Long-acting cabotegravir pharmacokinetics with and without oral lead-in for HIV PrEP.

Long-acting cabotegravir is approved for pre-exposure prophylaxis and combination HIV treatment, both initiated with optional short-term oral lead-in (OLI). We evaluated the impact of OLI on long-acting cabotegravir pharmacokinetics. Cabotegravir plasma concentrations were compared between HIV-positive participants initiating injections with (n = 278) or without (n = 110) OLI in phase III treatment study FLAIR and in HIV-negative participants using OLI (n = 263) in pivotal pre-exposure prophylaxis studies HPTN 083 and HPTN 084. Cabotegravir pharmacokinetic profiles were simulated in three populations (assigned-male-at-birth, 50%-assigned-female-at-birth, and assigned-female-at-birth) under three scenarios: first injection given (A) 1 or (B) 3 days after final OLI dose (OLI-injection gap) or (C) without OLI. The PK objective was 80% of participants achieving 4× in vitro protein-adjusted 90% maximal inhibitory concentration (PA-IC90) and 50% achieving 8× PA-IC90. Observed trough concentrations (Cτ) were similar with and without OLI (P > 0.3). With a 3-day OLI-injection gap, simulated pre-injection Cτ remained above PK objective. Approximately 1-2 weeks after the first injection, simulated PK profiles became nearly identical among all scenarios. Without OLI, it was predicted that 80% of participants achieve 4× PA-IC90 in 1.2, 1.8, and 2.8 days after the first injection in each population, respectively, and 50% achieve 8× PA-IC90 in 1.4, 2.1, and 3.8 days, respectively. Observed long-acting cabotegravir exposure was similar with or without OLI, supporting optional OLI use. Cabotegravir exposure was predicted to remain above PK objective for OLI-injection gaps of ≤3 days and rapidly achieve PK objective after first injection without OLI. Findings are consistent between assigned-male-at-birth and assigned-female-at-birth populations.This study is registered with ClinicalTrials.gov as NCT02720094.

Novel paper-based potentiometric combined sensors using coumarin derivatives modified with vanadium pentoxide nanoparticles for the selective determination of trace levels of lead ions.

Novel miniaturized Pb(II) paper-based potentiometric sensors are described using coumarin derivatives I and II as electroactive ionophores and nano vanadium pentoxide as a solid contact material for the sensitive and selective monitoring of trace lead ions. Density functional theory (DFT) confirms optimum geometries, electronic properties, and charge transfer behaviors of 1:2 Pb(II): coumarin complexes. The sensors are prepared by using two strips of 20 × 5 mm filter paper with two circular orifices. One orifice is coated with vanadium pentoxide (V2O5) nanoparticles in colloidal conductive carbon as a solid-contact, covered by a PVC membrane containing coumarin ionophore to act as a sensing probe. The other orifice is treated with Ag/AgCl in a polyvinyl butyral (PVB) film, to act as a reference electrode. Sensors with ionophores (I) and (II) exhibit Nernstian slopes of 27.7 ± 0.2 and 30.2 ± 0.2 mV/decade over the linear concentration range 4.5 × 10-7 to 6.2 × 10-3 M and 8.5 × 10-8 to 6.2 × 10-3 M, with detection limits of 1.3 × 10-7 M (26.9 ppb) and 2.1 × 10-8 M (4.4 ppb), respectively. The sensors are satisfactorily used for accurate determination of lead ions in drinking water, lead-acid battery wastewater, and electronic waste leachates. The results compare favourably well with data obtained by flameless atomic absorption spectrometry.

Usefulness of the placebo lead-in design for clinical trials with binary outcomes.

