Left ventricular assist device implantation outcomes in patients with subcutaneous implantable cardioverter-defibrillators: A case series.

Background: Left ventricular assist devices (LVADs) may induce electromagnetic interference (EMI) affecting implanted cardiac devices, including more novel subcutaneous implantable cardiac defibrillators (S-ICDs). Methods: In this case series, the authors retrospectively reviewed courses of 6 patients with S-ICDs who underwent LVAD implantation at a single center. Results: Of the 6 patients reviewed, 4 experienced inappropriate ICD shocks, of which 3 resulted from EMI. Five of the 6 patients ultimately had S-ICD therapies disabled. Conclusions: Due to EMI resulting in inappropriate shocks and improved tolerability of malignant arrhythmias, deactivation or removal of S-ICDs should be considered in patients undergoing LVAD implantation.

Screening, Synthesis, and Characterization of a More Rapidly Dissolving Celecoxib Crystal Form.

The prevalence of poor solubility in active pharmaceutical ingredients (APIs) such as celecoxib (CEL) is a major bottleneck in the pharmaceutical industry, leading to a low concentration gradient, poor passive diffusion, and in vivo failure. This study presents the synthesis and characterization of a new cocrystal of the API CEL. CEL is a nonsteroidal anti-inflammatory drug used for the treatment of osteoarthritis and rheumatoid arthritis. Computational screening was completed for CEL against a large library of generally recognized as safe (GRAS) coformers, based on molecular complementarity and hydrogen bond propensity (HBP). The generated list of 17 coformers with a likelihood for cocrystallization with CEL were experimentally screened using four techniques: liquid-assisted grinding (LAG), solvent evaporation (SE), gas antisolvent crystallization (GAS), and supercritical enhanced atomization (SEA). One new crystalline form was isolated, employing the liquid coformer N-ethylacetamide (NEA). This novel form, celecoxib-di-N-ethylacetamide (CEL·2NEA), was characterized by a variety of different techniques. The crystal structure was determined through single-crystal X-ray diffraction. Both NEA molecules are evolved from the crystal structure at a desolvation temperature of approximately 65 °C. The CEL·2NEA cocrystal exhibited a dissolution rate, with more than a twofold improvement in comparison to as-received CEL after only 15 min.

An Advanced Twin-Screw Granulation Technology: The use of Non-Volatile Solvents with High Solubilizing Capacity.

PURPOSE: Twin-screw wet granulation (TSWG) is a manufacturing process that offers several advantages for the processing of water-insoluble active pharmaceutical ingredients (APIs) and has been used for increasing the solubility and dissolution rates. Here we introduce a novel TSWG approach with reduced downstream processing steps by using non-volatile solvents as granulating binders. METHODS: Herein, TSWG was carried out using Transcutol a non-volatile protic solvent as a granulating binder and dissolution enhancer of ibuprofen (IBU) blends with cellulose polymer grades (Pharmacoat® 603, Affinisol™, and AQOAT®). RESULTS: The physicochemical characterisation of the produced granules showed excellent powder flow and the complete transformation of IBU into the amorphous state. Dissolution studies presented immediate release rates for all IBU formulations due to the high drug-polymer miscibility and the Transcutol solubilising capacity. CONCLUSIONS: Overall, the study demonstrated an innovative approach for the development of extruded granules by processing water-insoluble APIs with non-volatile solvents for enhanced dissolution rates at high drug loadings.

Baseline characteristics of people experiencing homelessness with a recent drug overdose in the PHOENIx pilot randomised controlled trial.

