Burst sine wave electroporation (B-SWE) for expansive blood-brain barrier disruption and controlled non-thermal tissue ablation for neurological disease.

The blood-brain barrier (BBB) limits the efficacy of treatments for malignant brain tumors, necessitating innovative approaches to breach the barrier. This study introduces burst sine wave electroporation (B-SWE) as a strategic modality for controlled BBB disruption without extensive tissue ablation and compares it against conventional pulsed square wave electroporation-based technologies such as high-frequency irreversible electroporation (H-FIRE). Using an in vivo rodent model, B-SWE and H-FIRE effects on BBB disruption, tissue ablation, and neuromuscular contractions are compared. Equivalent waveforms were designed for direct comparison between the two pulsing schemes, revealing that B-SWE induces larger BBB disruption volumes while minimizing tissue ablation. While B-SWE exhibited heightened neuromuscular contractions when compared to equivalent H-FIRE waveforms, an additional low-dose B-SWE group demonstrated that a reduced potential can achieve similar levels of BBB disruption while minimizing neuromuscular contractions. Repair kinetics indicated faster closure post B-SWE-induced BBB disruption when compared to equivalent H-FIRE protocols, emphasizing B-SWE's transient and controllable nature. Additionally, finite element modeling illustrated the potential for extensive BBB disruption while reducing ablation using B-SWE. B-SWE presents a promising avenue for tailored BBB disruption with minimal tissue ablation, offering a nuanced approach for glioblastoma treatment and beyond.

Defining futile and potentially avoidable interhospital trauma transfers.

PURPOSE: Interhospital transfer of critically injured patients to a major trauma service reduces preventable death in major trauma. Yet some of those transferred die without intervention. These 'futile' interhospital trauma transfers (IHTs), and other potentially avoidable IHTs place enormous stress on families of trauma victims, can delay care, and incur great cost to public health resources. This study sought to characterise these IHTs using current state guidelines for interhospital transfer. METHODS: A retrospective cohort study was conducted using our institution's trauma registry from January 2016-December 2020. All adult patients transferred to our major trauma service were analysed. Futile IHTs were defined as death or transfer to hospice care without surgical, endoscopic, or radiological intervention, and without ICU admission, within 72 h of admission. Potentially avoidable IHTs were defined as all patients discharged alive without intervention or ICU care, and secondary over-triage patients are a subset of these patients who were discharged within 72 h of admission. Patient demographics, injuries, and treatments were categorised from electronic records and analysed. RESULTS: Of 2,837 IHTs, seven (0.2 %) met criteria for futility. The majority were female, median age of 80 (IQR 85-75) and had a median Injury Severity Score (ISS) of 16 (IQR 25.5-11.5). By contrast, 1391 patients (49 %) were classified as potentially avoidable and 513 (18 %) were considered secondary over-triage. The majority were male, median age of 43 (IQR 62-28), and had a median ISS of 9 (IQR 13-4). Of these potentially avoidable IHTs, 984 (70.7 %) were discharged directly home. CONCLUSION: Futile IHTs were infrequent, however over half of all trauma patients transferred from other hospitals were discharged without tertiary-level intervention. Trauma services should consider developing systems such as telehealth to support regional general and orthopaedic surgeons to co-manage lower risk trauma, particularly minor head and minor spinal trauma patients. This could be an integral part of safely reducing potentially avoidable IHTs and their associated costs while maintaining a low rate of preventable mortality in trauma.

An Illustrated Scoping Review of the Magnetic Resonance Imaging Characteristics of Canine and Feline Brain Tumors.

