Efflux transporters in drug disposition during pregnancy.

Evidence-based dose selection of drugs in pregnant women has been lacking due to challenges in studying maternal-fetal pharmacokinetics. Hence, many drugs are administered off-label during pregnancy based on data obtained from non-pregnant women. During pregnancy, drug transporters play an important role in drug disposition along with known gestational age-dependent changes in physiology and drug-metabolizing enzymes. In this review, as Dr. Qingcheng Mao's former and current lab members, we summarize the collective contributions of Dr. Mao, who lost his life to cancer, focusing on the role of drug transporters in drug disposition during pregnancy. Dr. Mao and his team initiated their research by characterizing the structure of Breast Cancer Resistance Protein [BCRP, ATP-Binding Cassette (ABC) G2]. Subsequently, they have made significant contributions to the understanding of the role of BCRP and other transporters, particularly P-glycoprotein (P-gp/ABCB1), in the exposure of pregnant women and their fetuses to various drugs, including nitrofurantoin, glyburide, buprenorphine, bupropion, tetrahydrocannabinol, and their metabolites. This review also highlights the gestation- and pregnancy-dependent transporter expression at the blood-brain and blood-placenta barriers in mice. Significance Statement Dr. Qingcheng Mao and his team have made significant contributions to the investigation of the role of efflux transporters, especially P-glycoprotein and breast cancer resistance protein, in maternal-fetal exposure to many xenobiotics: nitrofurantoin, glyburide, buprenorphine, bupropion, tetrahydrocannabinol and their metabolites. Studies of individual compounds and the expression of transporters during gestation and pregnancy have improved the understanding of maternal-fetal pharmacokinetics.

Translational PK/PD framework for antibody-drug conjugates to inform drug discovery and development.

(171/200)ADCs represent a transformative class of medicine that combines the specificity of monoclonal antibodies with the potency of highly cytotoxic agents through linkers, aiming to enhance the therapeutic index of cytotoxic drugs. Given the complex molecular structures of ADCs, combining the molecular characteristics of small-molecule drugs and those of large-molecule biotherapeutics, there are several unique considerations when designing nonclinical-to-clinical PK/PD translation strategies.This complexity also demands a thorough understanding of the ADC's components-antibody, linker, and payload-to the overall toxicological, PK/PD, and efficacy profile. ADC development is a multidisciplinary endeavor requiring a strategic integration of nonclinical safety, pharmacology, and PK/PD modeling to translate from bench to bedside successfully.The ADC development underscores the necessity for a robust scientific foundation, leveraging advanced analytical and modeling tools to predict human responses and optimize therapeutic outcomes.This review aims to provide an ADC translational PK/PD framework by discussing unique aspects of ADC nonclinical to clinical PK translation, starting dose determination, and leveraging PK/PD modeling for human efficacious dose prediction and potential safety mitigation.

Borazine Promoted Growth of Highly Oriented Thin Films.

We report on a phenomenon, where thin films sputter-deposited on single-crystalline Al2O3(0001) substrates exposed to borazine─a precursor commonly used for the synthesis of hexagonal boron nitride layers─are more highly oriented than those grown on bare Al2O3(0001) under the same conditions. We observed this phenomenon in face-centered cubic Pd, body-centered cubic Mo, and trigonal Ta2C thin films grown on Al2O3(0001). Interestingly, intermittent exposure to borazine during the growth of Ta2C thin films on Ta2C yields better crystallinity than direct deposition of monolithic Ta2C. We attribute these rather unusual results to a combination of both enhanced adatom mobilities on, and epitaxial registry with, surfaces exposed to borazine during the deposition. We expect that our approach can potentially help improve the crystalline quality of thin films deposited on a variety of substrates.

Self-Organized Growth of 111-Oriented (VNbTaMoW)N Nanorods on MgO(001).