BACKGROUND: Drug-related deaths in Scotland are the highest in Europe. Half of all deaths in people experiencing homelessness are drug related, yet we know little about the unmet health needs of people experiencing homelessness with recent non-fatal overdose, limiting a tailored practice and policy response to a public health crisis. METHODS: People experiencing homelessness with at least one non-fatal street drug overdose in the previous 6 months were recruited from 20 venues in Glasgow, Scotland, and randomised into PHOENIx plus usual care, or usual care. PHOENIx is a collaborative assertive outreach intervention by independent prescriber NHS Pharmacists and third sector homelessness workers, offering repeated integrated, holistic physical, mental and addictions health and social care support including prescribing. We describe comprehensive baseline characteristics of randomised participants. RESULTS: One hundred and twenty-eight participants had a mean age of 42 years (SD 8.4); 71% male, homelessness for a median of 24 years (IQR 12-30). One hundred and eighteen (92%) lived in large, congregate city centre temporary accommodation. A quarter (25%) were not registered with a General Practitioner. Participants had overdosed a mean of 3.2 (SD 3.2) times in the preceding 6 months, using a median of 3 (IQR 2-4) non-prescription drugs concurrently: 112 (87.5%) street valium (benzodiazepine-type new psychoactive substances); 77 (60%) heroin; and 76 (59%) cocaine. Half (50%) were injecting, 50% into their groins. 90% were receiving care from Alcohol and Drug Recovery Services (ADRS), and in addition to using street drugs, 90% received opioid substitution therapy (OST), 10% diazepam for street valium use and one participant received heroin-assisted treatment. Participants had a mean of 2.2 (SD 1.3) mental health problems and 5.4 (SD 2.5) physical health problems; 50% received treatment for physical or mental health problems. Ninety-one per cent had at least one mental health problem; 66% had no specialist mental health support. Participants were frail (70%) or pre-frail (28%), with maximal levels of psychological distress, 44% received one or no daily meal, and 58% had previously attempted suicide. CONCLUSIONS: People at high risk of drug-related death continue to overdose repeatedly despite receiving OST. High levels of frailty, multimorbidity, unsuitable accommodation and unmet mental and physical health care needs require a reorientation of services informed by evidence of effectiveness and cost-effectiveness. Trial registration UK Clinical Trials Registry identifier: ISRCTN 10585019.

Designing and evaluating complex educational research to meet federal grant requirement: A demonstration of a funded large-scale protocol.

Federal funding agencies have invested significant resources supporting evidence-based, innovative approaches that address education problems and incorporate rigorous design and evaluation, particularly through randomized controlled trials (RCTs), the gold standard for yielding causal inference in scientific research. In this study, we introduced factors (i.e., evaluation design, attrition, outcome measures, analytic approach, and fidelity of implementation) that are often times required in the Federal Notice for application by the U.S. Department of Education, with an emphasis on What Works Clearinghouse (WWC) standards. We further presented a federally funded research protocol with a multi-year, clustered RCT design to determine the impact of an instructional intervention on students' academic performance in high-needs schools. In the protocol, we elaborated on how our research design, evaluation plan, power analysis, as well as confirmatory research questions and analytical approaches were aligned with the grant requirement and WWC standards. We intend to provide a road map to meeting WWC standards and to increase the likelihood of successful grant applications.

Protocol for a pilot randomised controlled trial to evaluate integrated support from pharmacist independent prescriber and third sector worker for people experiencing homelessness: the PHOENIx community pharmacy study.

BACKGROUND: People experiencing homelessness (PEH) have complex health and social care needs and most die in their early 40 s. PEH frequently use community pharmacies; however, evaluation of the delivery of structured, integrated, holistic health and social care intervention has not been previously undertaken in community pharmacies for PEH. PHOENIx (Pharmacy Homeless Outreach Engagement Non-medical Independent prescribing Rx) has been delivered and tested in Glasgow, Scotland, by NHS pharmacist independent prescribers and third sector homelessness support workers offering health and social care intervention in low threshold homeless drop-in venues, emergency accommodation and emergency departments, to PEH. Building on this work, this study aims to test recruitment, retention, intervention adherence and fidelity of community pharmacy-based PHOENIx intervention. METHODS: Randomised, multi-centre, open, parallel-group external pilot trial. A total of 100 PEH aged 18 years and over will be recruited from community pharmacies in Glasgow and Birmingham. PHOENIx intervention includes structured assessment in the community pharmacy of health, housing, benefits and activities, in addition to usual care, through weekly visits lasting up to six months. A primary outcome is whether to proceed to a definitive trial based on pre-specified progression criteria. Secondary outcomes include drug/alcohol treatment uptake and treatment retention; overdose rates; mortality and time to death; prison/criminal justice encounters; healthcare utilisation; housing tenure; patient-reported measures and intervention acceptability. Analysis will include descriptive statistics of recruitment and retention rates. Process evaluation will be conducted using Normalisation Process Theory. Health, social care and personal resource use data will be identified, measured and valued. DISCUSSION: If the findings of this pilot study suggest progression to a definitive trial, and if the definitive trial offers positive outcomes, it is intended that PHOENIx will be a publicly funded free-to-access service in community pharmacy for PEH. The study results will be shared with wider stakeholders and patients in addition to dissemination through medical journals and scientific conferences. TRIAL REGISTRATION: International Clinical Trial Registration ISRCTN88146807. Approved protocol version 2.0 dated July 19, 2022.

Progression of ECG in hydroxychloroquine overdose.

Hydroxychloroquine overdose is associated with myocardial toxicity and conduction disorders. We report a case of hydroxychloroquine overdose that demonstrated a rapid progressive intraventricular conduction delay and QT prolongation resulting in significant bradycardia and shock despite aggressive treatment. We describe the rare capture of abrupt abnormalities of this overdose in sequential electrocardiograms in the immediate hours post-ingestion.

