An Internal Medicine Learning Collaborative Facilitating a Virtual Continuing Medical Education Program in Guyana and the Wider Caribbean During the COVID-19 Pandemic.

OBJECTIVES: To collaborate and share medical knowledge between US and Caribbean physicians during the COVID-19 pandemic via a free online continuing medical education (CME) series.  Method: This was a multi-institution collaborative effort between the Southern Regional Area Health Education Center and Cape Fear Valley Medical Center, both located in North Carolina, USA, and its Caribbean partners, the Guyana Medical Council and Ministry of Health, and the University of the West Indies Medical Alumni Association, Jamaica. The lecture series ran from July 2021 to October 2022. The Zoom (Zoom Video Communications Inc., San Jose, CA, USA) meeting platform was used for the monthly lectures on the fourth Thursday between 7 and 8 p.m. Eastern Standard Time (EST).  Results: Analysis of program data from July 2021 through October 2022 (excluding December 2021) found 1,105 unique individuals engaged in the 15 continuing education sessions. The series had a cumulative total of 2,411 participants, with a mean session participation of 161 and a range of 94 to 299 participants per lecture. An outcome survey assessing the reasons for attendance identified that the most significant factors in their participation in the series were: a) the quality of educational content (83.21%), b) the ease of access and Zoom platform (81.76%), and c) the lectures being offered at no cost (61.31%), and 80.84% gained new medical knowledge leading to practice changes.  Conclusion: The Internal Medicine Learning Collaborative (IMLC) model can be easily replicated by following the steps outlined. It overcomes barriers such as travel and quarantine restrictions and is cost-effective to initiate and maintain. It allows physicians with access to resources and specialty training in the United States to share medical knowledge with colleagues in the developing world where such access may be limited, thus promoting health care and continuing education activity in their respective regions using freely available technologies.

An Unsuspecting Case of Familial Adenomatous Polyposis (FAP).

Familial adenomatous polyposis (FAP) is an inherited and rare disease that typically manifests in the second decade of life. FAP presents as an asymptomatic disease state in its early stages, which affects the gastrointestinal (GI) tract, making it difficult to diagnose. The disease is characterized by numerous adenomatous polyps in the colon or rectum. Adenomatous polyposis coli (APC) gene mutation allows for the unchecked growth of polyps and provides the path for cancerous proliferation. In FAP, APC mutation inheritance has a moderate preponderance for paternal origin. A family history of FAP is an indicator to start early screening in patients, especially those with a paternal family history of the disease. We present a 21-year-old male patient who presented to the clinic with normal hemoglobin, heme-positive stools, and no family history of FAP or colon cancer. The initial assessment and plan was an endoscopy to look for upper and lower GI causes, but if negative, a further hematologic workup would be required. This case highlighted the need for thorough follow-up and workup of occult GI bleed. Clinical suspicion for FAP should be kept in mind, especially in young patients without a family history and unexplained heme-positive stool. Other findings that could suggest FAP include a personal or family history of extra-colonic manifestations such as fibromas, osteomas, or dentition abnormalities.

Evaluation of effect of single vector mandibular distraction for correction of postankylotic mandibular hypoplasia requiring multiplanar correction: A prospective case series.

Introduction: Uniplanar devices have been criticized for being insufficient to correct complex mandibular deformities and associated problems of open bite and cross bite. The use of oblique vector to correct complex multiplanar deformities using uniplanar mandibular distraction devices is the uniqueness of the present case series. Aim and Objective: The aim of the present case series is to describe the successful use of uniplanar mandibular distraction devices for the correction of complex multiplanar deformities. Material and Method: The technique of callous molding was employed to overcome any open bite. A total of 40 mandibular distractors in 20 patients (mean age 13 ± 2.67 years) were placed on the mandible for correction of the facial deformity associated with the lower jaw(mandible) in vertical, horizontal and/or sagittal plane, secondary to temporomandibular joint ankylosis. The distraction was done before and after the gap arthroplasty in 15 and 5 patients, respectively. A latency period of 3-5 days was applied, and distraction was performed at a rate of 1 mm/day with the rhythm of 0.5 mm twice daily. Results: The significant lengthening was observed in both mandibular height (Ar Go) (50.40 ± 1.52 mm from 38.80 ± 4.38mm, P = 0.006) as well as in mandibular corpus length (Go Pg) (79.40 ± 2.28 from 58.80 ± 4.09, P = 0.001). Statistically significant changes in mandibular dimensions, facial proportions, and soft tissue profile were seen, which was assessed with the help of COGS analysis done on lateral cephalogram taken preoperatively and postoperatively. Conclusion: With intelligent vector planning and callus molding multiplanar complex deformities can be corrected by using semiburieduniplanar devices.

