Search

When a new molecular entity is predicted to exhibit high clearance in humans, pharmaceutical sponsors almost universally search for similar acting back-up compounds that will demonstrate low clearance. Here we show that, except for oral dosing, there can be marked advantages to developing and commercializing controlled release formulations of high clearance drugs, the expertise of readers of this journal. Our recent publications demonstrate that the universally held pharmacokinetic principle that drug delivery rate has no effect on measured drug clearance is not correct. Rather, we show that if clearance from the drug delivery site is markedly less than the iv bolus clearance of a drug, the in vivo drug clearance can be the drug delivery clearance controlled by the designed dosage form. This approach will be especially advantageous for high hepatic clearance drugs. These advantages include not being concerned with: a) saturable nonlinear kinetics, b) significant pharmacogenomic differences, c) drug-drug induction mechanisms, and d) in many cases drug-drug inhibition interactions. This is due to the ability of a drug sponsor to design clearance, independent of the pharmacokinetic characteristics for high clearance compounds, where clearance from the dosage form becomes the drug clearance from the patient. Recognition of this principle, as described here, results from our development of the use of Kirchhoff's Laws from physics to derive rate-defining clearance and rate constant elimination processes independent of differential equation derivations. The key message for readers of this journal is that high clearance drugs are potentially drugable through formulation design and should not be outright disregarded, since for such drugs the dose-corrected area under the curve can be increased if the release rate from the injection site is controlled and slow resulting in drug clearance from the body controlled by clearance from the dosage form. The concepts presented here describe previously unrecognized advantages of controlled release formulations.

Recently, we have proposed simple methodology to derive clearance and rate constant equations, independent of differential equations, based on Kirchhoff's Laws, a common methodology from physics used to describe rate-defining processes either in series or parallel. Our approach has been challenged in three recent publications, two published in this journal, but notably what is lacking is that none evaluate experimental pharmacokinetic data. As reviewed here, manuscripts from our laboratory have evaluated published experimental data, demonstrating that the Kirchhoff's Laws approach explains (1) why all of the experimental perfused liver clearance data appear to fit the equation that was previously believed to be the well-stirred model, (2) why linear pharmacokinetic systemic bioavailability determinations can be greater than 1, (3) why renal clearance can be a function of drug input processes, and (4) why statistically different bioavailability measures may be found for urinary excretion versus systemic concentration measurements. Our most recent paper demonstrates (5) how the universally accepted steady-state clearance approach used by the field for the past 50 years leads to unrealistic outcomes concerning the relationship between liver-to-blood Kpuu and hepatic availability FH , highlighting the potential for errors in pharmacokinetic evaluations based on differential equations. The Kirchhoff's Laws approach is applicable to all pharmacokinetic analyses of quality experimental data, those that were previously adequately explained with present pharmacokinetic theory, and those that were not. The publications that have attempted to rebut our position do not address unexplained experimental data, and we show here why their analyses are not valid. SIGNIFICANCE STATEMENT: The Kirchhoff's Laws approach to deriving clearance equations for linear systems in parallel or in series, independent of differential equations, successfully describes published pharmacokinetic data that has previously been unexplained. Three recent publications claim to refute our proposed methodology; these publications only make theoretical arguments, do not evaluate experimental data, and never demonstrate that the Kirchhoff methodology provides incorrect interpretations of experimental pharmacokinetic data, including statistically significant data not explained by present pharmacokinetic theory. We demonstrate why these analyses are invalid.