Refractory high-entropy alloy nitride, (VNbTaMoW)N, layers are grown on single-crystalline MgO(001) via ultrahigh vacuum direct current magnetron sputtering of a VNbTaMoW target in Kr/N2 gas mixtures at 1073 K. X-ray diffraction, scanning and transmission electron microscopy, and energy dispersive X-ray spectroscopy characterizations revealed the formation of B1-structured, 111-textured (V0.21Nb0.18Ta0.19Mo0.21W0.21)N1.05 with lattice parameter a = 0.4249 nm. The alloy nitride film exhibits dense columnar microstructure near the substrate-film interface with coherent 001 grain growth limited to a few tens of nanometers, followed by an outgrowth of quasi one-dimensional nanorods with 3-fold symmetric facets. We attribute the self-organized growth of rather unusual 111-textured nanorods on isostructural MgO(001) to kinetic limitations of the sputter-deposition process exacerbated by the sluggish diffusion of the multicomponent adspecies and the preferential growth of {111} crystals.

Surface Reconstruction of Halide Perovskites During Post-treatment.

Postfabrication surface treatment strategies have been instrumental to the stability and performance improvements of halide perovskite photovoltaics in recent years. However, a consensus understanding of the complex reconstruction processes occurring at the surface is still lacking. Here, we combined complementary surface-sensitive and depth-resolved techniques to investigate the mechanistic reconstruction of the perovskite surface at the microscale level. We observed a reconstruction toward a more PbI2-rich top surface induced by the commonly used solvent isopropyl alcohol (IPA). We discuss several implications of this reconstruction on the surface thermodynamics and energetics. Particularly, our observations suggest that IPA assists in the adsorption process of organic ammonium salts to the surface to enhance their defect passivation effects.

Effects of Pregnancy on the Pharmacokinetics of Metformin.

This study's primary objective was to fully characterize the pharmacokinetics of metformin in pregnant women with gestational diabetes mellitus (GDM) versus nonpregnant controls. Steady-state oral metformin pharmacokinetics in pregnant women with GDM receiving either metformin monotherapy (n = 24) or a combination with glyburide (n = 30) as well as in nonpregnant women with type 2 diabetes mellitus (T2DM) (n = 24) were determined utilizing noncompartmental techniques. Maternal and umbilical cord blood samples were collected at delivery from 38 women. With both 500- and 1000-mg doses, metformin bioavailability, volume of distribution beta (V ß ), clearance, and renal clearance were significantly increased during pregnancy. In addition, in the women receiving metformin 500 mg, significantly higher metformin apparent oral clearance (CL/F) (27%), weight-adjusted renal secretion clearance (64%), and apparent oral volume of distribution beta (V ß /F) (33%) were seen during pregnancy. Creatinine clearance was significantly higher during pregnancy. Increasing metformin dose from 500 to 1000 mg orally twice daily significantly increased V ß /F by 28%, weight-adjusted V ß /F by 32% and CL/F by 25%, and weight-adjusted CL/F by 28% during pregnancy. Mean metformin umbilical cord arterial-to-venous plasma concentration ratio was 1.0 ± 0.1, venous umbilical cord-to-maternal concentration ratio was 1.4 ± 0.5, and arterial umbilical cord-to-maternal concentration ratio was 1.5 ± 0.5. Systemic exposure after a 500-mg dose of metformin was lower during pregnancy compared with the nonpregnant women with T2DM. However, in patients receiving metformin 1000 mg, changes in estimated bioavailability during pregnancy offset the changes in clearance leading to no significant change in CL/F with the higher dose. SIGNIFICANCE STATEMENT: Gestational diabetes mellitus complicates 5%-13% of pregnancies and is often treated with metformin. Pregnant women undergo physiological changes that alter drug disposition. Preliminary data suggest that pregnancy lowers metformin concentrations, potentially affecting efficacy and safety. This study definitively describes pregnancy's effects on metformin pharmacokinetics and expands the mechanistic understanding of pharmacokinetic changes across the dosage range. Here we report the nonlinearity of metformin pharmacokinetics and the increase in bioavailability, clearance, renal clearance, and volume of distribution during pregnancy.

Randomised comparison of techniques for control of the dorsal venous complex during robot-assisted laparoscopic radical prostatectomy.