Postpartum Idiopathic Pancreatitis Complicated by Acute Necrotizing Pancreatitis.

Acute pancreatitis (AP) is a common medical condition with a wide variety of etiologies. One of the common but frequently undetected causes of acute pancreatitis is microlithiasis, which can appear as biliary "sludge" in the gallbladder on imaging. While a broad workup should be initiated, endoscopic retrograde cholangiopancreatography (ERCP) is the gold standard for the diagnosis of microlithiasis. In this case, we present a severe presentation of acute pancreatitis in a teenager within the postpartum period. A 19-year-old woman presented with severe 10 out of 10 right upper quadrant (RUQ) pain with episodes of nausea that radiated to her back. She had no history of chronic alcoholism, illicit drug use, or over-the-counter supplement use, and no familial history of autoimmune disease, or pancreatitis. The patient was diagnosed with necrotizing acute pancreatitis with gallbladder "sludge" using contrast-enhanced computed tomography (CT) and magnetic resonance cholangiopancreatography (MRCP). She followed up with gastroenterology and had a great clinical recovery. Therefore, it is important to consider acute pancreatitis in patients with idiopathic pancreatitis in their postpartum period as they are prone to forming gallbladder "sludge" which can precipitate and cause a variation in gallbladder pancreatitis which can be difficult to detect on imaging.

Nanoparticle-based oral formulation can surprise you with inferior in vivo absorption in humans.

Particle size reduction leads to an increase in the drug dissolution rate, which in turn can lead to a substantial increase in the bioavailability of a poorly soluble compound. To improve bioavailability, a practically insoluble investigational drug, ODM-106, was nanomilled and capsule formulations with three different drug amounts were prepared for the first-in-man study. Fast in vitro dissolution was achieved from all the capsules containing different amounts of drug nanoparticles but in the clinical study, surprisingly, low bioavailability was observed from the highest capsule strength (100 mg) in comparison to a lower strength (10 mg). In order to study further the discrepant in vitro-in vivo correlation (IVIVC), a discriminative dissolution method was developed. It was noticed that the degree of supersaturation increased significantly as the stabilizers' concentration within the dried nanoformulations was increased. Hypromellose provided a physical barrier between nanoparticles to prevent aggregation during drying. SLS on the other hand improved wettability and provided supersaturation. The drug load, nanoparticle/polymer/surfactant/filler ratios and selected drying step were discovered to be critical to the nanoformulations' performance. Aggregation of nanoparticles, in the absence of optimal stabilizer concentration, compromised dissolution due to decreased surface area. In conclusion, the early development of a discriminative dissolution method and cautious selection of the nanoparticle/polymer ratio before manufacturing clinical batches is recommended.

Current profile controlled transdermal delivery of pramipexole from an iontophoretic patch system in vitro and in vivo.

The objective was to evaluate the transdermal iontophoretic delivery of pramipexole using constant and complex multi-phasic current profiles from an iontophoretic patch system in vitro and in vivo. Preliminary in vitro experiments were performed to optimize iontophoretic patch design and configuration. "Single" compartment systems containing only pramipexole dihydrochloride, and designed to maximize delivery efficiency, suffered from an insufficiency of chloride ions with anodal electrochemistry passing from an Ag/AgCl couple to an Ag dissolution electrode. Addition of NaCl to provide more chloride ions decreased pramipexole delivery efficiency due to competition between pramipexole and sodium cations. A "two-compartment" iontophoretic patch where the drug reservoir was separated from the anodal compartment, which now included NaCl, was shown to be a good compromise since it ensured Ag/AgCl electrochemistry at the anode and an acceptable delivery efficiency. In vivo studies using this iontophoretic patch demonstrated that the plasma concentration of pramipexole closely followed the variation of the applied continuous and multi-phasic current profiles and underlined the control provided by iontophoresis and its unique ability to rapidly change drug input rates. The applied current density and duration of current application were also shown to modulate pramipexole delivery to the brain and CSF.

