Frequency Rhythmic Electrical Modulation System (FREMS) to alleviate painful diabetic peripheral neuropathy: A pilot, randomised controlled trial (The FREMSTOP study).

BACKGROUND: Frequency Rhythmic Electrical Modulated System (FREMS) is a non-invasive treatment for chronic pain conditions, but its place in the treatment algorithm for painful diabetic peripheral neuropathy (PDPN) is unknown. METHODS: A pilot, open-label, randomised controlled trial in individuals with PDPN inadequately controlled on at least dual neuropathic pain treatments recruited from primary and secondary care. Participants were randomised 1:1 to FREMS + usual care (n = 13) versus usual care (n = 12). Primary outcome was change from baseline in perceived pain (assessed by visual analogue scale) at 12 weeks between treatment groups. RESULTS: Of 25 participants, 14 (56%) were men, and 21 (84%) were White Europeans. Median (IQR) age and duration of diabetes were 64 (56, 68) and 14 (10, 20) years, respectively. At 12 weeks, FREMS showed improvements in perceived pain compared with baseline, although the change was not statistically significant from control group (-4.0[-5.0,0.4] vs. 0[-0.3,0.7], p = 0.087). There were significant improvements in pain with FREMS, assessed by McGill Pain questionnaire (p = 0.042) and Douleur neuropathique-4 questionnaire (p = 0.042). More participants on FREMS had greater than 30 percent reductions in perceived pain compared with controls [7/13(54%) vs 0/12(0%), p = 0.042] and significant improvements in Patient Global Impression of Change (p = 0.005). FREMS intervention had moderate benefits in quality of life, sleep, depression and pain medication use, but these were not statistically significant. CONCLUSIONS: FREMS might be used to treat individuals with PDPN inadequately controlled on two classes of neuropathic pain medications and is associated with improvements in pain severity and perceived impact of treatment. A larger, appropriately designed trial assessing its impact in this population is needed.

A Systematic Review to Assess the Impact of Hyperbaric Oxygen Therapy on Glycaemia in People with Diabetes Mellitus.

Background and Objectives: Hyperbaric oxygen is a recognised treatment for a range of medical conditions, including treatment of diabetic foot disease. A number of studies have reported an impact of hyperbaric oxygen treatment on glycaemic control in patients undergoing treatment for diabetic foot disease. There has been no systematic review considering the impact of hyperbaric oxygen on glycaemia in people with diabetes. Materials and Methods: A prospectively PROSPERO-registered (PROSPERO registration: CRD42021255528) systematic review of eligible studies published in English in the PUBMED, MEDLINE, and EMBASE databases, based on the following search terms: hyperbaric oxygen therapy, HBO2, hyperbaric oxygenation, glycaemic control, diabetes, diabetes Mellitus, diabetic, HbA1c. Data extraction to pre-determined piloted data collection form, with individual assessment of bias. Results: In total, 10 eligible publications were identified after screening. Of these, six articles reported a statistically significant reduction in blood glucose from hyperbaric oxygen treatment, while two articles reported a statistically significant increase in peripheral insulin sensitivity. Two articles also identified a statistically significant reduction in HbA1c following hyperbaric oxygen treatment. Conclusions: There is emerging evidence suggesting a reduction in glycaemia following hyperbaric oxygen treatment in patients with diabetes mellitus, but the existing studies are in relatively small cohorts and potentially underpowered. Additional large prospective clinical trials are required to understand the precise impact of hyperbaric oxygen treatment on glycaemia for people with diabetes mellitus.

A Comparison Between Lab-Scale and Hot-Melt-Extruder-Based Anti-inflammatory Ointment Manufacturing.