OBJECTIVE: To prospectively compare the effects of endoscopic stapling, division and suture ligation, and suture ligation with suspension of the dorsal venous complex (DVC) on continence during robot-assisted laparoscopic radical prostatectomy (RARP). PATIENTS AND METHODS: In all, 300 consecutive patients undergoing RARP by a single surgeon were randomised to three groups: endoscopic stapling, cut and suture ligation, and suture ligation with suspension. The only difference between the groups was the technique to control the DVC. Pad-free continence (PFC) and overall continence (0 pads/day with or without security pad) were assessed with patient reported pad usage records and validated questionnaires (Expanded Prostate Cancer Index) at 3, 12, and 15 months. Secondary endpoints were erectile function (EF) recovery (defined as erections sufficient for sexual activity) and the rate of apical surgical margins. Univariate and multivariate analyses were conducted to determine predictors for recovery of both urinary continence and EF. RESULTS: The three groups were comparable in terms of age, body mass index, prostate size, American Urological Association symptom score, Sexual Health Inventory for Men, and clinical stage. There were no differences found in terms of operative times, estimated blood loss, pathological stage, and positive apical margin. There was no difference between the three groups with regard to overall continence or PFC at 3 months. However, overall continence at 15 months for ligation and suspension was 99% and was superior to stapler (88%) (P = 0.002) and cut and suture ligation (88%) (P = 0.002). Additionally, PFC at 15 months was superior for ligation and suspension (87%) as compared to stapler (73%) and cut and suture ligation (75%) (P = 0.045). The technique of DVC control did not impact EF. Men with nerve sparing had better continence compared to no nerve sparing at 3 months (62% vs 42%, P = 0.045), but not at 15 months. The median time to continence was 2 months for patients receiving nerve sparing compared to 4.5 months for non-nerve sparing (P = 0.02). CONCLUSION: Suture suspension of the DVC during RARP contributes to higher overall continence rates compared to stapling and cut and suture. Nerve sparing contributes to earlier return of continence than non-nerve sparing.

Robotic versus laparoscopic radical nephrectomy: a large multi-institutional analysis (ROSULA Collaborative Group).

OBJECTIVE: To compare the outcomes of robotic radical nephrectomy (RRN) to those of laparoscopic radical nephrectomy (LRN) for large renal masses. METHODS: This was a retrospective analysis of RRN and LRN cases performed for large (≥ cT2) renal masses from 2004 to 2017 and collected in the multi-institutional international database (ROSULA: RObotic SUrgery for LArge renal masses). Peri-operative, functional, and oncologic outcomes were compared between each approach. Descriptive analyses were performed and presented as medians with interquartile ranges. Inverse probability of treatment weighting-adjusted multivariable analyses were used to identify predictors of peri-operative complications. Kaplan-Meier analysis and Cox regression models were used to assess survival outcomes. RESULTS: A total of 941 patients (RRN = 404, LRN = 537) were identified. There was no difference in terms of gender, age, and clinical tumor size. Over the study period, RRN had an annual increase of 11.75% (95% CI [7.34, 17.01] p < 0.001) and LRN had an annual decline of 5.39% (95% CI [-6.94, -3.86] p < 0.001). Patients undergoing RRN had higher BMI (27.6 [IQR 24.8-31.1] vs. 26.5 [24.1-30.0] kg/m2, p < 0.01). Operative duration was longer for RRN (185.0 [150.0-237.2] vs. 126 [90.8-180.0] min, p < 0.001). Length of stay was shorter for RRN (3.0 [2.0-4.0] vs. 5.0 [4.0-7.0] days, p < 0.001). RRN cases presented more advanced disease (higher pathologic staging [pT3-4 52.5 vs. 24.2%, p < 0.001], histologic grade [high grade 49.3 vs. 30.4%, p < 0.001], and rate of nodal disease [pN1 5.4 vs. 1.9%, p < 0.01]). Surgical approach did not represent an independent risk factor for peri-operative complications (OR 1.81 95% CI [0.97-3.39], adjusted p = 0.2). The main study limitation is the retrospective design. CONCLUSIONS: This study represents the largest known multi-center comparison between RRN and LRN. The two procedures seem to offer similar peri-operative outcomes. Notably, RRN has been increasingly utilized, especially in the setting of more advanced and surgically challenging disease without increasing the risk of peri-operative complications.

Hepatic Transport of 25-Hydroxyvitamin D3 Conjugates: A Mechanism of 25-Hydroxyvitamin D3 Delivery to the Intestinal Tract.

