In Situ Eutectic Formation in a Polymeric Matrix via Hot-Melt Reactive Extrusion and the Use of Partial Least Squares Regression Modeling for Reaction Yield Determination.

There has been a significant volume of work investigating the design and synthesis of new crystalline multicomponent systems via examining complementary functional groups that can reliably interact through the formation of noncovalent bonds, such as hydrogen bonds (H-bonds). Crystalline multicomponent molecular adducts formed using this approach, such as cocrystals, salts, and eutectics, have emerged as drug product intermediates that can lead to effective drug property modifications. Recent advancement in the production for these multicomponent molecular adducts has moved from batch techniques that rely upon intensive solvent use to those that are solvent-free, continuous, and industry-ready, such as reactive extrusion. In this study, a novel eutectic system was found when processing albendazole and maleic acid at a 1:2 molar ratio and successfully prepared using mechanochemical methods including liquid-assisted grinding and hot-melt reactive extrusion. The produced eutectic was characterized to exhibit a 100 °C reduction in melting temperature and enhanced dissolution performance (>12-fold increase at 2 h point), when compared to the native drug compound. To remove handling of the eutectic as a formulation intermediate, an end-to-end continuous-manufacturing-ready process enables feeding of the raw parent reagents in their respective natural forms along with a chosen polymeric excipient, Eudragit EPO. The formation of the eutectic was confirmed to have taken place in situ in the presence of the polymer, with the reaction yield determined using a multivariate calibration model constructed by combining spectroscopic analysis with partial least-squares regression modeling. The ternary extrudates exhibited a dissolution profile similar to that of the 1:2 prepared eutectic, suggesting a physical distribution (or suspension) of the in situ synthesized eutectic contents within the polymeric matrix.

Kinetic and Thermodynamic Interplay of Polymer-Mediated Liquid-Liquid Phase Separation for Poorly Water-Soluble Drugs.

Understanding the interplay between kinetics and thermodynamics of polymer-mediated liquid-liquid phase separation is crucial for designing and implementing an amorphous solid dispersion formulation strategy for poorly water-soluble drugs. This work investigates the phase behaviors of a poorly water-soluble model drug, celecoxib (CXB), in a supersaturated aqueous solution with and without polymeric additives (PVP, PVPVA, HPMCAS, and HPMCP). Drug-polymer-water ternary phase diagrams were also constructed to estimate the thermodynamic behaviors of the mixtures at room temperature. The liquid-liquid phase separation onset point for CXB was detected using an inline UV/vis spectrometer equipped with a fiber optic probe. Varying CXB concentrations were achieved using an accurate syringe pump throughout this study. The appearance of the transient nanodroplets was verified by cryo-EM and total internal reflection fluoresence microscopic techniques. The impacts of various factors, such as polymer composition, drug stock solution pumping rates, and the types of drug-polymer interactions, are tested against the onset points of the CXB liquid-liquid phase separation (LLPS). It was found that the types of drug-polymer interactions, i.e., hydrogen bonding and hydrophobic interactions, are vital to the position and shapes of LLPS in the supersaturation drug solution. A relation between the behaviors of LLPS and its location in the CXB-polymer-water ternary phase diagram was drawn from the findings.

Towards a greater understanding of the deep eutectic phenomenon through examination of the lidocaine-NSAID therapeutic deep eutectic systems.

Therapeutic deep eutectic solvents (THEDES) have been attracting increasing attention in the pharmaceutical literature as a promising enabling technology capable of improving physicochemical and biopharmaceutical properties for difficult-to-deliver drug compounds. The current literature has explored amide local anaesthetics and carboxylic acid nonsteroidal anti-inflammatories (NSAIDs) as commonly used THEDES formers for their active hydrogen-bonding functionality. However, little is known about what happens within the "deep eutectic" region where a range of binary compositions present simply as a liquid with no melting events detectable across experimentally achievable conditions. There is also very limited understanding of how parent compounds' physicochemical properties could impact upon the formation, interaction mechanism, and stability of the formed liquid systems, despite the significance of these information in dose adjustment, industrial handling, and scaling-up of these liquids. In the current work, we probed the "deep eutectic" phenomenon by investigating the formation and physicochemical behaviours of some chosen lidocaine-NSAID systems across a wide range of composition ratios. Our data revealed that successfully formed THEDES exhibited composition dependent Tg variations with strong positive deviations from predicted Tg values using the Gordon-Taylor theory, suggesting substantial interactions within the formed supramolecular structure. Interestingly, it was found that the parent compound's glass forming ability had a noticeable impact upon such profound interaction and hence could dictate the success of THEDES formation. It has also been confirmed that all successful systems were formed based on charge-assisted hydrogen bonding within their THEDES network, affirming the significant role of partial protonisation on achieving a profound melting point depression. More importantly, the work found that within the "deep eutectic" region there was still an ideal, or thermodynamically preferrable "THEDES point", which would exhibit excellent stability upon exposure to stress storage conditions. The discoveries of this study bring the literature one step closer to fully understanding the "therapeutic deep eutectic" phenomenon. Through correlation between parent reagents' physicochemical properties and the synthesised products' characteristics, we establish a more educated process for the prediction and engineering of THEDES.

