The UTH-UMB Global Health Education Collaboration: Building a Bidirectional Exchange Based on Equity and Reciprocity.

The global health exchange program between the University Teaching Hospitals (UTH) of Lusaka, Zambia and the University of Maryland, Baltimore (UMB) has been operating since 2015. As trainees and facilitators of this exchange program, we describe our experiences working in Lusaka and Baltimore, and strengths and challenges of the partnership. Since 2015, we have facilitated rotations for 71 UMB trainees, who spent four weeks on the Infectious Disease (ID) team at UTH. Since 2019 with funding from UMB, nine UTH ID trainee physicians spent up to six weeks each rotating on various ID consult services at University of Maryland Medical Center (UMMC). Challenges in global health rotations can include inadequate preparation or inappropriate expectations among high-income country trainees, low-value experiences for low- and middle-income country trainees, lack of appropriate mentorship at sites, and power imbalances in research collaborations. We try to mitigate these issues by ensuring pre-departure and on-site orientation for UMB trainees, cross-cultural mentored experiences for all trainees, and intentional sharing of authorship and credit on scientific collaborations. We present a description of our medical education collaboration as a successful model for building equitable and reciprocal collaborations between low- and middle-income countries and high-income countries, and offer suggestions for future program initiatives to enhance global health education equity among participants and organizations.

Assessing the Impact of Punch Geometries on Tablet Capping Using a Newly Proposed Capping Index.

PURPOSE: Increased tablet anisotropy could lead to increased tablet capping propensity. Tooling design variables such as cup depth could serve as a key player for inducing tablet anisotropy. METHODS: A new capping index (CI) consisting of the ratio of compact anisotropic index (CAI) and material anisotropic index (MAI) is proposed to evaluate tablet capping propensity as a function of punch cup depth. CAI is the ratio of axial to radial breaking force. MAI is the ratio of axial to radial Young's modulus. The impact of various punch cup depths [flat face, flat face beveled edge, flat face radius edge, standard concave, shallow concave, compound concave, deep concave, and extra deep concave] on the capping propensity of model acetaminophen tablets was studied. Tablets were manufactured at 50, 100, 200, 250, and 300 MPa compression pressure at 20 RPM on different cup depth tools using Natoli NP-RD30 tablet press. A partial least squares model (PLS) was computed to model the impact of the cup depth and compression parameters on the CI. RESULTS: The PLS model exhibited a positive correlation of increased cup depth to the capping index. The finite elemental analysis confirmed that a high capping tendency with increased cup depth is a direct result of non-uniform stress distribution across powder bed. CONCLUSIONS: Certainly, a proposed new capping index with multivariate statistical analysis gives guidance in selecting tool design and compression parameters for robust tablets.

Evaluating the effect of glidants on tablet sticking propensity of ketoprofen using powder rheology.

Punch sticking has been a leading drawback that has challenged successful tablet manufacturing since its initial conception. Due to the capricious nature of the complication, this can arise during any phase of the development process. Even now, identifying such a problem is a prerequisite during the initial stage of development. The present study evaluated the role of Aerosil®200, talc, and Syloid®244 as glidants in varying amounts ranging from 0.0 percent to 2.0 percent w/w on tablets sticking relatively to five different metal surfaces, with ketoprofen as the model drug. Powder rheology is a predictable technique used to calculate the sticking index. The sticking index of each formulation in comparison to each metal coupon was identified by calculating the kinematic angle of internal friction and the angle of wall friction using the shear cell test and wall friction test, respectively. Interestingly, glidants were found to reduce the sticking propensity of the powder blend in a concentration-dependent manner. In addition, the compression study validated the expected sticking tendency ranking order. According to the research data, the sticking index could effectively be utilized to envisage the possibility of tablet sticking, i.e., by selecting the formulation's excipient and their percentages or selecting appropriate punched metal surfaces in the tableting process.

A comparative analysis of pharmaceutical workforce development needs across the commonwealth.