Effect of continuous and multi-phasic current profiles on the iontophoretic transport of pramipexole, rasagiline and huperzine A: Depicting temporal variation and biodistribution in the skin.

Transdermal iontophoresis is an interesting option for the non-invasive controlled delivery of therapeutic agents to treat neurodegenerative diseases. The current profile controls drug delivery kinetics and enables complex drug input profiles to be obtained. The aim of this study was to investigate the temporal variation in transport of pramipexole (PRA), rasagiline (RAS) and huperzine A (HUP) using continuous and multi-phasic current profiles by measuring cumulative permeation, transdermal flux and drug retention in the skin upon modulation of the applied current profile during a single experiment in vitro. Initial experiments with continuous current were conducted to establish a correlation between total delivery of PRA, RAS and HUP (i.e. sum of the cumulative permeation and skin deposition) and the amount of charge transferred. Subsequent experiments with multi-phasic current profiles, confirmed that the relationship between amounts of charge transferred and total delivery was able to predict the total delivery of each drug. Experimental values were within ± 15% of the predicted values. Current density and duration of current application were also shown to have a significant impact on the skin biodistribution of PRA. These results also provide insight into the rate of formation of iontophoretic drug reservoirs in the skin.

Nanosuspensions of a poorly soluble investigational molecule ODM-106: Impact of milling bead diameter and stabilizer concentration.

Aqueous solubility of a drug substance is an important attribute affecting oral bioavailability. Nanonization, particle size reduction to submicron level, is an elegant approach to improve drug solubility and dissolution by increasing the surface energy, which in turn necessitates the use of stabilizers. The purpose of this study was to develop a nanosuspension of a practically water-insoluble investigational molecule by nanomilling approach using wet media milling. A variety of polymeric and surface active excipients were tested for their wettability. A combination of hydroxypropyl methylcellulose and sodium lauryl sulfate (SLS) were selected as stabilizers on the bases of compatibility studies and efficient wettability behaviour in contact angle measurements (≈80˚). A factorial design set-up was used to study the effect of milling bead diameter and stabilizer concentration on the efficiency of particle size reduction. Nanonization outcome was different when milling beads of 0.5 mm and 1 mm diameter were used at different concentrations of the stabilizers, which demonstrated the complex nature of the whole system. Storage of the nanosuspensions under different temperature conditions resulted only in minor changes of the particle size fractions.

A Multi-Modality Treatment of Retroperitoneal De-Differentiated Liposarcoma.

BACKGROUND Retroperitoneal sarcomas are rare tumors, only affecting 2 to 5 people per million population and accounting for 0.1% of all malignancies. Liposarcoma is the most common of all retroperitoneal sarcomas, responsible for approximately 20% of all sarcomas in adults. The most important prognostic factors are tumor grade, the presence of positive margins, tumor integrity, and degree of resection. CASE REPORT Our patient was a 73-year-old man with abdominal pain whose CT scan of the abdomen and pelvis demonstrated a 15×15 cm heterogeneous, left-sided intra-abdominal mass. He underwent resection of the retroperitoneal tumor, left colectomy, and left nephrectomy. Final pathology demonstrated a high-grade, de-differentiated liposarcoma with a rhabdosarcomatous component. The postoperative course was complicated by a small intra-abdominal abscess and abdominal dehiscence. a CT scan after surgery showed a residual tumor of the retroperitoneal posterior margin. Re-exploration to resect the residual tumor and repair the fascial dehiscence were performed. The patient underwent an initial chemotherapy regimen with doxorubicin, then moved to targeted therapy with Palbociclib, and is now on chemotherapy using Eribulin. CONCLUSIONS Achieving complete resection and the grade of the tumor at diagnosis are the 2 most important prognostic factors for patient survival in retroperitoneal liposarcoma, as survival rates are inversely proportional to the grade of the tumor. Even with the best resection attempts, there is always a risk of residual tumor cells within the tumor bed, which contribute to recurrence and need for additional surgical interventions. It is important to approach this disease process with a multidisciplinary team that includes surgical, medical, and radiation oncology to ensure the best survival outcomes. Retroperitoneal sarcoma recurrence and survival are directly related to the ability to achieve negative margins of resection, as well as the grade and size of the primary tumor. Adjuvant therapies that include radiation and immunotherapy may be effective in treating recurrent disease.