BACKGROUND: In placebo-controlled clinical trials to develop new drugs for the treatment of psychiatric or neurological disorders, a high and sometimes greater-than-expected placebo response makes it difficult to show the superiority of an investigational drug over a corresponding placebo. To avoid such difficulty, a placebo lead-in design has been presented, but its usefulness has been open to discussion. Although the statistical properties of the placebo lead-in design are investigated in the context of continuous outcomes, whether these properties can be generalized for binary or ordinal cases remains unclear. METHODS: We investigate whether the placebo lead-in design is useful in clinical trials with binary outcomes through mathematical formulae and a numerical investigation. Specifically, we compare the proportion of placebo responders, the drug-placebo difference, and the effect size between two populations: one enriched for placebo nonresponders and the other comprising the all-comers. RESULTS: Under positive correlation of the data between the lead-in stage and the randomized stage for both treatment groups, we mathematically show that the proportion of responders in the population enriched for placebo nonresponders is less than that in the all-comers population, and whether the placebo lead-in design increases the drug-placebo difference depends on the variances of outcomes in both treatment groups as well as the correlations of the outcomes between two stages. Further, through a numerical investigation, we show that whether the placebo lead-in design increases the effect size strongly depends on the magnitude of the correlations and their difference. CONCLUSION: If the correlation of the placebo-placebo group is much higher than that of the placebo-drug group, the placebo lead-in design is advantageous in most cases but has an impact on an estimand in placebo nonresponders. Therefore, we do not recommend using the placebo lead-in design for clinical trials with binary outcomes.

Lead removal in flue gas from sludge incineration by denitrification: Insights from metagenomics and metaproteomics.

Flue gas lead emission during sludge incineration damages to human health and ecological environment seriously. Therefore, a denitrifying bio-trickling filter (DNBTF) for lead removal in flue gas from sludge incineration was investigated. Lead removal efficiency was up to 90.7% in 60 days' operation. Lead speciation in biofilms of DNBTF consists of 84.27% residue lead, 15.18% organic bound lead, and less than 1% exchangeable and reducible lead. Lead resistant bacteria and lead resistant-denitrifying bacteria accounted for 85.04% and 58.25%, respectively. Lead resistant microorganisms(Pseudomonas, Azoarcus, Stappia, Pararhodobacter, Paracoccus, Azospirillum, Hyphomonas, Rhodobacter, Polymorphum, Brevunimonas, Stenotrophomonas) could resist the toxicity of Pb2+ in flue gas by transport protein and binding protein, and detoxify Pb2+ in flue gas by extracellular polymeric substances (EPS) adsorption, protein binding and precipitation under the action of resistance genes, such as pbrAB, golT, troABCD, znuABC, czcABCD, pcoB, copA, as shown by integrated metagenomic and metaproteomic analyses. The biofilm was characterized by FTIR, XRD, 3D-EEM, and SEM-EDS. XRD and SEM-EDS spectra indicated the formation of pyromorphite from bioconversion of lead in flue gas. Lead-containing flue gas was bio-stabilized in the form of pyromorphite and HA-Pb via complexation of humic acids in extracellular polymeric substances (EPS), biosorption and biodeposition. This provides a new way of sludge incineration flue gas lead removal using a denitrifying biotricking filter.

Coupling Square Wave Anodic Stripping Voltammetry with Support Vector Regression to Detect the Concentration of Lead in Soil under the Interference of Copper Accurately.

In this study, an effective method for accurately detecting Pb(II) concentration was developed by coupling square wave anodic stripping voltammetry (SWASV) with support vector regression (SVR) based on a bismuth-film modified electrode. The interference of different Cu2+ contents on the SWASV signals of Pb2+ was investigated, and a nonlinear relationship between Pb2+ concentration and the peak currents of Pb2+ and Cu2+ was determined. Thus, an SVR model with two inputs (i.e., peak currents of Pb2+ and Cu2+) and one output (i.e., Pb2+ concentration) was trained to quantify the above nonlinear relationship. The SWASV measurement conditions and the SVR parameters were optimized. In addition, the SVR mode, multiple linear regression model, and direct calibration mode were compared to verify the detection performance by using the determination coefficient (R2) and root-mean-square error (RMSE). Results showed that the SVR model with R2 and RMSE of the test dataset of 0.9942 and 1.1204 µg/L, respectively, had better detection accuracy than other models. Lastly, real soil samples were applied to validate the practicality and accuracy of the developed method for the detection of Pb2+ with approximately equal detection results to the atomic absorption spectroscopy method and a satisfactory average recovery rate of 98.70%. This paper provided a new method for accurately detecting the concentration of heavy metals (HMs) under the interference of non-target HMs for environmental monitoring.

