Applying the conformational bias of amides to the synthesis of triarylmethanes, difluoromethyl arenes and medium-sized rings

Chapter 1 — Triarylmethanes by the Truce–Smiles rearrangement of benzanilidesThe triarylmethane (TRAM) motif can be found embedded within the structures of compounds with applications across diverse fields, rendering methods to construct TRAMs of significant value. In Chapter 1, we present a new approach to TRAM synthesis, employing the intramolecular nucleophilic aromatic substitution, or Truce–Smiles rearrangement, of readily accessible 2-benzylbenzanilide precursors. In contrast to classical rearrangements of this kind, the reaction succeeds without electronic activation of the arene that serves as electrophile, with rate acceleration instead provided by the conformational preference of an amide tether within the substrate. Access to TRAM products of varied structure was achieved, with the methodology allowing for independent modification of each of the three aromatic rings. It was demonstrated that the amide function of the reaction products can be removed or used as a functional handle in further transformations. Mechanistic investigation by in situ infrared spectroscopy, a deuterium exchange study and Hammett analysis suggest the reaction proceeds through a partially concerted aryl migration. In addition, a ring-expanding version of the rearrangement provided access to novel TRAM-containing medium ring lactams. On account of the broad tolerance of steric and electronic parameters tolerated for each of the three (hetero)aromatic rings, this methodology is expected to be an attractive approach to TRAM derivatives that are important within various areas of science.Chapter 2 — Difluoromethyl arenes by the monodefluorination of trifluoromethyl arenesAs a consequence of being an unusual hydrogen bond donor, and a potential bioisostere for a range of functionalities, the difluoromethyl group has attracted much interest amongst designers of pharmaceutical and crop protection agents. In addition, it has emerged as an appealing substitute for the trifluoromethyl group, whose inclusion in industrial products is thought to be having unforeseen negative impacts on the environment. Hence, the defluorination of trifluoromethylated precursors to valuable difluoromethylated products is an intriguing prospect. In Chapter 2, we describe the realisation of this transformation by designing a four-step protocol that employs an amide-based auxiliary to selectively delete one fluorine atom from the CF3 group of widely available trifluoromethylated benzaldehydes. Diversely substituted CF2H-containing products could be obtained, including building blocks relevant to medicinal and agrochemical discovery, which highlights the utility and practicality of the method for industrial application. The defluorination of other polyfluoroalkyl groups could also be effected by the method. By probing the defluorination reaction using in situ infrared spectroscopy, and deuterium studies that allowed for measurement of a primary kinetic isotope effect, a viable mechanism was proposed, which includes loss of fluoride by a rate-limiting elimination reaction. We anticipate this is a timely discovery of a highly applicable entry into CF2H-functionalised arenes that allows for direct replacement of trifluoromethylated intermediates within industrial settings.Chapter 3 — Medium-sized rings by the migratory ring expansion of alkenesOwing to their characteristic conformational properties, medium-sized rings are favourable scaffolds for exploration within drug and agrochemical discovery. However, these conformational properties are often a double-edged sword, precluding medium ring formation by the cyclisation of an acyclic precursor. This remains a considerable barrier to the inclusion of medium-sized rings in screening libraries or novel compound designs. The strategy of ring expansion has recently been fruitful for unlocking methods that access medium ring products. In Chapter 3, we describe investigations into employing a ring expansion strategy towards the synthesis of medium-sized rings by the conformationally-enhanced migration of alkenes. This is both an enticing and ambitious endeavour, which could offer a route to enlarged cyclic frameworks with diverse structure. An amide linkage between a 1-phenylethyl anion-stabilising group and a migrating alkene provided the conformational bias to promote vinyl transfer, generating sterically congested olefin products. Although reactivity was unfortunately limited to this specific system, some degree of structural variation was attainable through a carbolithiation–vinyl migration cascade of a related amide-containing substrate. Significantly, the availability of common-sized heterocycles could be leveraged to rapidly access ring expansion precursors from pyridine. Furthermore, progress has been made towards elucidating the mechanism of unactivated vinyl migration processes by identification of a candidate system for a kinetic isotope effect study.</div

Early and long-term outcomes following long posterior flap vs. skew flap for below knee amputations