Controlled Iontophoretic Delivery in Vitro and in Vivo of ARN14140-A Multitarget Compound for Alzheimer's Disease.

ARN14140 is a galantamine-memantine conjugate that acts upon both cholinergic and glutamatergic pathways for better management of Alzheimer's disease. Poor oral bioavailability and pharmacokinetics meant that earlier preclinical in vivo studies employed intracerebroventricular injection to administer ARN14140 directly to the brain. The aim of the present study was to evaluate the feasibility of using constant current transdermal iontophoresis for the noninvasive systemic delivery of ARN14140 and to quantify the amounts present in the blood and the brain. Preliminary experiments in vitro were performed using porcine skin and validated with human skin. Cumulative ARN14140 permeation across the skin increased linearly with current density and concentration. Delivery efficiency (i.e., fraction of the amount applied that is delivered) reached an exceptional 76.9%. Statistically equivalent delivery was observed after iontophoresis across human and porcine skin. In vivo studies in male Wistar rats showed that iontophoretic transport of ARN14140 could be controlled using the current density (426.7 ± 42 and 1118.3 ± 73 nmol/cm2 at 0.15 and 0.5 mA/cm2 for 6 h) and demonstrated that transdermal iontophoresis was able to deliver ARN14140 noninvasively to the brain. This is the first report quantifying drug levels in the blood and the brain following transdermal iontophoresis.

Er:YAG fractional laser ablation for cutaneous co-delivery of pentoxifylline and d-α-tocopherol succinate: A new approach for topical treatment of radiation-induced skin fibrosis.

Radiation induced fibrosis is a common side-effect after radiotherapy. Pentoxifylline is reported to reverse radiation injuries when used in conjunction with D-α-tocopherol. However, pentoxifylline has a short half-life, limited oral bioavailability, and induces several systemic adverse effects. The objective of this study was to investigate the feasibility of using Er:YAG fractional laser ablation to enable simultaneous cutaneous delivery of pentoxifylline and D- α -tocopherol succinate from poly(lactide-co-glycolide) microparticles prepared using the freeze-fracture technique. In vitro release experiments demonstrated the different release profiles of the two molecules, which were influenced by their very different lipophilicities and aqueous solubilities. Experiments were then performed to investigate the effect of laser fluence on pore depth and so determine the pore volume available to host the topically applied microparticles. Application of the pentoxifylline and D-α-tocopherol succinate containing microparticles, prepared with RESOMER® RG 502H, to laser porated skin for 48 h, resulted in simultaneous delivery of pentoxifylline (69.63 ±â€¯6.41 µg/cm2; delivery efficiency 46.4%) and D-α-tocopherol succinate (33.25 ±â€¯8.91 µg/cm2; delivery efficiency 22.2%). After deposition into the micropores, the poly(lactide-co-glycolide) microparticles containing pentoxifylline and D-α-tocopherol succinate could serve as an intraepidermal depot to enable sustained drug delivery after micropore closure and thereby reduce the need for repeated microporation.

Polymeric micelle nanocarriers for targeted epidermal delivery of the hedgehog pathway inhibitor vismodegib: formulation development and cutaneous biodistribution in human skin.

Background: The aim was to investigate cutaneous delivery and biodistribution of the hedgehog pathway inhibitor, vismodegib (VSD), indicated for basal cell carcinoma (BCC), from polymeric micelle formulations under infinite/finite dose conditions. Methods: VSD-loaded micelles were characterized for drug content, particle size, and shape; a micelle gel was characterized for its rheological behavior. Cutaneous deposition and biodistribution of VSD were determined using porcine and human skin in vitro with quantification by UHPLC-MS/MS. Results: The optimal micelle solution (Zav 20-30 nm) increased the aqueous solubility of VSD by >8000-fold; drug content was stable after 4 weeks at 4°C. Application of micelle solution and micelle gel (0.086% w/v) to human skin for 12 h under infinite dose conditions resulted in statistically equivalent VSD deposition (0.62 ± 0.11 and 0.67 ± 0.14 µg/cm2, respectively). Cutaneous biodistribution in human skin under infinite (micelle solution and gel) and finite (micelle gel) dose conditions showed that the VSD concentrations obtained in the basal epidermis, at depths of 120-200 µm, were ˃3800- and ˃2300-fold greater than the IC50 reported for hedgehog signaling pathway inhibition in vitro. Conclusion: Cutaneous delivery of VSD from micelle-based formulations might enable targeted, topical treatment of superficial BCC with minimal risk of systemic exposure.

