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Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of various solid and hematologic malignancies by targeting dysregulated signaling pathways critical for malignant cell growth. However, these therapeutic benefits are often accompanied by cardiotoxicities, such as hypertension, left ventricular dysfunction, QT prolongation, and tachyarrhythmias, among others. These cardiotoxicities post a significant challenge in clinical management, often limiting the use of otherwise effective therapies. The underlying mechanism of TKI-induced cardiotoxicity appears to be multifaceted, involving several pathways including: direct cardiomyocyte damage, mitochondrial dysfunction, endothelial damage, and disruption of signaling pathways critical for cardiac function. The range and severity of cardiotoxicities vary significantly across different TKIs, necessitating a comprehensive understanding of each agent’s specific cardiovascular risk profile. Preventing and managing TKI-induced cardiotoxicity requires a comprehensive, multidisciplinary approach. Early identification of at-risk patients through baseline cardiovascular risk assessments and appropriate monitoring during therapy is crucial. Strategies to mitigate cardiotoxic effects include dose modification, the use of cardioprotective agents, and temporary discontinuation of therapy. Additionally, decision making via multidisciplinary teams ensures minimization of cardiovascular complications while also continuing effective cancer treatment. Historically, data have been limited regarding cardiotoxicity and most cancer therapies, which certainly includes TKIs. This review aims to synthesize the current body of knowledge on TKI-associated cardiotoxicities, while highlighting the importance of vigilance and proactive management to minimize cardiovascular complications.

High-density brines have been recognized beneficial for oilfield applications, with various key areas such as drilling, completion and formation evaluation. High-density brines can play a critical role in the development and production of oil and gas reservoirs during the primary, secondary, and tertiary recovery phases. High-density brines can enhance the mobility and recovery of the oil in the reservoir by controlling the density and viscosity. However, a less attention has been given to the application of high-density brine in the area of reservoir development. This review is shedding light on a concise overview of reservoir development stages in association with the recovery mechanisms. In addition, most possible applications of high-density fluids have also been reviewed in the field of the reservoir development. In summary, this review state that high-density brines can be used to stimulate reservoirs by hydraulic fracturing during the primary recovery phase. However, the risk of increased interfacial tension, which relies on the density difference of two fluids, can trap more residual oil relative to conventional water flooding. In addition, high-density brines are effective in decreasing the mobility ratio and facilitating favorable displacement during polymer flooding. However, they can be least effective in alkaline flooding due to the high IFT related to large density differences. Thus, it is suggested to consider the utilization of sustainable high-density brines by taking into account effective factors in petroleum engineering aspects such as stimulation, secondary recovery and polymer flooding.

Drilling through shale formations can be expensive and time-consuming due to the instability of the wellbore. Further, there is a need to develop inhibitors that are environmentally friendly. Our study discovered a cost-effective solution to this problem using Gum Arabic (ArG). We evaluated the inhibition potential of an ArG clay swelling inhibitor and fluid loss controller in water-based mud (WBM) by conducting a linear swelling test, capillary suction timer test, and zeta potential, fluid loss, and rheology tests. Our results displayed a significant reduction in linear swelling of bentonite clay (Na-Ben) by up to 36.1% at a concentration of 1.0 wt. % ArG. The capillary suction timer (CST) showed that capillary suction time also increased with the increase in the concentration of ArG, which indicates the fluid-loss-controlling potential of ArG. Adding ArG to the drilling mud prominently decreased fluid loss by up to 50%. Further, ArG reduced the shear stresses of the base mud, showing its inhibition and friction-reducing effect. These findings suggest that ArG is a strong candidate for an alternate green swelling inhibitor and fluid loss controller in WBM. Introducing this new green additive could significantly reduce non-productive time and costs associated with wellbore instability while drilling. Further, a dynamic linear swelling model, based on machine learning (ML), was created to forecast the linear swelling capacity of clay samples treated with ArG. The ML model proposed demonstrates exceptional accuracy (R2 score = 0.998 on testing) in predicting the swelling properties of ArG in drilling mud.

