Identification of benzothiazole derived monosaccharides as potent, selective, and orally bioavailable inhibitors of human and mouse galectin-3; a rare example of using a S···O binding interaction for drug design.

As a result of our continued efforts to pursue Gal-3 inhibitors that could be used to fully evaluate the potential of Gal-3 as a therapeutic target, two novel series of benzothiazole derived monosaccharides as potent (against both human and mouse Gal-3) and orally bioavailable Gal-3 inhibitors, represented by 4 and 5, respectively, were identified. These discoveries were made based on proposals that the benzothiazole sulfur atom could interact with the carbonyl oxygen of G182/G196 in h/mGal-3, and that the anomeric triazole moiety could be modified into an N-methyl carboxamide functionality. The interaction between the benzothiazole sulfur and the carbonyl oxygen of G196 in mGal-3 was confirmed by an X-ray co-crystal structure of early lead 9, providing a rare example of using a S···O binding interaction for drug design. It was found that for both the series, methylation of 3-OH in the monosaccharides caused no loss in h & mGal-3 potencies but significantly improved permeability of the molecules.

Deconstructing the skin: cytoarchitectural determinants of epidermal morphogenesis.

To provide a stable environmental barrier, the epidermis requires an integrated network of cytoskeletal elements and cellular junctions. Nevertheless, the epidermis ranks among the body's most dynamic tissues, continually regenerating itself and responding to cutaneous insults. As keratinocytes journey from the basal compartment towards the cornified layers, they completely reorganize their adhesive junctions and cytoskeleton. These architectural components are more than just rivets and scaffolds - they are active participants in epidermal morphogenesis that regulate epidermal polarization, signalling and barrier formation.

Kidney cysts in patients with HOGA1 variants.

In an era of increased accessibility to genetic testing, nephrologists may be able to better understand pathophysiologic mechanisms by which their patients develop specific conditions. In this study, we describe clinical and genetic findings of two patients with kidney cysts, who were found to have variants in HOGA1, a mitochondrial 4-hydroxy-2-oxoglutarate aldolase enzyme associated with primary hyperoxaluria type 3 and the development of oxalate-containing kidney stones. We describe possible mechanisms by which mutations in this enzyme could result in the kidney cyst formation seen in our two patients. We propose that patients with mutations in HOGA1 are predisposed to crystal or stone deposition, tubule dilation, and inflammasome activation, which can result in kidney cyst formation.

Association of plasma-soluble ST2 and galectin-3 with cardiovascular events and mortality following cardiac surgery.

BACKGROUND: Cardiac surgery induces hemodynamic stress on the myocardium, and this process can be associated with significant post-operative morbidity and mortality. Soluble suppression of tumorigenicity 2 (sST2) and galectin-3 (gal-3) are biomarkers of myocardial remodeling and fibrosis; however, their potential association with post-operative changes is unknown. METHODS: We measured peri-operative plasma sST2 and gal-3 levels in two prospective cohorts (TRIBE-AKI and NNE) of over 1800 patients who underwent cardiac surgery. sST2 and gal-3 levels were evaluated for association with a composite primary outcome of cardiovascular event or mortality over median follow-up periods of 3.4 and 6.0 years, respectively, for the two cohorts. Meta-analysis of hazard ratio estimates from the cohorts was performed using random effects models. RESULTS: Cohorts demonstrated event rates of 70.2 and 66.8 per 1000 person-years for the primary composite outcome. After adjustment for clinical covariates, higher post-operative sST2 and gal-3 levels were significantly associated with cardiovascular event or mortality [pooled estimate HRs: sST2 1.29 (95% CI 1.16, 1.44); gal-3 1.26 (95% CI 1.09, 1.46)]. These associations were not significantly modified by pre-operative congestive heart failure or AKI. CONCLUSIONS: Higher post-operative sST2 and gal-3 values were associated with increased incidence of cardiovascular event or mortality. These two biomarkers should be further studied for potential clinical utility for patients undergoing cardiac surgery.

Application and Impact of Human Dose Projection from Discovery to Early Drug Development.