BACKGROUND: Increasing demographic healthcare challenges, such as increased life expectancy coupled with increased use of medicines for complex morbidities, point to the need for globally applicable transformative policies in health workforce development. The International Pharmaceutical Federation (FIP) has established a set of 21 Global Development Goals (FIP DGs) to strengthen pharmacy workforce and benchmark professional developmental needs. OBJECTIVE: This study aimed to identify policy directions and factors affecting pharmacy workforce development across the Commonwealth, and to examine country progress made towards implementing workforce oriented FIP DGs. METHODS: The study involved a literature review and a global survey of commonwealth countries professional leadership bodies. The literature database search included PubMed/Medline, CINAHL, Scopus and PsychINFO databases as well as the websites of the respective national pharmacy organisations of Commonwealth countries. A global survey was also conducted to assess country-level alignment with the workforce component of FIP DGs. RESULTS: Thirty-one articles representing 21 Commonwealth countries were included in the literature overview. The development needs identified were workforce shortages and inequitable distribution across practice areas and geographical regions, low workforce supply capacity, workforce feminisation, lack of professional recognition, limited training opportunities, low job satisfaction, high workload and attrition. The survey showed disparities in country-level progress and alignment with the FIP DGs. High-income countries in the survey sample reported alignment with most of the FIP DGs, while the low-income countries reported alignment with fewer DGs. More than two-thirds of the countries showed alignment with the FIP DGs related to academic capacity, early career training, quality assurance and advancing integrated services. About half reported alignment with the FIP DGs related to competency and leadership development, respectively, while only a third aligned with the equity and equality DG. CONCLUSION: This study identified realistic pharmacy workforce developmental needs across a range of Commonwealth countries. Addressing these needs through appropriate policy interventions will be essential for increasing the pharmacy workforce capacity and assuring the delivery of high-quality pharmaceutical care and medicines expertise in these countries.

Compression-decompression modulus (CDM) - an alternative/complementary approach to Heckel's analysis.

The novel modulus-based approach was developed to characterize the compression behavior of the materials and how it results into tablet mechanical strength (TMS) of the final tablet. The force-displacement profile for the model materials (Vivapur® 101, Starch 1500®, Emcompress®, and Tablettose® 100) was generated at different compression pressures (100, 150, and 200 MPa) and speeds (0.35, 0.55, and 0.75 m/s) using compaction emulator (Presster™). A generated continuous compression profile was evaluated with Heckel plot and the proposed material modulus method. The computed compression parameters were qualitatively and quantitatively correlated with TMS by principal component analysis and principal component regression, respectively. Compression modulus has negatively correlated, while decompression modulus is positively correlated to TMS. Proposed modulus descriptors are independent of particle density measurements required for the Heckel method and could overcome the limitations of the Heckel method to evaluate the decompression phase. Based on the outcome of the study, a two-dimensional compression and decompression modulus classification system (CDMCS) was proposed. The proposed CDMCS could be used to define critical material attributes in the early development stage or to understand reasons for tablet failure in the late development stage.

Negative porosity issue in the Heckel analysis: A possible solution.

A parameterization of compaction simulator generated dynamic compression profile with a few grams of powder provides important information about the material deformation and compact elasticity. The Heckel equation is by far the most popular choice among pharmaceutical scientists for such parametrization. A general approach of Heckel analysis uses pycnometric powder density (ρP0) for relative density calculation. However, as 'in-die' tablet bulk density at applied compression pressure (ρBP) becomes greater than or equal to the measured ρP0, the general approach typically poses a negative porosity challenge at high compression pressure regions. It is only theoretically possible to have a tablet with zero or negative porosity. Negative porosity may be detected during 'in-die' compression analysis, but it will not exist after ejection of the tablet in practical aspect. Thus, the present work proposes a new approach to using pycnometric tablet density (ρPP) in the relative density calculations of Heckel analysis. This ρPP may be a better representation of actual tablet particle volume, as it is composed of non-accessible intra-particulate pores, which are broken under applied compression pressure. A new approach showed its immunity for Heckel high-pressure negative porosity. It enables the utilization of the compression and decompression phases of dynamic compression profiles to evaluate macroscopic compaction performance. The proposed approach was validated with a reported modified Heckel approach. The Heckel parameters computed with both methodologies for microcrystalline cellulose and lactose were not statistically different. However, a modified Heckel approach was unable to compute Heckel parameters of poorly compacting starch unlike the new approach. A modified Heckel approach became invalid during starch compaction at low compression pressures (below 400 MPa), where starch was forming weaker but still intact tablets. Certainly, a complete Heckel profiling with a new approach could save time and costs in an early development stage for designing and screening scientifically based lead prototype formulations.

