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X-ray Diffraction Computed Tomography (XRD-CT) represents a cutting-edge method for non-destructive material analysis, offering the unique capability of providing molecular-level information with spatial resolution. In this study, we have applied XRD-CT to investigate pharmaceutically relevant tablets that have been subjected to a range of compression pressures typical in tablet manufacturing. By employing XRD-CT to pharmaceutical tablets, we reveal material changes without tablet destruction, thereby avoiding potential phase transformations during sample preparation that could lead to errors in the interpretation of the processes that have occurred. Utilizing a pressure-sensitive marker, glycolide, we have tracked changes within tablet structures induced by compression, pinpointing locations where glycolide undergoes pressure-induced transformation. Additionally, we conducted a follow-up study with analysis one month later, observing an in-situ hydrolysis reaction of glycolide within the tablets. Through the complementary use of electron diffraction, we have elucidated the structure of the hydrolysis product, further enhancing our understanding of temporal changes in the tablets., (© 2024 Wiley‐VCH GmbH.)

Septal artery perforations are an uncommon complication of percutaneous coronary intervention. Unlike epicardial vessels, septal perforations do not result in pericardial effusions but rather produce septal haematomas. While most can be managed expectantly, a small proportion requires active management to prevent rapid haematoma expansion resulting in compromise of right ventricular filling and 'dry tamponade'. We present two cases of septal artery perforation during percutaneous coronary intervention and propose a management approach that takes into account the unique haemodynamic consequences of this complication., Competing Interests: Declaration of Competing Interest There are no conflicts of interest to disclose., (Crown Copyright © 2024. Published by Elsevier B.V. All rights reserved.)

Numerous guidelines on the diagnosis and management of hypertrophic cardiomyopathy (HCM) have been published, by learned societies, over the past decade. Although helpful they are often long and less adapted to nonexperts. This writing panel was challenged to produce a document that grew as much from years of practical experience as it did from the peer-reviewed literature. As such, rather than produce yet another set of guidelines, we aim herein to deliver a concentrate of our own experiential learning and distill for the reader the essence of effective and appropriate HCM care. This Clinical Practice Update on HCM is therefore aimed at general cardiologists and other cardiovascular practitioners rather than for HCM specialists. We set the stage with a description of the condition and its clinical presentation, discuss the central importance of "obstruction" and how to look for it, review the role of cardiac magnetic resonance imaging, reflect on the appropriate use of genetic testing, review the treatment options for symptomatic HCM-crucially including cardiac myosin inhibitors, and deal concisely with practical issues surrounding risk assessment for sudden cardiac death, and management of the end-stage HCM patient. Uniquely, we have captured the pediatric experience on our panel to discuss appropriate differences in the management of younger patients with HCM. We ask the reader to remember that this document represents expert consensus opinion rather than dogma and to use their best judgement when dealing with the HCM patient in front of them., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The management of diabetes mellitus and its resultant end organ dysfunction represents a major challenge to global health-care systems. Diabetic cardiac and kidney disease commonly co-occur and are significant contributors to the morbidity and mortality of patients with diabetes, carrying a poor prognosis. The tight link of these parallel end organ manifestations suggests a deeper common underlying pathology. Here, we outline the mechanistic link between diabetic cardiac and kidney disease, providing evidence for the role of endothelial dysfunction in both processes and the potential for cellular therapy to correct these disorders. Specifically, we review the preclinical and clinical evidence for endothelial progenitor cell therapy in cardiac, kidney, and cardio-renal disease applications. Finally, we outline novel approaches to endothelial progenitor cell therapy through cell enhancement and the use of extracellular vesicles, discussing published and future work., (© The Author(s) 2024. Published by Oxford University Press.)

Pharmaceutical cocrystals use common robust hydrogen bonding synthons to create novel materials with different physicochemical properties. In this systematic study of a series of cocrystals, we explore the effect of high pressure on one of these commonly used motifs, the acid-pyridine motif, to assess the commonality of behaviour under extreme conditions. We have surveyed five pyridine dicarboxylic acid systems using both synchrotron and neutron diffraction methods to elucidate the changes in structure. We observe that the hydrogen bonding in these systems compress at a similar rate despite the changes to the molecular make-up of the solids and that on compression the changes in structure are indicative that the layers move along the major slip planes in the structure. We have observed two phase transitions to new forms of the pyrazine:malonic acid system, one for each stoichiometric ratio. This study demonstrates that the combination of two complementary diffraction approaches is key to understanding polymorphic behaviour at high pressure., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Iain D H Oswald reports financial support was provided by Engineering and Physical Sciences Research Council. Iain D H Oswald reports financial support was provided by Science and Technology Facilities Council. Iain D H Oswald reports a relationship with Science and Technology Facilities Council that includes: board membership, consulting or advisory, and travel reimbursement., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