The application and impact of human dose projection (HDP) has been well recognized in the late drug development phase, with increasing appreciation earlier during discovery and early development. This commentary describes the perspective of pharmaceutical scientists on the evolving application and impact of HDP at various phases from discovery to early development, including lead generation, lead optimization, lead up to candidate nomination, and early drug development. The underlying fundamental concepts and key input parameters for HDP are briefly discussed. A broad overview of phase-specific tools and approaches commonly utilized for human dose projection in the pharmaceutical industry is provided. A discussion of phase-appropriate implementation strategies, associated limitations/assumptions and continuous refinement for HDP from discovery to early development is presented. The authors describe the phase-specific applications of human dose projection to facilitate key assessments and relative impact on decision points.

Management of COVID-19 in an Outpatient Dialysis Program.

In March 2020, the COVID-19 pandemic became an increasingly urgent issue of public health concern in the United States. Patients on dialysis are considered to be at increased risk for infection due to their medical comorbidities and need for continued face-to-face encounters in dialysis units. In our outpatient dialysis practice, 42 out of 269 patients (15.6%) were infected with COVID-19 during the first wave of the pandemic. In this retrospective report, we review issues of infection control, access to interventional procedures, and communication encountered in our practice. We discuss lessons learned in patient outcomes and the importance of transitioning patients to home modalities. Further planning for a potential second wave of COVID-19 may help ensure improved quality of care for patients in the dialysis program.

Membrane-based therapeutic plasma exchange (mTPE): Technical and clinical experience.

Therapeutic plasma exchange (TPE) has long been utilized to manage a variety of immune-mediated diseases. The basic principle relies on removal of circulating pathogenic substances from the bloodstream. Methods of plasma separation include centrifuge (cTPE) and membrane (mTPE). Although mTPE has existed for a few decades, recent advances in developing highly permeable filters that are compatible with currently existing dialysis machines has opened a new frontier. Published data in the area of technical and clinical experience with mTPE is lacking. We report our single center experience of 998 inpatient mTPE treatments performed in 237 patients at a large tertiary care academic center. The most common treatment indication was neurologic. We found a very low incidence of patient-reported complications. Filter clotting without the use of anticoagulation occurred in 7.7% of treatments. Laboratory parameters that significantly changed during the course of therapy included serum potassium, platelet count, and partial thromboplastin time. We found that mTPE can be safely and efficiently performed as an alternative to cTPE, and suggest an individualized approach when prescribing this therapy.

Inhibition of Intestinal OATP2B1 by the Calcium Receptor Antagonist Ronacaleret Results in a Significant Drug-Drug Interaction by Causing a 2-Fold Decrease in Exposure of Rosuvastatin.

Rosuvastatin is a widely prescribed antihyperlipidemic which undergoes limited metabolism, but is an in vitro substrate of multiple transporters [organic anion transporting polypeptide 1B1 (OATP1B1), OATP1B3, OATP1A2, OATP2B1, sodium-taurocholate cotransporting polypeptide, breast cancer resistance protein (BCRP), multidrug resistance protein 2 (MRP2), MRP4, organic anion transporter 3]. It is therefore frequently used as a probe substrate in clinical drug-drug interaction (DDI) studies to investigate transporter inhibition. Although each of these transporters is believed to play a role in rosuvastatin disposition, multiple pharmacogenetic studies confirm that OATP1B1 and BCRP play an important role in vivo. Ronacaleret, a drug-development candidate for treatment of osteoporosis (now terminated), was shown to inhibit OATP1B1 in vitro (IC50 = 11 µM), whereas it did not inhibit BCRP. Since a DDI risk through inhibition of OATP1B1 could not be discharged, a clinical DDI study was performed with rosuvastatin before initiation of phase II trials. Unexpectedly, coadministration with ronacaleret decreased rosuvastatin exposure by approximately 50%, whereas time of maximal plasma concentration and terminal half-life remained unchanged, suggesting decreased absorption and/or enhanced first-pass elimination of rosuvastatin. Of the potential in vivo rosuvastatin transporter pathways, two might explain the observed results: intestinal OATP2B1 and hepatic MRP4. Further investigations revealed that ronacaleret inhibited OATP2B1 (in vitro IC50 = 12 µM), indicating a DDI risk through inhibition of absorption. Ronacaleret did not inhibit MRP4, discharging the possibility of enhanced first-pass elimination of rosuvastatin (reduced basolateral secretion from hepatocytes into blood). Therefore, a likely mechanism of the observed DDI is inhibition of intestinal OATP2B1, demonstrating the in vivo importance of this transporter in rosuvastatin absorption in humans.

