Age-induced accumulation of methylmalonic acid promotes tumour progression.

The risk of cancer and associated mortality increases substantially in humans from the age of 65 years onwards1-6. Nonetheless, our understanding of the complex relationship between age and cancer is still in its infancy2,3,7,8. For decades, this link has largely been attributed to increased exposure time to mutagens in older individuals. However, this view does not account for the established role of diet, exercise and small molecules that target the pace of metabolic ageing9-12. Here we show that metabolic alterations that occur with age can produce a systemic environment that favours the progression and aggressiveness of tumours. Specifically, we show that methylmalonic acid (MMA), a by-product of propionate metabolism, is upregulated in the serum of older people and functions as a mediator of tumour progression. We traced this to the ability of MMA to induce SOX4 expression and consequently to elicit transcriptional reprogramming that can endow cancer cells with aggressive properties. Thus, the accumulation of MMA represents a link between ageing and cancer progression, suggesting that MMA is a promising therapeutic target for advanced carcinomas.

Outcomes of hybrid surgical ablation and concomitant left atrial appendage exclusion in long-standing persistent atrial fibrillation.

INTRODUCTION: Management of patients with long-standing persistent atrial fibrillation (LSPAF) presents a clinical challenge. Hybrid convergent ablation has been shown to have superior efficacy compared to endocardial-only ablation. However, data on concomitant left atrial appendage (LAA) management along with hybrid ablation is sparse. METHODS: We aimed to evaluate the effectiveness of concomitant hybrid convergent ablation and LAA clipping in patients with LSPAF. We conducted a retrospective analysis of all patients with LSPAF who underwent hybrid surgical ablation with LAA clipping at our institution. The primary endpoint was a recurrence of atrial arrhythmias at 12 months. Further, the durability of surgical left atrial posterior wall ablation was examined during the endocardial catheter ablation using standing electrophysiological criteria. RESULTS: A total of 79 patients were included. Mean age was 63.5 ± 9.6 years, and 71% were males. LAA clipping was performed in 99% of patients. The mean time between the surgical and endocardial stages of the procedure was 2.6 ± 1.7 months. Persistent posterior wall activity was observed in 34.2% (n = 27/79) patients during the endocardial phase of the procedure. Cardiac implantable electronic device was used in 74% of patients for monitoring of recurrence of atrial fibrillation (AF). The primary effectiveness of AF freedom at 12 months was 73.8% (45/61). Over a 12-month follow-up period, 11.4% (9/79) of patients required repeat catheter ablation, of which 88.9% (8/9) had evidence of persistent posterior wall activity. CONCLUSION: Concomitant hybrid convergent ablation and LAA exclusion with an atrial clip provides reasonable long-term AF-free survival in patients with LSPAF. Persistent posterior wall activity is seen commonly in patients presenting with recurrent AF following hybrid convergent AF ablation.

Mechanism and management of leaks arising after left atrial appendage closure (LAAC).

This article reviews the latest available data in regard to the diagnosis, management, and intervention of both central and peri-device leaks that arise after left atrial appendage closure (LAAC). The aim of this article is to have a better understanding of both addressing leaks arising after LAAC, and which interventions and closure methods are best served for each type of residual leak based on etiology, size, and operator experience.

Three-dimensional intracardiac echocardiography for left atrial appendage sizing and percutaneous occlusion guidance.

