2‐Methyltetrahydrofuran (2‐MeTHF) as a versatile green solvent for the synthesis of amphiphilic copolymers via ROP, FRP, and RAFT tandem polymerizations

2‐methyltetrahydrofuran (2‐MeTHF) is a readily available, inexpensive, neoteric, bio‐based solvent. It has been adopted across a wide range of chemical processes including the batch manufacture of fine chemicals, enzymatic polycondensations and ring opening polymerizations. To reduce the environmental burden related to the synthesis of pharmaceutical‐grade polymers based on lactide and caprolactone, we envisaged the use of 2‐MeTHF. For the first time, we combined a series of metal‐free and enzymatic ROPs with free radical and controlled RAFT polymerizations (carried out separately and in tandem) in 2‐MeTHF, in order to easily tune the chemistry and the architecture of the final polymers. After a simple purification, the amphiphilic polymers were formulated into nanoparticles and tested for their cytocompatibility in three model cell lines, to assess their application as potential polymeric excipients for nanomedicines

Post Exposure Prophylaxis for HIV in the sexual exposure scenario (PEPSE): Development of a novel nanoformulation

Since the year 2012, 2 million newly diagnosed cases of human immunodeficiency virus (HIV) have been found every year. Prevention schemes based on condoms, and other pharmacological interventions such as post exposure prophylaxis in a sexual exposure scenario (PEPSE) have had positive impact in the pandemic. Under current PEPSE guidelines due to risk to benefit ratios, only high-risk unprotected sexual events (>1/1000) are prescribed antiviral prophylaxis. Such a situation leaves a population unprotected, whose size is unknown, that is in a low to moderate risk of HIV acquisition. To assess the size and views of a population that is currently unprotected by current prevention schemes, two online survey studies were set up in Thailand and the UK (Chapter 2). Both questionnaires were designed to probe for unplanned low to moderate risk of sexual exposure to HIV. Both data sets were analysed through demographic statistics and logistic regression to assess for unsafe intercourse. The results suggest that the proportion of the population reporting unplanned unsafe sexual intercourse events is as high as 29.1% in the UK study and 15.8% in the study in Thailand. Such a high proportion of sexually active population presents a target for further alternative prevention schemes and a research priority. One such alternative prevention scheme would be a localised (anal or vaginal delivery) nanoparticle drug delivery system, with high drug content, targeting local lymphatic nodes (Chapter 3). Dolutegravir (DTG) was chosen as the model antiretroviral agent due to its favourable side effect profile, high genetic barrier and high antiviral potency. However, the physiochemical properties of DTG such as its hydrophilicity are a challenge for the entrapment of DTG under traditional nanoformualtions. A DTG prodrug, dolutegravir myristate (MDTG) was synthesized based on Sillman et al. to generate a high drug content formulation, a two-step solvent displacement experimental set up was designed. The first step was designed to formulate a MDTG nanocrystal emulsion, and the second step was designed to coat the nanocrystal with a minimal mass of a polymeric nanocarrier. The formulation developed through a coating method has a fast release of compound, as 100% of the payload gets released before 2 hours. This work provides evidence that a substantial percentage of the sexually active population, may find themselves in an unplanned low to moderate risk scenario for sexual HIV acquisition. A potential solution for this population may lie in a localised nanoparticle delivery system to the vaginal or anal tissue (Chapter 4). In this work, proof of concept of coating an MDTG nanocrystal for this purpose was achieved. However, the drug release profile is not ideal for PEPSE purposes, thus future research is needed to perfect such a delivery system

Post Exposure Prophylaxis for HIV in the sexual exposure scenario (PEPSE): Development of a novel nanoformulation

Since the year 2012, 2 million newly diagnosed cases of human immunodeficiency virus (HIV) have been found every year. Prevention schemes based on condoms, and other pharmacological interventions such as post exposure prophylaxis in a sexual exposure scenario (PEPSE) have had positive impact in the pandemic. Under current PEPSE guidelines due to risk to benefit ratios, only high-risk unprotected sexual events (>1/1000) are prescribed antiviral prophylaxis. Such a situation leaves a population unprotected, whose size is unknown, that is in a low to moderate risk of HIV acquisition. To assess the size and views of a population that is currently unprotected by current prevention schemes, two online survey studies were set up in Thailand and the UK (Chapter 2). Both questionnaires were designed to probe for unplanned low to moderate risk of sexual exposure to HIV. Both data sets were analysed through demographic statistics and logistic regression to assess for unsafe intercourse. The results suggest that the proportion of the population reporting unplanned unsafe sexual intercourse events is as high as 29.1% in the UK study and 15.8% in the study in Thailand. Such a high proportion of sexually active population presents a target for further alternative prevention schemes and a research priority. One such alternative prevention scheme would be a localised (anal or vaginal delivery) nanoparticle drug delivery system, with high drug content, targeting local lymphatic nodes (Chapter 3). Dolutegravir (DTG) was chosen as the model antiretroviral agent due to its favourable side effect profile, high genetic barrier and high antiviral potency. However, the physiochemical properties of DTG such as its hydrophilicity are a challenge for the entrapment of DTG under traditional nanoformualtions. A DTG prodrug, dolutegravir myristate (MDTG) was synthesized based on Sillman et al. to generate a high drug content formulation, a two-step solvent displacement experimental set up was designed. The first step was designed to formulate a MDTG nanocrystal emulsion, and the second step was designed to coat the nanocrystal with a minimal mass of a polymeric nanocarrier. The formulation developed through a coating method has a fast release of compound, as 100% of the payload gets released before 2 hours. This work provides evidence that a substantial percentage of the sexually active population, may find themselves in an unplanned low to moderate risk scenario for sexual HIV acquisition. A potential solution for this population may lie in a localised nanoparticle delivery system to the vaginal or anal tissue (Chapter 4). In this work, proof of concept of coating an MDTG nanocrystal for this purpose was achieved. However, the drug release profile is not ideal for PEPSE purposes, thus future research is needed to perfect such a delivery system