Magnetic resonance imaging (MRI) is used pervasively in veterinary practice for the antemortem diagnosis of intracranial tumors. Here, we provide an illustrated summary of the published MRI features of primary and secondary intracranial tumors of dogs and cats, following PRISMA scoping review guidelines. The PubMed and Web of Science databases were searched for relevant records, and input from stakeholders was solicited to select data for extraction. Sixty-seven studies of moderate to low-level evidence quality describing the MRI features of pathologically confirmed canine and feline brain tumors met inclusion criteria. Considerable variability in data inclusion and reporting, as well as low case numbers, prohibited comparative data analyses. Available data support a holistic MRI approach incorporating lesion number, location within the brain, shape, intrinsic signal appearances on multiparametric sequences, patterns of contrast enhancement, and associated secondary changes in the brain to prioritize differential imaging diagnoses, and often allows for accurate presumptive diagnosis of common intracranial tumors. Quantitative MRI techniques show promise for improving discrimination of neoplastic from non-neoplastic brain lesions, as well as differentiating brain tumor types and grades, but sample size limitations will likely remain a significant practical obstacle to the design of robustly powered radiomic studies. For many brain tumor variants, particularly in cats, there remains a need for standardized studies that correlate clinicopathologic and neuroimaging data.

Customisable Silicone Vessels and Tissue Phantoms for In Vitro Photoplethysmography Investigations into Cardiovascular Disease.

Age-related vessel deterioration leads to changes in the structure and function of the heart and blood vessels, notably stiffening of vessel walls, increasing the risk of developing cardiovascular disease (CVD), which accounts for 17.9 million global deaths annually. This study describes the fabrication of custom-made silicon vessels with varying mechanical properties (arterial stiffness). The primary objective of this study was to explore how changes in silicone formulations influenced vessel properties and their correlation with features extracted from signals obtained from photoplethysmography (PPG) reflectance sensors in an in vitro setting. Through alterations in the silicone formulations, it was found that it is possible to create elastomers exhibiting an elasticity range of 0.2 MPa to 1.22 MPa. It was observed that altering vessel elasticity significantly impacted PPG signal morphology, particularly reducing amplitude with increasing vessel stiffness (p < 0.001). A p-value of 5.176 × 10-15 and 1.831 × 10-14 was reported in the red and infrared signals, respectively. It has been concluded in this study that a femoral artery can be recreated using the silicone material, with the addition of a softener to achieve the required mechanical properties. This research lays the foundation for future studies to replicate healthy and unhealthy vascular systems. Additional pathologies can be introduced by carefully adjusting the elastomer materials or incorporating geometrical features consistent with various CVDs.

Multimodal Imaging in Unusual Alport Retinopathy.

Alport syndrome, a rare genetic condition, can manifest various ocular abnormalities. This case report presents a unique instance of Alport syndrome where bilateral reduced visual acuity led to cataract surgery and subsequent central serous chorioretinopathy due to steroid treatment. By utilizing multiple imaging modalities, we aim to illustrate classical and atypical findings, addressing a literature gap and sharing our experience for educational purposes.

A High-Yielding Active Template Click Reaction (AT-CuAAC) for the Synthesis of Mechanically Interlocked Nanohoops.

Mechanically interlocked molecules (MIMs) represent an exciting yet underexplored area of research in the context of carbon nanoscience. Recently, work from our group and others has shown that small carbon nanotube fragments-[n]cycloparaphenylenes ([n]CPPs) and related nanohoop macrocycles-may be integrated into mechanically interlocked architectures by leveraging supramolecular interactions, covalent tethers, or metal-ion templates. Still, available synthetic methods are typically difficult and low yielding, and general methods that allow for the creation of a wide variety of these structures are limited. Here we report an efficient route to interlocked nanohoop structures via the active template Cu-catalyzed azide-alkyne cycloaddition (AT-CuAAC) reaction. With the appropriate choice of substituents, a macrocyclic precursor to 2,2'-bipyridyl embedded [9]CPP (bipy[9]CPP) participates in the AT-CuAAC reaction to provide [2]rotaxanes in near-quantitative yield, which can then be converted into the fully π-conjugated catenane structures. Through this approach, two nanohoop[2]catenanes are synthesized which consist of a bipy[9]CPP catenated with either Tz[10]CPP or Tz[12]CPP (where Tz denotes a 1,2,3-triazole moiety replacing one phenylene ring in the [n]CPP backbone).

A Case Report of Fedratinib-Associated Uveitis.