AIMS: Left atrial appendage (LAA) imaging is critical during percutaneous occlusion procedures. 3D-intracardiac echocardiography (ICE) features direct visualization of LAA from multiple cross-sectional planes at a time. We aimed at reporting procedural success of 3D-ICE-guided LAA occlusion and the correlation between pre-procedural transoesophageal echocardiography (TEE) and intraprocedural 3D-ICE for LAA sizing. METHODS AND RESULTS: Among 274 patients undergoing left atrial appendage occlusion (LAAO) with a Watchman FLX, periprocedural ICE guidance was achieved via a commercially available 2D-ICE catheter (220 patients) or a novel (NUVISION™) 3D-ICE one (54 patients). Primary endpoint was a composite of procedural success and LAA sealing at follow-up TEE. Secondary endpoint was a composite of periprocedural device recapture/resizing plus presence of leaks ≥ 3 mm at follow-up TEE. 3D-ICE measurements of maximum landing zone correlated highly with pre-procedural TEE reference values [Pearson's: 0.94; P < 0.001; bias: -0.06 (-2.39, 2.27)]. The agreement between 3D-ICE-based device selection and final device size was 96.3% vs. 79.1% with 2D-ICE (P = 0.005). The incidence of the primary endpoint was 98.1% with 3D-ICE and 97.3% with 2D-ICE (P = 0.99). 2D-ICE patients had a trend towards a higher incidence of periprocedural device recapture/redeployment (31.5% vs. 44.5%; P = 0.09). The secondary endpoint occurred in 31.5% of 3D-ICE patients vs. 45.9% of 2D-ICE ones (P = 0.065). CONCLUSION: Intracardiac echocardiography-guided LAAO showed a very high success, with no major adverse events. A very high level of agreement for LAA sizing was found between pre-procedural TEE and periprocedural 3D-ICE. 3D-ICE performed significantly better than 2D-ICE for FLX size selection and may provide better guidance during device deployment.

Residual leak following left atrial appendage occlusion with lariat closed with amplatzer PFO occluder device.

BACKGROUND: Leaks from incomplete ligation of the left atrial appendage (LAA) following closure with Lariat device are not uncommon and associated with higher stroke rate. CLINICAL VIGNETTE: This clinical vignette highlights a procedure of closure of residual leak following closure with Lariat device. There was a persistent central leak of 3-4 mm with bidirectional flow, confirmed on TEE. The Amplatzer Talisman PFO Occluder was chosen for the closure of the leak because of its asymmetric discs with a smaller distal disc and expandable waist. CONCLUSION: In situations where the options are limited for PDL closure, such as the one described in this vignette, it is paramount to continue to find innovative solutions to emerging challenges in transcatheter interventions.

Design of three-bit binary to gray converter based on metal-insulator-metal plasmonic waveguides.

Using the finite element method and COMSOL version 5.5, a three-bit binary to gray converter with three plasmonic substructures and five input and three output ports was designed. Using a 520n m×200n m metal-insulator-metal plasmonic structure, the plasmonic converter was developed. In this configuration, the transmission threshold (T t h r e s h o l d ) is set to 45% at an operating wavelength of 1310 nm. Utilizing the modulation depth, contrast ratio (CR), and insertion loss criteria, the effectiveness of the plasmonic converter is evaluated. For the first, second, and third output terminals, the CR has respective values of 40.1 dB, 9.3 dB, and 9.2 dB.

Left Atrial Appendage Closure with Watchman vs Amulet Devices: Similarities and Differences.

PURPOSE OF REVIEW: Left atrial appendage closure (LAAC) has shown to be non-inferior to oral anticoagulation (OAC) for non-valvular atrial fibrillation (AF). LAAC is now becoming a leading method for stroke prophylaxis in patients who have atrial fibrillation and are unable to tolerate OAC. There are currently two FDA-approved endocardial closure devices, namely, the Watchman FLX and Amplatzer Amulet. RECENT FINDINGS: Current data highlights that both devices offer similar efficacy and safety for LAAC. While the two devices differ in terms of intraprocedural complication rates, they offer similar short- to long-term outcomes in regard to peri-device leaks, device-related thrombosis, and mortality. With similar risk and safety profiles, both devices are indicated for patients who are unable to tolerate OAC. Newer clinical studies are directed to establish the efficacy of both devices as the primary method for stroke prevention in AF as an alternate to OAC.

Double Lumbar Localization of Myelomeningocele: Case Report.