Pharmacist and Homeless Outreach Engagement and Non-medical Independent prescribing Rx (PHOENIx): a study protocol for a pilot randomised controlled trial.

INTRODUCTION: The number of people experiencing homelessness (PEH) is increasing worldwide. Systematic reviews show high levels of multimorbidity and mortality. Integrated health and social care outreach interventions may improve outcomes. No previous studies have targeted PEH with recent drug overdose despite high levels of drug-related deaths and few data describe their health/social care problems. Feasibility work suggests a collaborative health and social care intervention (Pharmacist and Homeless Outreach Engagement and Non-medical Independent prescribing Rx, PHOENIx) is potentially beneficial. We describe the methods of a pilot randomised controlled trial (RCT) with parallel process and economic evaluation of PEH with recent overdose. METHODS AND ANALYSIS: Detailed health and social care information will be collected before randomisation to care-as-usual plus visits from a pharmacist and a homeless outreach worker (PHOENIx) for 6-9 months or to care-as-usual. The outcomes are the rates of presentations to emergency department for overdose or other causes and whether to progress to a definitive RCT: recruitment of ≥100 participants within 4 months, ≥60% of patients remaining in the study at 6 and 9 months, ≥60% of patients receiving the intervention, and ≥80% of patients with data collected. The secondary outcomes include health-related quality of life, hospitalisations, treatment uptake and patient-reported measures. Semistructured interviews will explore the future implementation of PHOENIx, the reasons for overdose and protective factors. We will assess the feasibility of conducting a cost-effectiveness analysis. ETHICS AND DISSEMINATION: The study was approved by South East Scotland National Health Service Research Ethics Committee 01. Results will be made available to PEH, the study funders and other researchers. TRIAL REGISTRATION NUMBER: ISRCTN10585019.

Complete mitochondrial genome of endangered Arabian tahr (Arabitragus jayakari) and phylogenetic placement.

The Arabian tahr (Arabitragus jayakari) endemic to mountains of northern Oman and the United Arab Emirates, however, the species is faced with significant threats to its population. Because of its small and dwindling population, it is listed as Endangered. Here, we sequenced and assembled the mitochondrial (mt) genome of A. jayakari into 16,485 bp with 39.6% GC content. It also contains 13 protein-coding genes, 22 tRNA genes, and two rRNA genes. Phylogenetic analysis of A. jayakari with related 12 species mt genomes showed that A. jayakari forms a monophyletic clade with Hemitragus jayakri. In the current context of a changing environment, evolutionary analysis based on mitochondrial genome will aid in identifying evolutionary changes among different species and analyzing shared gene pools to counteract threats.

The Effect of Exercise Compliance on Risk Reduction for Hamstring Strain Injury: A Systematic Review and Meta-Analyses.

Eccentric strength training can reduce the risk of hamstring strain injury (HSI) occurrence; however, its implementation can be impacted by athlete compliance and prescription. The aim of this review was to investigate the effects of intervention compliance, consistency and modality, on the prevention of HSIs among athletes. A literature search was conducted. 868 studies were identified prior to the application of the exclusion criteria which resulted in 13 studies identified. Random effects models were used to produce log odds ratios and 95% confidence intervals. Very high (>75.1%), moderate-high (50.1-75%), low-moderate (25.1-50%) and very low (<25%) and <1-, 1.01-3.00-, >3.01-weeks/session were used as thresholds of compliance and consistency, respectively. Modality was also observed. A positive effect on HSI incidence -0.61 (-1.05 to -0.17), favoring the intervention treatments (Z = -2.70, p = 0.007). There were non-significant, large differences between compliance (p = 0.203, Z = -1.272) and consistency (p = 0.137, Z = -1.488), with increased compliance and consistency showing greater effectiveness. A significant difference between intervention modalities was observed (p < 0.001, Z = -4.136), with eccentric interventions being superiorly effective. Compliance of >50.1% and consistent application with <3 weeks/session having positive effects on HSI incidence. Training interventions that can achieve high levels of compliance, and can be consistently performed, should be the objective of future practice.

Genetic diversity of the Nubian ibex in Oman as revealed by mitochondrial DNA.