Here we present, utilizing universally accepted relationships for hepatic clearance at steady state, that for all models of hepatic elimination the ratio of unbound liver drug concentration to unbound systemic blood concentration, Kpuu, is a function of or related to the hepatic bioavailability for that drug, FH. According to the derivation for the well-stirred model, Kpuu can never exceed unity, can frequently be a function of hepatic blood flow, and is equivalent to the value of FH as determined following oral dosing. For the parallel tube model, Kpuu will not equal FH but will be a function of FH and will also never be a value greater than 1. When hepatic clearance is rate limited by basolateral transporters, Kpuu will be less than 1, and less than FH. We believe that such outcomes are highly unlikely, and that the error arises from a basic assumption concerning hepatic clearance that leads to the mechanistic models of hepatic elimination, the well-stirred, parallel tube and dispersion models. That basic assumption is that the steady-state systemic concentration multiplied by the hepatic systemic clearance is equal to the product of the average unbound liver steady-state concentration and the intrinsic hepatic clearance (Css · CL = CH,u · CLint). Calculations of Kpuu and FH based on present methods of analysis provide a strong argument as to why this universally accepted relationship is not correct. Alternatively, we have shown in recent publications that hepatic clearance may be adequately determined based on Kirchhoff's Laws where no assumption of the above equality concerning hepatic intrinsic clearance is required, and where Kpuu is independent of hepatic extraction ratio and FH.

This collaborative theoretical essay considers how an Embodied Ethic of Care Framework (Sodhi, 2022), which is informed by Black feminist thought and Indigenous African thought, offers a different way of being in international education. We describe international education in Canada, which focuses on the economy and leads to "conditional hospitality" (Ahmed, 2012) and the commodification of international students (Guo & Guo, 2017). We juxtapose the five elements of the framework to instances of international education in Canada. We demonstrate how current connections with international students are transactional which replicates harmful historical relationships between people of colour, capitalism, and colonialism. The Embodied Ethic of Care Framework is an antidote for this colonial violence because it places relationship building at the center. We invite readers to consider how an ethic of care might inspire a different way of being that could redress coloniality and systemic racism in their own internationalized contexts.

Non-neovascular or dry age-related macular degeneration (AMD) is a multi-factorial disease with degeneration of the aging retinal-pigmented epithelium (RPE). Lysosomes play a crucial role in RPE health via phagocytosis and autophagy, which are regulated by transcription factor EB/E3 (TFEB/E3). Here, we find that increased AKT2 inhibits PGC-1α to downregulate SIRT5, which we identify as an AKT2 binding partner. Crosstalk between SIRT5 and AKT2 facilitates TFEB-dependent lysosomal function in the RPE. AKT2/SIRT5/TFEB pathway inhibition in the RPE induced lysosome/autophagy signaling abnormalities, disrupted mitochondrial function and induced release of debris contributing to drusen. Accordingly, AKT2 overexpression in the RPE caused a dry AMD-like phenotype in aging Akt2 KI mice, as evident from decline in retinal function. Importantly, we show that induced pluripotent stem cell-derived RPE encoding the major risk variant associated with AMD (complement factor H; CFH Y402H) express increased AKT2, impairing TFEB/TFE3-dependent lysosomal function. Collectively, these findings suggest that targeting the AKT2/SIRT5/TFEB pathway may be an effective therapy to delay the progression of dry AMD.

The popularity of Glycosaminoglycans (GAGs) in drug delivery systems has grown as their innate ability to sequester and release charged molecules makes them adept in the controlled release of therapeutics. However, peptide therapeutics have been relegated to synthetic, polymeric systems, despite their high specificity and efficacy as therapeutics because they are rapidly degraded in vivo when not encapsulated. We present a GAG-based nanoparticle system for the easy encapsulation of cationic peptides, which offers control over particle diameter, peptide release behavior, and swelling behavior, as well as protection from proteolytic degradation, using a singular, organic polymer and no covalent linkages. These nanoparticles can encapsulate cargo with a particle diameter range spanning 130-220 nm and can be tuned to release cargo over a pH range of 4.5 to neutral through the modulation of the degree of sulfation and the molecular weight of the GAG. This particle system also confers better in vitro performance than the unencapsulated peptide via protection from enzymatic degradation. This method provides a facile way to protect therapeutic peptides via the inclusion of the presented binding sequence and can likely be expanded to larger, more diverse cargo as well, abrogating the complexity of previously demonstrated systems while offering broader tunability.