INTRODUCTION: Myelomeningocele (MMC) is a malformation resulting from the neural tube's failure to close during embryonic development, and the majority of the cases of neural tube defects (NTDs) were prevalent as single location lesions along the spine; however, multiple NTDs (MNTDs) are a very rare condition. Only a few cases of MNTDs were found in the literature. CASE PRESENTATION: We report the case of a 2-month-old male infant prenatally diagnosed with MMC, presented with two unconnected lumbar and lumbosacral epidermal, soft, dome-shaped swellings located on both sides of the midline (paravertebral) covered by intact skin. MRI revealed double MMC at the level of L4-L5, with spinal nerve roots. The patient underwent surgical repair of the defects by replacing the spinal cord and its nerve roots inside the thecal sac and recreating a covering layer around the neural structures to resemble thecal sac. The outcome was favorable, and postoperative head CT scan did not show any complication. CONCLUSION: Our case report is considered the first from Algeria to report the condition and the first to report the occurrence of double lesions in the same spine region. MMC can be associated with neurological deficits or other congenital anomalies, thus it is necessary to thoroughly examine such patients. However, there was no antenatal folic acid deficiency in our case. We recommend antenatal care with adequate folic acid supplementation given that its deficiency during pregnancy is considered a ubiquitous risk factor for the condition. The optimal timing for surgery of MMC cases is 8 ± 5 days. Prenatal intrauterine repair of the condition provides favorable outcomes but carries high fetal and maternal risks. Surgical repair should include the sac removal, the reconstruction of the placode, and the closure of the overlying meninges. With early diagnosis and proper repair of such cases, MMC has good prognosis and favorable outcomes.

Catheter directed compared to systemically delivered thrombolysis for pulmonary embolism: a systematic review and meta-analysis.

To compare the efficacy and safety of systemic and catheter directed thrombolysis for patients with pulmonary embolism. Pubmed and Cochrane Central Register of Controlled Trials were systematically searched from inception to May 31st 2020 to identify relevant studies. Outcomes of interest were in-hospital mortality and major bleeding including intracranial hemorrhage. We included 8 observational studies comprising 11,932 patients with PE. Catheter directed thrombolysis was associated with lower in-hospital mortality [RR 0.52; 95% confidence interval (CI) 0.40-0.68]. Although there was no difference in major bleeding by treatment strategy (RR 0.80; 95% CI 0.37-1.76), intracranial hemorrhage was lower in patients receiving catheter directed therapy (RR 0.66; 95% CI, 0.47-0.94).The certainty in these estimates was low. Non-randomized studies suggest that catheter directed delivery of thrombolytic therapy may be associated with lower in-hospital mortality and intracranial hemorrhage rates. These results may help inform management strategies for health care and pulmonary embolism response teams (PERT) involved in the management of high risk patients with massive or submassive pulmonary emboli.

Recent Advances in Sensors for Fire Detection.

Fire is indeed one of the major contributing factors to fatalities, property damage, and economic disruption. A large number of fire incidents across the world cause devastation beyond measure and description every year. To minimalize their impacts, the implementation of innovative and effective fire early warning technologies is essential. Despite the fact that research publications on fire detection technology have addressed the issue to some extent, fire detection technology still confronts hurdles in decreasing false alerts, improving sensitivity and dynamic responsibility, and providing protection for costly and complicated installations. In this review, we aim to provide a comprehensive analysis of the current futuristic practices in the context of fire detection and monitoring strategies, with an emphasis on the methods of detecting fire through the continuous monitoring of variables, such as temperature, flame, gaseous content, and smoke, along with their respective benefits and drawbacks, measuring standards, and parameter measurement spans. Current research directions and challenges related to the technology of fire detection and future perspectives on fabricating advanced fire sensors are also provided. We hope such a review can provide inspiration for fire sensor research dedicated to the development of advanced fire detection techniques.

Wide-Range Humidity-Temperature Hybrid Flexible Sensor Based on Strontium Titanate and Poly 3,4 Ethylenedioxythiophene Polystyrene Sulfonate for Wearable 3D-Printed Mask Applications.