The evolutionarily conserved arginyltransferase 1 mediates a pVHL-independent oxygen-sensing pathway in mammalian cells.

The response to oxygen availability is a fundamental process concerning metabolism and survival/death in all mitochondria-containing eukaryotes. However, the known oxygen-sensing mechanism in mammalian cells depends on pVHL, which is only found among metazoans but not in other species. Here, we present an alternative oxygen-sensing pathway regulated by ATE1, an enzyme ubiquitously conserved in eukaryotes that influences protein degradation by posttranslational arginylation. We report that ATE1 centrally controls the hypoxic response and glycolysis in mammalian cells by preferentially arginylating HIF1α that is hydroxylated by PHD in the presence of oxygen. Furthermore, the degradation of arginylated HIF1α is independent of pVHL E3 ubiquitin ligase but dependent on the UBR family proteins. Bioinformatic analysis of human tumor data reveals that the ATE1/UBR and pVHL pathways jointly regulate oxygen sensing in a transcription-independent manner with different tissue specificities. Phylogenetic analysis suggests that eukaryotic ATE1 likely evolved during mitochondrial domestication, much earlier than pVHL.

Hemophagocytic lymphohistiocytosis presenting in a patient with human immunodeficiency virus and reactivated Hepatitis B infection.

Hemophagocytic lymphohistiocytosis (HLH) is a rare clinical syndrome of inappropriate immune activation which can present at any age and is commonly associated with other conditions of either excessive or impaired immune response, such as malignancy, infection, autoimmunity or immunodeficiency. In cases associated with human immunodeficiency virus (HIV) infection, an additional trigger such as acute infection or malignancy is frequently identified. We report a case of HLH presenting in a patient with uncontrolled HIV and reactivated hepatitis B infection, which to our knowledge has only been reported once before. Given challenges with diagnosis and its life-threatening course, HLH is an important consideration especially in critically ill patients with underlying HIV and nonspecific presentations such as fevers, cytopenias and encephalopathy.

Chitosan as Functional Biomaterial for Designing Delivery Systems in Cardiac Therapies.

Cardiovascular diseases are a leading cause of mortality across the globe, and transplant surgeries are not always successful since it is not always possible to replace most of the damaged heart tissues, for example in myocardial infarction. Chitosan, a natural polysaccharide, is an important biomaterial for many biomedical and pharmaceutical industries. Based on the origin, degree of deacetylation, structure, and biological functions, chitosan has emerged for vital tissue engineering applications. Recent studies reported that chitosan coupled with innovative technologies helped to load or deliver drugs or stem cells to repair the damaged heart tissue not just in a myocardial infarction but even in other cardiac therapies. Herein, we outlined the latest advances in cardiac tissue engineering mediated by chitosan overcoming the barriers in cardiac diseases. We reviewed in vitro and in vivo data reported dealing with drug delivery systems, scaffolds, or carriers fabricated using chitosan for stem cell therapy essential in cardiac tissue engineering. This comprehensive review also summarizes the properties of chitosan as a biomaterial substrate having sufficient mechanical stability that can stimulate the native collagen fibril structure for differentiating pluripotent stem cells and mesenchymal stem cells into cardiomyocytes for cardiac tissue engineering.

Subacute Polymicrobial Bacterial Pericarditis Mimicking Tuberculous Pericarditis: A Case Report.