Dosimetry and Calorimetry Performance of a Scientific CMOS Camera for Environmental Monitoring.

This paper explores the prospect of CMOS devices to assay lead in drinking water, using calorimetry. Lead occurs together with traces of radioisotopes, e.g., 210Pb, producing g-emissions with energies ranging from 10 keV to several 100 keV when they decay; this range is detectable in silicon sensors. In this paper we test a CMOS camera (OXFORD INSTRUMENTS Neo 5.5) for its general performance as a detector of X-rays and low energy g-rays and assess its sensitivity relative to the World Health Organization upper limit on lead in drinking water. Energies from 6 keV to 60 keV are examined. The CMOS camera has a linear energy response over this range and its energy resolution is for the most part slightly better than 2%. The Neo sCMOS is not sensitive to X-rays with energies below ~10 keV. The smallest detectable rate is 40 ± 3 mHz, corresponding to an incident activity on the chip of 7 ± 4 Bq. The estimation of the incident activity sensitivity from the detected activity relies on geometric acceptance and the measured efficiency vs. energy. We report the efficiency measurement, which is 0.08(2)% (0.0011(2)%) at 26.3 keV (59.5 keV). Taking calorimetric information into account we measure a minimal detectable rate of 4 ± 1 mHz (1.5 ± 0.1 mHz) for 26.3 keV (59.5 keV) g-rays, which corresponds to an incident activity of 1.0 ± 0.6 Bq (57 ± 33 Bq). Toy Monte Carlo and Geant4 simulations agree with these results. These results show this CMOS sensor is well-suited as a g- and X-ray detector with sensitivity at the few to 100 ppb level for 210Pb in a sample.

Application and impact of run-in studies.

BACKGROUND: A run-in phase is often employed prior to randomization in a clinical trial to exclude non-adherent patients, placebo responders, active drug non-responders, or patients who do not tolerate the active drug. This may impact the generalizability of trial results. OBJECTIVE: To determine if clinical outcomes differed between randomized controlled trials with run-in phases compared with randomized controlled trials of the same medication without run-in phases. DESIGN, PARTICIPANTS: From 2006 to 2014, the Food and Drug Administration approved 258 new medications. Sitaglitpin, saxagliptin, linagliptin, and alogliptin were among the only drugs with a common mechanism of action that each had multiple clinical trials, some of which had run-in phases and some of which did not. We identified all published randomized controlled trials for these four medications from MEDLINE and EMBASE as well as prior systematic reviews. MAIN MEASURES: We extracted key measures of medication efficacy (reduction in hemoglobin A1C) and safety (serious adverse events) from qualifying trials. Study results were pooled for each medication using random effects meta-analysis. KEY RESULTS: We identified 106 qualifying trials for DPP4 inhibitors, of which 88 had run-in phases and 18 did not. The average run-in phase duration was 4.0 weeks (range 1-21), and 73% of run-in phases administered placebo rather than active drug. The reduction in hemoglobin A1C compared to baseline was similar for trials with and without run-in phases (0.70%, 95% confidence interval [CI] 0.65-0.75 vs 0.76%, 95% CI 0.69-0.84, p = 0.27). The proportion of patients with serious adverse events was also similar for trials with and without run-in phases (4%, 95% CI: 3-5% vs 3%, 95% CI: 1-4%, p = 0.35). CONCLUSION: Trials with run-in phases provided similar estimates for medication efficacy and safety compared to trials without run-in phases. Because run-in phases are costly and time-consuming, these results call their utility into question for clinical trials of short duration.