Vitamin D3 is an important prohormone critical for maintaining calcium and phosphate homeostasis in the body and regulating drug-metabolizing enzymes and transporters. 25-Hydroxyvitamin D3 (25OHD3), the most abundant circulating metabolite of vitamin D3, is further transformed to the biologically active metabolite 1α,25-dihydroxyvitamin D3 (1α,25-(OH)2D3) by CYP27B1 in the kidney and extrarenal tissues, and to nonactive metabolites by other cytochrome P450 enzymes. In addition, 25OHD3 undergoes sulfation and glucuronidation in the liver, forming two major conjugative metabolites, 25OHD3-3-O-sulfate (25OHD3-S) and 25OHD3-3-O-glucuronide (25OHD3-G), both of which were detected in human blood and bile. Considering that the conjugates excreted into the bile may be circulated to and reabsorbed from the intestinal lumen, deconjugated to 25OHD3, and then converted to 1α,25-(OH)2D3, exerting local intestinal cellular effects, it is crucial to characterize enterohepatic transport mechanisms of 25OHD3-S and 25OHD3-G, and thereby understand and predict mechanisms of interindividual variability in mineral homeostasis. In the present study, with plasma membrane vesicle and cell-based transport studies, we showed that 25OHD3-G is a substrate of multidrug resistance proteins 2 and 3, OATP1B1, and OATP1B3, and that 25OHD3-S is probably a substrate of breast cancer resistance protein, OATP2B1, and OATP1B3. We also demonstrated sinusoidal and canalicular efflux of both conjugates using sandwich-cultured human hepatocytes. Given substantial expression of these transporters in liver hepatocytes and intestinal enterocytes, this study demonstrates for the first time that transporters could play important roles in the enterohepatic circulation of 25OHD3 conjugates, providing an alternative pathway of 25OHD3 delivery to the intestinal tract, which could be critical for vitamin D receptor-dependent gene regulation in enterocytes.

Pregnancy Increases Norbuprenorphine Clearance in Mice by Induction of Hepatic Glucuronidation.

Norbuprenorphine (NBUP) is the major active metabolite of buprenorphine (BUP) that is commonly used to treat opiate addiction during pregnancy; it possesses 25% of BUP's analgesic activity and 10 times BUP's respiratory depression effect. To optimize BUP's dosing regimen during pregnancy with better efficacy and safety, it is important to understand how pregnancy affects NBUP disposition. In this study, we examined the pharmacokinetics of NBUP in pregnant and nonpregnant mice by administering the same amount of NBUP through retro-orbital injection. We demonstrated that the systemic clearance (CL) of NBUP in pregnant mice increased ∼2.5-fold compared with nonpregnant mice. Intrinsic CL of NBUP by glucuronidation in mouse liver microsomes from pregnant mice was ∼2 times greater than that from nonpregnant mice. Targeted liquid chromatography tandem-mass spectrometry proteomics quantification revealed that hepatic Ugt1a1 and Ugt2b1 protein levels in the same amount of total liver membrane proteins were significantly increased by ∼50% in pregnant mice versus nonpregnant mice. After scaling to the whole liver with consideration of the increase in liver protein content and liver weight, we found that the amounts of Ugt1a1, Ugt1a10, Ugt2b1, and Ugt2b35 protein in the whole liver of pregnant mice were significantly increased ∼2-fold compared with nonpregnant mice. These data suggest that the increased systemic CL of NBUP in pregnant mice is likely caused by an induction of hepatic Ugt expression and activity. The data provide a basis for further mechanistic analysis of pregnancy-induced changes in the disposition of NBUP and drugs that are predominately and extensively metabolized by Ugts.

Buprenorphine, Norbuprenorphine, R-Methadone, and S-Methadone Upregulate BCRP/ABCG2 Expression by Activating Aryl Hydrocarbon Receptor in Human Placental Trophoblasts.