In this paper, we report a fast, linear wide-range hybrid flexible sensor based on a novel composite of strontium titanate (SrTiO3) and poly 3,4 ethylenedioxythiophene polystyrene sulfonate (PEDOT: PSS) as a sensing layer. Inter-digitate electrodes (IDEs) were printed for humidity monitoring (finger: 250 µm; spacing: 140 µm; length: 8 mm) whilst a meander-based pattern was printed for the temperature measurement (meander thickness: 180 µm; spacing: 400 µm) on each side of the PET substrate using silver ink. Moreover, active layers with different concentration ratios were coated on the electrodes using a spray coating technique. The as-developed sensor showed an excellent performance, with a humidity measurement range of (10-90% RH) and temperature measurement range of (25-90 °C) with a fast response (humidity: 5 s; temperature: 4.2 s) and recovery time (humidity: 8 s; temperature: 4.4 s). The reliability of the sensor during mechanical bending of up to 5.5 mm was validated with a reliable performance. The sensor was also used in real-world applications to measure human respiration. For this, a suggested sensor-based autonomous wireless node was included in a 3D-printed mask. The manufactured sensor was an excellent contender for wearable and environmental applications because of its exceptional performance, which allowed for the simultaneous measurement of both quantities by a single sensing device.

Development of extended-release metformin core tablet and synergistic coating of sitagliptin for the treatment of type-II diabetes mellitus - A comparative drug release evaluation with reference product.

Diabetes is getting a common disease and is spreading rapidly, affecting 6.6 percent world's population. Metformin HCl is an effective pharmacological treatment for type 2 diabetic patients because of its lowering blood glucose level ability, better weight-neutral effects and reduced risk of hypoglycemia. Nevertheless, gastrointestinal (GI) sensitivities are a concern in many patients using its immediate-release formulations. This study aimed to develop extended-release (ER) formulations to control the release into the body and minimize the dosage-related side effects of metformin and to develop an effective method of coating Sitagliptin immediate-release (IR) formulation over the core tablet. This study evaluated different formulations of Metformin HCl ER tablet using hydrophilic polymers. Different concentrations of Sitagliptin were used to develop immediate release coating. The dissolution profile of the designed formulation was compared with the reference 50/500mg tablet. In vitro dissolution of Metformin HCl (MT5), containing Methocel K4M and Methocel K100 polymer, showed 37.62% release at 1hr, 53.46% at 2hr, 84.75% at 6hr and 94.81% at 10hr. The Sitagliptin (ST8) with 10% excess released 103.64% in 30min. Similarity factor values suggested that developed Metformin ER and Sitagliptin IR formulation were like the reference product.

Clinical phenotyping of atopic dermatitis using combined itch and lesional severity: A prospective observational study.

BACKGROUND: Patients with atopic dermatitis (AD) have heterogeneous clinical phenotypes, including different combinations of itch and lesional severity. Little is known about the characteristics and course of these subtypes. OBJECTIVE: To determine the characteristics, associations, burden, and course of patients with AD using combined itch and lesional severity. METHODS: A prospective practice-based study was performed using questionnaires and physical examination (n=592). AD subsets were defined using verbal rating scale for average itch combined with either eczema area and severity index, objective-scoring atopic dermatitis (SCORAD), or validated investigator's global assessment as follows: mild-moderate itch and lesions (MI-ML), mild-moderate itch and severe lesions (MI-SL), severe itch and mild-moderate lesions (SI-ML), and severe itch and lesions (SI-SL). RESULTS: At baseline, there were only weak-moderate correlations of numerical rating scales for worst itch or average itch or SCORAD itch with eczema area and severity index, objective-SCORAD, body surface area, and validated investigator's global assessment (Spearman's rho = 0.32-0.62). Most patients had MI-ML (59.4%-62.3%), followed by SI-ML (21.3%-29.1%), SI-SL (6.0%-12.9%), and MI-SL (3.8%-6.4%). Patients with SI-SL, followed by SI-ML and MI-SL, described their AD as being more severe overall and had worse impairment in sleep, mental health, and quality of life. However, those with MI-SL or SI-SL were far more likely to be classified as severe by a physician (multivariable logistic and linear regression, P < .005 for all). Baseline MI-SL, SI-ML, and SI-SL were associated with similar longitudinal courses over time and more AD flares and itch triggers than MI-ML. CONCLUSION: Combined itch and lesional severity seem to describe unique AD phenotypes. Further studies are needed to confirm these findings and understand the optimal treatments for these groups.