Abstract Aims To summarize published case reports of patients diagnosed with coronavirus disease 2019 (COVID‐19) and Brugada pattern electrocardiogram (ECG). Methods The Preferred Reporting Items for Systematic Reviews and Meta‐Analyses checklist were followed. A literature search was conducted using PubMed, EMBASE, and Scopus up until September 2021. The incidence, clinical characteristics, and management outcomes of COVID‐19 patients with a Brugada pattern ECG were identified. Results A total of 18 cases were collected. The mean age was 47.1 years and 11.1% were women. No patients had prior confirmed diagnosis of Brugada syndrome. The most common presenting clinical symptoms were fever (83.3%), chest pain (38.8%), shortness of breath (38.8%), and syncope (16.6%). All 18 patients presented with type 1 Brugada pattern ECG. Four patients (22.2%) underwent left heart catheterization, and none demonstrated the presence of obstructive coronary disease. The most common reported therapies included antipyretics (55.5%), hydroxychloroquine (27.7%), and antibiotics (16.6%). One patient (5.5%) died during hospitalization. Three patients (16.6%) who presented with syncope received either an implantable cardioverter defibrillator or wearable cardioverter defibrillator at discharge. At follow‐up, 13 patients (72.2%) had resolution of type 1 Brugada pattern ECG. Conclusion COVID‐19‐associated Brugada pattern ECG seems relatively rare. Most patients had resolution of the ECG pattern once their symptoms have improved. Increased awareness and timely use of antipyretics is warranted in this population.

Arcobacter spp. is an emerging pathogen that is increasingly recognized as a cause of human infections. Gastrointestinal manifestations are most described in the case report literature. We present a case of the first documented case of Arcobacter spp. isolated in pericardial fluid in an immunocompromised patient with worsening cardiac tamponade that was successfully managed with an urgent pericardiocentesis and ensuing steroids, antibiotics, and a pericardial drain. The patient had a past medical history of HIV, latent syphilis, PCP pneumonia, ESRD, and hypertension, and presented with worsening dyspnea, subjective fever, myalgias, cough, pleuritic chest pain, and pericardial rub. Diagnostic workup revealed a positive COVID-19 PCR test, elevated high-sensitive cardiac troponins, elevated CRP, elevated D-dimer, and elevated creatinine. An ECG revealed diffuse ST-segment elevation, and imaging showed cardiomegaly with pulmonary vascular congestion and diffuse interstitial edema. Urgent TTE showed a large circumferential pericardial effusion with tamponade physiology present. Culture on aerobic blood agar grew Arcobacter spp. of unknown specific species, and blood cultures were also positive for Arcobacter spp. Treatment involved intravenous meropenem for five days, followed by oral ciprofloxacin, low-dose colchicine, and a tapered dose of ibuprofen. Repeat laboratory data and TTE showed complete resolution of the pericardial effusion and improved left ventricular function. This case highlights the potential for Arcobacter spp. to cause severe infections and the importance of considering it as a possible pathogen in patients with atypical presentations.