Hot-melt extrusion (HME) has been extensively investigated for continuous manufacturing of amorphous solid dispersions, to improve the solubility of poorly water-soluble drug substances, impart abuse deterrence to controlled substances, taste masking for pediatric and geriatric formulations and development of cocrystal system. Much research has been conducted on the continuous manufacturing of solid dosage forms using HME, but its applicability in the manufacturing of semisolids remains an unexplored domain. This study aimed to explore the applicability of HME in the continuous manufacturing of topical semi-solid formulations with two active pharmaceutical ingredients (APIs). Ointments containing a combination of triamcinolone acetonide and lidocaine hydrochloride were screened based on a quality target product profile (QTPP) and established critical quality attributes (CQAs) using design of experiments (DoE). Three selected formulations, manufactured by a lab-scale fusion method and HME, were subjected to further characterization studies including work of adhesion, stiffness, apparent pH, content uniformity, differential scanning calorimetry, accelerated stability, and in vitro drug release testing. Selected formulations met design characteristics and demonstrated the applicability of HME in the continuous manufacturing of semi-solid formulations. Graphical abstract.

Emerging topical onychomycosis therapies - quo vadis?

INTRODUCTION: Onychomycosis, a common chronic fungal infection affecting fingernails and toenails, globally may affect 10 - 30% of the population. This chronic disease is difficult to eradicate. The goal of developing a highly effective and safe topical treatment has not yet been reached as it depends on the type of onychomycosis and the variety of invaders. AREAS COVERED: Topical drug delivery to the nail is highly desirable in treating nail disorders. However, efficacy of topical therapies is low due to their limited permeability across the nail plate. Advances have especially been made by the development of new therapeutic options including new drug entities, new formulations and reformulations. This overview updates emerging topical treatments for onychomycosis, research progress and future perspectives. EXPERT OPINION: Development of novel effective noninvasive topical therapy for treating onychomycosis and other nail diseases such as psoriasis is long overdue. Previously there was a lack of basic knowledge about nail and its barrier properties, but with the recent increased interest in this field both from industry and academia, we hope extensive research will continue in this field to bring about successful and safe treatments for such chronic diseases.

Real-world evaluation of glucose-lowering therapies and the use of weight-adjusted variable rate intravenous insulin infusion in the management of hyperglycaemia in patients with acute coronary syndrome (REGULATE-ACS).

INTRODUCTION: Admission hyperglycaemia in acute coronary syndromes (ACS) is a strong independent predictor of adverse clinical outcomes post-ACS. We examined the safety, efficacy, and feasibility of a modified, weight-adjusted variable rate intravenous insulin infusion (VRIII) and evaluated current practice of prescribing novel cardio-protective glucose-lowering therapies in patients presenting with acute hyperglycaemia across the ACS spectrum. METHODS: REGULATE-ACS was an observational single-centre study of consecutive patients admitted with acute hyperglycaemia post-ACS between 2020 and 2021. Following updated local guidance on a modified VRIII, we evaluated its safety and efficacy in glycaemic control, cardio-metabolic complications including hypoglycaemia (blood glucose <3 mmol/L) and 30-day mortality. We also determined the prescription of glucose-lowering therapies pre-discharge. RESULTS: Out of 107 patients, mean age was 64.9 ± 12.2 years, 82% had known diabetes, and 15% newly diagnosed diabetes. 86.9% (n = 93) had an admission glucose ≥11 mmol/L. In patients treated with VRIII (n = 63/93, 67.7%), glucose improved from 17.5 to 9.0 mmol/L (IQR 7.1-12.1), which was 3 mmol/L lower (p = 0.03) than in patients not treated with VRIII (n = 30/93, 32.3%) where median glucose reduced from 12.6 to 12 mmol/L (IQR 8.6-13.9). No significant hypoglycaemia, arrhythmia or worsening pulmonary oedema associated with VRIII was found. Novel glucose-lowering therapies were initiated in 20/71 (28.2%) and 3/15 (20.0%) of patients with prior and newly diagnosed diabetes, respectively. CONCLUSION: This real-world analysis provides further support of efficacy, safety, and feasibility of a modified, weight-adjusted VRIII in managing acute hyperglycaemia in ACS. Despite established cardio-protective benefits of novel glucose-lowering therapies, <1/3 of eligible patients received such agents pre-discharge, demanding further research and awareness.

Klucel™ EF and ELF polymers for immediate-release oral dosage forms prepared by melt extrusion technology.