Sequential parallel comparison design with binary and time-to-event outcomes.

Sequential parallel comparison design (SPCD) has been proposed to increase the likelihood of success of clinical trials especially trials with possibly high placebo effect. Sequential parallel comparison design is conducted with 2 stages. Participants are randomized between active therapy and placebo in stage 1. Then, stage 1 placebo nonresponders are rerandomized between active therapy and placebo. Data from the 2 stages are pooled to yield a single P value. We consider SPCD with binary and with time-to-event outcomes. For time-to-event outcomes, response is defined as a favorable event prior to the end of follow-up for a given stage of SPCD. We show that for these cases, the usual test statistics from stages 1 and 2 are asymptotically normal and uncorrelated under the null hypothesis, leading to a straightforward combined testing procedure. In addition, we show that the estimators of the treatment effects from the 2 stages are asymptotically normal and uncorrelated under the null and alternative hypothesis, yielding confidence interval procedures with correct coverage. Simulations and real data analysis demonstrate the utility of the binary and time-to-event SPCD.

Efficacy of a lead based paint XRF analyzer and a commercially available colorimetric lead test kit as qualitative field tools for determining presence of lead in religious powders.

The performances of a portable X-Ray Fluorescence (XRF) lead paint analyzer (RMD LPA-1, Protec Instrument Corp., Waltham, MA) and a commercially available colorimetric lead test kit (First Alert Lead Test Kit, eAccess Solutions, Inc., Palatine, IL) were evaluated for use by local or state health departments as potential cost-effective rapid analysis or "spot test" field techniques for tentative identification of lead content in sindoor powders. For both field-sampling methods, sensitivity, specificity and predictive values varied widely for samples containing <300,000 µg/g lead. For samples containing ≥300,000 µg/g lead, the aforementioned metrics were 100% (however, the CIs had a wide range). In addition, both field sampling methods showed clear, consistent positive readings only for samples containing ≥300,000 µg/g lead. Even samples with lead content as high as 5,110 µg/g were not positively identified by either field analysis technique. The results of this study suggest the XRF analyzer and colorimetric lead test kit cannot be used as a rapid field test for sindoor by health department inspectors.

"Managing" the Placebo Effect: The Single-Blind Placebo Lead-in Response in Two Pain Models.

OBJECTIVE: "Placebo effects" in analgesic medication trials for chronic pain are pervasive; however, little is known regarding mechanisms or factors that may influence the presence or magnitude of these effects. Our objective is to consider elements of the placebo response in the context of two pain models using a "single-blind placebo lead-in" design (SBPLI). METHODS: As part of two pilot drug trials using knee osteoarthritis (KOA) and non-radicular low back pain (LBP) subjects, SBPLI protocols were conducted. We examined whether gender and/or diagnosis affected placebo responses as observed in changes in patient self-reported pain, depressive and pain anxiety symptoms. We also evaluated the placebo response on performance-based tests (stair climbing, range of motion (ROM), sit to stand repetitions, and 6-minute treadmill distance). RESULTS: VAS Pain Intensity (Now) values decreased significantly during the SBPLI for the sample as a whole, but the effects appeared stronger among LBP subjects. CES-D short form values (depressive symptoms) did not decrease significantly during the SBPLI for the sample as a whole, but some placebo effects appeared to emerge for women in the KOA group. PASS values (pain anxiety symptoms) decreased significantly, albeit mildly, during the SBPLI for the sample as a whole.Stair Climb (time) revealed no significant SBPLI effects. Bend Forward to Floor (ROM) increased significantly at the end of the SBPLI period for the sample as a whole, but the effects appeared stronger among KOA subjects. Sit to Stand Repetitions increased during the SBPLI for the sample as a whole. Treadmill Distance did not change significantly from Visit 1 to Visit 2; however, a significant Sex difference for the KOA group was found such that women showed greater Treadmill Distance at Visit 2. CONCLUSION: Placebo effects emerged across psychometric and performance-based measures, indicating the pervasiveness of this phenomenon. In this design, diagnostic and (to a lesser extent) gender categories differentials were observed during the placebo period. The SBPLI design may prove not only a robust method in studying the placebo phenomena, but also as a design element to mitigate some aspects of the placebo response in clinical trials.

