A phase 1 study in healthy volunteers to investigate the safety, tolerability, and pharmacokinetics of VIR-2482: a monoclonal antibody for the prevention of severe influenza A illness.

The objective of this study was to evaluate the safety, tolerability, pharmacokinetics (PK), and immunogenicity of VIR-2482 in healthy adult subjects. A phase 1, first-in-human, randomized, double-blind, placebo-controlled dose-escalation study was conducted. One hundred participants were allocated to four cohorts (60 mg, 300 mg, 1,200 mg, and 1,800 mg). In each cohort, participants were randomized in a 4:1 ratio (active:placebo) to receive either VIR-2482 or volume-matched placebo by gluteal intramuscular injection. Participants remained at the investigative site under observation for 48 h, and adverse events (AEs) were collected for 56 days. PK and immunogenicity were measured up to 52 weeks post-dose. VIR-2482 was well tolerated at all doses studied. The overall incidence of AEs was comparable between VIR-2482 (68.8%) and placebo (85.0%). Nineteen VIR-2482 (23.8%) and six placebo (30.0%) recipients had Grade 1 or 2 AEs that were considered to be related to the study intervention. There were no treatment-related serious AEs. Injection-site reactions (ISRs) were reported in six (7.5%) VIR-2482 recipients, while no such reactions were reported among the placebo recipients. All ISRs were Grade 1, and there was no relationship with the dose. Median VIR-2482 serum elimination half-life ranged from 56.7 to 70.6 days across cohorts. The serum area under the curve and Cmax were dose-proportional. Nasopharyngeal VIR-2482 concentrations were approximately 2%-5% of serum levels and were less than dose-proportional. The incidence of immunogenicity across all cohorts was 1.3%. Overall, the safety, tolerability, and pharmacokinetic profile of VIR-2482 at doses up to 1,800 mg supported its further investigation as a long-acting antibody for the prevention of influenza A illness. This study has been registered at ClinicalTrials.gov under identifier NCT04033406.

Immunogenicity and safety of heterologous Omicron BA.1 and bivalent SARS-CoV-2 recombinant spike protein booster vaccines: a phase 3, randomized, clinical trial.

BACKGROUND: Mutations present in emerging SARS-CoV-2 variants permit evasion of neutralization with prototype vaccines. A novel Omicron BA.1 subvariant-specific vaccine (NVX-CoV2515) was tested alone, or as a bivalent preparation in combination with the prototype vaccine (NVX-CoV2373), to assess antibody responses to SARS-CoV-2. METHODS: Participants aged 18 to 64 years immunized with 3 doses of prototype mRNA vaccines were randomized 1:1:1 to receive a single dose of NVX-CoV2515, NVX-CoV2373, or bivalent mixture in a phase 3 study investigating heterologous boosting with SARS-CoV-2 recombinant spike protein vaccines. Immunogenicity was measured 14 and 28 days after vaccination for the SARS-CoV-2 Omicron BA.1 sublineage and ancestral strain. Safety profiles of vaccines were assessed. RESULTS: Of participants who received trial vaccine (N = 829), those administered NVX-CoV2515 (n = 286) demonstrated superior neutralizing antibody response to BA.1 versus NVX-CoV2373 (n = 274) at Day 14 (geometric mean titer ratio [95% CI]: 1.6 [1.33, 2.03]). Seroresponse rates [n/N; 95% CI] were 73.4% [91/124; 64.7, 80.9] for NVX-CoV2515 versus 50.9% [59/116; 41.4, 60.3] for NVX-CoV2373. All formulations were similarly well-tolerated. CONCLUSIONS: NVX-CoV2515 elicited a superior neutralizing antibody response against the Omicron BA.1 subvariant compared with NVX-CoV2373 when administered as a fourth dose. Safety data were consistent with the established safety profile of NVX-CoV2373.

Rapid Electron Transfer Self-Exchange in Conformationally Dynamic Copper Coordination Complexes.