The objective of this research work was to evaluate Klucel™ hydroxypropylcellulose (HPC) EF and ELF polymers, for solubility enhancement as well as to address some of the disadvantages associated with solid dispersions. Ketoprofen (KPR), a Biopharmaceutics Classification System class II drug with poor solubility, was utilized as a model compound. Preliminary thermal studies were performed to confirm formation of a solid solution/dispersion of KPR in HPC matrix and also to establish processing conditions for hot-melt extrusion. Extrudates pelletized and filled into capsules exhibited a carrier-dependent release with ELF polymer exhibiting a faster release. Tablets compressed from milled extrudates exhibited rapid release owing to the increased surface area of the milled extrudate. Addition of mannitol (MNT) further enhanced the release by forming micro-pores and increasing the porosity of the extrudates. An optimized tablet formulation constituting KPR, MNT, and ELF in a 1:1:1 ratio exhibited 90% release in 15 min similar to a commercial capsule formulation. HPC polymers are non-ionic hydrophilic polymers that undergo polymer-chain-length-dependent solubilization and can be used to enhance solubility or dissolution rate of poorly soluble drugs. Dissolution/release rate could be tailored for rapid-release applications by selecting a suitable HPC polymer and altering the final dosage form. The release obtained from pellets was carrier-dependent and not drug-dependent, and hence, such a system can be effectively utilized to address solubility or precipitation issues with poorly soluble drugs in the gastrointestinal environment.

Late maternal diagnosis of DiGeorge syndrome with congenital hypoparathyroidism following antenatal detection of the same 22q11.2 microdeletion syndrome in the fetus.

Genetic causes of hypocalcaemia can be overlooked in patients who present without apparent syndromic features. One relatively common but under-recognised genetic disorder is DiGeorge syndrome, which is often diagnosed in childhood but rarely in adulthood. Its enigmatic diagnosis can be attributed to its broad heterogeneous clinical presentation, such as the absence of cardiac abnormalities with only subtly abnormal facies. The presence of hypoparathyroidism-related hypocalcaemia may be the first early sign. We describe a young female adult with childhood-onset hypocalcaemia who was diagnosed with DiGeorge syndrome during her pregnancy when the fetus was found to have the same condition on antenatal screening and autopsy. This case reminds clinicians to consider the genetic causes of hypoparathyroidism-induced hypocalcaemia early on in childhood, while acknowledging the possibility of a late diagnosis in adulthood. We also highlight the risks of severe hypocalcaemia in pregnancy and outline a systematic approach to the evaluation of chronic hypocalcaemia.

Comparison of scoring systems for invasive pests using ROC analysis and Monte Carlo simulations.

Different international plant protection organisations advocate different schemes for conducting pest risk assessments. Most of these schemes use structured questionnaire in which experts are asked to score several items using an ordinal scale. The scores are then combined using a range of procedures, such as simple arithmetic mean, weighted averages, multiplication of scores, and cumulative sums. The most useful schemes will correctly identify harmful pests and identify ones that are not. As the quality of a pest risk assessment can depend on the characteristics of the scoring system used by the risk assessors (i.e., on the number of points of the scale and on the method used for combining the component scores), it is important to assess and compare the performance of different scoring systems. In this article, we proposed a new method for assessing scoring systems. Its principle is to simulate virtual data using a stochastic model and, then, to estimate sensitivity and specificity values from these data for different scoring systems. The interest of our approach was illustrated in a case study where several scoring systems were compared. Data for this analysis were generated using a probabilistic model describing the pest introduction process. The generated data were then used to simulate the outcome of scoring systems and to assess the accuracy of the decisions about positive and negative introduction. The results showed that ordinal scales with at most 5 or 6 points were sufficient and that the multiplication-based scoring systems performed better than their sum-based counterparts. The proposed method could be used in the future to assess a great diversity of scoring systems.

Facial twitching: calcium or concussion conundrum? Hypocalcaemia in a young American football player masking an internal carotid artery dissection.

