Ten years of the manufacturing classification system: a review of literature applications and an extension of the framework to continuous manufacture.

The MCS initiative was first introduced in 2013. Since then, two MCS papers have been published: the first proposing a structured approach to consider the impact of drug substance physical properties on manufacturability and the second outlining real world examples of MCS principles. By 2023, both publications had been extensively cited by over 240 publications. This article firstly reviews this citing work and considers how the MCS concepts have been received and are being applied. Secondly, we will extend the MCS framework to continuous manufacture. The review structure follows the flow of drug product development focussing first on optimisation of API properties. The exploitation of links between API particle properties and manufacturability using large datasets seems particularly promising. Subsequently, applications of the MCS for formulation design include a detailed look at the impact of percolation threshold, the role of excipients and how other classification systems can be of assistance. The final review section focusses on manufacturing process development, covering the impact of strain rate sensitivity and modelling applications. The second part of the paper focuses on continuous processing proposing a parallel MCS framework alongside the existing batch manufacturing guidance. Specifically, we propose that continuous direct compression can accommodate a wider range of API properties compared to its batch equivalent.

Reliability of the modified Frailty Index (mFI) for intervention and continued surveillance in elective infrarenal abdominal aortic aneurysm (AAA).

INTRODUCTION: Frailty has been proven to lead to higher morbidity and mortality rates in surgical patients, independent of age. The modified Frailty Index (mFI) is a validated means of assessing for frailty. AIM OF STUDY: The aim of this study is to ascertain if the mFI correlates with clinician experience in turning down patients for abdominal aortic aneurysm (AAA) surgery and/or AAA surveillance. METHODS: A contemporaneously recorded database of all AAA patients treated during 2017 at a large University Hospital was reviewed. Patients were categorised into the following groups; continued surveillance, turned down for surveillance, patient declined surveillance, patient offered surgery, patient turned down for surgery and patient declined surgery. RESULTS: One hundred and forty two patients were included. Twenty-eight patients <5.5 cm were turned down for surveillance with a mFI of 0.27. Forty-one patients <5.5 cm continued with surveillance, with a mFI of 0.09 (p < 0.0001). Eighteen patients >5.5 cm were turned down for surgical intervention with a median mFI of 0.36. Forty-two patients were offered surgical intervention had a median mFI of 0.09 (p < 0.0001). CONCLUSION: Frailty is associated with higher morbidity and mortality amongst frail patient cohorts. mFI is a valid and easy to use tool to predict perioperative outcomes in AAA intervention. It correlates well with senior, experienced clinicians' decision-making in relation to who should and who should not undergo elective AAA surgery and those patients who should have ongoing aneurysm surveillance.

Clinical outcomes from profundoplasty performed as a sole procedure for revascularization in critically ischaemic limbs.

OBJECTIVES: The aim of this study is to investigate the durability and clinical efficacy of profundoplasty as a sole procedure in patients presenting with critical limb ischaemia associated with profunda femoral artery disease and superficial femoral artery occlusion. METHODS: Retrospective analysis of outcomes from all patients who underwent surgical profundoplasty in a single tertiary referral centre was performed. Patients who presented with either rest pain or tissue loss and had combined profunda femoral artery disease and superficial femoral artery occlusion were included in the study. Outcomes were compared between the rest pain and the tissue loss groups. RESULTS: Between 2009 and 2019, 51 procedures were performed in 49 patients; 27 (53%) procedures were performed for rest pain and 24 (47%) for tissue loss. Technical success was 100% in both groups. Procedure success was significantly better in the rest pain group owing to lower procedure-related complications (p = 0.037). Incidence of major adverse cardiovascular events was higher in the tissue loss group with five reported cases compared to only one in the rest pain group (p = .05); 85.2% of patients with rest pain experienced clinical improvement compared to only 33.3% in the tissue loss group (p < .001). Higher rates of re-intervention were recorded in the tissue loss group, but this was not statistically significant. Amputation-free survival at 3, 6 and 12 months was 96%, 96% and 92% in the rest pain group, respectively, compared to 77%, 67% and 54% in the tissue loss group (p = .004). At one-year, freedom from major adverse limb events was lower in patients with tissue loss at 43% compared to 81% in patients with rest pain (p = .009). CONCLUSIONS: Profundoplasty performed as a sole procedure for revascularisation of the critically ischaemic limb is a viable straightforward option. However, our results suggest that it may be more effective in the treatment of rest pain rather than in the setting of tissue loss when a combined superficial femoral artery angioplasty or distal bypass may be required.

