Long-term antitrypanosomal effect of quinapyramine sulphate-loaded oil-based nanosuspension in T. evansi-infected mouse model.

The goal of the present work consisted of the formulation development and evaluation of quinapyramine sulphate (QS)-loaded long-acting oil-based nanosuspension for improved antitrypanosomal effect. QS was transformed into a hydrophobic ionic complex using anionic sodium cholate (Na.C). The complex was characterized by FTIR, DSC, and XRD. Oil-based nanosuspension was prepared by dispersing the QS-Na.C complex in thixotropically thickened olive oil. The nanoformulation was found to be cytocompatible (82.5 ± 5.87% cell viability at the minimum effective concentration [MEC]) in THP-1 cell lines and selectively trypanotoxic (p < 0.0001). The pharmacokinetic studies of QS-Na.C complex-loaded oily nanosuspension showed 13.54-fold, 7.09-fold, 1.78-fold, and 17.35-fold increases in t1/2, AUC0-∞, Vz/F, and MRT0-ꝏ, respectively, as compared to free QS. Moreover, a 7.08-fold reduction in plasma clearance was observed after the treatment with the optimized formulation in Wistar rats. Furthermore, treatment with QS-Na.C complex-loaded oily nanosuspension (7.5 mg/kg) in T. evansi-infected mice model showed the absence of parasitaemia for more than 75 days after the treatment during in vivo efficacy studies. The efficacy of the treatment was assessed by observation of blood smear and PCR assay for DNA amplification. To conclude, our findings suggest that the efficient delivery of QS from the developed QS-Na.C complex-loaded oily nanosuspension could be a promising treatment option for veterinary infections against trypanosomiasis.

Safety outcomes of pembrolizumab with platinum agent chemotherapy combined with 5-fluorouracil or taxane derivative in head and neck cancer.

INTRODUCTION: For patients with metastatic head and neck squamous cell cancer (HNSCC), the outcomes of pembrolizumab in combination with a platinum agent and taxane as first-line therapy remain unknown. The purpose of this study is to characterize the impact of substituting the 5-fluorouracil (5-FU) backbone for a taxane in this chemoimmunotherapy regimen on safety/tolerability and survival outcomes. METHODS: This was an IRB-approved, single-center, retrospective, active comparator, new-user design study in adult patients with HNSCC treated between January 2018 and September 2021. The primary objective was to assess safety and tolerability of pembrolizumab in combination with a platinum agent and taxane against an active comparator arm of pembrolizumab in combination with a platinum agent and 5-FU. Safety and tolerability were evaluated by assessing differences in overall toxicities, with further secondary analysis evaluating differences in hematologic toxicities and pre-defined non-hematologic toxicities. RESULTS: There was no statistical difference demonstrated with the primary endpoint between the cohorts. Reduced toxicity rates were found in the taxane arm for mucositis and creatinine levels. No grade 4 non-hematologic toxicities were reported. Patients receiving 5-FU were more likely to have dose reductions upfront, discontinue treatment due to intolerances and had significantly higher mucositis. CONCLUSIONS: This study helps to characterize the safety profile and activity of pembrolizumab in combination with a platinum agent and taxane derivative in HNSCC patients. Within our study, substitution of 5-FU with a taxane did not show an increased risk of toxicities, worsened survival, or decreased odds of achieving a response. Mucositis and elevated creatinine rates were significantly reduced within the taxane arm.

Crosstalk between NLRP3 inflammasome and calpain in Alzheimer's disease.

Amyloid plaques are considered to be the pathological hallmark of Alzheimer's disease (AD). Neuroinflammation further aggravates the pathogenesis of Alzheimer's disease. Calpains and NOD-like receptor protein-3 (NLRP3) inflammasomes are involved in the neuroinflammatory pathway and affect the progression of Alzheimer's disease. Hyperactivation of calpains is responsible for the activation of NLRP3 inflammasome, thereby affecting each other's molecular mechanism and causing astrogliosis, microgliosis, and neuronal dysfunction. Further, calpain hyperactivation is also associated with calcium homeostasis that acts as one of the triggers in the activation of NLRP3 inflammasome. Calpain activity is required for the maturation of interleukin-1ß, a key mediator of neuroinflammatory responses. The membrane potential/calcium/calpain/caspase-1 axis acts as an unconventional regulator of inflammasomes. The complex crosstalk between NLRP3 inflammasome and calpain leads to a series of events. Targeting the molecular mechanism associated with calpain-NLRP3 inflammasome activation and regulation can be a therapeutic and prophylactic perspective towards Alzheimer's disease. This review discusses calpains and NLRP3 inflammasome crosstalk in the pathogenesis of AD.

Carotid artery dissections from transcarotid artery revascularization as reported by the Food and Drug Administration.