Remarks on designs enriching for placebo non-responders.

BACKGROUND: High response under placebo constitutes a concern in clinical studies, particularly in psychiatry. Discontinuation of placebo responders identified during a placebo run-in is often recommended to avoid failures of clinical trials in the presence of high placebo effects. Evidence for the benefit of this approach is ambiguous. PURPOSE: We investigate under which conditions a placebo lead-in can be beneficial in the context of continuous data, assuming that the data in the placebo run-in and the treatment stage follow a bivariate normal distribution. Placebo responders are defined as patients with an effect during placebo lead-in which is larger than a pre-defined threshold on the absolute value or the absolute or relative change from baseline or a combination thereof. RESULTS: Data are less variable under either placebo or test treatment after placebo responders have been removed. Whether the effect of test over placebo increases or decreases after enrichment for placebo non-responders depends on the parameters of the distribution, in particular the covariance structure, and the threshold in the definition of placebo responders. LIMITATIONS: The results apply in the continuous case, and the binary or ordinary case is not studied. The findings explain to some extent the ambiguity in the assessments of the usefulness of placebo lead-in periods in clinical trials; however, besides the clear statement on variability reduction, it is not straightforward to judge upfront whether placebo lead-in is useful. Concerns relating to the conduct and interpretation of results of such trials are mentioned.

[Lead-in period and week 8 as predictive tools for response to boceprevir therapy: a retrospective study of Spanish real clinical practice]. / Período de lead-in y semana 8 como herramientas de predicción de la respuesta en el tratamiento con boceprevir: estudio retrospectivo de la práctica clínica real en España.

INTRODUCTION: Most discontinuations due to lack of virological response occur during the first few weeks of hepatitis C virus (HCV) triple therapy. Improved knowledge of baseline factors and their correlation with boceprevir decision points may predict treatment success. METHODS: An observational, retrospective study was conducted to describe the lead-in period as a clinical decision tool in HCV genotype 1 patients treated with boceprevir. Data were collected from the medical records of 186 consecutive patients distributed across 20 Spanish general hospitals. RESULTS: This study included 171 patients. A total of 80% had fibrosis F3/F4, 74% were previously treated, and 26% were treatment-naïve. After the lead-in period, 54.5% of the patients had a reduction of ≥1 log10; this reduction occurred in 52.5% of those with advanced fibrosis. Boceprevir therapy was started in 94% of the patients. Discontinuations at week 4 were limited to null responders with cirrhosis. The baseline factors associated with virological response at week 4 were IL28B, previous response, and fibrosis score. At week 8, HCV-RNA was undetectable in 48.8% of the patients. The correlation between responses at weeks 8 and 12 was 88%. CONCLUSION: In the Spanish clinical setting, lead-in was mainly used as a clinical decision point for non-responders with cirrhosis. The good correlation between stopping rules at weeks 8 and 12 could be used to anticipate discontinuation, thus saving adverse events and costs.

Optimal initial duration of low molecular weight heparin lead-in before direct oral anticoagulants for short-term outcomes of hospitalized patients with non-high-risk acute pulmonary embolism.