We present an extensive exploration of the solid-form landscape of chlorpropamide (CPA) using a combined experimental-computational approach at the frontiers of both fields. We have obtained new conformational polymorphs of CPA, placing them into context with known forms using flexible-molecule crystal structure prediction. We highlight the formation of a new polymorph (ζ-CPA) via spray-drying experiments despite its notable metastability (14 kJ/mol) relative to the thermodynamic α-form, and we identify and resolve the ball-milled η-form isolated in 2019. Additionally, we employ impurity- and gel-assisted crystallization to control polymorphism and the formation of novel multicomponent forms. We, thus, demonstrate the power of this collaborative screening approach to observe, rationalize, and control the formation of new metastable forms., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Postsynthetic modification of metal-organic frameworks (MOFs) has proven to be a hugely powerful tool to tune physical properties and introduce functionality, by exploiting reactive sites on both the MOF linkers and their inorganic secondary building units (SBUs), and so has facilitated a wide range of applications. Studies into the reactivity of MOF SBUs have focussed solely on removal of neutral coordinating solvents, or direct exchange of linkers such as carboxylates, despite the prevalence of ancillary charge-balancing oxide and hydroxide ligands found in many SBUs. Herein, we show that the μ 2 -OH ligands in the MIL-53 topology Sc MOF, GUF-1, are labile, and can be substituted for μ 2 -OCH 3 units through reaction with pore-bound methanol molecules in a very rare example of pressure-induced postsynthetic modification. Using comprehensive solid-state NMR spectroscopic analysis, we show an order of magnitude increase in this cluster anion substitution process after exposing bulk samples suspended in methanol to a pressure of 0.8 GPa in a large volume press. Additionally, single crystals compressed in diamond anvil cells with methanol as the pressure-transmitting medium have enabled full structural characterisation of the process across a range of pressures, leading to a quantitative single-crystal to single-crystal conversion at 4.98 GPa. This unexpected SBU reactivity - in this case chemisorption of methanol - has implications across a range of MOF chemistry, from activation of small molecules for heterogeneous catalysis to chemical stability, and we expect cluster anion substitution to be developed into a highly convenient novel method for modifying the internal pore surface and chemistry of a range of porous materials., Competing Interests: The authors declare no competing interests., (This journal is © The Royal Society of Chemistry.)

Understanding the solvation and desolvation of pharmaceutical materials is an important part of materials discovery and development. In situ structural data are vital to understand the changes to crystal form that may occur in the system. In this study, the isolation and characterization of seven solvates of the L-type calcium channel antagonist, nifedipine, is described using variable-temperature powder X-ray diffraction so that the structural evolution as a function of temperature can be followed. The solvates reported herein can be split into those that are structurally similar to the previously reported dimethyl sulfoxide (DMSO) and dioxane solvates and those that have a novel packing arrangement. Of particular note is the solvate with tetrahydrofuran (THF) which has a hydrogen-bonding motif between the nifedipine molecules very similar to that of metastable β-nifedipine. In addition to variable-temperature X-ray diffraction, the stability of the solid forms was assessed using differential scanning calorimetry and thermogravimetric analysis and indicates that in all cases desolvation results in the thermodynamically stable α-polymorph of nifedipine even with the THF solvate. From the diffraction data the pathway of desolvation during heating of the DMF solvate showed conversion to another likely 1:1 polymorph before desolvation to α-nifedipine. The desolvation of this material indicated a two-stage process; first the initial loss of 90% of the solvent before the last 10% is lost on melting. The methanol solvate shows interesting negative thermal expansion on heating, which is rarely reported in organic materials, but this behaviour can be linked back to the winerack-type hydrogen-bonding pattern of the nifedipine molecules., (open access.)

Adjuvants are essential components of subunit vaccines added to enhance immune responses to antigens through immunomodulation. Very few adjuvants have been approved for human use by regulatory agencies due to safety concerns. Current subunit vaccine adjuvants approved for human use are very effective in promoting humoral immune responses but are less effective at promoting T-cell immunity. In this study, we evaluated a novel pure enantio-specific cationic lipid 1,2-dioleoyl-3-trimethylammonium-propane (R-DOTAP) as an immunomodulator for subunit vaccines capable of inducing both humoral- and cellular-mediated immunity. Using recombinant protein antigens derived from SARS-CoV2 spike or novel computationally optimized broadly reactive influenza antigen (COBRA) proteins, we demonstrated that R-DOTAP nanoparticles promoted strong cellular- and antibody-mediated immune responses in both monovalent and bivalent vaccines. R-DOTAP-based vaccines induced antigen-specific and polyfunctional CD8 + and CD4 + effector T cells and memory T cells, respectively. Antibody responses induced by R-DOTAP showed a balanced Th1/Th2 type immunity, neutralizing activity and protection of mice from challenge with live SARS-CoV2 or influenza viruses. R-DOTAP also facilitated significant dose sparing of the vaccine antigens. These studies demonstrate that R-DOTAP is an excellent immune stimulator for the production of next-generation subunit vaccines containing multiple recombinant proteins.