Mucoadhesive Polymeric Polyologels Designed for the Treatment of Periodontal and Related Diseases of the Oral Cavity.

The study objective was to design and characterise herein unreported polyologels composed of a range of diol and triol solvents and polyvinyl methyl ether-co-maleic acid (PVM/MA) and, determine their potential suitability for the treatment of periodontal and related diseases in the oral cavity using suitable in vitro methodologies. Polyologel flow and viscoelastic properties were controlled by the choice of solvent and the concentration of polymer. At equivalent polymer concentrations, polyologels prepared with glycerol (a triol) exhibited the greatest elasticity and resistance to deformation. Within the diol solvents (PEG 400, pentane 1,5-diol, propane 1,2-diol, propane 1,3-diol, and ethylene glycol), PEG 400 polyologels possessed the greatest elasticity and resistance to deformation, suggesting the importance of distance of separation between the diol groups. Using Raman spectroscopy bond formation between the polymer carbonyl group and the diol hydroxyl groups was observed. Polyologel mucoadhesion was influenced by viscoelasticity; maximum mucoadhesion was shown by glycerol polyologels at the highest polymer concentration (20% w/w). Similarly, the choice of solvent and concentration of PVM/MA affected the release of tetracycline from the polyologels. The controlled release of tetracycline for at least 10 h was observed for several polyologels, which, in combination with their excellent mucoadhesion and flow properties, offer possibilities for the clinical use of these systems to treat diseases within the oral cavity.

"The Water in Which We Swim:" A Unique, Post-Clerkship Multidisciplinary Course.

OBJECTIVE: To improve patient outcomes and promote health equity, medical students must be taught not only biomedicine, but also the social sciences to understand the larger contexts in which patients live and health care operates. Yet, most undergraduate medical education does not explicitly cover these topics in a required, longitudinal curriculum. METHODS: In January 2015 at Harvard Medical School, we created a two-part sequence (pre- and post-clerkship) of required, 4-week multidisciplinary courses-"Essentials of the Profession I and II"-to fill this gap. "Essentials of the Profession II (EOP2)" is an advanced social sciences course anchored in patient narratives and the lived experiences of students and includes clinical epidemiology and population health, healthcare delivery and leadership, health policy, medical ethics and professionalism, and social medicine that engages students to conduct structural analyses to be effective healers, advocates, and leaders. RESULTS: Per student course evaluations, the overall course rating was 1.7 (SD 0.9, 1 = excellent and 5 = poor); its overall rating has improved over time; and it has scored well even when run virtually. It was rated highly in application of critical thinking, integration of the disciplines, and relevance for clinical work. Qualitative analyses of student responses revealed the following key course strengths: breadth of topics, teaching faculty and guest speakers, and small group discussions. The weaknesses included workload, lack of diversity of opinions, repetition, and time spent in lectures. CONCLUSIONS: We argue that EOP2 is "essential" for post-clerkship medical education. It offers an opportunity to re-ignite and enhance humanism and activism; remind students why they chose the medical profession; equip them with frameworks and toolkits to help them to overcome challenges; and devise solutions to improve health care and patient outcomes that are applicable to their future training and ongoing practice of medicine.

The historical sociology of medicine in India: Introduction to the special section.

This introduction to a special section brings together three papers first presented at a panel, 'Medical Professions in South Asia: Historical and Contemporary Analyses', at the 26th European Conference on South Asian Studies, held in Vienna, Austria and online, in July 2021. All three papers deal with aspects of the professionalisation of biomedical doctors in India since its independence in 1947. The authors bring together historical and sociological approaches to illuminate the growth of specialisms, patterns of practitioner-patient interactions and efforts to maintain occupational closure and maintain status in the face of growing challenges. The introduction concludes with a discussion of the relevance of these papers for the sociology of health and illness in India and beyond.

Learning Harmony: Medical Student Reflections on the Intersection of the Arts & Humanities and Medicine, A Mixed Methods Study.