Objective To compare outcomes between long posterior flap (LPF) and skew flap (SF) amputation over a 13 year period. Methods This was a retrospective observational cohort study. Consecutive patients undergoing a LPF or SF below knee amputation (BKA) over a 13 year period at one hospital were identified. Both techniques were performed regularly, depending on tissue loss and surgeon preference. The primary outcome was surgical revision of any kind. Secondary outcomes included revision to above knee amputation (AKA), length of hospital stay (LOS), and mortality. A smaller cohort of patients who were alive and unilateral below knee amputees were contacted to ascertain prosthetic use and functional status. Results In total, 242 BKAs were performed in 212 patients (125 LPF and 117 SF; median follow up 25.8 months). Outcomes for the two groups were equivalent for surgical revision of any kind (27 LPF vs. 31 SF; p = .37), revision to an AKA (18 LPF vs. 14 SF; p = .58), LOS (29 days for LPF vs. 28 days for SF; p = .83), and median survival (23.9 months for LPF vs. 28.8 months for SF; p = .89). Multivariable analysis found amputation type had no effect on any outcome. Functional scores from a smaller cohort of 40 unilateral amputees who were contactable demonstrated improved outcomes with the LPF vs. the SF (p = .038). Conclusion Both techniques appear equivalent for rates of surgical residual limb failure. Functional outcomes may be better with the LPF

How Civil Society Organisations Changed the Regulation of Clinical Trials in India

In 2005 India changed its pharmaceutical and innovation policy that facilitated a dramatic increase in international clinical trials involving study sites in India. This policy shift was surrounded by controversies; civil society organisations (CSOs) criticised the Indian government for promoting the commercialisation of pharmaceutical research and development. Health social movements in India fought for social justice through collective action, and engaged in normative reasoning of the benefits, burdens and equality of research. They lobbied to protect trial participants from structural violence that occurred especially in the first 5–6 years of the new policy. CSOs played a major role in the introduction of new regulations in 2013, which accelerated a decline in the number of global trials carried out in India. This activism applied interpretations of global social justice as key ideas in mobilisation, eventually helping to institutionalise stricter ethical regulation on a national level. Like government and industry, activists believed in randomised controlled trials and comparison as key methods for scientific knowledge production. However, they had significant concerns about the global hierarchies of commercial pharmaceutical research, and their impact on the rights of participants and on benefits for India overall. Pointing to ethical malpractices and lobbying for stricter ethical regulations, they aimed to ensure justice for research participants, and developed effective strategies to increase controls over the business side of clinical research

How Civil Society Organisations Changed the Regulation of Clinical Trials in India

In 2005 India changed its pharmaceutical and innovation policy that facilitated a dramatic increase in international clinical trials involving study sites in India. This policy shift was surrounded by controversies; civil society organisations (CSOs) criticised the Indian government for promoting the commercialisation of pharmaceutical research and development. Health social movements in India fought for social justice through collective action, and engaged in normative reasoning of the benefits, burdens and equality of research. They lobbied to protect trial participants from structural violence that occurred especially in the first 5–6 years of the new policy. CSOs played a major role in the introduction of new regulations in 2013, which accelerated a decline in the number of global trials carried out in India. This activism applied interpretations of global social justice as key ideas in mobilisation, eventually helping to institutionalise stricter ethical regulation on a national level. Like government and industry, activists believed in randomised controlled trials and comparison as key methods for scientific knowledge production. However, they had significant concerns about the global hierarchies of commercial pharmaceutical research, and their impact on the rights of participants and on benefits for India overall. Pointing to ethical malpractices and lobbying for stricter ethical regulations, they aimed to ensure justice for research participants, and developed effective strategies to increase controls over the business side of clinical research.</p

Erosion of Trust in the Medical Profession in India : Time for Doctors to Act

In India, over the last decade, a series of stewardship failures in the health system, particularly in the medical profession, have led to a massive erosion of trust in these institutions. In many low- and middle-income countries (LMICs), the situation is similar and has reached crisis proportions; this crisis requires urgent attention. This paper draws on the insights from the recent developments in India, to argue that a purely control-based regulatory response to this crisis in the medical profession, as is being currently envisaged by the Parliament and the Supreme Court of India, runs the risk of undermining the trusting interpersonal relations between doctors and their patients. A more balanced approach which takes into account the differences between system and interpersonal forms of trust and distrust is warranted. Such an approach should on one hand strongly regulate the institutions mandated with the stewardship and qualities of care functions, and simultaneously on the other hand, initiate measures to nurture the trusting interpersonal relations between doctors and patients. The paper concludes by calling for doctors, and those mandated with the stewardship of the profession, to individually and collectively, critically self-reflect upon the state of their profession, its priorities and its future direction