Purpose: This study aimed to investigate hamstring architectural, strength, and morphological adaptations after an eccentric or isometric hip extension exercise intervention., Methods: Twenty-four recreationally active males performed either an eccentric ( n = 12) or an isometric hip extension ( n = 12) exercise intervention, twice per week for 6 wk, followed by a 4-wk detraining period. Biceps femoris long head (BFlh) architecture was assessed pre-intervention, mid-intervention, post-intervention, and post-detraining via two-dimensional ultrasound. Strength was assessed pre-intervention, post-intervention, and post-detraining during an isokinetic knee flexion, an isometric hip extension, a Nordic hamstring exercise, and a single-leg hamstring bridge repetition to fatigue test. Hamstring muscle morphology was assessed via magnetic resonance imaging before strength testing sessions., Results: The eccentric hip extension exercise intervention significantly lengthened BFlh fascicles (+19.7%, P < 0.001, d = 1.57), increased eccentric knee flexion torque (ECC 60°·s -1 , +12%, P < 0.005, d = 0.66; ECC 180°·s -1 , +8.3%, P < 0.05, d = 0.41), and increased BFlh (+13.3%, P < 0.001, d = 1.96) and semimembranosus (SM) muscle volume (+12.5%, P < 0.001, d = 2.25). After 4 wk of detraining, BFlh fascicles were significantly shortened in the eccentric group (-14.8%, P < 0.005, d = -1.25), whereas eccentric knee flexion torque and BFlh and SM volumes were unchanged. The isometric hip extension exercise intervention significantly increased isometric knee flexion torque (+10.4%, P < 0.05, d = 0.54), isometric hip extension force (+12.4%, P < 0.05, d = 0.41), and semitendinosus volume (+15%, P = 0.054, d = 1.57). All other outcome measures saw no significant changes. After 4 wk of detraining, no significant changes to any variables were observed in the isometric group., Conclusions: The eccentric but not isometric hip extension exercise intervention significantly increased BFlh fascicle length. Both exercise interventions demonstrated contraction mode-specific increases in strength. However, the eccentric hip extension exercise intervention resulted in preferential hypertrophy of BFlh and SM, and the isometric hip extension exercise intervention led to selective hypertrophy of semitendinosus., (Copyright © 2022 by the American College of Sports Medicine.)

Background: Treating known risk factors for coronary artery disease (CAD) has substantially reduced CAD morbidity and mortality. However, a significant burden of CAD remains unexplained. Immunoglobulin E sensitization to mammalian oligosaccharide galactose-α-1,3-galactose (α-Gal) was recently associated with CAD in a small observational study. We sought to confirm that α-Gal sensitization is associated with CAD burden, in particular noncalcified plaque. Additionally, we sort to assess whether that α-Gal sensitization is associated with ST-segment-elevated myocardial infarction (STEMI) Methods: We performed a cross-sectional analysis of participants enrolled in the BioHEART cohort study. We measured α-Gal specific-immunoglobulin E antibodies in serum of 1056 patients referred for CT coronary angiography for suspected CAD and 100 selected patients presenting with STEMI, enriched for patients without standard modifiable risk factors. CT coronary angiograms were assessed using coronary artery calcium scores and segmental plaque scores., Results: α-Gal sensitization was associated with presence of noncalcified plaque (odds ratio, 1.62 [95% CI, 1.04-2.53], P =0.03) and obstructive CAD (odds ratio, 2.05 [95% CI, 1.29-3.25], P =0.002), independent of age, sex, and traditional risk factors. The α-Gal sensitization rate was 12.8-fold higher in patients with STEMI compared with matched healthy controls and 2.2-fold higher in the patients with STEMI compared with matched stable CAD patients (17% versus 1.3%, P =0.01 and 20% versus 9%, P =0.03, respectively)., Conclusions: α-Gal sensitization is independently associated with noncalcified plaque burden and obstructive CAD and occurs at higher frequency in patients with STEMI than those with stable or no CAD. These findings may have implications for individuals exposed to ticks, as well as public health policy. Registration: URL: https://www.anzctr.org.au; Unique identifier: ACTRN12618001322224.