We report the electron transfer (ET) self-exchange rate constants (k11) for a pair of CuII/I complexes utilizing dpaR (dpa = dipicolylaniline, R = OMe, SMe) ligands assessed by NMR line broadening experiments. These ligands afford copper complexes that are conformationally dynamic in one oxidation state. With R = OMe, the CuI complex is dynamic, while with R = SMe, the CuII complex is dynamic. Both complexes exhibit unexpectedly large k11 values of 2.48(6) × 105 and 2.21(9) × 106 M-1 s-1 for [CuCl(dpaOMe)]+/0 and [CuCl(dpaSMe)]+/0, respectively. Among the fastest reported molecular copper coordination complexes to date, that of [CuCl(dpaSMe)]+/0 exceeds all others by an order of magnitude and compares only with those observed in type 1 blue copper proteins. The dynamicity of these complexes establishes pre-steady-state conformational equilibria that minimize the inner-sphere reorganization energies to 0.71 and 0.62 eV for R = OMe and SMe, respectively. In contrast to the emphasis on rigidity in the formulation of entatic states applied to blue copper proteins, the success of these two systems highlights the relevance of conformational dynamicity in mediating rapid ET.

Phase 1-2 Trial of a SARS-CoV-2 Recombinant Spike Protein Nanoparticle Vaccine.

BACKGROUND: NVX-CoV2373 is a recombinant severe acute respiratory syndrome coronavirus 2 (rSARS-CoV-2) nanoparticle vaccine composed of trimeric full-length SARS-CoV-2 spike glycoproteins and Matrix-M1 adjuvant. METHODS: We initiated a randomized, placebo-controlled, phase 1-2 trial to evaluate the safety and immunogenicity of the rSARS-CoV-2 vaccine (in 5-µg and 25-µg doses, with or without Matrix-M1 adjuvant, and with observers unaware of trial-group assignments) in 131 healthy adults. In phase 1, vaccination comprised two intramuscular injections, 21 days apart. The primary outcomes were reactogenicity; laboratory values (serum chemistry and hematology), according to Food and Drug Administration toxicity scoring, to assess safety; and IgG anti-spike protein response (in enzyme-linked immunosorbent assay [ELISA] units). Secondary outcomes included unsolicited adverse events, wild-type virus neutralization (microneutralization assay), and T-cell responses (cytokine staining). IgG and microneutralization assay results were compared with 32 (IgG) and 29 (neutralization) convalescent serum samples from patients with Covid-19, most of whom were symptomatic. We performed a primary analysis at day 35. RESULTS: After randomization, 83 participants were assigned to receive the vaccine with adjuvant and 25 without adjuvant, and 23 participants were assigned to receive placebo. No serious adverse events were noted. Reactogenicity was absent or mild in the majority of participants, more common with adjuvant, and of short duration (mean, ≤2 days). One participant had mild fever that lasted 1 day. Unsolicited adverse events were mild in most participants; there were no severe adverse events. The addition of adjuvant resulted in enhanced immune responses, was antigen dose-sparing, and induced a T helper 1 (Th1) response. The two-dose 5-µg adjuvanted regimen induced geometric mean anti-spike IgG (63,160 ELISA units) and neutralization (3906) responses that exceeded geometric mean responses in convalescent serum from mostly symptomatic Covid-19 patients (8344 and 983, respectively). CONCLUSIONS: At 35 days, NVX-CoV2373 appeared to be safe, and it elicited immune responses that exceeded levels in Covid-19 convalescent serum. The Matrix-M1 adjuvant induced CD4+ T-cell responses that were biased toward a Th1 phenotype. (Funded by the Coalition for Epidemic Preparedness Innovations; ClinicalTrials.gov number, NCT04368988).

Free-induction-decay magnetic field imaging with a microfabricated Cs vapor cell.

Magnetic field imaging is a valuable resource for signal source localization and characterization. This work reports an optically pumped magnetometer (OPM) based on the free-induction-decay (FID) protocol, that implements microfabricated cesium (Cs) vapor cell technology to visualize the magnetic field distributions resulting from various magnetic sources placed close to the cell. The slow diffusion of Cs atoms in the presence of a nitrogen (N2) buffer gas enables spatially independent measurements to be made within the same vapor cell by translating a 175 µm diameter probe beam over the sensing area. For example, the OPM was used to record temporal and spatial information to reconstruct magnetic field distributions in one and two dimensions. The optimal magnetometer sensitivity was estimated to be 0.43 pT/H z within a Nyquist limited bandwidth of 500 Hz. Furthermore, the sensor's dynamic range exceeds the Earth's field of approximately 50 µT, which provides a framework for magnetic field imaging in unshielded environments.