Background: The arts and humanities form a critical part of medical education. In this study, we explore medical students' reflections following an arts and humanities experience. An intensive day and a half long program focused on music and reflection was designed for first-year students at Harvard Medical School. Methods: Students completed an evaluation of the experience with both open-ended and Likert scale questions. Data were analyzed using a mixed methods approach. Descriptive statistics were used to analyze quantitative data and inductive content analysis for qualitative data. Results: 168 first-year medical and dental students participated in the activity. Survey response rate was 73% (n =122). Quantitatively, the overall quality of the experience was assessed at a mean value of 4.86 points (SD = 0.37 points) out of a maximum of 5, with 5 being excellent. The qualitative evaluation illustrated how the arts and humanities experience encouraged students to reflect on their leadership and doctoring skills, taking a holistic approach to their medical education, and integrating the lessons of the arts and humanities into their medical practice. Conclusion: The arts and humanities program encouraged student reflection on profound questions in medicine related to empathy, vulnerability, and authenticity. This experience broadened students' perspectives regarding the relationship between medicine and the arts and humanities.

An Ethical Framework for Research Using Genetic Ancestry.

A wide range of research uses patterns of genetic variation to infer genetic similarity between individuals, typically referred to as genetic ancestry. This research includes inference of human demographic history, understanding the genetic architecture of traits, and predicting disease risk. Researchers are not just structuring an intellectual inquiry when using genetic ancestry, they are also creating analytical frameworks with broader societal ramifications. This essay presents an ethics framework in the spirit of virtue ethics for these researchers: rather than focus on rule following, the framework is designed to build researchers' capacities to react to the ethical dimensions of their work. The authors identify one overarching principle of intellectual freedom and responsibility, noting that freedom in all its guises comes with responsibility, and they identify and define four principles that collectively uphold researchers' intellectual responsibility: truthfulness, justice and fairness, anti-racism, and public beneficence. Researchers should bring their practices into alignment with these principles, and to aid this, the authors name three common ways research practices infringe these principles, suggest a step-by-step process for aligning research choices with the principles, provide rules of thumb for achieving alignment, and give a worked case. The essay concludes by identifying support needed by researchers to act in accord with the proposed framework.

Changes of heart: Debating the role of cardiology and cardiac surgery in India, 1948-1968.

In 1950, the leaders of independent India celebrated the contributions that surgeons could make to modernising India. Surgeons, however, faced a difficult choice. Some wanted to invest in generalist surgeons to make basic surgical care available to all Indians. Others wanted to invest in specialists to ensure that India participated in cutting-edge surgical research and care. These debates shaped the emergence of cardiac surgery at two centres: the Christian Medical College in Vellore and the King Edward Memorial Hospital in Bombay. CMC invested in thoracic surgery in the 1940s to offer new treatments for tuberculosis. This gave surgeons the opportunity to explore new techniques of cardiac surgery. Debate quickly emerged about whether investments in cardiology and cardiac surgery made sense. In the end, the specialities were supported in order to attract paying patients. A parallel controversy took place at KEM, where the dean debated the Bombay Municipal Corporation about the role of surgical research at a public hospital. The Rockefeller Foundation influenced both sites, offering financial support if they adopted an American model of full-time faculty clinician-researchers. The two case studies reveal how unusual dynamics could contribute to the establishment of new medical specialities in India.

Malaria transmission-blocking vaccines Pfs230D1-EPA and Pfs25-EPA in Alhydrogel in healthy Malian adults; a phase 1, randomised, controlled trial.