It is generally believed that bioavailability (F) calculated based on systemic concentration area under the curve (AUC) measurements cannot exceed 1.0, yet some published studies report this inconsistency. We teach and believe, based on differential equation derivations, that rate of absorption has no influence on measured systemic clearance following an oral dose, i.e., determined as available dose divided by AUC. Previously, it was thought that any difference in calculating F from urine data versus that from systemic concentration AUC data was due to the inability to accurately measure urine data. A PubMed literature search for drugs exhibiting F > 1.0 and studies for which F was measured using both AUC and urinary excretion dose-corrected analyses yielded data for 35 drugs. We show and explain, using Kirchhoff's Laws, that these universally held concepts concerning bioavailability may not be valid in all situations. Bioavailability, determined using systemic concentration measurements, for many drugs may be overestimated since AUC reflects not only systemic elimination but also absorption rate characteristics, which is most easily seen for renal clearance measures. Clearance of drug from the absorption site must be significantly greater than clearance following an iv bolus dose for F(AUC) to correctly correspond with F(urine). The primary purpose of this paper is to demonstrate that studies resulting in F > 1.0 and/or greater systemic vs urine bioavailability predictions may be accurate. Importantly, these explications have no significant impact on current regulatory guidance for bioequivalence testing, nor on the use of exposure (AUC) measures in making drug dosing decisions.

Abstract Short bowel syndrome (SBS) leads to severe morbidity and mortality. Intestinal adaptation is crucial in improving outcomes. To understand the human gene pathways associated with adaptation, we perform single-cell transcriptomic analysis of human small intestinal organoids explanted from mice with experimental SBS. We show that transmembrane ion pathways, specifically the transepithelial zinc transport pathway genes SLC39A4 and SLC39A5, are upregulated in SBS. This discovery is corroborated by an external dataset, bulk RT-qPCR, and Western blots. Oral zinc supplementation is shown to improve survival and weight gain of SBS mice and increase the proliferation of intestinal crypt cells in vitro. Finally, we identify the upregulation of SLC39A5 and associated transcription factor KLF5 in biopsied intestinal tissue specimens from patients with SBS. Thus, we identify zinc supplementation as a potential therapy for SBS and describe a xenotransplantation model that provides a platform for discovery in other intestinal diseases.

Abstract Background Point-of-care ultrasound (POCUS) has emerged as an essential bedside tool for clinicians, but lack of access to ultrasound equipment has been a top barrier to POCUS use. Recently, several handheld ultrasound devices (“handhelds”) have become available, and clinicians are seeking data to guide purchasing decisions. Few comparative studies of different handhelds have been done. We conducted a cross-sectional study comparing 6 handhelds readily available in the United States (Butterfly iQ + ™ by Butterfly Network Inc.; Clarius™ by Clarius Mobile Health; Kosmos™ by EchoNous; TE Air™ by Mindray; Vscan Air™ SL and CL by General Electric; and Lumify™ by Philips Healthcare). A multi-specialty group of physician POCUS experts (n = 35) acquired three standard ultrasound views (abdominal right upper quadrant, cardiac apical 4-chamber, and superficial neck and lung views) in random order on the same standardized patients and rated the image quality. Afterward, a final survey of the overall ease of use, image quality, and satisfaction of each handheld was completed. Results Thirty-five POCUS experts specializing in internal medicine/hospital medicine, critical care, emergency medicine, and nephrology acquired and rated right upper quadrant, apical 4-chamber, and superficial neck and lung views with 6 different handhelds. For image quality, the highest-rated handhelds were Vscan Air™ for the right upper quadrant view, Mindray TE Air™ for the cardiac apical 4-chamber view, and Lumify™ for superficial views of the neck and lung. Overall satisfaction with image quality was highest with Vscan Air™, Lumify™, and Mindray, while overall satisfaction with ease of use was highest with Vscan Air™. The 5 most desirable characteristics of handhelds were image quality, ease of use, portability, probe size, and battery life. Ultimately, all 6 handhelds had notable advantages and disadvantages, with no single device having all desired qualities or features. Conclusions The overall satisfaction with image quality was rated highest with Vscan Air™, Lumify™, and Mindray TE Air™when acquiring right upper quadrant, apical 4-chamber, and superficial neck and lung views. No single handheld was perceived to be superior in image quality for all views. Vscan Air™ was rated highest for overall ease of use and was the most preferred handheld for purchase by POCUS experts.