Abstract Background Understanding how physical activity (PA) influences cognitive function in populations with cognitive impairments, such as dementia, is an increasingly studied topic yielding numerous published systematic reviews. In contrast, however, there appears to be less interest in examining associations between PA and cognition in cognitively healthy individuals. Therefore, the objective of this review was to evaluate and synthesize randomized controlled trial (RCT) studies that investigated the effects of both chronic and acute PA on working memory performance (WMP) in physically and cognitively healthy individuals. Methods Following the preferred reporting items for systematic review and meta-analysis (PRISMA) guidelines, a systematic review of studies published between August 2009 and December 2016 was performed on RCTs investigating the effects of chronic and acute PA on WMP with healthy participants as the sample populations. Searches were conducted in Annual Reviews, ProQuest, PsycARTICLES, PsycINFO, PubMed, and Web of Science. Main inclusion criteria stipulated (1) healthy sample populations, (2) PA interventions, (3) WMP as an outcome, and (4) RCT designs. Descriptive statistics included cohort and intervention characteristics and a risk of bias assessment. Analytical statistics included meta-analyses and moderation analyses. Results From 7345 non-duplicates, 15 studies (eight chronic PA and seven acute PA studies) met the inclusion criteria and were evaluated. Overall, there was noticeable variance between both cohort and intervention characteristics. Sample populations ranged from primary school children to retirement community members with PA ranging from cycling to yoga. The majority of studies were characterized by “low” or “unclear” risk of selection, performance, detection, attrition, reporting, or other biases. Meta-analysis of chronic PA revealed a significant, small effect size while analysis of acute PA revealed a non-significant, trivial result. Age and intensity were significant moderators while allocation concealment, blinding, and intervention length were not. Conclusions Chronic PA can significantly improve WMP while acute PA cannot. The limiting factors for acute PA studies point to the diversity of working memory instruments utilized, unequal sample sizes between studies, and the sample age groups. Large-scale, high-quality RCTs are needed in order to provide generalizable and more powerful analysis between PA and WMP in a systematic approach.

Background: The optimal management of breech presentation remains a debate among obstetricians worldwide. The Term Breech Trial (2000) highlighted elective caesarean section as a preferable method over vaginal delivery for breech presentations. This study investigates delivery modes in women who had an elective caesarean section for breech presentation in their first pregnancy. Objective was to evaluate delivery outcomes in the second pregnancy of women who had an elective caesarean section for breech presentation in their first pregnancy., Methods: A cross-sectional study was conducted at Jinnah International Hospital Abbottabad from October 10, 2018, to April 10, 2019. Data was collected from 321 women who had an elective caesarean section for breech presentation during their first pregnancy. The study used per-abdominal examination and obstetrical ultrasound to assess foetal presentation and recorded the mode of delivery in the second pregnancy., Results: Participants' ages ranged from 18 to 49 years, with a mean age of 28.87±4.07 years. The average interval between deliveries was 1.92±0.92 years, labour duration averaged 5.56±2.41 hours, and foetal head engagement averaged 2.92±1.35. Of the participants, 18.7% achieved a vaginal delivery, while 81.3% had a repeat caesarean section. Reasons for repeat caesarean included recurrent breech presentation in 44.9% and foetal distress in 32.4%., Conclusions: Approximately 18.7% of women who had an elective caesarean section for breech presentation in their first pregnancy achieved vaginal delivery in their second pregnancy, whereas the majority underwent another elective caesarean section.