Optimal binary gratings for multi-wavelength magneto-optical traps.

Grating magneto-optical traps are an enabling quantum technology for portable metrological devices with ultracold atoms. However, beam diffraction efficiency and angle are affected by wavelength, creating a single-optic design challenge for laser cooling in two stages at two distinct wavelengths - as commonly used for loading, e.g., Sr or Yb atoms into optical lattice or tweezer clocks. Here, we optically characterize a wide variety of binary gratings at different wavelengths to find a simple empirical fit to experimental grating diffraction efficiency data in terms of dimensionless etch depth and period for various duty cycles. The model avoids complex 3D light-grating surface calculations, yet still yields results accurate to a few percent across a broad range of parameters. Gratings optimized for two (or more) wavelengths can now be designed in an informed manner suitable for a wide class of atomic species enabling advanced quantum technologies.

Cold-atom shaping with MEMS scanning mirrors.

We demonstrate the integration of micro-electro-mechanical-systems (MEMS) scanning mirrors as active elements for the local optical pumping of ultra-cold atoms in a magneto-optical trap. A pair of MEMS mirrors steer a focused resonant beam through a cloud of trapped atoms shelved in the F = 1 ground-state of 87Rb for spatially selective fluorescence of the atom cloud. Two-dimensional control is demonstrated by forming geometrical patterns along the imaging axis of the cold atom ensemble. Such control of the atomic ensemble with a microfabricated mirror pair could find applications in single atom selection, local optical pumping, and arbitrary cloud shaping. This approach has significant potential for miniaturization and in creating portable control systems for quantum optic experiments.

Disability-Adjusted Life-Years for Drug Overdose Crisis and COVID-19 Are Comparable During the Two Years of Pandemic in the United States.

OBJECTIVES: The drug overdose crisis with shifting patterns from primarily opioid to polysubstance uses and COVID-19 infections are 2 concurrent public health crises in the United States, affecting the population of sizes in different magnitudes (approximately < 10 million for substance use disorder [SUD] and drug overdoses vs 80 million for COVID-19 within 2 years of the pandemic). Our objective is to compare the relative scale of disease burden for the 2 crises within a common framework, which could help inform policy makers with resource allocation and prioritization strategies. METHODS: We calculated disability-adjusted life-years (DALYs) for SUD (including opioids and stimulants) and COVID-19 infections, respectively. We collected estimates for SUD prevalence, overdose deaths, COVID-19 cases and deaths, disability weights, and life expectancy from multiple publicly available sources. We then compared age distributions of estimated DALYs. RESULTS: We estimated a total burden of 13.83 million DALYs for SUD and drug overdoses and 15.03 million DALYs for COVID-19 in 2 years since March 2020. COVID-19 burden was dominated by the fatal burden (> 95% of total DALYs), whereas SUD burden was attributed to both fatal (53%) and nonfatal burdens (47%). The highest disease burden was among individuals aged 30 to 39 years for SUD (27%) and 50 to 64 years for COVID-19 (31%). CONCLUSIONS: Despite the smaller size of the affected population, SUD and drug overdoses resulted in comparable disease burden with the COVID-19 pandemic. Additional resources supporting evidence-based interventions in prevention and treatment may be warranted to ameliorate SUD and drug overdoses during both the pandemic and postpandemic recovery.

Barriers to optimal management of syphilis in pregnancy and congenital syphilis in south-east Queensland: a qualitative investigation.

BACKGROUND: Australia, like many high-income countries, is experiencing a resurgence of infectious syphilis in pregnancy and congenital syphilis. Evaluations of public health notifications and clinical records suggest that healthcare systems may not be providing optimal care to women and their neonates. This study aims to explore the barriers to optimal management of syphilis in pregnancy and congenital syphilis to identify key areas for improvement. METHODS: Between 2021 and 2022, 34 healthcare workers (HCW) practicing in south-east Queensland (SEQ) Australia were recruited to complete semi-structured interviews regarding their perceptions towards management of syphilis in pregnancy and congenital syphilis. Interviews were analysed thematically. RESULTS: Thematic analysis identified four themes related to the management of syphilis in pregnancy. These included poor communication between disciplines, services, and teams from delivery through to management and post-delivery, lack of formal internal and external referral pathways, unclear and often complex maternal and congenital syphilis management procedures, and limited HCW knowledge of infectious syphilis in pregnancy and congenital syphilis. CONCLUSION: As congenital syphilis numbers continue to rise in SEQ, it is imperative that healthcare systems and HCWs identify and address gaps in the provision of health care.