BACKGROUND: Malaria transmission-blocking vaccines target mosquito-stage parasites and will support elimination programmes. Gamete vaccine Pfs230D1-EPA/Alhydrogel induced superior activity to zygote vaccine Pfs25-EPA/Alhydrogel in malaria-naive US adults. Here, we compared these vaccines in malaria-experienced Malians. METHODS: We did a pilot safety study then double-blind, block-randomised, comparator-controlled main-phase trial in malaria-intense Bancoumana, Mali. 18-50-year-old healthy non-pregnant, non-breastfeeding consenting adult residents were randomly assigned (1:1:1:1) to receive four doses at months 0, 1, 4·5, and 16·5 of either 47 µg Pfs25, 40 µg Pfs230D1 or comparator (Twinrix or Menactra)-all co-administered with normal saline for blinding-or 47 µg Pfs25 plus 40 µg Pfs230D1 co-administered. We documented safety and tolerability (primary endpoint in the as-treated populations) and immunogenicity (secondary endpoint in the as-treated populations: ELISA, standard-membrane-feeding assay, and mosquito direct skin feed assay). This trial is registered at ClinicalTrials.gov, NCT02334462. FINDINGS: Between March 19, and June 2, 2015, we screened 471 individuals. Of 225 enrolled for the pilot and main cohorts, we randomly assigned 25 participants to pilot safety cohort groups of five (20%) to receive a two-dose series of Pfs25-EPA/Alhydrogel (16 µg), Pfs230D1-EPA/Alhydrogel (15 µg) or comparator, followed by Pfs25-EPA/Alhydrogel (16 µg) plus Pfs230D1-EPA/Alhydrogel (15 µg) or comparator plus saline. For the main cohort, we enrolled 200 participants between May 11 and June 2, 2015, to receive a four-dose series of 47 µg Pfs25-EPA/Alhydrogel plus saline (n=50 [25%]; Pfs25), 40 µg Pfs230D1-EPA/Alhydrogel plus saline (n=49 [25%]; Pfs230D1), 47 µg Pfs25-EPA/Alhydrogel plus 40 µg Pfs230D1-EPA/Alhydrogel (n=50 [25%]; Pfs25 plus Pfs230D1), or comparator (Twinrix or Menactra) plus saline (n=51 [25%]). Vaccinations were well tolerated in the pilot safety and main phases. Most vaccinees became seropositive after two Pfs230D1 or three Pfs25 doses; peak titres increased with each dose thereafter (Pfs230D1 geometric mean: 77·8 [95% CI 56·9-106·3], 146·4 [108·3-198·0], and 410·2 [301·6-558·0]; Pfs25 geometric mean 177·7 [130·3-242·4] and 315·7 [209·9-474·6]). Functional activity (mean peak transmission-reducing activity) appeared for Pfs230D1 (74·5% [66·6-82·5]) and Pfs25 plus Pfs230D1 (68·6% [57·3-79·8]), after the third dose and after the fourth dose (88·9% [81·7-96·2] for Pfs230D1 and 85·0% [78·4-91·5] Pfs25 plus Pfs230D1) but not for Pfs25 (58·2% [49·1-67·3] after the third dose and 58·2% [48·5-67·9] after the fourth dose). Pfs230D1 transmission-reducing activity (73·7% [64·1-83·3]) persisted 10 weeks after the fourth dose. Transmission-reducing activity of 80% was estimated at 1659 ELISA units for Pfs25, 218 for Pfs230D1, and 223 for Pfs230D1 plus Pfs25. After 3850 direct skin feed assays, 35 participants (12 Pfs25, eight Pfs230D1, five Pfs25 plus Pfs230D1, and ten comparator) had transmitted parasites at least once. The proportion of positive assays in vaccine groups (Pfs25 33 [3%] of 982 [-0·013 to 0·014], Pfs230D1 22 [2%] of 954 [-0·005 to 0·027], and combination 11 [1%] of 940 [-0·024 to 0·002]) did not differ from that of the comparator (22 [2%] of 974), nor did Pfs230D1 and combination groups differ (-0·024 to 0·001). INTERPRETATION: Pfs230D1 but not Pfs25 vaccine induces durable serum functional activity in Malian adults. Direct skin feed assays detect parasite transmission to mosquitoes but increased event rates are needed to assess vaccine effectiveness. FUNDING: Intramural Research Program of the National Institute of Allergy and Infectious Diseases and US National Institutes of Health.

Structural and immunological differences in Plasmodium falciparum sexual stage transmission-blocking vaccines comprised of Pfs25-EPA nanoparticles.

Development of a malaria vaccine that blocks transmission of different parasite stages to humans and mosquitoes is considered critical for elimination efforts. A vaccine using Pfs25, a protein on the surface of zygotes and ookinetes, is under investigation as a transmission-blocking vaccine (TBV) that would interrupt parasite passage from mosquitoes to humans. The most extensively studied Pfs25 TBVs use Pichia pastoris-produced recombinant forms of Pfs25, chemically conjugated to a recombinant carrier protein, ExoProtein A (EPA). The recombinant form of Pfs25 first used in humans was identified as Pfs25H, which contained a total of 14 heterologous amino acid residues located at the amino- and carboxyl-termini including a His6 affinity tag. A second recombinant Pfs25, identified as Pfs25M, was produced to remove the heterologous amino acid residues and conjugated to EPA (Pfs25M-EPA). Here, monomeric Pfs25M was characterized biochemically and biophysically for identity, purity, and integrity including protein structure to assess its comparability with Pfs25H. Although the biological activities of Pfs25H and Pfs25M, whether generated by monomeric forms or conjugated nanoparticles, appeared similar, fine-mapping studies with two transmission-blocking monoclonal antibodies detected structural and immunological differences. In addition, evaluation of antisera generated against conjugated Pfs25H or Pfs25M nanoparticles in nonhuman primates identified polyclonal IgG that recognized these structural differences.