an alternate route to alkane upgrading.

InI3 catalyzes the reaction of branched alkanes with methanol to produce heavier and more highly branched alkanes, which are more valuable fuels. The reaction of 2,3-dimethylbutane with methanol in the presence of InI3 at 180-200 degrees C affords the maximally branched C7 alkane, 2,2,3-trimethylbutane (triptane). With the addition of catalytic amounts of adamantane the selectivity of this transformation can be increased up to 60%. The lighter branched alkanes isobutane and isopentane also react with methanol to generate triptane, while 2-methylpentane is converted into 2,3-dimethylpentane and other more highly branched species. Observations implicate a chain mechanism in which InI3 activates branched alkanes to produce tertiary carbocations which are in equilibrium with olefins. The latter react with a methylating species generated from methanol and InI3 to give the next-higher carbocation, which accepts a hydride from the starting alkane to form the homologated alkane and regenerate the original carbocation. Adamantane functions as a hydride transfer agent and thus helps to minimize competing side reactions, such as isomerization and cracking, that are detrimental to selectivity.