Syphilis in pregnancy: a qualitative investigation of healthcare provider perspectives on barriers to syphilis screening during pregnancy in south-east Queensland.

BACKGROUND: Increasing rates of syphilis in pregnancy (SiP) in Australia and other high-income countries, has led to the resurgence of congenital syphilis. Suboptimal syphilis screening during pregnancy has been identified as a key contributing factor. METHODS: This study aimed to explore, from the perspective of multidisciplinary healthcare providers (HCPs), the barriers to optimal screening during the antenatal care (ANC) pathway. Semi-structured interviews conducted with 34 HCPs across multiple disciplines practising in south-east Queensland (SEQ) were analysed through a process of reflexive thematic analysis. RESULTS: Barriers were found to occur at the system level of ANC, through difficulties in patient engagement in care, limitations in the current model of health care delivery and limitations in the communication pathways across health care disciplines; and at the individual HCP level, through HCP knowledge and awareness of epidemiological changes in syphilis in SEQ, and adequately assessing patient risk. CONCLUSION: It is imperative that the healthcare systems and HCPs involved in ANC address these barriers to improve screening in order to optimise management of women and prevent congenital syphilis cases in SEQ.

Automated Machine Learning Strategies for Multi-Parameter Optimisation of a Caesium-Based Portable Zero-Field Magnetometer.

Machine learning (ML) is an effective tool to interrogate complex systems to find optimal parameters more efficiently than through manual methods. This efficiency is particularly important for systems with complex dynamics between multiple parameters and a subsequent high number of parameter configurations, where an exhaustive optimisation search would be impractical. Here we present a number of automated machine learning strategies utilised for optimisation of a single-beam caesium (Cs) spin exchange relaxation free (SERF) optically pumped magnetometer (OPM). The sensitivity of the OPM (T/Hz), is optimised through direct measurement of the noise floor, and indirectly through measurement of the on-resonance demodulated gradient (mV/nT) of the zero-field resonance. Both methods provide a viable strategy for the optimisation of sensitivity through effective control of the OPM's operational parameters. Ultimately, this machine learning approach increased the optimal sensitivity from 500 fT/Hz to <109fT/Hz. The flexibility and efficiency of the ML approaches can be utilised to benchmark SERF OPM sensor hardware improvements, such as cell geometry, alkali species and sensor topologies.

Antimalarial Activity of Artefenomel Against Asexual Parasites and Transmissible Gametocytes During Experimental Blood-Stage Plasmodium vivax Infection.

BACKGROUND: Interventions that effectively target Plasmodium vivax are critical for the future control and elimination of malaria. We conducted a P. vivax volunteer infection study to characterize the antimalarial activity of artefenomel, a new drug candidate. METHODS: Eight healthy, malaria-naive participants were intravenously inoculated with blood-stage P. vivax and subsequently received a single oral 200-mg dose of artefenomel. Blood samples were collected to monitor the development and clearance of parasitemia, and plasma artefenomel concentration. Mosquito feeding assays were conducted before artefenomel dosing to investigate parasite transmissibility. RESULTS: Initial parasite clearance occurred in all participants after artefenomel administration (log10 parasite reduction ratio over 48 hours, 1.67; parasite clearance half-life, 8.67 hours). Recrudescence occurred in 7 participants 11-14 days after dosing. A minimum inhibitory concentration of 0.62 ng/mL and minimum parasiticidal concentration that achieves 90% of maximum effect of 0.83 ng/mL were estimated, and a single 300-mg dose was predicted to clear 109 parasites per milliliter with 95% certainty. Gametocytemia developed in all participants and was cleared 4-8 days after dosing. At peak gametocytemia, 75% of participants were infectious to mosquitoes. CONCLUSIONS: The in vivo antimalarial activity of artefenomel supports its further clinical development as a treatment for P. vivax malaria. CLINICAL TRIALS REGISTRATION: NCT02573857.

Toward Improved Charge Separation through Conformational Control in Copper Coordination Complexes.