OBJECTIVES: Transcarotid artery revascularization (TCAR) is a hybrid procedure that allows reversal of blood flow away from the brain while placing a stent through direct surgical access of the common carotid artery. It has been shown to have a lower risk of perioperative stroke compared with any prospective trial of transfemoral carotid artery stenting. However, intraoperative injuries related to the procedure and its management are not well characterized. One of the intraoperative complications seen in TCAR is iatrogenic carotid artery dissection (CD). We aim to add qualitative insight in further characterizing CDs and its management in this emerging technology. METHODS: The Food and Drug Administration (FDA) maintains the Manufacturer and User Facility Device Experience (MAUDE) database for surveillance of all medical devices approved for use. This database was queried for all cases associated with Silk Road Medical's ENROUTE Transcarotid Neuroprotection System from September 2016 to October 2020. Case narratives related to CD were individually analyzed to determine time of injury (intraoperative, recovery, and post-discharge follow-up). CD reporting was further analyzed for the associated procedural event at the time of injury, number of access attempts to CD repair, and type of CD repair. Reports associated with CD repair were further categorized into endovascular repair and open surgical repair. RESULTS: Of the 115 unique adverse events in the database, there were 58 CDs. Most were identified intraoperatively (n = 55), while three were incidentally found postoperatively. Overall, sheath placement was the most common procedural event attributed to CD (N = 34). There was adequate narrative information about CD repair in 54 patients. Intraoperative repair was performed in 52 cases and two were repaired after post-discharge follow-up imaging was performed.Among CDs that did not require additional access to engage the true lumen, the proportion of endovascular repair (62.5%) was significantly higher (p = .044) compared to the proportion of open surgical repair (37.5%). However, the proportion of open surgical repair (75%) was significantly higher than the proportion of endovascular repair (25%) in CDs with persistent failure to engage the true lumen despite ≥2 access attempts (p = .039). CONCLUSION: CD is the most common injury related to TCAR as reported on MAUDE. The most commonly reported procedural event associated with CD was sheath placement. The rate of intraoperative endovascular and open surgical CD repair was associated with whether the access to the true lumen of the carotid artery required additional access attempts or not. This should add qualitative insight among the vascular surgery community regarding intraoperative management of CDs from a TCAR procedure.

Carrollian Origins of Bjorken Flow.

Bjorken flow is among the simplest models of fluids moving near the speed of light (c), while Carroll symmetry arises as a contraction of Poincaré group when c→0. We show that Bjorken flow and its phenomenological approximations are completely captured by Carrollian fluids. Carrollian symmetries arise on generic null surfaces, and a fluid moving at c is restricted to such a surface, thereby naturally inheriting the symmetries. Carrollian hydrodynamics is, thus, not exotic, but rather ubiquitous, and provides a concrete framework for fluids moving at or near the speed of light.

Oncology Providers' and Professionals' Experiences With Suicide Risk Screening Among Patients With Head and Neck Cancer: A Qualitative Study.

PURPOSE: There has been limited study of the implementation of suicide risk screening for patients with head and neck cancer (HNC) as a part of routine care. To address this gap, this study assessed oncology providers' and professionals' perspectives about barriers and facilitators of implementing a suicide risk screening among patients with HNC. MATERIALS AND METHODS: All patients with HNC with an in-person visit completed a suicide risk screening on an electronic tablet. Patients reporting passive death wish were then screened for active suicidal ideation and referred for appropriate intervention. Interviews were conducted with 25 oncology providers and professionals who played a key role in implementation including nurses, medical assistants, patient access representatives, advanced practice providers, physicians, social workers, and informatics staff. The interview guide was based on the Consolidated Framework for Implementation Research. Interviews were transcribed and analyzed for themes. RESULTS: Participants identified multilevel implementation barriers, such as intervention level (eg, patient difficulty with using a tablet), process level (eg, limited nursing engagement), organizational level (eg, limited clinic Wi-Fi connectivity), and individual level (eg, low clinician self-efficacy for interpreting and acting upon patient-reported outcome scores). Participants noted facilitators, such as effective care coordination across nursing and social work staff and the opportunity for patients to be screened multiple times. Participants recommended strengthening patient and clinician education and providing patients with other modalities for data entry (eg, desktop computer in the waiting room). CONCLUSION: Participants identified important intervention modifications that may be needed to optimize suicide risk screening in cancer care settings.

The InSight HP3 Penetrator (Mole) on Mars: Soil Properties Derived from the Penetration Attempts and Related Activities.