BACKGROUND Bacterial pericarditis can present a diagnostic challenge due to the difficulty of obtaining tissue for bacterial identification. This report is of a 34-year-old man who presented with fever and cough. Diagnosis was initially delayed without a tissue sample, but the patient was later found to have polymicrobial bacterial pericarditis. CASE REPORT A 34-year-old man from the Democratic Republic of Congo presented to the emergency room with cough, fever, and night sweats. He was admitted and found to have pericardial thickening and fluid collection with calcifications. A tissue sample was not obtained for diagnosis, and he was discharged on RIPE (rifampin, isoniazid, pyrazinamide, and ethambutol) and steroids for presumed tuberculosis pericarditis. He worsened clinically and was readmitted to the hospital with evolving pericardial effusion with air present, in addition to new pleural effusion and parenchymal consolidation. He subsequently underwent thoracotomy and pericardial biopsy. Tissue cultures and sequence-based bacterial analysis eventually revealed the presence of Prevotella oris and Fusobacterium nucleatum. He improved dramatically with appropriate antibiotic therapy. CONCLUSIONS This report demonstrates the importance of undergoing further diagnostic work-up for bacterial pericarditis, especially in resource-rich settings. Although tuberculosis pericarditis should remain high on the differential, it is imperative not to anchor on that diagnosis. Instead, when feasible and safe, tissue biopsy should be obtained and sent for organism identification. AFB smears and cultures, Xpert MTB/RIF, and sequence-based bacterial analysis have all been used for identification. Delay in diagnosis can lead to progression of disease and unnecessary incorrect therapies.

Preparation, Optimization and Evaluation of Chitosan-Based Avanafil Nanocomplex Utilizing Antioxidants for Enhanced Neuroprotective Effect on PC12 Cells.

(1) Introduction: in recent decades, interdisciplinary research on the utilization of natural products as "active moiety carriers" was focused on due to their superior safety profile, biodegradability, biocompatibility and the ability for sustained or controlled release activity. The nano-based neuroprotective strategy is explored as an imperative treatment for diabetic neuropathy (DN). Avanafil (AV), that selectively inhibits the degradation of cGMP-specific phosphodiesterase, thereby increasing the levels of cGMP, makes a decisive mediator for cytoprotection. (2) Methods: AVnanocomplex formulations were prepared by a modified anti-solvent precipitation method and the method was optimized by Box-Behnken design. An optimized formulation was characterized and evaluated for various in vitro parameters; (3) results:based on the desirability approach, the formulation containing 2.176 g of chitosan, 7.984 g of zein and 90% v/v ethanol concentration can fulfill the prerequisites of optimum formulation (OB-AV-NC).OB-AV-NC was characterized and evaluated for various parameters. The neuroprotective mechanism of AV was evaluated by pretreatment of PC12 cells with plain AV, avanafil nanocomplex (NC) without antioxidants (AV-NC) and with antioxidants (α-Lipoic acid LP; Ellagic Acid EA), AV-LP-EA-Nanocomplex has also shown considerable attenuation in intracellular reactive oxygen species (ROS) and lipid peroxidation with a significant increase in the PC 12 viability under HG conditions in comparison to pure AV; (4) conclusion: the nanocomplex of AV prepared to utilize natural polymers and antioxidants aided for high solubility of AV and exhibited desired neuroprotective activity.This can be one of the promisingstrategy to translate the AV nanocomplex with safety and efficacy in treating DN.

Predicting lubricants effect on tablet sticking using ketoprofen as model drug and evaluating sticking propensity using different metals and powder rheology.

Tablet sticking occurrence is a persistent, costly, and time-consuming problem that needs to be resolved. Predicting the sticking tendency of a new formulation has been very difficult during the development batches because of short runs and limited data. A model formulation comprising ketoprofen and microcrystalline cellulose was used to predict the effect of magnesium stearate and sodium stearyl fumarate on the occurrence of tablet sticking relative to different punch metals. Lubricant amounts were varied from 0.0% to 2.0 %w/w. Five different metal coupons were used to represent punch metals. The sticking index (SI) of each formulation relative to each metal coupon was determined by measuring angle of internal friction and angle of wall friction by performing shear cell test and wall friction test, respectively. The SI was used to predict each formulation's sticking tendency rank order relative to metal coupon. Both lubricants show a decrease in the powder blend's sticking propensity with increased lubricant concentration. The predicted sticking propensity rank order was then validated by the compression study. The result suggests that the SI can be used to predict tablet sticking, such as by changing the composition of the formulation or changing the punch metal during tablet compression.