Drug-induced uveitis is a rare but important subgroup of uveitis particularly among newer drugs in the market. Establishing a diagnosis can be challenging and requires the physician to have a high index of suspicion and a holistic approach with consideration being afforded to history, clinical examination, and investigations. In this case report, we describe a case of hypopyon uveitis in a 64-year-old male with a background of myelofibrosis for which he was started on fedratinib. A thorough history, negative investigation panel, and temporal association between the start of the drug and uveitis helped establish the diagnosis. A literature review showed no other published cases of uveitis secondary to fedratinib. While he could not be withdrawn from the drug, collaboration with the medical team enabled close monitoring and follow-up. He recovered following a course of steroids and remains under observation.

Arterial stiffness assessment using PPG feature extraction and significance testing in an in vitro cardiovascular system.

Cardiovascular diseases (CVDs) remain the leading cause of global mortality, therefore understanding arterial stiffness is essential to developing innovative technologies to detect, monitor and treat them. The ubiquitous spread of photoplethysmography (PPG), a completely non-invasive blood-volume sensing technology suitable for all ages, highlights immense potential for arterial stiffness assessment in the wider healthcare setting outside specialist clinics, for example during routine visits to a General Practitioner or even at home with the use of mobile and wearable health devices. This study employs a custom-manufactured in vitro cardiovascular system with vessels of varying stiffness to test the hypothesis that PPG signals may be used to detect and assess the level of arterial stiffness under controlled conditions. Analysis of various morphological features demonstrated significant (p < 0.05) correlations with vessel stiffness. Particularly, area related features were closely linked to stiffness in red PPG signals, while for infrared PPG signals the most correlated features were related to pulse-width. This study demonstrates the utility of custom vessels and in vitro investigations to work towards non-invasive cardiovascular assessment using PPG, a valuable tool with applications in clinical healthcare, wearable health devices and beyond.

Photoplethysmography for the Assessment of Arterial Stiffness.

This review outlines the latest methods and innovations for assessing arterial stiffness, along with their respective advantages and disadvantages. Furthermore, we present compelling evidence indicating a recent growth in research focused on assessing arterial stiffness using photoplethysmography (PPG) and propose PPG as a potential tool for assessing vascular ageing in the future. Blood vessels deteriorate with age, losing elasticity and forming deposits. This raises the likelihood of developing cardiovascular disease (CVD), widely reported as the global leading cause of death. The ageing process induces structural modifications in the vascular system, such as increased arterial stiffness, which can cause various volumetric, mechanical, and haemodynamic alterations. Numerous techniques have been investigated to assess arterial stiffness, some of which are currently used in commercial medical devices and some, such as PPG, of which still remain in the research space.

Beyond epithelial damage: vascular and endothelial contributions to idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive scarring disease of the lung with poor survival. The incidence and mortality of IPF are rising, but treatment remains limited. Currently, two drugs can slow the scarring process but often at the expense of intolerable side effects, and without substantially changing overall survival. A better understanding of mechanisms underlying IPF is likely to lead to improved therapies. The current paradigm proposes that repetitive alveolar epithelial injury from noxious stimuli in a genetically primed individual is followed by abnormal wound healing, including aberrant activity of extracellular matrix-secreting cells, with resultant tissue fibrosis and parenchymal damage. However, this may underplay the importance of the vascular contribution to fibrogenesis. The lungs receive 100% of the cardiac output, and vascular abnormalities in IPF include (a) heterogeneous vessel formation throughout fibrotic lung, including the development of abnormal dilated vessels and anastomoses; (b) abnormal spatially distributed populations of endothelial cells (ECs); (c) dysregulation of endothelial protective pathways such as prostacyclin signaling; and (d) an increased frequency of common vascular and metabolic comorbidities. Here, we propose that vascular and EC abnormalities are both causal and consequential in the pathobiology of IPF and that fuller evaluation of dysregulated pathways may lead to effective therapies and a cure for this devastating disease.

Our Experience of Deep Sclerectomy at a Tertiary Center in the United Kingdom Over 14 Years.