BACKGROUND: There are currently three strategies for the duration of LMWH lead-in before DOACs in patients with acute PE: one is at least 5 days, the other is at least 3 days, and the last one is less than 3 days. Which one is the best is yet unknown. METHODS: We divided non-high-risk PE patients into short-LMWH (LMWH <3 days), intermediate-LMWH (LMWH 3-5 days), and long-LMWH (LMWH >5 days) groups, in a 1:1:2 ratio by using propensity score matching. Primary outcomes were a composite of mortality including all-cause and PE-related mortality, VTE recurrence, and major bleeding, as well as each one of them, at 3-month after PE diagnosis. RESULTS: The short-LMWH group (N = 504) had higher 3-month composite primary outcome (129 [25.6%] vs 67 [13.3%], P < 0.001), all-cause mortality (112 [22.2%] vs 39 [7.7%], P < 0.001), and PE-related mortality (48 [9.5%] vs 17 [3.4%], P < 0.001), than the intermediate-LMWH group (N = 504). The short-LMWH group also had higher 3-month composite primary outcome (129 [25.6%] vs 151 [15.0%], P < 0.001), all-cause mortality (112 [22.2%] vs 90 [8.9%], P < 0.001), and PE-related mortality (48 [9.5%] vs 41 [4.1%], P < 0.001) than the long-LMWH group (N = 1008). The VTE recurrence and major bleeding rates were similar between the short-LMWH and intermediate-LMWH groups, and between the short-LMWH and long-LMWH groups. The intermediate-LMWH and long-LMWH groups had similar 3-month primary outcomes rates in whole or in part with each other. CONCLUSIONS: For patients with non-high-risk acute PE, the optimal duration of initial LMWH lead-in before switching to DOACs could be 3 to 5 days.

Validation of the lead-in method in a practical shooting scenario.

The ability to determine bullet trajectories after a shooting incident can allow investigators to reconstruct the locations of individuals and the sequence of events that took place. By using trajectory rods, investigators can be provided with an immediate visual estimate as to what the path of the projectile may have been. In certain instances, the use of the probing method with trajectory rods is not appropriate due to their being a single, thin target material, or no secondary bullet impact site. In these cases, other methods such as the lead-in or the ellipse method may be useful. Overall, the lead-in method has not been well studied in the application to practical scenarios, such as those including bullet impacts on vehicle metal surfaces. This study has explored the accuracy of the lead-in method when a bullet impacts a typical vehicle metal surface using three firearm calibers, three blind participants, and two non-blind participants. The results of this study have shown that each caliber has its own characteristic error curve. In general, it was found that the lower the impact angle, the less errors were made by the participants. As the impact angle increases, the measurement errors increased, due to the smaller lead-in area present. The errors were found to have a wide range, with some being as low as 1° and some being as high as 13.9°. Further, it was found there was no significant effect on the errors of blind versus non-blind participants.

Standards for levels of lead in soil and dust around the world.

Lead poisoning is a serious environmental health problem in every country in the world. Exposure to lead results in neurocognitive and behavioral changes, has adverse effects on the immune system, causes anemia, hypertension and perturbs other organ systems. The effects of lead poisoning are most critical for children because their bodies are growing and developing, and particularly because agents that reduce cognitive function and attention span as well as promote disruptive behavior will have life-long consequences. Lead exposure, especially to children, is a major health disparity issue. If the next generation starts with reduced cognitive ability, there will be significant barriers for development of skills and country-wide development. While there are many sources of exposure to lead, the commonest source is lead in soil and dust. Since lead is an element, it does not go away and past releases of lead into the environment remain as soil and dust contamination. This is an especially important route of exposure to children because children regularly play in soil and are exposed via hand-to-mouth activity. In addition to indoor sources of lead, contaminated soil is tracked on shoes or feet and blown by air currents into homes, accumulating in household dust which is a major source of exposure for both children and adults. The purpose of this review is to determine standards presumed to be health protective for lead and dust in different countries. We find that many countries have no standards for lead in soil and dust and rely on standards set by the World Health Organization or the US Environmental Protection Agency, and these standards may or may not be enforced. There is considerable variation in standards set by other countries.

Real-World Evaluation of the Safety and Effectiveness of Apixaban & Rivaroxaban Lead-in Dosing Compared to Parenteral Lead-in Dosing in the Treatment of Venous Thromboembolism: A Multi-Center Retrospective Cohort Study.