Opioid dependence during pregnancy is a rising concern. Maintaining addicted pregnant women on long-acting opioid receptor agonist is the most common strategy to manage drug abuse in pregnant women. Methadone (MET) and buprenorphine (BUP) are widely prescribed for opiate maintenance therapy. Norbuprenorphine (NBUP) is the primary active metabolite of BUP. These medications can cross the placenta to the fetus, leading to postpartum neonatal abstinence syndrome. Despite their use during pregnancy, little is known about the cellular changes in the placenta brought about by these drugs. In this study, we showed that BUP, NBUP, and MET at clinically relevant plasma concentrations significantly induced BCRP mRNA up to 10-fold in human model placental JEG3 and BeWo cells and in primary human villous trophoblasts, and this induction was abrogated by CH223191, an aryl hydrocarbon receptor (AhR)-specific antagonist. These drugs increased AhR recruitment onto the AhR-response elements and significantly induced breast cancer resistance protein (BCRP) gene transcription. AhR overexpression further increased BCRP mRNA and protein expression. Knockdown of AhR by shRNA decreased BCRP expression, and this decrease was reversed by rescuing AhR expression. Finally, induction of BCRP expression in JEG3 and BeWo cells was accompanied by an increase in its efflux activity. Collectively, we have demonstrated, for the first time, that BUP, NBUP, and MET are potent AhR agonists and can induce BCRP in human placental trophoblasts by activating AhR. Given the critical role of BCRP in limiting fetal exposure to drugs and xenobiotics, long-term use of these medications may affect fetal drug exposure by altering BCRP expression in human placenta.

P-gp/ABCB1 exerts differential impacts on brain and fetal exposure to norbuprenorphine.

Norbuprenorphine is the major active metabolite of buprenorphine which is commonly used to treat opiate addiction during pregnancy. Norbuprenorphine produces marked respiratory depression and was 10 times more potent than buprenorphine. Therefore, it is important to understand the mechanism that controls fetal exposure to norbuprenorphine, as exposure to this compound may pose a significant risk to the developing fetus. P-gp/ABCB1 and BCRP/ABCG2 are two major efflux transporters regulating tissue distribution of drugs. Previous studies have shown that norbuprenorphine, but not buprenorphine, is a P-gp substrate. In this study, we systematically examined and compared the roles of P-gp and BCRP in determining maternal brain and fetal distribution of norbuprenorphine using transporter knockout mouse models. We administered 1mg/kg norbuprenorphine by retro-orbital injection to pregnant FVB wild-type, Abcb1a-/-/1b-/-, and Abcb1a-/-/1b-/-/Abcg2-/- mice on gestation day 15. The fetal AUC of norbuprenorphine was ∼64% of the maternal plasma AUC in wild-type mice, suggesting substantial fetal exposure to norbuprenorphine. The maternal plasma AUCs of norbuprenorphine in Abcb1a-/-/1b-/- and Abcb1a-/-/1b-/-/Abcg2-/- mice were ∼2 times greater than that in wild-type mice. Fetal AUCs in Abcb1a-/-/1b-/- and Abcb1a-/-/1b-/-/Abcg2-/- mice were also increased compared to wild-type mice; however, the fetal-to-maternal plasma AUC ratio remained relatively unchanged by the knockout of Abcb1a/1b or Abcb1a/1b/Abcg2. In contrast, the maternal brain-to-maternal plasma AUC ratio in Abcb1a-/-/1b-/- or Abcb1a-/-/1b-/-/Abcg2-/- mice was increased ∼30-fold compared to wild-type mice. Protein quantification by LC-MS/MS proteomics revealed significantly higher amounts of P-gp protein in the wild-type mice brain than that in the placenta. These results indicate that fetal exposure to norbuprenorphine is substantial and that P-gp has a minor impact on fetal exposure to norbuprenorphine, but plays a significant role in restricting its brain distribution. The differential impacts of P-gp on norbuprenorphine distribution into the brain and fetus are likely, at least in part, due to the differences in amounts of P-gp protein expressed in the blood-brain and blood-placental barriers. BCRP is not as important as P-gp in determining both the systemic and tissue exposure to norbuprenorphine. Finally, fetal AUCs of the metabolite norbuprenorphine-ß-d-glucuronide were 3-7 times greater than maternal plasma AUCs, while the maternal brain AUCs were <50% of maternal plasma AUCs, suggesting that a reversible pool of conjugated metabolite in the fetus may contribute to the high fetal exposure to norbuprenorphine.

Test Characteristics of Emergency Physician-Performed Limited Compression Ultrasound for Lower-Extremity Deep Vein Thrombosis.