Background The Pre-Conception and Pre-Natal Diagnostic Techniques (Prohibition of Sex Selection) Act (PC&PNDT Act), 1994 was enacted to prevent sex determination and female feticide. As a mandatory statutory requirement, All India Institute of Medical Sciences, New Delhi, India has to renew its PC&PNDT license after every 5 years.

Abstract Gaucher disease (GD) type 3 is an autosomal recessive lysosomal disease caused by deficiency of β‐glucocerebrosidase (GCase) and encompasses a spectrum of cardiac, neurological, and ophthalmological abnormalities. Although the clinical presentations can be diverse, a recognized clinical trajectory points to an early onset, predominantly before 18 years. GD type 3c is primarily caused by homozygosity for GBA pathogenic variant c.1342G>C (p.Asp448His; historically referred to as D409H) and includes visceral, hematological, skeletal, and cardiac abnormalities. Notably, GD type 3c is distinct from other GD types because it is primarily characterized by valvular heart disease. Yet, with less than 50 patients with GD type 3c reported to date, the phenotypic spectrum and extent of cardiac involvement remains ill‐defined. We present a 20‐year‐old female with an atypical presentation of GD type 3c consisting of chronic intermediate uveitis as the presenting feature and the presence of extensive polyneuropathy starting in adolescence which has been previously unreported in GD type 3c. Distinctively, she has maintained normal cardiac function. Moreover, we compare our case with those reported in the literature to broaden awareness of the varied initial presentations of this disease. The diverse presentations seen in GD type 3c, underscored by our case and those previously reported, demonstrate the need for standardized evaluation and management protocols.

This paper presents a competition-based active learning approach that prepares undergraduate students for careers in the drone industry. The competition-based learning (CBL) approach focuses on preparing students for three key drone industry requirements (1) drone assembly, testing, and validation using commercial off-the-shelf (COTS) parts, (2) simulation of drone flight missions and (3) manual and semi-autonomous drone piloting. The CBL curricular modules were developed using the Interactive-Constructive-Active-Passive (ICAP) framework of cognitive engagement. These modules immersed students in the technical challenges corresponding to the three essential drone industry requirements. The approach was implemented through fourteen (14) drone workshops that culminated in a final drone piloting competition at a STEM research university in the United States. Ninety-seven (97) students from various backgrounds with little to no prior experience in building drones participated in the competition as part of 22 teams in total. Multiple assessment methods were used to evaluate the students' progress and the perceived drone-related skills gained by the end of the workshops. Assessment methods included data from direct formative (weekly or biweekly curricular milestones), direct summative (drone piloting for multiple flight tests), indirect quantitative (Likert-style feedback survey about student perceptions), and indirect qualitative (descriptive feedback comments) tools. Direct quantitative assessments indicated that most students successfully reached the technical milestones of the workshop sessions and gained practical drone piloting skills. The indirect quantitative assessment revealed that students perceived the workshops to be a valuable experience in their drone industry skills and knowledge. Indirect qualitative analysis of the feedback comments revealed that students perceived CBL as an engaging and effective method of introducing drone technology.