Background: Although parenteral anticoagulation lead-in is not recommended with apixaban and rivaroxaban, parenteral anticoagulation is often used to replace apixaban or rivaroxaban lead-in doses for the initial phase treatment of VTE. Thus, our study compares the safety and effectiveness of lead-in parenteral anticoagulation to lead-in apixaban or rivaroxaban in patients who received apixaban or rivaroxaban for VTE treatment. Methods: A multi-center retrospective cohort study included adult patients (aged ≥ 18 years) admitted to the hospital with acute VTE and treated with either apixaban or rivaroxaban. Patients were grouped depending on the lead-in anticoagulation received for initial VTE treatment into the "Direct oral anticoagulation (DOAC) lead-in" group if patients received an appropriate lead-in dose of apixaban and rivaroxaban and patients who received parenteral lead-in the "parenteral lead-in" group. Results: A total of 389 patients were included; the DOAC lead-in group included 296 patients, whereas 93 patients were in the parenteral lead-in group. VTE recurrence (rVTE) during hospitalization and within 30 days was numerically higher in the parenteral lead-in group compared to the DOAC lead-in group (3.3% vs 0.6%; p=0.09 and 1.1% vs 0.7%; p=0.560), with a significantly higher number of patients with rVTE at 90 days (5.4% vs 1.4%; p=0.039). However, none of the patient's characteristics were significantly associated with the incidence of rVTE. In addition, the major bleeding rate during hospitalization was significantly higher among the parenteral lead-in group than in the DOAC lead-in group (14.0% vs 3.7%; p<0.001). Conclusion: Parenteral anticoagulation lead-in before starting maintenance of apixaban and rivaroxaban showed a significantly higher risk of bleeding and a trend toward higher VTE recurrence than the DOAC lead-in. This study adds to the evidence supporting the utilization of the DOAC lead-in regimen in treating patients with VTE. Still, larger studies with robust designs are needed to confirm these findings.

Factors Associated with Health Care Providers' Preference for Forgoing an Oral Lead-In Phase When Initiating Long-Acting Injectable Cabotegravir and Rilpivirine in the SOLAR Clinical Trial.

Cabotegravir and rilpivirine long-acting (LA) antiretroviral therapy (ART) demonstrated similar safety and efficacy in maintaining viral suppression among participants switching from daily oral to LA ART in the Extension Phase of the FLAIR trial. The Phase IIIb SOLAR study comparing efficacy and safety of daily oral versus LA ART every 2 months allowed participants and health care providers (HCPs) to choose an oral lead-in (OLI) before LA initiation or proceed by immediately starting with injections (SWI). We conducted an online survey among SOLAR HCPs (n = 110) in 13 countries to assess reasons for choosing OLI versus SWI. Logistic regression was used to identify factors influencing this decision. Thirty-two percent of HCPs reported a future preference to use OLI, whereas 54% reported a future preference for SWI. HCPs had greater odds of reporting future intentions for SWI if they were from Continental Europe versus North America [adjusted odds ratio (aOR): 3.83, p < 0.05], from sites with a greater number of participants who initiated LA ART without OLI (aOR: 1.56, p < 0.01), and those who reported comfort with the medication safety profile (aOR: 6.39, p < 0.01). HCPs who participated in LA ART trials before SOLAR had decreased odds of reporting a preference for SWI compared to those with no prior LA ART trial experience (aOR: 0.11; p < 0.01). Results indicated higher intentions to SWI over OLI among HCPs initiating participants on LA ART. A major factor associated with SWI was provider comfort with safety data, reinforcing the role of continued training regarding an SWI approach.

Comparative Effectiveness of Apixaban and Rivaroxaban Lead-in Dosing in VTE Treatment: Observational Multicenter Real-World Study.