The continued development of solar energy as a renewable resource necessitates new approaches to sustaining photodriven charge separation (CS). We present a bioinspired approach in which photoinduced conformational rearrangements at a ligand are translated into changes in coordination geometry and environment about a bound metal ion. Taking advantage of the differential coordination properties of CuI and CuII, these dynamics aim to facilitate intramolecular electron transfer (ET) from CuI to the ligand to create a CS state. The synthesis and photophysical characterization of CuCl(dpaaR) (dpaa = dipicolylaminoacetophenone, with R = H and OMe) are presented. These ligands incorporate a fluorophore that gives rise to a twisted intramolecular charge transfer (TICT) excited state. Excited-state ligand twisting provides a tetragonal coordination geometry capable of capturing CuII when an internal ortho-OMe binding site is present. NMR, IR, electron paramagnetic resonance (EPR), and optical spectroscopies, X-ray diffraction, and electrochemical methods establish the ground-state properties of these CuI and CuII complexes. The photophysical dynamics of the CuI complexes are explored by time-resolved photoluminescence and optical transient absorption spectroscopies. Relative to control complexes lacking a TICT-active ligand, the lifetimes of CS states are enhanced ∼1000-fold. Further, the presence of the ortho-OMe substituent greatly enhances the lifetime of the TICT* state and biases the coordination environment toward CuII. The presence of CuI decreases photoinduced degradation from 14 to <2% but does not result in significant quenching via ET. Factors affecting CS in these systems are discussed, laying the groundwork for our strategy toward solar energy conversion.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Coadministered Ruxolitinib and Artemether-Lumefantrine in Healthy Adults.

Despite repeated malaria infection, individuals living in areas where malaria is endemic remain vulnerable to reinfection. The Janus kinase (JAK1/2) inhibitor ruxolitinib could potentially disrupt the parasite-induced dysfunctional immune response when administered with antimalarial therapy. This randomized, single-blind, placebo-controlled, single-center phase 1 trial investigated the safety, tolerability, and pharmacokinetic and pharmacodynamic profile of ruxolitinib and the approved antimalarial artemether-lumefantrine in combination. Ruxolitinib pharmacodynamics were assessed by inhibition of phosphorylation of signal transducer and activator of transcription 3 (pSTAT3). Eight healthy male and female participants ages 18 to 55 years were randomized to either ruxolitinib (20 mg) (n = 6) or placebo (n = 2) administered 2 h after artemether-lumefantrine (80/480 mg) twice daily for 3 days. Mild adverse events occurred in six participants (four ruxolitinib; two placebo). The combination of artemether-lumefantrine and ruxolitinib was well tolerated, with adverse events and pharmacokinetics consistent with the known profiles of both drugs. The incidence of adverse events and artemether, dihydroartemisinin (the major active metabolite of artemether), and lumefantrine exposure were not affected by ruxolitinib coadministration. Ruxolitinib coadministration resulted in a 3-fold-greater pSTAT3 inhibition compared to placebo (geometric mean ratio = 3.01 [90% confidence interval = 2.14 to 4.24]), with a direct and predictable relationship between ruxolitinib plasma concentrations and %pSTAT3 inhibition. This study supports the investigation of the combination of artemether-lumefantrine and ruxolitinib in healthy volunteers infected with Plasmodium falciparum malaria. (This study has been registered at ClinicalTrials.gov under registration no. NCT04456634.).

Using CUSUM in real time to signal clinically relevant decreases in estimated glomerular filtration rate.

BACKGROUND: The electronic health record (EHR), utilized to apply statistical methodology, assists provider decision-making, including during the care of chronic kidney disease (CKD) patients. When estimated glomerular filtration (eGFR) decreases, the rate of that change adds meaning to a patient's single eGFR and may represent severity of renal injury. Since the cumulative sum chart technique (CUSUM), often used in quality control and surveillance, continuously checks for change in a series of measurements, we selected this statistical tool to detect clinically relevant eGFR decreases and developed CUSUMGFR. METHODS: In a retrospective analysis we applied an age adjusted CUSUMGFR, to signal identification of eventual ESKD patients prior to diagnosis date. When the patient signaled by reaching a specified threshold value, days from CUSUM signal date to ESKD diagnosis date (earliness days) were measured, along with the corresponding eGFR measurement at the signal. RESULTS: Signaling occurred by CUSUMGFR on average 791 days (se = 12 days) prior to ESKD diagnosis date with sensitivity = 0.897, specificity = 0.877, and accuracy = .878. Mean days prior to ESKD diagnosis were significantly greater in Black patients (905 days) and patients with hypertension (852 days), diabetes (940 days), cardiovascular disease (1027 days), and hypercholesterolemia (971 days). Sensitivity and specificity did not vary by sociodemographic and clinical risk factors. CONCLUSIONS: CUSUMGFR correctly identified 30.6% of CKD patients destined for ESKD when eGFR was > 60 ml/min/1.73 m2 and signaled 12.3% of patients that did not go on to ESKD (though almost all went on to later-stage CKD). If utilized in an EHR, signaling patients could focus providers' efforts to slow or prevent progression to later stage CKD and ESKD.