A 30-year-old male American football player presented to the acute medical unit with left-hand and hemifacial spasms. History and examination revealed hemifacial spasms in keeping with seizure-like activity possibly due to symptomatic hypocalcaemia. Subsequent investigations revealed an adjusted calcium of 1.87 mmol/L and, hence, he was managed with intravenous calcium replacement. He presented two further times in a 1-month period, with subjective limb weakness, despite normal adjusted calcium. During his third admission, he developed slurred speech and a marked facial droop, with absence of power in the right upper limb. Imaging revealed acute and old infarctions in the left middle cerebral artery territory and appearances consistent with left internal carotid artery dissection. This presentation of arterial stroke is atypical but with potentially grave consequences if missed. There is limited literature on the presentation of hemifacial spasm, and its association with ischaemic or haemorrhagic stroke represents a key learning point.

Coligand modulated oxidative O-demethylation of a methyl ether appended tetradentate N-ligand in Co(ii) complexes.

Two Co(ii) complexes of the formula CoLOMeX2 (X = Cl- (1a); X = I- (1b)), where LOMe is 2-methoxy-N,N-bis(pyridin-2-ylmethyl) aniline, were synthesized and their structure, spectra and reactivity were studied. Upon oxidation of 1a and 1b, the ligand LOMe undergoes demethylation at the metal centre resulting in the formation of Co(iii) complexes with modified phenoxide ligands. This is the very first example of oxidative O-demethylation reported at a Co(ii) centre. The oxidative behaviour exhibits a striking dependence on the nature of coligands coordinated to the metal centre. The Co(ii) complex 1a with stronger chloro coligands requires a strong oxidising agent like t-BuOOH for oxidative demethylation and the subsequent formation of a mononuclear Co(iii) complex with a demethylated ligand, CoLO-Cl2 (2). On the other hand, complex 1b with weaker iodo coligands undergoes oxidation in the presence of the weak oxidant O2 to form a dihydroxo bridged binuclear Co(iii) complex [Co2(LO-)2(OH)2]2+ (3) with modified phenoxide ligands. The oxidation of 1b to 3 is monitored and the intermediate Co(ii) iodo aqua complex [CoLOMeI(H2O)]+ and Co(ii) diaqua complex [CoLOMe(H2O)2]2+ are isolated and characterised.

Managing high-acuity outpatient services during the COVID-19 pandemic: lessons from the acute diabetes foot service.

COVID-19 has created unprecedented challenges for healthcare services internationally. Many NHS organisations have cancelled outpatient clinics to release frontline clinical staff and minimise risk of patients contracting COVID-19. While many outpatient services manage chronic diseases, a number of services manage high-acuity patients. Delivery of these acute outpatient services during the pandemic has posed particular challenges and required significant service model reconfiguration. The acute diabetes foot clinic is an important example of such a service. We explore the important lessons learnt during the COVID-19 pandemic for managing high-acuity outpatient services through the context of the diabetic foot clinic. Learning can be divided into the following categories: remote and digital working, physical changes in service delivery, workforce challenges and post-pandemic preparedness. This learning is applicable to a wide range of high-acuity services during and following the pandemic. It is particularly relevant as we expand outpatient care provision to avoid hospital admissions.

Improving MRCP PACES pass rates through the introduction of a regional multifaceted support framework.

INTRODUCTION: Practical Assessment of Clinical Examination Skills (PACES) constitutes the final part of the mandatory Royal College of Physicians exam series for progression to higher specialty training. Pass rates were lower for core medical trainees (CMTs) in Coventry and Warwickshire in comparison to other regions within the West Midlands and nationally. OBJECTIVES: Our aim was to improve pass rates in the region through the introduction of a stimulating and supportive teaching framework, designed to enhance the quality and frequency of PACES teaching. METHODS: To identify key areas for change a baseline questionnaire, including Likert Scale and free text questions related to PACES teaching, was distributed to all CMTs in the region. Many trainees highlighted concern over lack of PACES-orientated teaching and support, with particular emphasis on: lack of bedside-teaching with feedback; infrequent opportunities for practising communication skills; and difficulty identifying suitable patients in an efficient manner. To address these concerns the following interventions were implemented over two Plan, Do, Study, Act (PDSA) cycles which were analysed at 6 months and 12months: a digital forum to highlight relevant inpatients for examination practice; a peer-to-peer mentoring scheme; a consultant-led bedside-teaching rota; and classroom-based communication skills sessions. RESULTS: Pass rates at Annual Review of Competence Progression improved from baseline to the end of the first year of implementation, 56.3% to 77.3%, respectively. Furthermore, following analysis of questionnaires at each PDSA cycle, we demonstrated a progressive improvement in trainee satisfaction in exposure, quality and relevance of teaching. CONCLUSION: Our innovative, cost-effective teaching framework for PACES preparation has improved exam outcomes and facilitated swift junior doctor career progression, while raising the profile of the trust. Furthermore, this innovation provides a template for potential adoption in other National Health Service institutions.