Antibiogram Development in the Setting of a High Frequency of Multi-Drug Resistant Organisms at University Teaching Hospital, Lusaka, Zambia.

Antimicrobial resistance is a global challenge requiring reliable surveillance data collection and use. Prior studies on resistance in Zambia depended on laboratory methods with limited standardization. Since 2015, the University Teaching Hospital (UTH) microbiology laboratory has used the Vitek 2 Compact (bioMerieux, Inc., Marcy-l'Étoile, France) for standardized identification and susceptibility testing. We conducted a cross-sectional study of 2019 bacterial isolates collected from July 2015 to April 2017 to identify bacterial causes of infections, their susceptibility to commonly used antibiotics at UTH, and develop hospital antibiograms with a multidisciplinary team using World Health Organization guidance. We found high levels of antibiotic resistance among Gram negative bacteria. Escherichia coli and Klebsiella pneumoniae were highly resistant to all antibiotics except amikacin and carbapenems. E. coli had susceptibilities of 42.4% to amoxicillin/clavulanic acid, 41.4% to ceftriaxone, 40.2% to ciprofloxacin, and 10.4% to trimethoprim/sulfamethoxazole (TMP/SMX). K. pneumoniae had susceptibilities of 20.7% to amoxicillin/clavulanic acid, 15.6% to ceftriaxone, 48.5% to ciprofloxacin, and 12.3% to TMP/SMX. The high resistance to 3rd generation cephalosporins indicates high rates of beta-lactamase production. This is information that clinicians need to inform clinical decision making and choice of empiric antibiotics and that UTH requires to inform antimicrobial stewardship such as improvements in antibiotic use.

Discoidin domain receptor 1 activation links extracellular matrix to podocyte lipotoxicity in Alport syndrome.

BACKGROUND: Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase that is activated by collagens that is involved in the pathogenesis of fibrotic disorders. Interestingly, de novo production of the collagen type I (Col I) has been observed in Col4a3 knockout mice, a mouse model of Alport Syndrome (AS mice). Deletion of the DDR1 in AS mice was shown to improve survival and renal function. However, the mechanisms driving DDR1-dependent fibrosis remain largely unknown. METHODS: Podocyte pDDR1 levels, Collagen and cluster of differentiation 36 (CD36) expression was analyzed by Real-time PCR and Western blot. Lipid droplet accumulation and content was determined using Bodipy staining and enzymatic analysis. CD36 and DDR1 interaction was determined by co-immunoprecipitation. Creatinine, BUN, albuminuria, lipid content, and histological and morphological assessment of kidneys harvested from AS mice treated with Ezetimibe and/or Ramipril or vehicle was performed. FINDINGS: We demonstrate that Col I-mediated DDR1 activation induces CD36-mediated podocyte lipotoxic injury. We show that Ezetimibe interferes with the CD36/DDR1 interaction in vitro and prevents lipotoxicity in AS mice thus preserving renal function similarly to ramipril. INTERPRETATION: Our study suggests that Col I/DDR1-mediated lipotoxicity contributes to renal failure in AS and that targeting this pathway may represent a new therapeutic strategy for patients with AS and with chronic kidney diseases (CKD) associated with Col4 mutations. FUNDING: This study is supported by the NIH grants R01DK117599, R01DK104753, R01CA227493, U54DK083912, UM1DK100846, U01DK116101, UL1TR000460 (Miami Clinical Translational Science Institute, National Center for Advancing Translational Sciences and the National Institute on Minority Health and Health Disparities), F32DK115109, Hoffmann-La Roche and Alport Syndrome Foundation.

Beginning a new medical school curriculum amidst a global pandemic.

The University of Maryland School of Medicine embarked on our first major curriculum revision since 1994 with a plan to implement this Renaissance Curriculum in August 2020. However, in the Spring of 2020, the coronavirus disease (COVID-19) pandemic disrupted clinical care and medical education on a large scale requiring expeditious modifications to our Renaissance Curriculum as well as our traditional Legacy Curriculum in order to meet our goal of educating the next-generation of physicians. The rippling effects of the COVID-19 pandemic led to major changes in the delivery of the pre-clerkship curriculum, the way we assessed and evaluated students, entry into the clinical environment, length of clinical rotations, and orientation for our new medical students. We relied on "new" technology, digital medical resources, and the creativity of our educators to ensure that our learners continue to acquire the skills necessary to become skilled clinicians in these unprecedented times.