Liraglutide Attenuates Preestablished Atherosclerosis in Apolipoprotein E-Deficient Mice via Regulation of Immune Cell Phenotypes and Proinflammatory Mediators.

We have shown that the glucagon-like peptide-1 receptor agonist (GLP-1RA) liraglutide (Lir) inhibits development of early atherosclerosis in vivo by modulating immune cell function. We hypothesized that Lir could attenuate pre-established disease by modulating monocyte or macrophage phenotype to induce atheroprotective responses. Human atherosclerotic plaques obtained postendarterectomy and human peripheral blood macrophages were treated ex vivo with Lir. In parallel, apolipoprotein E-deficient (ApoE-/-) mice received a high-fat, high-cholesterol diet to induce atherosclerosis for 8 weeks, after which ApoE-/- mice received 300 µg/kg of Lir daily or vehicle control for a further 4 weeks to investigate the attenuation of atherosclerosis. Lir inhibited proinflammatory monocyte chemoattractant protein-1 secretion from human endarterectomy samples and monocyte chemoattractant protein-1, tumor necrosis factor-α, and interleukin (IL)-1ß secretion from human macrophages after ex vivo treatment. An increase in CD206 mRNA and IL-10 secretion was also detected, which implies resolution of inflammation. Importantly, Lir significantly attenuated pre-established atherosclerosis in ApoE-/- mice in the whole aorta and aortic root. Proteomic analysis of ApoE-/- bone marrow cells showed that Lir upregulated the proinflammatory cathepsin protein family, which was abolished in differentiated macrophages. In addition, flow cytometry analysis of bone marrow cells induced a shift toward reduced proinflammatory and increased anti-inflammatory macrophages. We concluded that Lir attenuates pre-established atherosclerosis in vivo by altering proinflammatory mediators. This is the first study to describe a mechanism through which Lir attenuates atherosclerosis by increasing bone marrow proinflammatory protein expression, which is lost in differentiated bone marrow-derived macrophages. This study contributes to our understanding of the anti-inflammatory and cardioprotective role of GLP-1RAs. SIGNIFICANCE STATEMENT: It is critical to understand the mechanisms through which liraglutide (Lir) mediates a cardioprotective effect as many type 2 diabetic medications increase the risk of myocardial infarction and stroke. We have identified that Lir reduces proinflammatory immune cell populations and mediators from plaque-burdened murine aortas in vivo and augments proresolving bone marrow-derived macrophages in attenuation of atherosclerotic disease, which provides further insight into the atheroprotective effect of Lir.

A study of outcomes in conservatively managed patients with large abdominal aortic aneurysms deemed unfit for surgical repair.

BACKGROUND: The current advancement and increasing use of diagnostic imaging has led to increased detection of abdominal aortic aneurysms (AAA). Many of these patients are unfit for elective AAA surgery. AIM: To investigate the outcome of conservative management of unfit patients with large AAA (>5.5 cm) who are turned down for elective surgical intervention. PATIENTS AND METHODS: Between January 2006 and April 2017, 457 patients presented with AAA >5.5 cm. Seventy-six patients (M: F 54:22) were deemed unfit for elective repair. Mean age was 79.8 years (range 64-96). Mean AAA size was 60.22 mm (55-83). RESULTS: Forty-nine of the 76 patients (64%) had died by April 2017. Fifteen (19.7%) patients died directly because of their aneurysm rupture. A further 34 (44.7%) patients died from non-aneurysm-related causes. CONCLUSION: Patients with large AAA deemed unfit for elective surgery have an overall poor prognosis and die mainly from other causes than AAA. Surgical intervention when rupture occurs results in poor survival.

Remote ischemic preconditioning does not affect the incidence of acute kidney injury after elective abdominal aortic aneurysm repair.