The Nubian ibex (Capra nubiana) is patchily distributed across parts of Africa and Arabia. In Oman, it is one of the few free-ranging wild mammals found in the central and southern regions. Its population is declining due to habitat degradation, human expansion, poaching and fragmentation. Here, we investigated the population's genetic diversity using mitochondrial DNA (D-loop 186 bp and cytochrome b 487 bp). We found that the Nubian ibex in the southern region of Oman was more diverse (D-loop HD; 0.838) compared with the central region (0.511) and gene flow between them was restricted. We compared the genetic profiles of wild Nubian ibex from Oman with captive ibex. A Bayesian phylogenetic tree showed that wild Nubian ibex form a distinct clade independent from captive animals. This divergence was supported by high mean distances (D-loop 0.126, cytochrome b 0.0528) and high F ST statistics (D-loop 0.725, cytochrome b 0.968). These results indicate that captive ibex are highly unlikely to have originated from the wild population in Oman and the considerable divergence suggests that the wild population in Oman should be treated as a distinct taxonomic unit. Further nuclear genetic work will be required to fully elucidate the degree of global taxonomic divergence of Nubian ibex populations.

Biomechanical Evaluation of a Cadaveric Flatfoot Model and Lateral Column Lengthening Technique.

Patients with adult acquired flatfoot have progressive worsening of bony alignment with many being unable to perform a heel rise. Following reconstruction, pathologic skeletal alignment is corrected and the ability to perform a heel rise is often restored. The purpose of this study was to evaluate the relationship between forefoot liftoff forces and skeletal alignment in a cadaveric flatfoot model by assessing the effect of sequential lengthening of the lateral column using an Evans-type calcaneal osteotomy. Bony alignment was measured in 8 cadaveric specimens with the use of a 3-dimensional digitizing system. Transection of the spring ligament, pie-crusting of the plantar fascia, and cyclic axial loading of the foot was performed to create an anatomic and functional flatfoot model. An Evans-type calcaneal osteotomy using 6, 8, 10, and 12 mm wedges was performed. Specimens were mounted to a custom jig that applies tensile loads to the Achilles, peroneus brevis, peroneus longus, and tibialis posterior tendons. Creation of a flatfoot reduced the lateral talo-first metatarsal angle (Meary's angle) by 13° (23.6° ± 2.8° vs 10.6° ± 3.8°, p < .05) and forefoot force by 7% (199.3 N ± 7.3 N vs 185.4 N ± 9 N, p < .05). Sequential lengthening of the lateral column restored skeletal alignment and force transfer to the forefoot (12 mm wedge: Meary's angle 22.7° ± 3.9°, liftoff force 206.8 N ± 7.5 N). The cadaveric flatfoot model demonstrated decreased forefoot forces that were restored with an Evans-type calcaneal osteotomy wedge. This highlights the importance of restoring skeletal alignment when correcting advanced adult acquired flatfoot.

Advances in Twin-Screw Granulation Processing.

Twin-screw granulation (TSG) is a pharmaceutical process that has gained increased interest from the pharmaceutical industry for its potential for the development of oral dosage forms. The technology has evolved rapidly due to the flexibility of the equipment design, the selection of the process variables and the wide range of processed materials. Most importantly, TSG offers the benefits of both batch and continuous manufacturing for pharmaceutical products, accompanied by excellent process control, high product quality which can be achieved through the implementation of Quality by Design (QbD) approaches and the integration of Process Analytical Tools (PAT). Here, we present basic concepts of the various twin-screw granulation techniques and present in detail their advantages and disadvantages. In addition, we discuss the detail of the instrumentation used for TSG and how the critical processing paraments (CPP) affect the critical quality attributes (CQA) of the produced granules. Finally, we present recent advances in TSG continuous manufacturing including the paradigms of modelling of continuous granulation process, QbD approaches coupled with PAT monitoring for granule optimization and process understanding.

Comparative taste-masking evaluation of microencapsulated bitter drugs using Smartseal 30D and ReadyMix for paediatric dosage forms.

The taste of drug substances plays a key role in the development of paediatric formulations with suitable organoleptic properties. The aim of the study was to evaluate the taste masking effectiveness of Smartseal 30D and ReadyMix on a range of bitter drug substances such as diphenhydramine HCl (DPD), ibuprofen lysine (IBU-LS), and phenylephrine HCl (PPH) for the development of paediatric dosage forms. The drugs were microencapsulated in the polymer carriers at 10-20% loadings using spray-drying processing. Spray drying of drug formulations was optimized in terms of percent yield and encapsulation efficiency followed by physicochemical characterization in order to identify the drugs' physical state in the polymer microparticles. The in vivo taste masking efficiency was evaluated using human test panel and showed noticeable reduction of drug's bitterness at all loadings in comparison to the bulk substances.

Continuous Manufacture and Scale-Up of Theophylline-Nicotinamide Cocrystals.