Abstract Non-neovascular or dry age-related macular degeneration (AMD) is a multi-factorial disease with degeneration of the aging retinal-pigmented epithelium (RPE). Lysosomes play a crucial role in RPE health via phagocytosis and autophagy, which are regulated by transcription factor EB/E3 (TFEB/E3). Here, we find that increased AKT2 inhibits PGC-1α to downregulate SIRT5, which we identify as an AKT2 binding partner. Crosstalk between SIRT5 and AKT2 facilitates TFEB-dependent lysosomal function in the RPE. AKT2/SIRT5/TFEB pathway inhibition in the RPE induced lysosome/autophagy signaling abnormalities, disrupted mitochondrial function and induced release of debris contributing to drusen. Accordingly, AKT2 overexpression in the RPE caused a dry AMD-like phenotype in aging Akt2 KI mice, as evident from decline in retinal function. Importantly, we show that induced pluripotent stem cell-derived RPE encoding the major risk variant associated with AMD (complement factor H; CFH Y402H) express increased AKT2, impairing TFEB/TFE3-dependent lysosomal function. Collectively, these findings suggest that targeting the AKT2/SIRT5/TFEB pathway may be an effective therapy to delay the progression of dry AMD.

Background: In Retzius-sparing robot-assisted radical prostatectomy (RARP), lymphocele formation is a troublesome complication. The use of peritoneal flaps has emerged as a promising novel technique to tackle this complication. We explored this technique by suturing both the medial peritoneal flaps to each other and keeping them distracted so that the lymphadenectomy beds are left wide open. Objective: To assess the efficacy of our peritoneal distraction technique on lymphocele rates following Retzius-sparing RARP. Materials and Methods: This retrospective study included patients with localized prostate carcinoma who underwent Retzius-sparing RARP with standard pelvic lymph node dissection between May 2014 and September 2022 at Aster Medcity, Kochi, India. Based on the use of the technique, patients were divided into two groups: peritoneal distraction and closed groups. Both groups were matched using the propensity scoring method in a 1:1 ratio. Results: A total of 272 patients were included, of which 89 (32.7%) belonged to the peritoneal distraction group. Although the overall incidence of lymphocele between the two groups were comparable, none of the patients in the peritoneal distraction group required any intervention for lymphocele management, as opposed to 7 patients from the closed group (3.9%; P = 0.015). No significant association was found between lymphocele formation and serum prostate-specific antigen level, Gleason score, and the number of lymph nodes harvested. Conclusions: This study found that peritoneal distraction stitch is a simple and effective technique to reduce the incidence of symptomatic lymphocele that require intervention after Retzius-sparing RARP.

A feature of severe COVID-19 is the onset of an acute and intense systemic inflammatory response referred to as the "cytokine storm". The cytokine storm is characterized by high serum levels of inflammatory cytokines and the subsequent transport of inflammatory cells to damaging levels in vital organs (e.g., myocarditis). Immune trafficking and its effect on underlying tissues (e.g., myocardium) are challenging to observe at a high spatial and temporal resolution in mouse models. In this study, we created a vascularized organ-on-a-chip system to mimic cytokine storm-like conditions and tested the effectiveness of a novel multivalent selectin-targeting carbohydrate conjugate (composed of DS - dermatan sulfate and IkL - a selectin-binding peptide, termed DS-IkL) in blocking infiltration of polymorphonuclear leukocytes (PMN). Our data shows that cytokine storm-like conditions induce endothelial cells to produce additional inflammatory cytokines and facilitate infiltration of PMNs into tissue. Treatment of tissues with DS-IkL (60 μM) reduced PMN accumulation in the tissue by >50%. We then created cytokine storm-like conditions in a vascularized cardiac tissue-chip and found that PMN infiltration increases the spontaneous beating rate of the cardiac tissue, and this effect is eliminated by treatment with DS-IkL (60 μM). In summary, we demonstrate the utility of an organ-on-a-chip platform to mimic COVID-19 related cytokine storm and that blocking leukocyte infiltration with DS-IkL could be a viable strategy to mitigate associated cardiac complications.