Addressing the crisis of congenital syphilis: Key findings from an evaluation of the management of syphilis in pregnancy and the newborn in South-East Queensland.

BACKGROUND: Syphilis in pregnancy and congenital syphilis (CS) are increasing in Australia. Prevention of adverse outcomes requires adherence to management guidelines. AIMS: The aim is to evaluate the management of syphilis in pregnant women and their newborns. MATERIALS AND METHODS: A retrospective study of public health notifications, clinical records and testing results of women with positive syphilis serology in pregnancy requiring treatment from 2016 to 2018 inclusive across South-East Queensland was conducted. Management was described and compared with contemporary guidelines from the Australasian Society of Infectious Diseases, the Communicable Diseases Network Australia and the United States Centers for Disease Control and Prevention. RESULTS: Of 30 women identified, 22 (73%) had management consistent with the guidelines (stage-appropriate penicillin regimen, appropriate dosing interval and treatment completed greater than 30 days before delivery). Only 14 (47%) women had documentation of partner testing and/or treatment. Of 26 mother-infant pairs with complete data, 16 (62%) had investigations at delivery consistent with recommendations (parallel maternal-infant rapid plasma reagin, infant syphilis immunoglobulin M, placental histopathology +/- syphilis polymerase chain reaction and infant clinical examination). One infant met the criteria for confirmed CS. Five infants received penicillin therapy. Only seven (27%) infants had serological monitoring after discharge. CONCLUSIONS: Management can be optimised with timely maternal testing and treatment, comprehensive partner screening and treatment, strict adherence to seven-day penicillin dosing for late latent syphilis and thorough maternal and infant testing after treatment and delivery. If maternal treatment was inadequate in pregnancy, consideration needs to be given to close evaluation and empiric treatment of the infant.

Defining the Antimalarial Activity of Cipargamin in Healthy Volunteers Experimentally Infected with Blood-Stage Plasmodium falciparum.

The spiroindolone cipargamin, a new antimalarial compound that inhibits Plasmodium ATP4, is currently in clinical development. This study aimed to characterize the antimalarial activity of cipargamin in healthy volunteers experimentally infected with blood-stage Plasmodium falciparum Eight subjects were intravenously inoculated with parasite-infected erythrocytes and received a single oral dose of 10 mg cipargamin 7 days later. Blood samples were collected to monitor the development and clearance of parasitemia and plasma cipargamin concentrations. Parasite regrowth was treated with piperaquine monotherapy to clear asexual parasites, while allowing gametocyte transmissibility to mosquitoes to be investigated. An initial rapid decrease in parasitemia occurred in all participants following cipargamin dosing, with a parasite clearance half-life of 3.99 h. As anticipated from the dose selected, parasite regrowth occurred in all 8 subjects 3 to 8 days after dosing and allowed the pharmacokinetic/pharmacodynamic relationship to be determined. Based on the limited data from the single subtherapeutic dose cohort, a MIC of 11.6 ng/ml and minimum parasiticidal concentration that achieves 90% of maximum effect of 23.5 ng/ml were estimated, and a single 95-mg dose (95% confidence interval [CI], 50 to 270) was predicted to clear 109 parasites/ml. Low gametocyte densities were detected in all subjects following piperaquine treatment, which did not transmit to mosquitoes. Serious adverse liver function changes were observed in three subjects, which led to premature study termination. The antimalarial activity characterized in this study supports the further clinical development of cipargamin as a new treatment for P. falciparum malaria, although the hepatic safety profile of the compound warrants further evaluation. (This study has been registered at ClinicalTrials.gov under identifier NCT02543086.).

Safety, infectivity and immunogenicity of a genetically attenuated blood-stage malaria vaccine.