Standing from the Floor in Community-Dwelling Older Adults.

While considerable research has targeted physical performance in older adults, less is known about the ability to rise from the floor among community-dwelling elders. The purposes of the study were to (1) examine physical performance correlates of timed supine to stand performance and (2) identify the predominant motor pattern used to complete floor rise. Fifty-three community-dwelling adults over the age of 60 (x = 78.5 ± 8.5; 36 [68%] females) performed a timed supine to stand test and physical performance assessments. Forty-eight subjects (90.6%) demonstrated an initial roll with asymmetrical squat sequence when rising to stand. Supine to stand performance time was significantly correlated with all physical performance tests, including gait speed (r = -.61; p < .001), grip strength (r = -.30; p < .05), and Timed Up and Go (TUG) performance (r = .71; p < .001). Forty-eight percent of the variance in rise time (p < .001) was attributed to TUG velocity. Findings serve to enhance both functional performance assessment and floor rise interventions.

Impedance analysis of inherently redox-active ionic-liquid-based photoelectrochemical cells: charge-transfer mechanism in the presence of an additional redox couple.

An intensive electrochemical impedance study was carried out to understand the charge-transfer processes in photoelectrochemical (PEC) cells based on ionic liquid (IL) electrolytes. Three different electrolytes were utilized to understand the role of redox species as well as the medium on the charge-transfer mechanism. The negligible diffusion resistance, despite the presence of two different redox species in the case of Fe(CN)(6) (-4/-3) in IL, was explained on the basis of charge transfer between species of two different redox couples. Accordingly, the redox species are not required to travel through the bulk of the electrolyte for the removal of accumulated charges, as short-range charge transfer between the IL and the Fe(CN)(6) (-4/-3) species facilitates the removal of accumulated charges. It is also shown that PEC cells utilizing dual redox couples are highly stable with larger photoelectrochmeical windows, >3 V.

Development and in-vivo evaluation of ondansetron gels for transdermal delivery.

Nausea and vomiting are some of the major side effects caused by certain drug therapies, e.g. chemotherapy, radiotherapy and general anesthesia. Because of the nature of the symptoms, oral delivery is inappropriate, while intravenous administration may be unpractical. The aim of the present study was to develop a transdermal gel (2% Klucel®) for ondansetron, a first line 5-HT3-receptor-antagonist antiemetic. The effects of the penetration enhancer camphor and isopropyl-myristate (IPM) were first investigated in-vitro using modified Franz diffusion-cells and then tested in-vivo in a rabbit model by measuring skin and plasma concentrations. Since a disadvantage of transdermal delivery is a prolonged lag-time, the effect of skin treatment with a micro-needle roller was tested. The in-vitro permeation studies through excised porcine ear skin showed that the presence of 2.5% camphor or IPM increased steady state flux by 1.2- and 2.5-fold, respectively, compared to the control gel. Ondansetron was not detectable in either skin or plasma following in-vivo application of the base-gel, whereas the camphor gel and IPM gel delivered 20 and 81 µg/cm(2) of ondansetron, respectively. Microporation led to an increase in plasma Cmax and AUC by 10.47 ± 1.68-fold and 9.31 ± 4.91-fold, respectively, for the camphor gel, and by 2.31 ± 0.53-fold and 1.59 ± 0.38-fold, respectively for the IPM gel. In conclusion, the 2.5% IPM gel demonstrated optimal in-vivo transdermal flux. Skin pretreatment with a micro-needle roller slightly improved the delivery of the IPM gel, whereas dramatically increased the transdermal delivery of the camphor gel.