Investigation of Different Iontophoretic Currents Profiles for Short-Term Applications in Cosmetics.

This study aimed at investigating the effect of electrical current profile upon the iontophoretic transport of (i) ascorbic acid (AA) and (ii) ellagic acid (EA), into porcine skin in vitro, and the impact of the physicochemical properties of both actives on their mechanism of transport when formulated in cosmetic compositions. The experiments were performed using a proprietary iontophoretic device containing a roller to apply the formulation. Three current profiles were tested: (i) galvanic direct current (DC), (ii) square unipolar pulse current (SPC), and (iii) galvanic direct current (DC) + pulse current (PC). The skin samples were collected at different sampling points, extracted and analyzed by HPLC. Results suggested that the DC + PC mode for only 5 min was able to significantly increase the delivery of AA from o/w cosmetic compositions. The use of this current profile might improve the skin penetration of AA due to electromigration and passive diffusion, the latter being facilitated by the physical enhancement method. The SPC mode significantly improved the passage of EA in its neutral form from cosmetic o/w formulations by electroosmosis. Tailoring specific electrical current modes considering the ionization state of active ingredients would allow the design of short and personalized cosmetic treatments that significantly improve the penetration efficiency of the active ingredients and possibly reduce the doses applied.

Fish, Fish Oils and Cardioprotection: Promise or Fish Tale?

Fish and commercially available fish oil preparations are rich sources of long-chain omega-3 polyunsaturated fatty acids. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are the most important fatty acids in fish oil. Following dietary intake, these fatty acids get incorporated into the cell membrane phospholipids throughout the body, especially in the heart and brain. They play an important role in early brain development during infancy, and have also been shown to be of benefit in dementia, depression, and other neuropsychiatric disorders. Early epidemiologic studies show an inverse relationship between fish consumption and the risk of coronary heart disease. This led to the identification of the cardioprotective role of these marine-derived fatty acids. Many experimental studies and some clinical trials have documented the benefits of fish oil supplementation in decreasing the incidence and progression of atherosclerosis, myocardial infarction, heart failure, arrhythmias, and stroke. Possible mechanisms include reduction in triglycerides, alteration in membrane fluidity, modulation of cardiac ion channels, and anti-inflammatory, anti-thrombotic, and anti-arrhythmic effects. Fish oil supplements are generally safe, and the risk of toxicity with methylmercury, an environmental toxin found in fish, is minimal. Current guidelines recommend the consumption of either one to two servings of oily fish per week or daily fish oil supplements (around 1 g of omega-3 polyunsaturated fatty acids per day) in adults. However, recent large-scale studies have failed to demonstrate any benefit of fish oil supplements on cardiovascular outcomes and mortality. Here, we review the different trials that evaluated the role of fish oil in cardiovascular diseases.

Simultaneous controlled iontophoretic delivery of pramipexole and rasagiline in vitro and in vivo: Transdermal polypharmacy to treat Parkinson's disease.

Effective treatment of Parkinson's disease (PD) involves administration of therapeutic agents with complementary mechanisms of action in order to replenish, sustain or substitute endogenous dopamine. The objective of this study was to investigate anodal co-iontophoresis of pramipexole (PRAM; dopamine agonist) and rasagiline (RAS; MAO-B inhibitor) in vitro and in vivo. Passive permeation of PRAM and RAS (20 mM each) across porcine skin after 6 h was 15.7 ±â€¯1.9 and 16.0 ±â€¯2.9 µg/cm2, respectively. Co-iontophoresis at 0.15, 0.3 and 0.5 mA/cm2 resulted in statistically significant increases in delivery of PRAM and RAS; at 0.5 mA/cm2, cumulative permeation of PRAM and RAS was 613.5 ±â€¯114.6 and 441.1 ±â€¯169.2 µg/cm2, respectively - corresponding to 38- and 27-fold increases over passive diffusion. Electromigration was the dominant mechanism for both molecules (>80%) and there was no effect on convective solvent flow. Statistically equivalent delivery was observed with human skin. The co-iontophoretic system showed high delivery efficiency with 29% and 35% of the applied amounts of PRAM and RAS being delivered. Preliminary pharmacokinetics studies in rats confirmed that the input rate in vivo was such that therapeutic amounts of the two drugs could be co-administered to humans by transdermal iontophoresis using reasonably sized patches and moderate current densities.