OBJECTIVE: Open abdominal aortic aneurysm (AAA) repair is associated with a high risk of renal injury with few known strategies demonstrating a reduction in this risk. Remote ischemic preconditioning (RIPC) has been identified as having the potential to minimize organ injury following major vascular surgery. This trial investigated the potential for RIPC to attenuate renal and myocardial injury in patients undergoing elective open AAA repair. DESIGN: Prospective, randomized double-blinded control trial. SETTING: Tertiary referral hospital. PARTICIPANTS: Sixty-two patients undergoing elective open AAA repair. INTERVENTION: RIPC was achieved via three 5-minute cycles of upper limb ischemia using a blood pressure cuff or control (sham cuff). MEASUREMENTS: Primary outcome was the occurrence of renal injury, as measured by an increase in creatinine during the first 4 postoperative days. Secondary outcomes included urinary neutrophil-gelatinase-associated lipocalin (NGAL), occurrence of acute kidney injury (AKI), occurrence of myocardial injury as defined by troponin rise, incidence of postoperative complications, and mortality. There was no difference in postoperative creatinine levels, NGAL levels, or the occurrence of AKI between the groups at any postoperative time point. Similarly, there was no difference in the occurrence of myocardial injury or mortality. Of note, 6 patients in the RIPC group, while no patient in the control group, experienced postoperative complications that required repeat surgical laparotomy, potentially masking any renoprotective effects of RIPC. CONCLUSION: RIPC did not reduce the risk of postoperative renal failure or myocardial injury in patients undergoing open AAA repair. The authors' results do not support the introduction of this technique to routine clinical practice.

Modelling the Compaction Step of a Platform Direct Compression Process.

The ability to predict formulation behaviour at production scale during formulation design can reduce the time to market and decrease product development costs. However, it is challenging to extrapolate compaction settings for direct compression formulations between tablet press models during scale-up and transfer from R&D to commercial production. The aim of this study was to develop statistical process models to predict tablet tensile strength, porosity and disintegration time from compaction parameters (pre-compression and main compression force, and press speed), for three formulations, with differing deformation characteristics (plastic, brittle and elastic), on three tablet press models (one pilot-scale tablet press (KG RoTab) and two production-scale presses (Fette 1200i and GEA Modul P)). The deformation characteristics of yield pressure and elastic recovery were determined for the model placebo formulations investigated. To facilitate comparison of dwell time settings between tablet press models, the design of experiments (DoE) approach was 9 individual 16-run response surface DoEs (3 formulation × 3 press models), whose results were combined to create a polynomial regression model for each tablet property. These models predicted tablet tensile strength, porosity and disintegration time and enabled the construction of design spaces to produce tablets with specified target properties, for each formulation on each press. The models were successfully validated. This modelling approach provides an understanding of the compaction behaviour of formulations with varying deformation behaviour on development and commercial tablet press models. This understanding can be applied to inform achievable production rates at a commercial scale, during the formulation development.

Superficial and deep vein thrombosis associated with congenital absence of the infrahepatic inferior vena cava in a young male patient.

BACKGROUND: Congenital absence of the inferior vena cava (AIVC) is a rare vascular anomaly that may be associated with deep vein thrombosis (DVT). It is underreported and may be present in up to 5% of young patients with DVT. We report a unique case of simultaneous thrombosis of both superficial and deep veins in a patient with AIVC. METHODS AND RESULTS: A 20-year-old man presented with a 2-week history of a swollen, painful, left lower limb. On examination, the left leg and thigh were found to be swollen and varicosities were present along the lower abdominal wall. Ultrasound showed extensive superficial and deep venous thrombosis of the entire left lower limb. Computed tomography venogram revealed an infrahepatic AIVC with lower limb drainage through enlarged intrathoracic continuations of the azygous and hemiazygous veins. The patient was put on oral anticoagulant therapy and was well at 6-month follow-up. CONCLUSION: The hypothesis for DVT in patients with AIVC is that venous drainage of the lower limbs is inadequate, leading to venous stasis and thrombosis. All young patients presenting with idiopathic DVT should be investigated for inferior vena cava anomalies with computed tomography if ultrasound does not visualize the inferior vena cava.

Process Model Approach to Predict Tablet Weight Variability for Direct Compression Formulations at Pilot and Production Scale.