Background Deep sclerectomy (DS) is a non-penetrating surgical procedure for glaucoma, reducing the resistance to aqueous outflow and lowering intraocular pressure while maintaining a physiological barrier between the anterior chamber and the sub-scleral space. This offers a lower complication profile than penetrating procedures, though with less intraocular pressure (IOP) reduction. Methods We retrospectively reviewed the electronic record for all DS undertaken at our hospital (a tertiary care center) over 14 years, collecting data on demographics, diagnosis, IOP, visual acuity, complications, medications, and further procedures required. Results Eighty eyes of 69 patients underwent DS, with a mean follow-up period of 53.5 months. The mean pre-operative IOP was 23.55 mmHg (range 11-52, standard deviation 8.46); the mean final IOP was 13.61 mmHg (range 5-35, SD 4.73), with a mean reduction of 42.21%. The mean change in glaucoma medications was -1.64. 78.40% experienced a reduction in glaucoma treatment. Post-operatively, 43.80% had no complications; this improved to 85.0% when numerical hypotony and raised IOP without visual sequelae were excluded. Further procedures required included Nd:YAG goniopuncture (10%), bleb needling (13.75%) or revision (7.5%), iridectomy (3.75%), goniosynechiolysis (1.25%), and autologous blood injection (1.25%). Two eyes were converted to trabeculectomy peri-operatively, with seven overall (8.75%) requiring trabeculectomy over the course of follow-up. 3.75% underwent glaucoma drainage device implantation, and 3.75% underwent cyclodiode laser. Conclusion We have found DS to be a safe, effective procedure for selected patients where trabeculectomy has a high likelihood of failure or where a higher IOP can be tolerated.

Acute and chronic cardiovascular responses to concentric and eccentric exercise in older adults with knee osteoarthritis.

PURPOSE: Muscle contraction type in resistance exercise training may confer benefits besides strength in individuals with osteoarthritis and cardiovascular disease (CVD) risks. The purpose of the study was to explore whether Eccentric-resistance training (RT) improved hemodynamic responses to acute walking exercise stress compared to Concentric-RT among individuals with knee OA over four months. METHODS: This was a secondary analysis from a randomized, controlled, single-blinded study. Participants (N = 88; 68.3 ± 6.4 yrs; 67.4% female) were randomized to one of two work-matched resistance training (RT) programs against a non-RT control group. Pre-training and month four, participants completed a self-paced Six-Minute Walk Test (6MWT) and progressive treadmill exercise test. Heart rates, blood pressures and mean arterial pressures (MAP) were captured during each test. Antihypertensive medications use was documented at each time point. RESULTS: Leg strength improved in both training groups by month four (p < .05). Changes in 6MWT distance and progressive treadmill test time were not different across groups over four months. Neither Concentric or Eccentric RT produced different hemodyamic responses during the 6MWT compared to the control group post-training. However, Concentric RT was associated with 6.0%-7.4% reductions in systolic blood pressure during the graded treadmill walking test at 50%, 75% and 100% of the test time compared to Eccentric RT and the controls (p = .045). MAP values were lower at 75% and 100% of the treadmill test after Concentric RT (5.7%-6.0% reductions) compared to Eccentric RT (1.0%-2.4% reductions) and controls (1.5% and 4.0% elevations) post-training (p = .024). Antihypertensive medication use did not change in any group. CONCLUSIONS: The repeated, progressive exposures of Concentric RT-induced blunted the hypertensive responses to acute exercise compared to Eccentric-RT. Among people with knee OA, Concentric-RT may confer strength benefits to manage OA and possibly reduce cardiovascular stress during exercise.

COVID-19 in Patients with Chronic Lung Disease.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus that causes an acute respiratory tract infection known as coronavirus disease 2019 (COVID-19). SARS-CoV-2 enters cells by binding the ACE2 receptor and coreceptors notably TMPRSS2 or Cathepsin L. Severe COVID-19 infection can lead to acute lung injury. Below we describe the current evidence of the impact of common chronic lung diseases (CLDs) on the development of COVID-19. The impact of treatment of CLD on COVID-19 and any risk of vaccination in patients with CLD are considered.

Active template strategy for the preparation of π-conjugated interlocked nanocarbons.