BACKGROUND: The current literature suggests that emergency physician (EP)-performed limited compression ultrasound (LCUS) is a rapid and accurate test for deep vein thrombosis (DVT). OBJECTIVE: Our primary objective was to determine the sensitivity and specificity of LCUS for the diagnosis of DVT when performed by a large heterogeneous group of EPs. METHODS: This was a prospective diagnostic test assessment of LCUS conducted at two urban academic emergency departments. The scanning protocol involved compression at the common femoral, superficial femoral, and popliteal veins. Patients were eligible if undergoing radiology department ultrasound of the lower extremity with moderate or high pretest probability for DVT, or low pretest probability for DVT with a positive d-dimer. The enrolling EP performed LCUS before radiology department ultrasound of the same lower extremity. Sensitivity, specificity, and associated 95% confidence intervals (CIs) were calculated with the radiologist interpretation of the radiology department ultrasound as the criterion standard. RESULTS: A total of 56 EPs enrolled 296 patients for LCUS, with a median age of 50 years and 50% female. Fifty (17%) DVTs were identified by radiology department ultrasound, and another five (2%) cases were deemed indeterminate. The sensitivity and specificity of EP-performed LCUS was 86% (95% CI 73-94%) and 93% (95% CI 89-96%), respectively. CONCLUSIONS: A large heterogeneous group of EPs with limited training can perform LCUS with intermediate diagnostic accuracy. Unfortunately, LCUS performed by EPs with limited ultrasound training is not sufficiently sensitive or specific to rule out or diagnose DVT as a single testing modality.

Effect of Interventional Program on the Utilization of PACS in Point-of-Care Ultrasound.

While the implementation of Picture Archiving and Communication Systems (PACS) has revolutionized the field of radiology, there has been considerably less utilization of PACS by emergency physicians with point-of-care ultrasound. Benefits of PACS archival of images include improved quality assurance, preservation of image quality, and accessibility of images. Our objective was to determine if a simple interventional program would influence the utilization of PACS in point-of-care ultrasound. A before-after study was conducted in an urban, academic emergency department. Data was collected during a 4-week baseline period, a 12-week intervention period, and a 12-week post-intervention period. The percentage of ultrasound studies archived to PACS was recorded during each week of the study. Interventions were designed to encourage the utilization of PACS. A significant increase in the mean percentage of PACS studies was found between the baseline and intervention period (59.4 %; 95 % CI: 34.76-84.08 %; p < 0.001). Mean percentage of PACS studies at 1-month (74.3 %), 2-month (61.0 %), and 3-month (74.8 %) post-intervention periods remained elevated and were all significantly increased compared to baseline values (p < 0.001). Mean percentages of PACS studies at 1-month, 2-month, and 3-month post-intervention periods were not statistically significant from the intervention period (p = 0.977, p = 0.849, p = 0.967, respectively). A simple interventional program for emergency physicians can significantly increase and sustain the utilization of PACS for point-of-care ultrasound.

Is long-axis view superior to short-axis view in ultrasound-guided central venous catheterization?

OBJECTIVE: To evaluate whether using long-axis or short-axis view during ultrasound-guided internal jugular and subclavian central venous catheterization results in fewer skin breaks, decreased time to cannulation, and fewer posterior wall penetrations. DESIGN: Prospective, randomized crossover study. SETTING: Urban emergency department with approximate annual census of 60,000. SUBJECTS: Emergency medicine resident physicians at the Denver Health Residency in Emergency Medicine, a postgraduate year 1-4 training program. INTERVENTIONS: Resident physicians blinded to the study hypothesis used ultrasound guidance to cannulate the internal jugular and subclavian of a human torso mannequin using the long-axis and short-axis views at each site. MEASUREMENTS AND MAIN RESULTS: An ultrasound fellow recorded skin breaks, redirections, and time to cannulation. An experienced ultrasound fellow or attending used a convex 8-4 MHz transducer during cannulation to monitor the needle path and determine posterior wall penetration. Generalized linear mixed models with a random subject effect were used to compare time to cannulation, number of skin breaks and redirections, and posterior wall penetration of the long axis and short axis at each cannulation site. Twenty-eight resident physicians participated: eight postgraduate year 1, eight postgraduate year 2, five postgraduate year 3, and seven postgraduate year 4. The median (interquartile range) number of total internal jugular central venous catheters placed was 27 (interquartile range, 9-42) and subclavian was six catheters (interquartile range, 2-20). The median number of previous ultrasound-guided internal jugular catheters was 25 (interquartile range, 9-40), and ultrasound-guided subclavian catheters were three (interquartile range, 0-5). The long-axis view was associated with a significant decrease in the number of redirections at the internal jugular and subclavian sites, relative risk 0.4 (95% CI, 0.2-0.9) and relative risk 0.5 (95% CI, 0.3-0.7), respectively. There was no significant difference in the number of skin breaks between the long axis and short axis at the subclavian and internal jugular sites. The long-axis view for subclavian was associated with decreased time to cannulation; there was no significant difference in time between the short-axis and long-axis views at the internal jugular site. The prevalence of posterior wall penetration was internal jugular short axis 25%, internal jugular long axis 21%, subclavian short axis 64%, and subclavian long axis 39%. The odds of posterior wall penetration were significantly less in the subclavian long axis (odds ratio, 0.3; 95% CI, 0.1-0.9). CONCLUSIONS: The long-axis view for the internal jugular was more efficient than the short-axis view with fewer redirections. The long-axis view for subclavian central venous catheterization was also more efficient with decreased time to cannulation and fewer redirections. The long-axis approach to subclavian central venous catheterization is also associated with fewer posterior wall penetrations. Using the long-axis view for subclavian central venous catheterization and avoiding posterior wall penetrations may result in fewer central venous catheter-related complications.