Optimizing processing conditions to achieve a critical quality attribute (CQA) is an integral part of pharmaceutical quality by design (QbD). It identifies combinations of material and processing parameters ensuring that processing conditions achieve a targeted CQA. Optimum processing conditions are formulation and equipment-dependent. Therefore, it is challenging to translate a process design between formulations, pilot-scale and production-scale equipment. In this study, an empirical model was developed to determine optimum processing conditions for direct compression formulations with varying flow properties, across pilot- and production-scale tablet presses. The CQA of interest was tablet weight variability, expressed as percentage relative standard deviation. An experimental design was executed for three model placebo blends with varying flow properties. These blends were compacted on one pilot-scale and two production-scale presses. The process model developed enabled the optimization of processing parameters for each formulation, on each press, with respect to a target tablet weight variability of <1%RSD. The model developed was successfully validated using data for additional placebo and active formulations. Validation formulations were benchmarked to formulations used for model development, employing permeability index values to indicate blend flow.

A comparison of outcomes of eversion versus conventional carotid endarterectomy: one centre experience.

INTRODUCTION: Prompt carotid endarterectomy for stroke prevention remains an essential component of treatment for symptomatic carotid stenosis. There exist a number of techniques, most commonly, access via a longitudinal arteriotomy for conventional carotid endarterectomy (CCEA), but eversion endarterectomy (ECEA) may also be used. Neither has been definitively proven as superior. We outline the experience in our institution of these two approaches. METHODS: All patients who had surgery over a 7-year period (2009-2015) under a single consultant vascular surgeon were included in this analysis. Midway through the study period, the operative technique was changed from exclusively CCEA to exclusively ECEA. Demographics, outcomes, and complications, including re-intervention and restenosis rate were gathered from a variety of sources to maximise data reliability and accuracy. RESULTS: Two hundred four interventions were performed during the study period; 114 in the CCEA group, 90 in the ECEA group. Demographics and indication for surgery was well matched between groups. A significant difference was found between operative time (128.6 ± 2.3 vs 70.7 ± 12.2 min) and need for shunting (19.3% vs 1.9%), between CCEA and ECEA. Haematoma rates were higher in the ECEA group (7.7% vs 1.7%), but this can be attributed to differing use of perioperative anti-platelet therapy. There was no other statistical difference in morbidity, mortality, restenosis rates, or re-intervention rates between groups. CONCLUSION: These two carotid endarterectomy techniques are equivalent in terms of outcome, but ECEA can be performed in a significantly shorter operative time and reduces need for shunting.

Lipoxins Protect Against Inflammation in Diabetes-Associated Atherosclerosis.

Increasing evidence points to the fact that defects in the resolution of inflammatory pathways predisposes individuals to the development of chronic inflammatory diseases, including diabetic complications such as accelerated atherosclerosis. The resolution of inflammation is dynamically regulated by the production of endogenous modulators of inflammation, including lipoxin A4 (LXA4). Here, we explored the therapeutic potential of LXA4 and a synthetic LX analog (Benzo-LXA4) to modulate diabetic complications in the streptozotocin-induced diabetic ApoE-/- mouse and in human carotid plaque tissue ex vivo. The development of diabetes-induced aortic plaques and inflammatory responses of aortic tissue, including the expression of vcam-1, mcp-1, il-6, and il-1ß, was significantly attenuated by both LXA4 and Benzo-LXA4 in diabetic ApoE-/- mice. Importantly, in mice with established atherosclerosis, treatment with LXs for a 6-week period, initiated 10 weeks after diabetes onset, led to a significant reduction in aortic arch plaque development (19.22 ± 2.01% [diabetic]; 12.67 ± 1.68% [diabetic + LXA4]; 13.19 ± 1.97% [diabetic + Benzo-LXA4]). Secretome profiling of human carotid plaque explants treated with LXs indicated changes to proinflammatory cytokine release, including tumor necrosis factor-α and interleukin-1ß. LXs also inhibited platelet-derived growth factor-stimulated vascular smooth muscle cell proliferation and transmigration and endothelial cell inflammation. These data suggest that LXs may have therapeutic potential in the context of diabetes-associated vascular complications.