Bite-Angle-Regulated Coordination Geometries: Tetrahedral and Trigonal Bipyramidal in Ni(II) with Biphenyl-Appended (2-Pyridyl)alkylamine N,N'-Bidentate Ligands.

Two simple biphenyl-appended (2-pyridyl)alkylamine N-bidentate ligands, Le and Lm, having ethylene and methylene spacers between donor groups, with bite angles Le ≈ 100° and Lm ≈ 80°, dictate pseudotetrahedral and trigonal-bipyramidal geometries in six high-spin Ni(II)-halide complexes, [Ni(Le)X2] and [Ni(Lm)2X](ClO4) (where X = Cl-, Br-, I-), respectively. The structures in the solid state, determined using X-ray crystallography, and in solution, determined using spectroscopic methods (UV-vis-NIR and paramagnetic 1H NMR), which complement each other, are described.

Controlling the oxidation of bis-tridentate cobalt(ii) complexes having bis(2-pyridylalkyl)amines: ligand vs. metal oxidation.

Two bis-tridentate chelated cobalt(ii) complexes, which differ in the ligand structure by a methylene group, activate molecular oxygen (O2), and give different oxidation products. The O2 reaction of [CoII(pepma)2]2+ (1) with unsymmetrical 2-(2-pyridyl)-N-(2-pyridylmethyl)ethanamine (pepma) results in ligand oxidation, to the corresponding Co(ii) imine complex [CoII(pepmi)2]2+ (2). Contrastingly, the Co(ii) complex [CoII(bpma)2]2+ (3) of similar symmetrical bis(2-pyridylmethyl)amine (bpma), undergoes metal oxidation, yielding a cobalt(iii) complex, [CoIII(bpma)2]2+ (4). The reversibility of the amine to imine conversion and the stability of the Co(ii) imine complex (2) are investigated. Furthermore, the solution dynamics of Co(ii) complexes are highlighted with the help of paramagnetic 1H-NMR spectroscopy.

Binuclear Copper Complexes Based on the 6,6'-Bis[[bis(2-pyridylmethyl)amino]methyl]-2,2'-bipyridine Ligand.

The tripodal tetradentate ligand TMPA (tris(2-pyridylmethyl)amine) has provided a wealth of valuable new Cu(I) and Cu(II) chemistry, in particular associated with copper(I)/dioxygen reactivity studies (Karlin, K. D.; Kaderli, S.; Zuberbühler, A. D. Acc. Chem. Res. 1997, 30, 139-147). Dinucleating analogues have also been recently investigated, and here we describe new copper complexes of the 6,6'-bis[[bis(2-pyridylmethyl)amino]methyl]-2,2'-bipyridine ligand (bTMPA). The synthesis and X-ray crystallographic characterization of [(bTMPA)Cu(II)(2)(CH(3)CN)(2)(ClO(4))(2)](2+) (1, as ClO(4)(-) salt) and [(bTMPA)Cu(II)(2)(N(3))(2)(ClO(4))(2)] (2) are provided. [1: space group C2/c; a = 15.907(4) Å, b = 29.268(7) Å, c = 13.941(2) Å; beta = 97.79(2) degrees; Z = 4; volume = 6431(2) Å(3). 2: space group P2(1)/c; a = 8.118(5) Å, b = 29.743(8) Å, c = 9.120(6) Å; beta = 114.00(5) degrees; Z = 2; volume = 2012(2) Å(3).] Both solid state structures possess six-coordinate copper(II) ions, and in neither case does the 2,2'-bipyridine (bipy) moiety within bTMPA chelate to a single metal ion. Dissociation of bound perchlorate and the presence of pentacoordinate solution structures are suggested by spectroscopic (UV-vis with two d-d absorptions; axial EPR spectra) along with conductivity data (1, 1:4 electrolyte; 2, 1:2 electrolyte). Electrochemical measurements by cyclic volammetry have been carried out, and for a dicopper(I) analogue, [(bTMPA)Cu(I)(2)](ClO(4))(2) (3(ClO(4))(2)), a single quasireversible redox wave is observed; E(1/2) = +199 mV (versus Ag/AgCl in dimethylformamide), which is approximately 280 mV more positive than that observed for the simple "parent" compound [Cu(I)(TMPA)(CH(3)CN)](ClO(4)). Unlike [Cu(I)(TMPA)(CH(3)CN)](ClO(4)), 3 does not readily form dioxygen adducts.