Towards Equitable, Diverse, and Inclusive science collaborations: The Multimessenger Diversity Network

International audienceThe Multimessenger Diversity Network (MDN), formed in 2018, extends the basic principle of multimessenger astronomy – that working collaboratively with different approaches enhances understanding and enables previously impossible discoveries – to equity, diversity, and inclusion (EDI) in science research collaborations. With support from the National Science Foundation INCLUDES program, the MDN focuses on increasing EDI by sharing knowledge, experiences, training, and resources among representatives from multimessenger science collaborations. Representatives to the MDN become engagement leads in their collaboration, extending the reach of the community of practice. An overview of the MDN structure, lessons learned, and how to join are presented

Long-term efficacy and safety of eculizumab in Japanese patients with generalized myasthenia gravis: A subgroup analysis of the REGAIN open-label extension study

The terminal complement inhibitor eculizumab was shown to improve myasthenia gravis-related symptoms in the 26-week, phase 3, randomized, double-blind, placebo-controlled REGAIN study (NCT01997229). In this 52-week sub-analysis of the open-label extension of REGAIN (NCT02301624), eculizumab's efficacy and safety were assessed in 11 Japanese and 88 Caucasian patients with anti-acetylcholine receptor antibody-positive refractory generalized myasthenia gravis. For patients who had received placebo during REGAIN, treatment with open-label eculizumab resulted in generally similar outcomes in the Japanese and Caucasian populations. Rapid improvements were maintained for 52 weeks, assessed by change in score from open-label extension baseline to week 52 (mean [standard error]) using the following scales (in Japanese and Caucasian patients, respectively): Myasthenia Gravis Activities of Daily Living (−2.4 [1.34] and − 3.3 [0.65]); Quantitative Myasthenia Gravis (−2.9 [1.98] and − 4.3 [0.79]); Myasthenia Gravis Composite (−4.5 [2.63] and − 4.9 [1.19]); and Myasthenia Gravis Quality of Life 15-item questionnaire (−8.6 [5.68] and − 6.5 [1.93]). Overall, the safety of eculizumab was consistent with its known safety profile. In this interim sub-analysis, the efficacy and safety of eculizumab in Japanese and Caucasian patients were generally similar, and consistent with the overall REGAIN population

Safety and efficacy of non-steroidal anti-inflammatory drugs to reduce ileus after colorectal surgery

Background: Ileus is common after elective colorectal surgery, and is associated with increased adverse events and prolonged hospital stay. The aim was to assess the role of non-steroidal anti-inflammatory drugs (NSAIDs) for reducing ileus after surgery. Methods: A prospective multicentre cohort study was delivered by an international, student- and trainee-led collaborative group. Adult patients undergoing elective colorectal resection between January and April 2018 were included. The primary outcome was time to gastrointestinal recovery, measured using a composite measure of bowel function and tolerance to oral intake. The impact of NSAIDs was explored using Cox regression analyses, including the results of a centre-specific survey of compliance to enhanced recovery principles. Secondary safety outcomes included anastomotic leak rate and acute kidney injury. Results: A total of 4164 patients were included, with a median age of 68 (i.q.r. 57\u201375) years (54\ub79 per cent men). Some 1153 (27\ub77 per cent) received NSAIDs on postoperative days 1\u20133, of whom 1061 (92\ub70 per cent) received non-selective cyclo-oxygenase inhibitors. After adjustment for baseline differences, the mean time to gastrointestinal recovery did not differ significantly between patients who received NSAIDs and those who did not (4\ub76 versus 4\ub78 days; hazard ratio 1\ub704, 95 per cent c.i. 0\ub796 to 1\ub712; P = 0\ub7360). There were no significant differences in anastomotic leak rate (5\ub74 versus 4\ub76 per cent; P = 0\ub7349) or acute kidney injury (14\ub73 versus 13\ub78 per cent; P = 0\ub7666) between the groups. Significantly fewer patients receiving NSAIDs required strong opioid analgesia (35\ub73 versus 56\ub77 per cent; P < 0\ub7001). Conclusion: NSAIDs did not reduce the time for gastrointestinal recovery after colorectal surgery, but they were safe and associated with reduced postoperative opioid requirement