How to inhibit transforming growth factor beta safely in diabetic kidney disease.

PURPOSE OF REVIEW: Diabetic kidney disease (DKD) is a leading cause of mortality and morbidity in diabetes. This review aims to discuss the major features of DKD, to identify the difficult barrier encountered in developing a therapeutic strategy and to provide a potentially superior novel approach to retard DKD. RECENT FINDINGS: Renal inflammation and fibrosis are prominent features of DKD. Transforming growth factor beta (TGFß) with its activity enhanced in DKD plays a key pathological profibrotic role in promoting renal fibrosis. However, TGFß is a difficult drug target because it has multiple important physiological functions, such as immunomodulation. These physiological functions of TGFß can be interrupted as a result of complete blockade of the TGFß pathway if TGFß is directly targeted, leading to catastrophic side-effects, such as fulminant inflammation. Cell division autoantigen 1 (CDA1) is recently identified as an enhancer of profibrotic TGFß signaling and inhibitor of anti-inflammatory SIRT1. Renal CDA1 expression is elevated in human DKD as well as in rodent models of DKD. Targeting CDA1, by either genetic approach or pharmacological approach in mice, leads to concurrent attenuation of renal fibrosis and inflammation without any deleterious effects observed. SUMMARY: Targeting CDA1, instead of directly targeting TGFß, represents a superior approach to retard DKD.

Autophagy and heat-shock response impair stress granule assembly during cellular senescence.

Stress granules (SGs) are membraneless organelles formed in response to insult. These granules are related to pathological granules found in age-related neurogenerative diseases such as Parkinson's and Alzheimer's. Previously, we demonstrated that senescent cells, which accumulate with age, exposed to chronic oxidative stress, are unable to form SGs. Here, we show that the senescent cells' inability to form SGs correlates with an upregulation in both the heat-shock response and autophagy pathways, both of which are well-established promoters of SG disassembly. Our data also reveals that the knockdown of HSP70 and ATG5, important components of the heat-shock response and autophagy pathways, respectively, restores the number of SGs formed in senescent cells exposed to chronic oxidative stress. Surprisingly, under these conditions, the depletion of HSP70 or ATG5 did not affect the clearance of these SGs during their recovery from chronic stress. These data reveal that senescent cells possess a unique heat-shock and autophagy-dependent ability to impair the formation of SGs in response to chronic stress, thereby expanding the existing understanding of SG dynamics in senescent cells and their potential contribution to age-related neurodegenerative diseases.

Mycobacterium szulgai pulmonary infection in a woman with anorexia nervosa.

A 40-year-old woman with severe anorexia nervosa was found to have a bilateral pulmonary infection with rare atypical mycobacterium Mycobacterium szulgai. Of note, she had no preexisting structural lung disease or history of tuberculosis, smoking, or HIV. Current data suggest that both impaired cell-mediated immunity and altered respiratory mechanics are risk factors for mycobacterial infection in patients with anorexia nervosa.

Glucose and Blood Pressure-Dependent Pathways-The Progression of Diabetic Kidney Disease.

The major clinical associations with the progression of diabetic kidney disease (DKD) are glycemic control and systemic hypertension. Recent studies have continued to emphasize vasoactive hormone pathways including aldosterone and endothelin which suggest a key role for vasoconstrictor pathways in promoting renal damage in diabetes. The role of glucose per se remains difficult to define in DKD but appears to involve key intermediates including reactive oxygen species (ROS) and dicarbonyls such as methylglyoxal which activate intracellular pathways to promote fibrosis and inflammation in the kidney. Recent studies have identified a novel molecular interaction between hemodynamic and metabolic pathways which could lead to new treatments for DKD. This should lead to a further improvement in the outlook of DKD building on positive results from RAAS blockade and more recently newer classes of glucose-lowering agents such as SGLT2 inhibitors and GLP1 receptor agonists.