Preprints in times of COVID19: The time is ripe for agreeing on terminology and good practices

Over recent years, the research community has been increasingly using preprint servers to share manuscripts that are not yet peer-reviewed. Even if it enables quick dissemination of research findings, this practice raises several challenges in publication ethics and integrity. In particular, preprints have become an important source of information for stakeholders interested in COVID19 research developments, including traditional media, social media, and policy makers. Despite caveats about their nature, many users can still confuse pre-prints with peer-reviewed manuscripts. If unconfirmed but already widely shared first-draft results later prove wrong or misinterpreted, it can be very difficult to unlearn what we thought was true. Complexity further increases if unconfirmed findings have been used to inform guidelines. To help achieve a balance between early access to research findings and its negative consequences, we formulated five recommendations: (a) consensus should be sought on a term clearer than \u27pre-print\u27, such as \u27Unrefereed manuscript\u27, Manuscript awaiting peer review or \u27\u27Non-reviewed manuscript ; (b) Caveats about unrefereed manuscripts should be prominent on their first page, and each page should include a red watermark stating \u27Caution-Not Peer Reviewed\u27; (c) pre-print authors should certify that their manuscript will be submitted to a peer-review journal, and should regularly update the manuscript status; (d) high level consultations should be convened, to formulate clear principles and policies for the publication and dissemination of non-peer reviewed research results; (e) in the longer term, an international initiative to certify servers that comply with good practices could be envisaged

Painless Presentation of a Deadly Disease:Type A Aortic Dissection Requiring the Bentall Procedure

Aortic dissection is a relatively uncommon, although catastrophic, disease which requires early and accurate diagnosis and treatment for patient survival. Aortic dissection can be difficult to diagnose due to the diverse symptom presentation, which can lead to later diagnosis, resulting in a higher mortality rate. Here we present a case of type A aortic dissection with a varied symptom presentation, highlighting the importance of early detection and the Bentall procedure for management of such cases. A 50-year-old man with no known medical history presented with bilateral lower extremity swelling and fatigue for 2 weeks. The patient denied any chest pain or dyspnoea. Vital signs showed blood pressure of 160/76 mmHg, pulse of 103 bpm, respiratory rate of 18, and temperature of 36.7°C. Laboratory findings indicated a BNP of 1901 pg/ml and troponin of 0.5 ng/ml. An initial diagnosis of decompensated heart failure was made, and IV Lasix was started. Subsequently, an echocardiogram indicated an EF of 50–55% and ascending dissection of the aorta. A CT angiogram of the chest and abdomen confirmed this diagnosis. This patient presented with unusual symptoms of aortic dissection without the typical presentation of chest pain. It is important to consider aortic dissection in a cardiac-related case as prompt imaging can help confirm the diagnosis. We explore the risks and benefits of the Bentall procedure for the management and early detection of aortic dissectio

A Rare Case of Elevated Osmolar Gap in Diabetic Ketoacidosis/Hyperosmolar Hyperglycaemic State in the Absence of Concomitant Toxic Alcohol Ingestion

The serum osmolar gap, defined as the difference between measured osmolality and calculated osmolarity, is a convenient method to screen for toxins in serum. In normal circumstances, the difference between the two is 6–10 mol/kg. Typical contributors to serum osmolarity are sodium bicarbonate, sodium chloride, glucose and urea. An elevated gap, defined as a difference >10 mol/kg, can occur if a sufficient quantity of an additional solute other than those mentioned above is present in the serum or there are inaccuracies in sodium measurement secondary to hyperlipidaemia and hyperproteinaemia. An elevated serum osmolar gap should thus prompt clinicians to check for toxic alcohol levels. Treatment with fomepizole should not be delayed if suspicion is high. Isolated diabetic ketoacidosis can occasionally present with an elevated osmolar gap in the absence of concomitant alcohol ingestion. This finding is attributed to the production of acetone and glycerol. We describe the case of a 62-year-old man presenting with diabetic ketoacidosis/hyperosmolar hyperglycaemic state and an elevated osmolar gap in the absence of toxic alcohol ingestion