The aim of the study was the manufacturing and scale-up of theophylline-nicotinamide (THL-NIC) pharmaceutical cocrystals processed by hot-melt extrusion (HME). The barrel temperature profile, feed rate and screw speed were found to be the critical processing parameters with a residence time of approximately 47 s for the scaled-up batches. Physicochemical characterization using scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and X-ray diffraction of bulk and extruded materials revealed the formation of high purity cocrystals (98.6%). The quality of THL-NIC remained unchanged under accelerated stability conditions.

First evaluation of the population structure, genetic diversity and landscape connectivity of the Endangered Arabian tahr.

The Arabian tahr (Arabitragus jayakari) occurs only in the mountains of northern Oman and the United Arab Emirates. The species is classified as Endangered due to its small declining population. In this study, we combined genetic and landscape ecology techniques in order to inform landscape scale conservation and genetic management of Arabian tahr. Using 540 base pairs of mitochondrial control region in a dataset of 53 samples, we found eight haplotypes, which fell into two haplogroups. Population genetic analysis using a panel of 14 microsatellite loci also showed a weak, but significant division. Analyses of landscape connectivity supported the genetic results showing poor connectivity between populations in the far south of the study area and those in the north. The most likely location of corridors connecting Arabian tahr populations were identified. Many corridors between tahr populations are impeded by multi-lane highways and restoration of these connections is required to maintain population viability of Arabian tahr. Owing to limited genetic samples outside of Wadi Sareen, further sampling is needed to elucidate both mtDNA and the nuclear structure of Arabian tahr more fully. Our study provides a toolkit that may be used for future genetic and connectivity monitoring of the Arabian tahr population.

An investigation into the formations of the internal microstructures of solid dispersions prepared by hot melt extrusion.

Hot melt extrusion (HME) is a widely used manufacturing process for pharmaceutical solid dispersions. The complexity of the HME formulations and the number of excipients used in the process are increasing with the advancement of the relevant knowledge. However, one of the areas that is still significantly lacking understanding is the control of internal microstructure of extrudates. Internal microstructure, consisting of voids, in hot melt extruded amorphous solid dispersions is often observed without the causes having been systemically investigated in the literature. In this study, we investigated a range of factors that demonstrated their impacts on the formation of the voids. These include the effect of the types of the materials (i.e. drug, polymer and additive) used in the formulation, the quantity of the drug and the additives used, the key extrusion processing parameters, the type of extruder, and the drying of the raw materials prior to extrusion. The results indicate that the appropriate viscosity and the presence of phase-separated particulates are essential for the formation of the voids. The particulates act as nuclei for the entrapped gas bubbles and the viscosity of the mixture during extrusion governs the collapse/escape of the bubbles. To minimise void formation, the results of this study indicate that slow screw speed, low moisture content of the raw materials, fewer particulates and the addition of lubricants, such as low melting lipid excipients, could be beneficial. This study systematically examines the mechanism of void formation in HME extrudates and generates new strategies that can be used to manage such void formations.

The Effect of Alcohol Consumption on Geriatric Trauma Outcomes.

BACKGROUND: There is little consensus in the literature regarding the effect of ethanol intoxication on trauma outcomes. Data on its effect in the elderly are even sparser. Our aim was to better define the impact of alcohol use in the geriatric trauma population. MATERIALS AND METHODS: We conducted a retrospective review at a level I trauma center looking at admissions from January 2015 through December 2018. Patients were grouped by age: 15-64 y old (YOUNG) versus ≥ 65 y old (OLD). Blood alcohol content (BAC) ≤0.10 g/dL was ETOH (-), and BAC >0.10 g/dL was ETOH (+). These were then propensity matched by injury severity score and mechanism of injury. Fisher's exact test and linear regression were applied as appropriate. Significance was defined as P < 0.05. RESULTS: There were 8754 patients admitted during the study time frame. A total of 6106 patients were YOUNG and 2647 were OLD. A total of 146 (5.5%) OLD patients were ETOH (+), whereas 1488 (24.4%) YOUNG patients were ETOH (+) (P < 0.0001). To assess the impact of alcohol between the two age groups, 285 OLD patients were propensity matched with 285 YOUNG patients. Mortality was significantly higher in the OLD (11.9%) group than that in the YOUNG (3.5%) group (P < 0.001). Morbidity was also higher in OLD versus YOUNG patients overall (P < 0.05). The presence of ethanol did not significantly impact morbidity or mortality in YOUNG or OLD patients. CONCLUSIONS: Higher mortality and morbidity is unsurprising in geriatric trauma patients; however, alcohol does not appear to play a significant role in these outcomes.