Objectives: Serum urate (SU) lowering with PEGylated uricases in gout can reduce flares and tophi. However, treatment-emergent anti-drug antibodies adversely affect safety and efficacy and the currently approved PEGylated uricase pegloticase requires twice-monthly infusions. Investigational SEL-212 therapy aims to promote uricase-specific tolerance via monthly sequential infusions of a proprietary rapamycin-containing nanoparticle (ImmTOR) and pegadricase., Methods: COMPARE was a randomized, phase 2, open-label trial of SEL-212 vs pegloticase in adults with refractory gout. SEL-212 [ImmTOR (0.15 mg/kg) and pegadricase (0.2 mg/kg)] was infused monthly or pegloticase (8 mg) twice monthly for 6 months. The primary endpoint was the proportion of participants with SU <6 mg/dl for ≥80% of the time during 3 and 6 months. Secondary outcomes were mean SU, gout flares, number of tender and/or swollen joints and safety., Results: During months 3 and 6 combined, numerically more participants achieved and maintained a SU <6 mg/dl for ≥80% of the time with SEL-212 vs pegloticase (53.0% vs 46.0%, P = 0.181). The percentage reductions in SU levels were statistically greater during months 3 and 6 with SEL-212 vs pegloticase (-73.79% and -47.96%, P = 0.0161). Reductions in gout flare incidence and number of tender and/or swollen joints were comparable between treatments. There were numerical differences between the most common treatment-related adverse events of interest with SEL-212 and pegloticase: gout flares (60.2% vs 50.6%), infections (25.3% vs 18.4%) and infusion-related reactions (15.7% vs 11.5%), respectively. Stomatitis (and related terms) was experienced by eight participants (9.6%) with SEL-212 and none with pegloticase. Stomatitis, a known event for rapamycin, was associated with ImmTOR only., Conclusions: SEL-212 efficacy and tolerability were comparable to pegloticase in refractory gout. This was associated with a substantial reduction in treatment burden with SEL-212 due to decreased infusion frequency vs pegloticase., Clinical Trial Registration: NCT03905512., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Introduction: SEL-212 is a developmental treatment for uncontrolled gout characterized by serum uric acid (sUA) levels ≥ 6 mg/dl despite treatment. It comprises a novel PEGylated uricase (SEL-037; also called pegadricase) co-administered with tolerogenic nanoparticles containing sirolimus (rapamycin) (SEL-110; also called ImmTOR ® ), which mitigates the formation of anti-drug antibodies (ADAs) against uricase and SEL-037 (PEGylated uricase), thereby enabling sustained sUA control (sUA < 6 mg/dl). The aim of this study was to identify appropriate dosing for SEL-037 and SEL-110 for use in phase 3 clinical trials., Methods: This open-label phase 2 study was conducted in adults with symptomatic gout and sUA ≥ 6 mg/dl. Participants received five monthly infusions of SEL-037 (0.2 or 0.4 mg/kg) alone or in combination with three or five monthly infusions of SEL-110 (0.05-0.15 mg/kg). Safety, tolerability, sUA, ADAs, and tophi were monitored for 6 months., Results: A total of 152 adults completed the study. SEL-037 alone resulted in rapid sUA reductions that were not sustained beyond 30 days in most participants due to ADA formation and loss of uricase activity. Levels of ADAs decreased with increasing doses of SEL-110 up to 0.1 mg/kg, with anti-uricase titers < 1080 correlating with sustained sUA control and reductions in tophi. Overall, 66% of evaluable participants achieved sUA control at week 20 following five monthly doses of SEL-037 0.2 mg/kg + SEL-110 0.1-0.15 mg/kg, whereas only 26% achieved sUA control at week 20 when SEL-110 was withdrawn after week 12. Compared to other dose combinations, SEL-037 0.2 mg/kg + SEL-110 0.15 mg/kg achieved the greatest sUA control at week 12 and was well-tolerated with no safety concerns., Conclusion: Results provide continued support for the use of multiple monthly administrations of SEL-037 0.2 mg/kg + SEL-110 0.1-0.15 mg/kg in clinical trials for SEL-212., Trial Registration: ClinicalTrials.gov identifier, NCT02959918., (© 2023. The Author(s).)

(1) Background: Type 2 diabetes mellitus (T2DM) is one of the rapidly growing healthcare problems, and several vitamin D receptor (VDR) polymorphisms seem to modulate the risk of T2DM. Our research was designed to investigate the allelic discrimination of VDR polymorphisms and T2DM occurrence risk. (2) Methods: This case-control research included 156 patients with T2DM and 145 healthy control subjects. Most of the study population were males 56.6% vs. 62.8% in the case and control groups, respectively. Genotyping for VDR single nucleotide polymorphisms (SNPs), rs228570 (Fok1), rs7975232 (Apa1), and rs1544410 (Bsm1) was compared between both groups. (3) Results: There was a negative link between vitamin D levels and insulin sensitivity. A significant difference was noted in the allelic discrimination of VDR polymorphism rs228570 and rs1544410 between the study groups ( p < 0.001). No difference was observed in the allelic discrimination of VDR polymorphism rs7975232 between the groups ( p = 0.063). Moreover, T2DM patients had significantly higher levels of fasting blood sugar (FBS), glycated hemoglobin HbA1c, 2-h post-prandial blood sugar (PP), serum glutamic oxaloacetic transaminase (SGOT), serum glutamic-pyruvic transaminase (SGPT), total cholesterol, and triglycerides ( p < 0.001), while High-Density Lipoprotein (HDL) Cholesterol (HDL-C) was significantly decreased ( p = 0.006). (4) Conclusions: VDR polymorphisms had a positive association with T2DM risk among the Egyptian population. Further large-scale research using deep sequencing of samples is strongly urged to investigate different vitamin D gene variants and interactions, as well as the influence of vitamin D on T2DM.