Midterm Analysis of Survival and Cause of Death Following Endovascular Abdominal Aortic Aneurysm Repair.

PURPOSE: To assess rates of complications, secondary interventions, survival, and cause of death following endovascular abdominal aortic aneurysm (AAA) repair over a 10-year period. MATERIALS AND METHODS: Single-institution retrospective cohort study of all patients undergoing primary endovascular aortic aneurysm repair (EVAR) between July 2006 and June 2015. The population constituted 175 patients with 163 fusiform and 12 saccular AAAs. Of these, 149 (85%) were male, with mean age 75.4 (±7.1) years. Patients were followed up until June 30, 2016. Cause of death was determined from the national death register. RESULTS: Mean follow-up was 34.4 (±24.4) months. The secondary intervention rate was 9.7%, and there were 4 aneurysm ruptures (0.8% annual incidence). Thirty-day mortality was 0.6%. Survival at 1, 3, and 5 years was 93.1%, 84%, and 64.9%, respectively. Forty-eight patients died during follow-up, 3 secondary to rupture, leading to overall and aneurysm-related death rates of 9.7 and 0.6 per 100 person-years. All other deaths were due to nonaneurysm causes, most commonly cardiovascular (n = 15), pulmonary (n = 13), and malignancy (n = 9). Baseline renal impairment ( P < .001), ischemic heart disease ( P < .05), age greater than 75 years ( P < .05), and urgent/emergency EVAR were associated with inferior long-term survival. Type II endoleak negatively influenced fusiform aneurysm sac regression ( P = .02), but there was no association between survival and occurrence of any complication or secondary intervention. CONCLUSION: The majority of deaths during medium-term follow-up post-EVAR are due to nonaneurysm-related causes. Survival is determined by the following baseline factors: renal impairment, ischemic heart disease, advanced age, and the presence of a symptomatic/ruptured aneurysm.

Resection and reconstruction of pelvic and extremity soft tissue sarcomas with major vascular involvement: Current concepts.

Soft tissue sarcoma accounts for approximately 1% of all cancers diagnosed annually in the United States. When these rare malignant mesodermal tumours arise in the pelvis and extremities, they may potentially encase or invade large calibre vascular structures. This presents a major challenge in terms of safe excision while also leaving acceptable surgical margins. In recent times, the trend has been towards limb salvage with vascular reconstruction in preference to amputation. Newer orthopaedic and vascular reconstructive techniques including both synthetic and autogenous graft reconstruction have made complex limb-salvage surgery feasible. Despite this, limb-salvage surgery with concomitant vascular reconstruction remains associated with higher rates of post-operative complications including infection and amputation. In this review we describe the initial presentation and investigation of patients presenting with soft tissue sarcomas in the pelvis and extremities, which involve vascular structures. We further discuss the key surgical reconstructive principles and techniques available for the management of these complex tumours, drawn from our institution's experience as a national tertiary referral sarcoma service.

Probing the redox states at the surface of electroactive nanoporous NiO thin films.

Nanoporous NiO thin film electrodes were obtained via plasma-assisted microwave sintering and characterized by means of a combination of electrochemical techniques and X-ray photoelectron spectroscopy (XPS). The aim of this study is the elucidation of the nature of the surface changes introduced by the redox processes of this nanostructured material. NiO undergoes two distinct electrochemical processes of oxidation in aqueous electrolyte with the progress of NiO anodic polarization. These findings are consistent with the sequential formation of oxyhydroxide species at the surface, the chemical nature of which was assessed by XPS. Electronic relaxation effects in the Ni 2p spectra clearly indicated that the superficial oxyhydroxide species resulted to be ß-NiOOH and γ-NiOOH. We also show for the first time spectral evidence of an electrochemically generated Ni(IV) species. This study has direct relevance for those applications in which NiO electrodes are utilized in aqueous electrolyte, namely catalytic water splitting or electrochromism, and may constitute a starting point for the comprehension of electronic phenomena at the NiO/organic electrolyte interface of cathodic dye-sensitized solar cells (p-DSCs).

Aortic plaque rupture in the setting of acute lower limb ischemia.