Unraveling the photoelectrochemical properties of ionic liquids: cognizance of partially reversible redox activity.

Ionic liquid based electrolytes are gaining great interest in the field of photoenergy conversion. We have found that the ionic liquids namely BMIm Cl, BMIm PF6 and BMIm Tf2N inherently offer redox activity. The device performance of the photoelectrochemical (PEC) cells of the configuration PbOx (0.25 cm(2))|blank ionic liquids|platinum (2 cm(2)) was analyzed in detail to get insights into the working principle of such systems. It was found that partially reversible redox ion pairs diminish the performance of such cells as power generating devices. The partial redox activity of the ionic liquids was confirmed by a number of observations derived from the PEC spectra. The important parameter, Vredox, which determines the performance of any PEC cell was also calculated for all the ionic liquids. The difficulties that arise in high frequency C-V measurements for ionic liquid systems were overcome by choosing the appropriate probing frequency. The evaluated Vredox of BMIm Cl, BMIm PF6 and BMIm Tf2N ionic liquids was found to be -0.30, -0.20 and -0.78 V (vs. NHE), respectively. This study will be beneficial to understand the role of ionic liquids as redox active electrolyte media in several applications.

Revealing the charge transport mechanism of a photoelectrochemical cell: analysis using A.C. voltage perturbation.

In this paper, we have carefully investigated the operation of a photoelectrochemical (PEC) cell configured of PbOx|Fe(CN)6(-4/-3)|Pt in the accumulation, flat band, depletion, inversion and deep-depletion regions using impedance measurements. The increases in the photocurrent for the different regions differ in their nature: a logarithmic increase in the depletion region, a linear increase in the inversion region along with a linear increase in the dark current and an exponential increase in the photo- and dark current in the deep-depletion region. All these variations are studied in detail to correlate these observations to the charge transfer mechanisms. The characteristics of the impedance spectrum itself can be assigned to the mentioned regions. We have found that the maximum photocurrent of the PEC cell, in the present investigation, can be extracted when the cell is working in the inversion region, while the maximum rate of the increase in photocurrent is found when the junction behaves as an ideal Schottky diode with a single RC element. Systematic experiments are suggested to establish a correlation between the observations obtained from the photocurrent, impedance, conductance, low frequency and high frequency capacitance measurements. It was found that light induced trap states in the semiconductor limit the photocurrent which has a linear dependency on the irradiance. A detailed investigation with A.C. conductivity measurements showed that the trap states actively participate in the current mechanism via a hopping phenomenon with small activation energies of 0.2 and 0.8 meV. The hopping rate increased exponentially with the applied bias under dark and illumination conditions. We also show a new way of finding the potential at which the maximum photocurrent will be extracted from the PEC cell, wherein the hopping via trap states is a dominating charge transfer mechanism. This study will help in pin pointing the key affecting parameters which limit the charge transfer process in the cell.

Study of hormone receptors and epidermal growth factor expression in invasive breast cancers in a cohort of Western India.

The objective of study was to evaluate and correlate the pathological characteristics of breast cancer patients with estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (Her2/neu) detected by immunohistochemistry and/or fluorescent in situ hybridization method. We have conducted 2 year study of 204 cases of breast cancer at HCG-Medisurge Hospitals, Ahmedabad from 2009 to 2011. Significant correlation was found in ER and PR expression whereas no correlation was found in hormonal receptors and Her2/neu expression. ER and PR positivity increased with advancing age in breast carcinoma patients while not affecting Her2/neu expression. The expression of hormone receptors were higher in infiltrating lobular carcinoma and infiltrating duct carcinoma subtypes of breast carcinoma as compared to other subtypes such medullary and in situ carcinoma. High-grade carcinoma patients were predominantly ER/PR negative and Her2/neu positive as compared to lower grade breast carcinoma whereas high-stage carcinoma patients were ER/PR positive and Her2/neu positive as compared to lower stage breast carcinoma.

Urinalysis: Interpretation and Clinical Correlations.