Myocardial Infarction Type 2: Avoiding Pitfalls and Preventing Adverse Outcomes.

Myocardial infarction type 2 (MI type 2) is an elevation of cardiac biomarkers in a physiologically stressful state leading to demand-supply mismatch of oxygen. This type of myocardial infarction is commonly seen in hospitalized patients. Since the introduction of clear definition, diagnostic criteria and International Classification of Disease (ICD) codes, the diagnosis has become increasingly common. There still remains plenty to learn about MI type 2 especially prevention and treatment strategies. Studies have shown that there is increased mortality and morbidity associated with MI type 2 when compared to MI type 1, and there may be benefit in having a multi-disciplinary approach including cardiology when treating such patients. Secondary prevention therapies may also play a role in decreasing adverse events from MI type 2. However, randomized control trials are insufficient, and results of studies are cautiously interpreted. In this article we have assessed the current evidence on MI type 2 and the gap in literature that will potentially be the focus of future analyses.

Robust, Reproducible, and Economical Phosphopeptide Enrichment Using Calcium Titanate.

Mass-spectrometry-based phosphoproteomics has revolutionized phosphoprotein analysis and enhanced our understanding of diverse and fundamental cellular processes important for human health and disease. Because of their relative scarcity, phosphopeptides must be enriched before analysis. Many different enrichment methods and materials have been described, and many reports have made claims about the advantages of particular materials and methodological variations. We demonstrate an effective and highly reproducible single-step enrichment method using an off-the-shelf preparation of calcium titanate. Using two different cell lines and replicate analysis, we show that our method achieves a purity and depth of analysis comparable or superior to a widely used TiO2-based method at a reduced cost and effort. This method provides a new and immediately available tool for expanding the reach of phosphoproteomic inquiry.

Treatment outcomes of tuberculosis cases by HIV status in Haramaya General Hospital, Ethiopia: A retrospective cross-sectional study.

Tuberculosis (TB) and human immunodeficiency virus (HIV) coinfection pose significant challenges to global health, particularly in achieving the target of ending TB. However, the impact of HIV status on TB treatment outcomes remains unclear, especially in eastern Ethiopia. This study aimed to assess the treatment outcomes of TB cases by HIV status and associated factors in Haramaya General Hospital from November 15 to December 30, 2022. A retrospective cross-sectional study was conducted, reviewing the TB registry and treatment cards of patients who received anti-TB treatment between September 2017 and August 2022. Of the 420 samples addressed, 91.0% (95% CI: 88.3%-96.7%) of all TB patients had successful treatment outcomes. The treatment success rates of HIV-positive and HIV-negative TB patients were 80.0% and 91.9%, respectively. Being HIV-negative (AOR: 2.561, 95% CI: 1.002-6.542), being in the age group of 20 to 35 years (AOR: 2.950, 95% CI: 1.171-7.431), and urban residence (AOR: 2.961, 95% CI: 1.466-5.981) were associated with the TB treatment success rate. There was a high treatment success rate among all patients with TB. HIV status was associated with TB treatment outcomes. Strengthening TB-HIV collaborative activities, providing patient-centered care and support, and frequent monitoring and evaluation are recommended to improve the TB success rate.

Incidental Finding of a Persistent Left Superior Vena Cava During Permanent Dual-Chamber Pacemaker Implantation: A Case Report.