Comparison of bag-valve-mask hand-sealing techniques in a simulated model.

STUDY OBJECTIVE: Bag-valve-mask ventilation remains an essential component of airway management. Rescuers continue to use both traditional 1- or 2-handed mask-face sealing techniques, as well as a newer modified 2-handed technique. We compare the efficacy of 1-handed, 2-handed, and modified 2-handed bag-valve-mask technique. METHODS: In this prospective, crossover study, health care providers performed 1-handed, 2-handed, and modified 2-handed bag-valve-mask ventilation on a standardized ventilation model. Subjects performed each technique for 5 minutes, with 3 minutes' rest between techniques. The primary outcome was expired tidal volume, defined as percentage of total possible expired tidal volume during a 5-minute bout. A specialized inline monitor measured expired tidal volume. We compared 2-handed versus modified 2-handed and 2-handed versus 1-handed techniques. RESULTS: We enrolled 52 subjects: 28 (54%) men, 32 (62%) with greater than or equal to 5 actual emergency bag-valve-mask situations. Median expired tidal volume percentage for 1-handed technique was 31% (95% confidence interval [CI] 17% to 51%); for 2-handed technique, 85% (95% CI 78% to 91%); and for modified 2-handed technique, 85% (95% CI 82% to 90%). Both 2-handed (median difference 47%; 95% CI 34% to 62%) and modified 2-handed technique (median difference 56%; 95% CI 29% to 65%) resulted in significantly higher median expired tidal volume percentages compared with 1-handed technique. The median expired tidal volume percentages between 2-handed and modified 2-handed techniques did not significantly differ from each other (median difference 0; 95% CI -2% to 2%). CONCLUSION: In a simulated model, both 2-handed mask-face sealing techniques resulted in higher ventilatory tidal volumes than 1-handed technique. Tidal volumes from 2-handed and modified 2-handed techniques did not differ. Rescuers should perform bag-valve-mask ventilation with 2-handed techniques.

Sensitivity of systemic inflammatory response syndrome for critical illness among ED patients.

BACKGROUND: Little is known about the diagnostic accuracy of systemic inflammatory response syndrome (SIRS) criteria for critical illness among emergency department (ED) patients with and without infection. Our objective was to assess the diagnostic accuracy of SIRS criteria for critical illness in ED patients. METHODS: This was a retrospective cohort study of ED patients at an urban academic hospital. Standardized chart abstraction was performed on a random sample of all adult ED medical patients admitted to the hospital during a 1-year period, excluding repeat visits, transfers, ED deaths, and primary surgical or psychiatric admissions. The binary composite outcome of critical illness was defined as 24 hours or longer in intensive care or inhospital death. Presumed infection was defined as receiving antibiotics within 48 hours of admission. Systemic inflammatory response syndrome criteria were calculated using ED triage vital signs and initial white blood cell count. RESULTS: We studied 1152 patients; 39% had SIRS, 27% had presumed infection, and 23% had critical illness (2% had inhospital mortality, and 22% had ≥24 hours in intensive care). Of patients with SIRS, 38% had presumed infection. Of patients without SIRS, 21% had presumed infection. The sensitivity of SIRS criteria for critical illness was 52% (95% confidence interval [CI], 46%-58%) in all patients, 66% (95% CI, 56%-75%) in patients with presumed infection, and 43% (95% CI, 36%-51%) in patients without presumed infection. CONCLUSIONS: Systemic inflammatory response syndrome at ED triage, as currently defined, has poor sensitivity for critical illness in medical patients admitted from the ED.