Urinalysis is a widely used diagnostic tool to assist clinicians in determining the etiology of various acute or chronic pathologies. Primary care, general internal medicine, and family medicine clinicians should be adept at identifying indications for urinalyses, in addition to appropriately interpreting their results. In this article, we provide an overview of urinalysis for non-nephrologists.

Health E Englewood Health and Wellness Program: A Social Determinants of Health Intervention in Englewood, New Jersey.

BACKGROUND: The Health E Englewood Health and Wellness Program is a social determinant of health (SDoH) intervention developed to address social factors affecting the health of the North Hudson Community Action Corporation (NHCAC) patients', a Federally Qualified Health Center located in Englewood, New Jersey. The main aim of this integrated wellness approach was to educate and motivate participants from the local community by strengthening the development of healthy lifestyles and providing the necessary tools for positive behavior change. METHODS: Health E Englewood was a four consecutive week workshop series focused on three areas of health: physical, emotional, and nutritional wellness. The program targeted Spanish-speaking patients from NHCAC and was offered virtually via Zoom in Spanish. RESULTS: The Health E Englewood program was launched in October 2021 with 40 active participants. About 63% of participants attended at least three of the four workshop sessions, with at least 60% of participants reporting improved lifestyle changes after the program. Additional follow-up data collected six months later also indicated evidence of the program's long-term benefits. DISCUSSION: Social factors are the primary drivers of health outcomes. While many determinant interventions have failed to show long-lasting benefits, studying these interventions and their impact is crucial as it avoids "re-creating the wheel" inside health care and increasing costs.

Dialysis Patient Experiences During the COVID-19 Pandemic: A Survey Study.

Rationale & Objective: The coronavirus disease 2019 (COVID-19) pandemic imposed several changes in the care of patients with kidney failure receiving dialysis. We explored patient care experiences during the pandemic. Study Design: The study team verbally administered surveys including Likert scale multiple-choice questions and open-ended questions and recorded responses. Setting & Participants: Surveys were administered to adults receiving dialysis through an academic nephrology practice after the first wave of the COVID-19 pandemic. Exposure: Outpatient dialysis treatment during the COVID-19 pandemic. Outcomes: Perceptions of care and changes in health. Analytical Approach: Multiple-choice responses were quantified using descriptive statistics. Thematic analysis was used to code open-ended responses and derive themes surrounding patient experiences. Results: A total of 172 patients receiving dialysis were surveyed. Most patients reported feeling "very connected" to the care teams. Seventeen percent of participants reported transportation issues, 6% reported difficulty obtaining medications, and 9% reported difficulty getting groceries. Four themes emerged as influencing patient experiences during the pandemic: 1) the COVID-19 pandemic did not significantly affect participants' experience of dialysis care; 2) the COVID-19 pandemic significantly impacted other aspects of participants' lives, which in turn were felt to affect mental and physical health; 3) regarding dialysis care experience more generally, participants valued consistency, dependability, and personal connection to staff; and 4) the COVID-19 pandemic highlighted the importance of external social support. Limitations: Surveys were administered early in the COVID-19 pandemic, and patient perspectives have not been reassessed. Further qualitative analysis using semi-structured interviews was not performed. Survey distribution in additional practice settings, using validated questionnaires, would increase generalizability of the study. The study was not powered for statistical analysis. Conclusions: Early in the COVID-19 pandemic, perceptions of dialysis care were unchanged for most patients. Other aspects of participants' lives were impacted, which affected their health. Subpopulations of patients receiving dialysis may be more vulnerable during the pandemic: those with histories of mental health conditions, non-White patients, and patients treated by in-center hemodialysis. Plain-language summary: Patients with kidney failure continue to receive life-sustaining dialysis treatments during the coronavirus disease 2019 (COVID-19) pandemic. We sought to understand perceived changes in care and mental health during this challenging time. We administered surveys to patients receiving dialysis after the initial wave of COVID-19, asking questions on topics including access to care, ability to reach care teams, and depression. Most participants did not feel that their dialysis care experiences had changed, but some reported difficulties in other aspects of living such as nutrition and social interactions. Participants highlighted the importance of consistent dialysis care teams and the availability of external support. We found that patients who are treated with in-center hemodialysis, are non-White, or have mental health conditions may have been more vulnerable during the pandemic.