Safety and Efficacy of a Single Dose of Anti-D (WinRho®) in Severe Thrombocytopenia Secondary to Dengue Virus Infection.

OBJECTIVE: To evaluate the efficacy of a single intravenous (IV) dose of anti-D in severe thrombocytopenia (<20,000) due to dengue virus (DEV) infection. MATERIALS AND METHODS: An open label, investigator-initiated, randomized interventional study was conducted that included thirty dengue patients (all positive for IgM enzyme-linked immunosorbent assay) with severe thrombocytopenia (<20,000/mm3). Patients were randomized to receive anti-D (50 µg/kg single IV dose) plus supportive therapy or supportive therapy alone. RESULTS: The rate of rise in platelet count was significantly high in the intervention group at 24, 36, and 48 h. At the end of 48 h, 60% patients in the intervention group achieved a platelet count of ≥50,000/mm3 as compared to 6.7% in the control group (P = 0.0019). The requirement of the platelet concentrate infusion in the control group was significantly higher, i.e. 342 ml (±193) as compared to the intervention group requiring only 187 ml (±79). The intervention group showed a significant improvement in bleeding manifestations in all the patients by 24 h in Grade 2 bleed (P = 0.032) and by 48 h in Grade 1 bleed (P = 0.014). CONCLUSIONS: Severe thrombocytopenia (≤20,000/mm3) secondary to DEV infection was rapidly and safely reversed by administration of a single dose of 50 µg/kg (250 IU/kg) anti-D IV.

Routine health check-ups: A boon or a burden?

Healthcare provider institutions in India now offer structured health check-up 'packages' for routine screening of common diseases. While some tests included within their ambit are in keeping with international and Indian recommendations, some are entirely unwarranted. Unnecessary and inappropriate screening tests may cause more harm than benefit. Besides financial and resource burden, there may be over-diagnosis and over-treatment, psychological distress due to false-positive test results, harm from invasive follow-up tests, and false reassurance due to false-negative test results. Clinicians must ensure a net benefit from tests and interventions in order to efficiently deliver preventive services. We reviewed current screening guidelines for cardiovascular disease and common cancers, and surveyed multiple 'packages' provided at 8 centres in Mumbai, India. We put forth our recommendations for routine health screening in asymptomatic adults in India.

Fractional Laser Ablation for the Cutaneous Delivery of Triamcinolone Acetonide from Cryomilled Polymeric Microparticles: Creating Intraepidermal Drug Depots.

The efficacy of some dermatological therapies might be improved by the use of "high dose" intraepidermal drug reservoir systems that enable sustained and targeted local drug delivery, e.g., in the treatment of keloids and hypertrophic scars. Here, a fractionally ablative erbium:YAG laser was used to enable "needle-less" cutaneous deposition of polymeric microparticles containing triamcinolone acetonide (TA). The microparticles were prepared using a freeze-fracture technique employing cryomilling that resulted in drug loading efficiencies of ∼100%. They were characterized by several different techniques, including scanning electron microscopy, powder X-ray diffraction and differential scanning calorimetry. TA was quantified by validated HPLC-UV and UHPLC-MS/MS analytical methods. In vitro release studies demonstrated the effect of polymer properties on TA release kinetics. Confocal laser scanning microscopy enabled visualization of cryomilled microparticles containing fluorescein and Nile Red in the cutaneous micropores and the subsequent release of fluorescein into the micropores and its diffusion throughout the epidermis and upper dermis. The biodistribution of TA, i.e. the amount of drug as a function of depth in skin, following microparticle application was much more uniform than with a TA suspension and delivery was selective for deposition with less transdermal permeation. These findings suggest that this approach may provide an effective, targeted and minimally invasive alternative to painful intralesional injections for the treatment of keloid scars.