Synthesis, Structure, and Solution NMR Studies of Cyanide-Copper(II) and Cyanide-Bridged Iron(III)-Copper(II) Complexes.

A range of small molecules, such as cyanide, are known to bind and/or inhibit the active site of the heme-copper oxidase enzymes. As such, model studies are aimed at elucidating ligand binding modes and their subsequent impact on spectroscopic properties of derived complexes. We describe here the isolation and characterization of two compounds containing the Fe-CN-Cu moiety, [(py)(F(8)-TPP)Fe(III)-CN-Cu(II)(TMPA)](2+) (5) and [(F(8)-TPP)Fe(III)-(CN)(2)-{Cu(II)(TMPA)}(2)](3+) (6) [py = pyridine, TMPA = tris(2-pyridylmethyl)amine, and (F(8)-TPP) = tetrakis(2,6-difluorophenyl)porphyrinate(2-)]. [Cu(II)(TMPA)(CH(3)CN)](ClO(4))(2) and [(py)(F(8)-TPP)Fe(III)(CN)] (3) react to yield 5, while 6 is formed by combination of [Cu(II)(TMPA)(CN)]PF(6) (2-(PF(6))) and [(F(8)-TPP)Fe(III)(PF(6))] (4). Complex 2-(PF(6)) crystallizes in the orthorhombic space group Iba2 with a = 17.2269(5) Å, b = 17.3143(4) Å, and c = 14.4971(4) Å, Z = 8, complex (5-(Sb/P)F(6))(1.5)(ClO(4))(0.5) was obtained in the orthorhombic space group P222 with a = 17.9541(2) Å, b = 20.5359(1) Å, and c = 21.2023(2) Å, Z = 4, and 6-(PF(6))(3) crystallized in the monoclinic space group P2(1)/c with a = 15.318(4) Å, b = 33.921(2) Å, and c = 19.649(6) Å, beta = 109.69(2) degrees, and Z = 4. Compound 5 possesses a low-spin iron(III) center, bridged via cyanide to copper. The iron-cyanide vector deviates slightly from linearity (174.6(5) degrees ). The copper(II) ion is five-coordinated by the TMPA N-donor atoms and the cyanide carbon atom. The Cu(TMPA) moiety is bent with an angle of 163.8(5) degrees around the cyanide-copper vector. Compound 6 possesses a low-spin iron(III) atom axially coordinated by two cyanide ligands capped on either side by trigonally coordinated [Cu(TMPA)] moieties. The [Cu(1)(TMPA)] unit is twisted somewhat ( angleCu1-N&tbd1;C = 168 degrees ), whereas the [Cu(2)(TMPA)] unit is coordinated in a nearly linear fashion with respect to the cyanide-iron vector ( angleCu2-N&tbd1;C4 = 175 degrees ). (1)H and (2)H NMR spectroscopy on 5 and 6 confirmed the low-spin nature of these iron complexes (pyrrole resonance found at -11.1 and -8 ppm, respectively). The NMR data as well as observed solution magnetic moment (&mgr;(B) = 2.7 for 5; &mgr;(B) = 3.4 for 6) suggest ferromagnetic coupling between the paramagnetic metal ions. This gives rise to an enhancement of the electronic relaxation rate for Cu(II) in both 5 and 6 allowing for the observation of the sharp and downfield shifted TMPA ligand proton signals.