Implementation of the Kidney Failure Risk Equation in a United States Nephrology Clinic.

Introduction: The kidney failure risk equation (KFRE) estimates a person's risk of kidney failure and has great potential utility in clinical care. Methods: We used mixed methods to explore implementation of the KFRE in nephrology clinics. Results: KFRE scores were integrated into the electronic health record at Johns Hopkins Medicine and were displayed to nephrology providers. Documentation of KFRE scores increased over time, reaching 25% of eligible outpatient nephrology clinic notes at month 11. Three providers documented KFRE scores in >75% of notes, whereas 25 documented scores in <10% of notes. Surveys and focus groups of nephrology providers were conducted to probe provider views on the KFRE. Survey respondents (n = 25) reported variability in use of KFRE for decisions such as maintaining nephrology care, referring for transplant evaluation, or providing dialysis modality education. Provider perspectives on the use of KFRE, assessed in 2 focus groups of 4 providers each, included 3 common themes as follows: (i) KFRE scores may be most impactful in the care of specific subsets of people with chronic kidney disease (CKD); (ii) there is uncertainty about KFRE risk-based thresholds to guide clinical care; and (iii) education of patients, nephrology providers, and non-nephrology providers on appropriate interpretations of KFRE scores may help maximize their utility. Conclusion: Implementation of the KFRE was limited by non-uniform provider adoption of its use, and limited knowledge about utilization of the KFRE in clinical decisions.

Identification of Monosaccharide Derivatives as Potent, Selective, and Orally Bioavailable Inhibitors of Human and Mouse Galectin-3.

Galectin-3 (Gal-3), a member of the ß-galactoside-binding protein family, is implicated in a wide variety of human diseases. Identification of Gal-3 inhibitors with the right combination of potency (against both human and mouse Gal-3) and pharmacokinetic properties to fully evaluate the potential of Gal-3 for therapeutic intervention has been a major challenge due to the characteristics of its binding pocket: high hydrophilicity and key structural differences between human Gal-3 and the mouse ortholog. We report the discovery of a novel series of monosaccharide-based, highly potent, and orally bioavailable inhibitors of human and mouse Gal-3. The novel monosaccharide derivatives proved to be selective for Gal-3, the only member of the chimeric type of galectins, over Gal-1 and Gal-9, representative of the prototype and tandem-repeat type of galectins, respectively. The proposed binding mode for the newly identified ligands was confirmed by an X-ray cocrystal structure of a representative analogue bound to Gal-3 protein.

Diagnostic dilemma: COVID-19 related cardiomyopathy or peripartum cardiomyopathy?

Peripartum cardiomyopathy is a relatively rare condition, that usually presents with features of heart failure in the peripartum period. The ongoing pandemic caused by coronavirus disease 2019 (COVID-19) has been reported to be associated with myocarditis, with progression to dilated cardiomyopathy and heart failure. Dilated cardiomyopathy in a peripartum patient with COVID-19 infection may present a diagnostic dilemma. We report a case of dilated cardiomyopathy in a peripartum patient with COVID-19 infection. She presented with shortness of breath in the peripartum period. Chest X-ray showed a grossly enlarged heart with bilateral pulmonary infiltrates consistent with congestive heart failure or viral pneumonia. Echocardiography revealed dilated chambers with 22% left ventricular ejection fraction (LVEF) and global hypokinesis. Despite completing 5 days of remdesivir and dexamethasone, she had worsening dyspnea on postpartum day 10, a repeat echocardiogram showed further reduction in LVEF to 10-15% and was discharged with a life-vest after acute management. She had multiple hospital admissions for decompensated heart failure. Myocardial core biopsy showed marked acute inflammation and necrosis. She had an intra-aortic balloon pump, left ventricular and right ventricular assist devices placed on account of persistent hemodynamic instability, and is now scheduled to have a cardiac transplant. .