Acute aortic plaque rupture is an uncommon cause of acute lower limb ischemia. The authors report sequence computed tomographic imaging of a distal aortic plaque rupture in a young man with bilateral lower limb complications. Clinical awareness, prompt recognition and imaging, and appropriate treatment of this uncommon condition are necessary to improve patient outcomes.

Frostbite: management options.

Frostbite is a condition that is associated with people living in countries with an extremely cold climate. It can also, however, affect people who are involved in winter sports, and is also associated with the homeless, people with a psychiatric illness, and those who misuse drugs and alcohol. We describe the case of a 47-year-old homeless man who was diagnosed with severe frostbite in both lower legs. The lesion consisted of hemorrhagic blistering with already visible demarcation. When sepsis developed both lower legs had to be amputated as a matter of urgency. We describe the assessment and management of a patient with frostbite and identify the challenges of managing these complex tissue injuries.

Prediction of the exact degree of internal carotid artery stenosis using an artificial neural network based on duplex velocity measurements.

Duplex ultrasound criteria use a combination of velocity measurements to evaluate internal carotid artery (ICA) stenosis. These evaluations divide ICA stenosis into broad categories. The aim of this study was to design an artificial neural network (ANN) capable of predicting the exact degree of ICA stenosis based on duplex velocity measurements. Consecutive patients with significant carotid atherosclerosis underwent carotid duplex ultrasound and angiography. Peak systolic and end-diastolic velocities in the ICA and common carotid artery were measured. Multilayered perceptron ANNs were constructed and trained to predict the degree of ICA stenosis and band the degree of ICA stenosis into 10% intervals based on these measurements. The accuracy of the ANN models in predicting the degree of ICA stenosis and classifying the ICA stenosis was compared with the angiographic degree of ICA stenosis and duplex velocity criteria. A total of 208 carotid bifurcations were studied. ANNs were able to accurately predict the degree of angiographic ICA stenosis (R2 = 0.9374, p < 0.0001) and band the ICA stenosis into the predefined 10% intervals [sensitivity 97.3% (95% CI 90.7-99.3), specificity 97.7 % (95% CI 93.6-99.2), accuracy 97.5%]. The ANN model was more accurate [discriminant power (DP) = 4.11] in banding the degree of ICA stenosis than duplex velocity criteria (DP = 1.67) (p < 0.05). The accuracy of the ANN in correctly identifying >70% ICA stenosis was 98.4% [sensitivity 96.4% (95% CI 93.8-99.3), specificity 98.7% (95% CI 93.4-99.8), DP = 4.21]. ANNs can accurately predict the degree of ICA stenosis. With further refinement, ANNs could replace velocity criteria in the assessment of ICA stenosis using duplex ultrasound.

Abdominal aortic aneurysms: elective endovascular repair versus conventional surgery--evaluation with evidence-based medicine techniques.

PURPOSE: To use evidence-based techniques to compare elective open surgical repair of abdominal aortic aneurysms with endovascular repair by means of stent placement. MATERIALS AND METHODS: A focused clinical question formed the basis of a literature search. Evidence-based criteria were used to appraise and assign a "level of evidence" to retrieved articles. The following data were determined from the best studies: systemic, local, and/or vascular complications; graft failure rates; blood loss; mortality; length of intensive care and/or hospital stay; mid- and long-term outcomes; cost of endovascular repair versus that of surgery; and eligibility for endovascular repair. Absolute risk reductions and/or increases and numbers needed to treat or harm were calculated. RESULTS: The best current evidence came from 22 studies, which showed that there is slight, if any, difference between mortality rates of endovascular repair and surgery. Hospital and/or intensive care stay is shorter, blood loss less, and systemic complications fewer (numbers needed to treat, two to 12) with endovascular repair. Some authors reported a significant increase in local and/or vascular complications with endovascular repair (numbers needed to harm, two to six). Graft failure is significantly more common with endovascular repair (numbers needed to harm, four), and substantive adjunctive interventions are needed. Endovascular repair is more expensive than surgery. CONCLUSION: Elective endovascular repair has short-term benefits compared with surgery. There is slight, if any, difference in mortality. Endovascular repair costs more than surgery. At follow-up, surgical grafts performed better.