BACKGROUND: There is a clear need for novel approaches to malaria vaccine development. We aimed to develop a genetically attenuated blood-stage vaccine and test its safety, infectivity, and immunogenicity in healthy volunteers. Our approach was to target the gene encoding the knob-associated histidine-rich protein (KAHRP), which is responsible for the assembly of knob structures at the infected erythrocyte surface. Knobs are required for correct display of the polymorphic adhesion ligand P. falciparum erythrocyte membrane protein 1 (PfEMP1), a key virulence determinant encoded by a repertoire of var genes. METHODS: The gene encoding KAHRP was deleted from P. falciparum 3D7 and a master cell bank was produced in accordance with Good Manufacturing Practice. Eight malaria naïve males were intravenously inoculated (day 0) with 1800 (2 subjects), 1.8 × 105 (2 subjects), or 3 × 106 viable parasites (4 subjects). Parasitemia was measured using qPCR; immunogenicity was determined using standard assays. Parasites were rescued into culture for in vitro analyses (genome sequencing, cytoadhesion assays, scanning electron microscopy, var gene expression). RESULTS: None of the subjects who were administered with 1800 or 1.8 × 105 parasites developed parasitemia; 3/4 subjects administered 3× 106 parasites developed significant parasitemia, first detected on days 13, 18, and 22. One of these three subjects developed symptoms of malaria simultaneously with influenza B (day 17; 14,022 parasites/mL); one subject developed mild symptoms on day 28 (19,956 parasites/mL); and one subject remained asymptomatic up to day 35 (5046 parasites/mL). Parasitemia rapidly cleared with artemether/lumefantrine. Parasitemia induced a parasite-specific antibody and cell-mediated immune response. Parasites cultured ex vivo exhibited genotypic and phenotypic properties similar to inoculated parasites, although the var gene expression profile changed during growth in vivo. CONCLUSIONS: This study represents the first clinical investigation of a genetically attenuated blood-stage human malaria vaccine. A P. falciparum 3D7 kahrp- strain was tested in vivo and found to be immunogenic but can lead to patent parasitemia at high doses. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (number: ACTRN12617000824369 ; date: 06 June 2017).

Engineering Approaches for Addressing Opioid Use Disorder in the Community.

Many communities in the United States are struggling to deal with the negative consequences of illicit opioid use. Effectively addressing this epidemic requires the coordination and support of community stakeholders in a change process with common goals and objectives, continuous engagement with individuals with opioid use disorder (OUD) through their treatment and recovery journeys, application of systems engineering principles to drive process change and sustain it, and use of a formal evaluation process to support a learning community that continuously adapts. This review presents strategies to improve OUD treatment and recovery with a focus on engineering approaches grounded in systems thinking.

Estimating the impact of self-management education, influenza vaccines, nebulizers, and spacers on health utilization and expenditures for Medicaid-enrolled children with asthma.

INTRODUCTION: We quantify the effect of a set of interventions including asthma self-management education, influenza vaccination, spacers, and nebulizers on healthcare utilization and expenditures for Medicaid-enrolled children with asthma in New York and Michigan. METHODS: We obtained patients' data from Medicaid Analytic eXtract files and evaluated patients with persistent asthma in 2010 and 2011. We used difference-in-difference regression to quantify the effect of the intervention on the probability of asthma-related healthcare utilization, asthma medication, and utilization costs. We estimated the average change in outcome measures from pre-intervention/intervention (2010) to post-intervention (2011) periods for the intervention group by comparing this with the average change in the control group over the same time horizon. RESULTS: All of the interventions reduced both utilization and asthma medication costs. Asthma self-management education, nebulizer, and spacer interventions reduced the probability of emergency department (20.8-1.5%, 95%CI 19.7-21.9% vs. 0.5-2.5%, respectively) and inpatient (3.5-0.8%, 95%CI 2.1-4.9% vs. 0.4-1.2%, respectively) utilizations. Influenza vaccine decreased the probability of primary care physician (6-3.5%, 95%CI 4.4-7.6% vs. 1.5-5.5%, respectively) visit. The reductions varied by state and intervention. CONCLUSIONS: Promoting asthma self-management education, influenza vaccinations, nebulizers, and spacers can decrease the frequency of healthcare utilization and asthma-related expenditures while improving medication adherence.