Mechanically interlocked carbon nanostructures represent a relatively unexplored frontier in carbon nanoscience due to the difficulty in preparing these unusual topological materials. Here we illustrate an active-template method in which a [n]cycloparaphenylene precursor macrocycle is decorated with two convergent pyridine donors that coordinate to a metal ion. The metal ion catalyses alkyne-alkyne cross-coupling reactions within the central cavity of the macrocycle, and the resultant interlocked products can be converted into fully π-conjugated structures in subsequent synthetic steps. Specifically, we report the synthesis of a family of catenanes that comprise two or three mutually interpenetrating [n]cycloparaphenylene-derived macrocycles of various sizes. Additionally, a fully π-conjugated [3]rotaxane was synthesized by the same method. The development of synthetic methods to access mechanically interlocked carbon nanostructures of varying topology can help elucidate the implications of mechanical bonding for this emerging class of nanomaterials and allow structure-property relationships to be established.

Monocyte chemotactic protein (MCP)-1 (CCL2) and its receptor (CCR2) are elevated in chronic heart failure facilitating lung monocyte infiltration and differentiation which may contribute to lung fibrosis.

BACKGROUND: Dyspnea, the cardinal manifestation of chronic heart failure (CHF), may reflect both pulmonary oedema and pulmonary remodeling resulting in tissue stiffening. Emerging evidence suggests that predominance of distinct phenotypes of alveolar and recruited macrophages, designated M1 and M2, may regulate the course of inflammatory tissue repair and remodeling in the lung. METHODS: In a CHF rat model, we found fibrotic reinforcement of the extracellular matrix with an increase in monocyte chemotactic protein (MCP)-1/CCL2 in bronchoalveolar lavage (BAL), corresponding to a 3-fold increase in recruited macrophages. In this clinical cross sectional study, we aimed to examine potential mediators of leukocyte activation and lung infiltration in parallel BAL and blood from CHF patients compared to non-CHF controls. RESULTS: Mini-BAL and peripheral blood samples were obtained from hospitalized CHF, acute decompensated CHF and non-CHF patients. CHF patients and decompensated CHF patients demonstrated increases from non-CHF patients in BAL MCP-1, as well as the M2 macrophage cytokines interleukin-10 and transforming growth factor-ß. BAL and plasma MCP-1 were significantly correlated; however, MCP-1 was 20-fold higher in epithelial lining fluid in BAL, indicative of an alveolar chemotactic gradient. An increase in transglutaminase 2 positive M2 macrophages in parallel with a decrease in the MCP-1 receptor, CC chemokine receptor 2 (CCR2), was apparent in BAL cells of CHF patients compared to non-CHF. CONCLUSION: These data suggest a pathway of MCP-1 mediated M2 macrophage prevalence in the lungs of CHF patients which may contribute to pulmonary fibrotic remodeling and consequent increased severity of dyspnea.

Can Routine Patients Be Safely Discharged After Neodymium-Doped Yttrium Aluminium Garnet Laser Posterior Capsulotomy?

Background Neodymium-doped yttrium aluminium garnet (Nd:YAG) posterior capsulotomy is a common treatment for posterior capsular opacification. Practice varies regarding routine follow-up. In this study, we reviewed follow-up rates and treatment-related complications from a district general hospital's ophthalmology unit to assess areas for improvement and cost-effectiveness. Methodology We conducted a retrospective review of electronic patient records for all patients treated with Nd:YAG capsulotomy in 2019 at our hospital. Primary outcomes included visual acuity, complications, and follow-up data. Secondary outcomes included medication prescribing and the grade of surgeon. Results In total, 912 eyes of 744 patients were included. Overall, 536 (58.8%) eyes were discharged immediately following their laser. Complication rate was 4.3% (39 eyes). Junior training grades had a higher rate of medication prescribing (40/46 eyes; 87.0%) and follow-up (36/40 eyes; 78.3%). Conclusions Certain selected patients may be safely discharged following capsulotomy with safety-netting advice. This strategy increases the capacity to follow-up patients at higher risk of complications. Higher rates of follow-up among junior ophthalmologists offers potential for training.

Effects of using different algorithms and fiducial points for the detection of interbeat intervals, and different sampling rates on the assessment of pulse rate variability from photoplethysmography.