Objective: To record the prevalence of suicidal ideation in the transgender population and assess the relationship of depression with the suicidal ideation., Study Design: Cross-sectional study., Methodology: The study group comprised of 156 transgender people of Rawalpindi and Islamabad. Suicidal ideation was assessed by the scale for suicide ideation (SSI). Hamilton rating scale for depression (HAM-D) was used to look for the presence and severity of depression among the target population. Relationship of the age, smoking, family income, illicit substance use, and depression was studied with the presence of suicidal intent among these transgender population of twin cities., Results: One hundred and fifty-six transgender people were included in this study. Mean age of the study participants was 39.26 ±4.28 years. Out of them, 89 (57.1%) had no suicidal ideations, while 67 (42.9%) had suicidal ideation. Fifty-seven (36.5%) did not showed depression, while 99 (63.5%) had depression on HAM-D. With binary logistic regression, depression and illicit substance were found to be significantly related to the presence of suicidal ideations in the target population (p <0.05)., Conclusion: A high prevalence of suicidal ideation among the transgender population of twin cities was found in this study. Depression, illicit substance use, and other mental health illnesses should be screened routinely on this high risk population for early recognition and treatment.

Objective: ITCA 650 (exenatide in osmotic mini-pump) continuously delivers exenatide subcutaneously for 3-6 months. Two doses of ITCA 650 were compared with placebo in patients with uncontrolled type 2 diabetes., Research Design and Methods: This 39-week, phase 3, double-blind, placebo-controlled trial randomized 460 patients aged 18-80 years with glycated hemoglobin (HbA 1c ) 7.5-10% [58-86 mmol/mol] 1:1:1 to placebo, ITCA 650 40 μg/day, or ITCA 650 60 μg/day. Primary end point was change in HbA 1c at 39 weeks., Results: Least squares (LS) mean change from baseline HbA 1c was -1.1% [-12.2 mmol/mol] and -1.2% [-13.2 mmol/mol] for ITCA 650 40 and 60 μg/day, respectively ( P < 0.001 vs. placebo -0.1% [-1.3 mmol/mol]). In a prespecified analysis, greater HbA 1c reductions occurred in patients not receiving sulfonylureas (SUs) versus those receiving SUs (-1.7% vs. -1.2% [-18.6 and -13.1 mmol/mol]). At week 39, HbA 1c <7% [53 mmol/mol] was attained in 37%, 44%, and 9% of ITCA 650 40 μg/day, ITCA 650 60 μg/day, and placebo groups, respectively ( P < 0.001 each dose vs. placebo). LS mean change from baseline body weight was -2.3 kg and -3.0 kg for ITCA 650 40 and 60 μg/day, respectively ( P ≤ 0.015 vs. placebo -1.0 kg). Nausea was the most common adverse event (AE) and subsided over time. Discontinuation for gastrointestinal AEs occurred in 7.2% with ITCA and 1.3% with placebo. Most AEs associated with procedures to place and remove ITCA 650 were mild and transient., Conclusions: ITCA 650 significantly reduced HbA 1c and weight compared with placebo and was well tolerated in patients with uncontrolled type 2 diabetes on oral antidiabetes medications., (© 2017 by the American Diabetes Association.)