Apixaban and rivaroxaban require lead-in dosing for 7 and 21 days, respectively, when treating venous thromboembolism (VTE). However, no evidence exists to support subtracting parenteral anticoagulation days from total lead-in dosing. A multicenter study was conducted, including adult patients with acute VTE who received apixaban or rivaroxaban. The patients were grouped as follows. The recommended group received oral lead-in anticoagulant for the full recommended duration. The mixed group received lead-in therapy as parenteral with oral anticoagulant. The incidence of recurrent VTE (rVTE) and major bleeding (MB) within 90 days were the main outcomes. Of the 368 included patients, 47.8% received apixaban, and 52.2% received rivaroxaban. The recommended lead-in was used in 296 patients (80.4%), whereas 72 (19.6%) received the mixed-lead-in regimen. Five patients had rVTE events within 90 days; two occurred during hospitalization in the recommended group versus none in the mixed group (0.7% vs. 0.0%; p = 1.000). After discharge, two events occurred in the recommended group and one in the mixed group (0.7% vs. 1.4%; p = 0.481). In terms of MB, 24 events occurred in 21 patients within 90 days. During hospitalization, 11 events occurred in the recommended group and seven in the mixed group (3.7% vs. 9.7%; p = 0.060). After discharge, five more events occurred in the recommended group and one in the mixed group (1.4% vs. 1.7%; p = 1.000). The mixed-lead-in regimen is safe and effective in comparison with the recommended-lead-in regimen.

Effects of pipeline geometry, sample volume, and flow rate on pb monitoring outcomes in copper pipe drinking water supply systems.

Pb in drinking water is one of the main sources of Pb in human bodies. Besides excess lead incidents caused by lead service lines, Pb contamination in non-lead pipe systems (e.g. copper and PVC) is also on the rise. Brass fixtures and lead-solder connections are the primary sources of lead in non-lead systems, which cause intermittent peaks of Pb at the consumer tap. The concentrations of lead in tap water depend on pipeline geometry, sampling methods, and the characteristic of the pipe flow. Using a 3-dimensional computational fluid dynamics model, this study analyzes the Pb concentration variations at taps of copper water supply systems. The turbulent diffusion and shear flow dispersion are fully simulated in the model to provide the most accurate prediction. Water parcels containing lead (clouds) are formed adjacent to lead sources during stagnation and are then dispersed with the flow of water through the pipe when the tap is opened. The geometry of the pipeline has a significant impact on the monitored Pb levels. The complex flow condition in elbow areas leads to a more intense mixing of lead ions. Therefore, the Pb levels at consumer taps in complex plumbing systems in high-rise buildings are higher than in straight pipelines. When the sampling flow rate is large, the peak height of Pb is slightly higher due to higher turbulent intensity. Pb concentrations in sequential samples are predicted with sample volumes of 50, 250, 500, and 1000 mL. Lead levels may be diluted significantly when samples are taken in large volumes (e.g. 500 mL or 1 L), resulting in an underestimation of Pb levels at taps. A sample volume of 250-500 mL is recommended in sequential sampling programs on non-lead service lines in order to identify Pb sources.

Prediction of lead leaching from galvanic corrosion of lead-containing components in copper pipe drinking water supply systems.

Galvanic corrosion is one of the main reasons for pipe degradation and lead contamination in drinking water systems. The electrical connection of dissimilar metals in corrosive tap water accelerates the dissolution rate of lead from leaded materials. This paper reports an electrochemistry based model to predict lead leaching from a copper pipe fitted with leaded connections. The corrosion of lead at the metal-electrolyte interface depends on the charge transfer and the electric field across the interface. The electric potential field and the mass transport process are dynamically coupled for corrosion propagation in stagnant water; they are respectively governed by the conservation of charge and reactant mass. Using polarization parameters for the electrodes as a function of concentration of oxidizing agents, a dynamic electrochemical model is developed to predict lead leaching from galvanic corrosion. The predicted lead and copper leaching curves are in good agreement with the experimental data for a lead-soldered coupled copper pipe, a brass valve coupled copper pipe, and a pure copper pipe. The findings offer a quantitative understanding on galvanic corrosion in drinking water supply systems and a practical modeling framework for prediction of lead leaching in tap water as a function of stagnation time.