Persistent left superior vena cava (PLSVC) is a rare congenital venous anomaly. It is often asymptomatic and has atypical venous drainage that can complicate central venous catheterisation, pacemaker implantation, and cardiac surgeries. In most cases, the PLSVC drains into the right atrium via the coronary sinus, but in a minority of cases, it drains into the left atrium, leading to a right-to-left shunt, which can cause mild hypoxia or paradoxical embolism. Due to its abnormal anatomy, PLSVC can complicate lead placement during permanent pacemaker (PPM) insertion. Lead navigation becomes more complex, sometimes necessitating alternative lead placement techniques or imaging guidance to ensure proper functionality. In most cases, the PLSVC is identified incidentally during the initial venogram. We present the case of a 64-year-old male with sarcoidosis, hypercholesterolemia, hypertension, hepatitis, and recent atrial fibrillation (AF) who presented for elective direct current cardioversion (DCCV). Pre-DCCV, the ECG showed AF with a slow ventricular response, and following a 200-joule synchronised shock as per local protocol, sinus rhythm was restored. Post-DCCV ECG showed a first-degree AV block, which progressed to an intermittent 2:1 block, leading to a decision to implant a dual-chamber PPM. An echocardiogram revealed normal left ventricular function, a dilated left atrium and normal right ventricle, mild tricuspid regurgitation, and a possible patent foramen ovale (PFO). A venogram performed during PPM implantation revealed a PLSVC, which posed challenges in lead placement. Despite initial success, a post-procedure chest X-ray revealed displacement of the atrial lead, prompting a successful repositioning. The patient remained stable and asymptomatic; outpatient follow-ups showed satisfactory PPM function. PLSVC is a congenital anomaly arising from incomplete regression of the left anterior cardinal vein during embryonic development. Though it is often discovered incidentally, the anomaly becomes clinically significant during procedures such as pacemaker implantation due to its impact on venous anatomy and lead placement. This case also underscores the need for specialised techniques when managing patients with PLSVC during device implantation. Given the abnormal venous pathway, alternative strategies such as utilising the coronary sinus or imaging guidance, like fluoroscopy, may be necessary to ensure proper lead placement and avoid complications such as lead displacement or venous thrombosis. The literature supports using advanced imaging modalities and tailored surgical approaches to improve outcomes in patients with PLSVC. Ultimately, this case illustrates the complexity of cardiac device implantation in the presence of venous anomalies and highlights the importance of individualised procedural planning to optimise patient care and reduce the risk of complications.

The Zero Calcium Score Paradox.

Our study presents a case of angina with a zero calcium score yet severe coronary stenosis from noncalcified plaque. We highlight the limitation of otherwise prognostically powerful coronary calcium score as a singular predictive tool especially when used in symptomatic patients.

Scrotal arteriovenous malformation (AVM) successfully resected without angioembolization: A case report.

INTRODUCTION AND IMPORTANCE: The main types of scrotal vascular lesions are varicocele, hemangioma, lymphangioma and arteriovenous malformation (AVM). AVM consists of network between arteries and veins without capillaries. It is the rarest type especially when in scrotum. CASE PRESENTATION: A 24-year-old male patient presented with a skin deformity and painless swelling in the left scrotum. Physical examination revealed this swelling that extended to the inguinal region. Duplex Ultrasound (DUS) followed by Multi-slice Computed Tomography (MSCT) were performed to establish the diagnosis. Management depended on surgical excision without angioembolization. Preoperative sperm analysis showed oligoasthenozoospermia that improves significantly after treatment and 1 year of follow-up. CLINICAL DISCUSSION: Surgical resection of scrotal AVM without embolization has been used in very few cases and has resulted in a satisfactory outcome with no signs of recurrence throughout the follow-up period. CONCLUSION: Based on our experience, surgical excision without embolization is a reasonable alternative approach to treat scrotal AVM in low-income countries alongside avoiding the negative consequences of radiation therapy. Treatment should be considered when fertility is affected.