OBJECTIVE: Pulse Rate Variability (PRV) has been widely used as a surrogate of Heart Rate Variability (HRV). However, there are several technical aspects that may affect the extraction of PRV information from pulse wave signals such as the photoplethysmogram (PPG). The aim of this study was to evaluate the effects of changing the algorithm and fiducial points used for determining inter-beat intervals (IBIs), as well as the PPG sampling rate, from simulated PPG signals with known PRV content. METHODS: PPG signals were simulated using a proposed model, in which PRV information can be modelled. Two independent experiments were performed. First, 5 IBIs detection algorithms and 8 fiducial points were used for assessing PRV information from the simulated PPG signals, and time-domain and Poincaré plot indices were extracted and compared to the expected values according to the simulated PRV. The best combination of algorithms and fiducial points were determined for each index, using factorial designs. Then, using one of the best combinations, PPG signals were simulated with varying sampling rates. PRV indices were extracted and compared to the expected values using Student t-tests or Mann-Whitney U-tests. RESULTS: From the first experiment, it was observed that AVNN and SD2 indices behaved similarly, and there was no significant influence of the fiducial points used. For other indices, there were several combinations that behaved similarly well, mostly based on the detection of the valleys of the PPG signal. There were differences according to the quality of the PPG signal. From the second experiment, it was observed that, for all indices but SDNN, the higher the sampling rate the better. AVNN and SD2 showed no statistical differences even at the lowest evaluated sampling rate (32 Hz), while RMSSD, pNN50, S, SD1 and SD1/SD2 showed good performance at sampling rates as low as 128 Hz. CONCLUSION: The best combination of IBIs detection algorithms and fiducial points differs according to the application, but those based on the detection of the valleys of the PPG signal tend to show a better performance. The sampling rate of PPG signals for PRV analysis could be lowered to around 128 Hz, although it could be further lowered according to the application. SIGNIFICANCE: The standardisation of PRV analysis could increase the reliability of this signal and allow for the comparison of results obtained from different studies. The obtained results allow for a first approach to establish guidelines for two important aspects in PRV analysis from PPG signals, i.e. the way the IBIs are segmented from PPG signals, and the sampling rate that should be used for these analyses. Moreover, a model for simulating PPG signals with PRV information has been proposed, which allows for the establishing of these guidelines while controlling for other variables, such as the quality of the PPG signal.

A 12-year experience in endobronchial intervention using rigid bronchoscopy - account of a tertiary referral centre.

We describe our experience of rigid bronchoscopy and endobronchial intervention at a single tertiary centre over a 12-year period. All rigid bronchoscopy procedures between July 2008 and July 2020 (inclusive) were reviewed. All procedures were performed in cardiothoracic theatres by a designated team under general anaesthesia. 2135 rigid bronchoscopies were performed on 1301 patients aged between 18 and 93 years. Complications occurred in 24 (1.12%) procedures. There was one fatality (0.05%). Haemorrhage >100mls occurred in seven (0.33%) all of which were successfully managed endobronchially. Ten procedures (0.5%) were complicated by pneumothorax and an intercostal drain was required for eight. Five patients required intensive care admission post operatively, all of whom were subsequently discharged from hospital. One patient had stent migration. To the best of our knowledge, this is amongst the largest single centre collection of data available for endobronchial intervention using rigid bronchoscopy. We show that rigid bronchoscopy is a safe and effective procedure when performed in a high-volume specialist centre with designated lists involving a specialist multidisciplinary team.

Surgically-induced necrotising scleritis complicated by Nocardia infection following routine cataract surgery.

Necrotising scleritis is a rare, inflammatory condition with potentially devastating visual consequences. It can be associated with inflammatory and infectious causes, and has been linked to several different ocular procedures. We present a difficult case of a patient with surgically-induced necrotising scleritis following routine phacoemulsification cataract surgery, who developed a secondary Nocardia bacterial infection. He required a number of surgical interventions and prolonged antibiotic therapy, suffering recurrent scleral abscesses. A literature review accompanies our case report. Prompt recognition and adequate investigation for underlying inflammatory and infective causes are vital to maintain integrity of the globe and ensure suitable treatment of this challenging condition.