Role of Clinical Pharmacology in Diversity and Inclusion in Global Drug Development: Current Practices and Industry Perspectives: White Paper.

The 2022 United States Food and Drug Administration (US FDA) draft guidance on diversity plan (DP), which will be implemented through the Diversity Action Plans by December 2025, under the 21st Century Cures Act, marks a pivotal effort by the FDA to ensure that registrational studies adequately reflect the target patient populations based on diversity in demographics and baseline characteristics. This white paper represents the culminated efforts of the International Consortium of Quality and Innovation (IQ) Diversity and Inclusion (D&I) Working Group (WG) to assess the implementation of the draft FDA guidance by members of the IQ consortium in the discipline of clinical pharmacology (CP). This article describes current practices in the industry and emphasizes the tools and techniques of quantitative pharmacology that can be applied to support the inclusion of a diverse population during global drug development, to support diversity and inclusion of underrepresented patient populations, in multiregional clinical trials (MRCTs). It outlines strategic and technical recommendations to integrate demographics, including age, sex/gender, race/ethnicity, and comorbidities, in multiregional phase III registrational studies, through the application of quantitative pharmacology. Finally, this article discusses the challenges faced during global drug development, which may otherwise limit the enrollment of a broader, potentially diverse population in registrational trials. Based on the outcomes of the IQ survey that provided the current awareness of diversity planning, it is envisioned that in the future, industry efforts in the inclusion of previously underrepresented populations during global drug development will culminate in drug labels that apply to the intended patient populations at the time of new drug application or biologics license application rather than through post-marketing requirements.

Clinical pharmacology strategies to accelerate the development of polatuzumab vedotin and summary of key findings.

The favorable benefit-risk profile of polatuzumab vedotin, as demonstrated in a pivotal Phase Ib/II randomized study (GO29365; NCT02257567), coupled with the need for effective therapies in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), prompted the need to accelerate polatuzumab vedotin development. An integrated, fit-for-purpose clinical pharmacology package was designed to support regulatory approval. To address key clinical pharmacology questions without dedicated clinical pharmacology studies, we leveraged non-clinical and clinical data for polatuzumab vedotin, published clinical data for brentuximab vedotin, a similar antibody-drug conjugate, and physiologically based pharmacokinetic and population pharmacokinetic modeling approaches. We review strategies and model-informed outcomes that contributed to regulatory approval of polatuzumab vedotin plus bendamustine and rituximab in R/R DLBCL. These strategies made polatuzumab vedotin available to patients earlier than previously possible; depending on the strength of available data and the regulatory/competitive environment, they may also prove useful in accelerating the development of other agents.

Population pharmacokinetics and exposure-response analyses of polatuzumab vedotin in patients with previously untreated DLBCL from the POLARIX study.

Polatuzumab vedotin is a CD79b-directed antibody-drug conjugate that targets B cells and delivers the cytotoxic payload monomethyl auristatin E (MMAE). The phase III POLARIX study (NCT03274492) evaluated polatuzumab vedotin in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) as first-line treatment of diffuse large B-cell lymphoma (DLBCL). To examine dosing decisions for this regimen, population pharmacokinetic (popPK) analysis, using a previously developed popPK model, and exposure-response (ER) analysis, were performed. The popPK analysis showed no clinically meaningful relationship between cycle 6 (C6) antibody-conjugated (acMMAE)/unconjugated MMAE area under the concentration-time curve (AUC) or maximum concentration, and weight, sex, ethnicity, region, mild or moderate renal impairment, mild hepatic impairment, or other patient and disease characteristics. In the ER analysis, C6 acMMAE AUC was significantly associated with longer progression-free and event-free survival (both p = 0.01). An increase of <50% in acMMAE/unconjugated MMAE exposure did not lead to a clinically meaningful increase in adverse events of special interest. ER data and the benefit-risk profile support the use of polatuzumab vedotin 1.8 mg/kg once every 3 weeks with R-CHP for six cycles in patients with previously untreated DLBCL.