The NASA InSight Lander on Mars includes the Heat Flow and Physical Properties Package HP3 to measure the surface heat flow of the planet. The package uses temperature sensors that would have been brought to the target depth of 3-5 m by a small penetrator, nicknamed the mole. The mole requiring friction on its hull to balance remaining recoil from its hammer mechanism did not penetrate to the targeted depth. Instead, by precessing about a point midway along its hull, it carved a 7 cm deep and 5-6 cm wide pit and reached a depth of initially 31 cm. The root cause of the failure - as was determined through an extensive, almost two years long campaign - was a lack of friction in an unexpectedly thick cohesive duricrust. During the campaign - described in detail in this paper - the mole penetrated further aided by friction applied using the scoop at the end of the robotic Instrument Deployment Arm and by direct support by the latter. The mole tip finally reached a depth of about 37 cm, bringing the mole back-end 1-2 cm below the surface. It reversed its downward motion twice during attempts to provide friction through pressure on the regolith instead of directly with the scoop to the mole hull. The penetration record of the mole was used to infer mechanical soil parameters such as the penetration resistance of the duricrust of 0.3-0.7 MPa and a penetration resistance of a deeper layer ( > 30 cm depth) of 4.9 ± 0.4 MPa . Using the mole's thermal sensors, thermal conductivity and diffusivity were measured. Applying cone penetration theory, the resistance of the duricrust was used to estimate a cohesion of the latter of 2-15 kPa depending on the internal friction angle of the duricrust. Pushing the scoop with its blade into the surface and chopping off a piece of duricrust provided another estimate of the cohesion of 5.8 kPa. The hammerings of the mole were recorded by the seismometer SEIS and the signals were used to derive P-wave and S-wave velocities representative of the topmost tens of cm of the regolith. Together with the density provided by a thermal conductivity and diffusivity measurement using the mole's thermal sensors, the elastic moduli were calculated from the seismic velocities. Using empirical correlations from terrestrial soil studies between the shear modulus and cohesion, the previous cohesion estimates were found to be consistent with the elastic moduli. The combined data were used to derive a model of the regolith that has an about 20 cm thick duricrust underneath a 1 cm thick unconsolidated layer of sand mixed with dust and above another 10 cm of unconsolidated sand. Underneath the latter, a layer more resistant to penetration and possibly containing debris from a small impact crater is inferred. The thermal conductivity increases from 14 mW/m K to 34 mW/m K through the 1 cm sand/dust layer, keeps the latter value in the duricrust and the sand layer underneath and then increases to 64 mW/m K in the sand/gravel layer below. Supplementary Information: The online version contains supplementary material available at 10.1007/s11214-022-00941-z.

Recent developments in polypyrrole/manganese oxide-based nanocomposites for thin film electrodes in supercapacitors: a minireview.

This review article highlights the recent developments in the synthesis and electrochemical performance of polypyrrole/manganese oxide thin-film electrodes synthesized by various chemical methods for supercapacitor applications. In the class of conducting polymers for electrode applications, polypyrrole (Ppy) is considered an important polymer due to its low cost and abundance. Ppy's polymeric composition and structural properties, however, pose stability concerns and have a drawback of a short life cycle over long-term charge-discharge processes, limiting its potential for industrial and commercial utilization. Recently, manganese oxide (MnO2) has been actively explored as a supercapacitor electrode material due to its low cost, high theoretical specific capacitance and abundance. Ppy/MnO2 thin film electrodes revealed high specific capacitance and stability, making them excellent candidates for next-generation supercapacitor electrode materials.

A Comparison of Patient and Device Issues Reported for Recalled Venous Stent Systems.

BACKGROUND: The first two Food and Drug Administration (FDA)-approved stents for treatment of iliofemoral vein obstruction, Boston Scientific's Vici and BD's Venovo venous stent systems, were both recalled in early 2021 within years of entering the market. Given the recent addition of patient issues as a publicly reported variable by the FDA Manufacturer and User Facility Device Experience (MAUDE) database, we set forth to analyze adverse event reports in MAUDE to better characterize issues reported for each system. METHODS: MAUDE was queried for all adverse event reports for brands "Vici" and "Venovo" from their respective US FDA market approval dates to August 19, 2021. Reported device issues, patient issues, and interventions performed for each adverse event were compiled and compared using Fisher's exact test. RESULTS: A total of 50 unique adverse event reports were compiled for the Vici system and 341 for the Venovo system. The most common device issue reported for the Vici system was migration (48% vs. 0%; P = 0.0001) versus activation failure in Venovo (85% vs. 4%; P = 0.0001). A significantly higher proportion of Venovo reports specified no patient complications or symptoms (90% vs. 26%; P = 0.0001), with no intervention performed (89% vs. 32%; P = 0.001). A significantly higher proportion of Vici devices were extracted (8% vs. 2%; P = 0.01), required use of a new device (26% vs. 5%; P = 0.0001), and required application of a second stent within the venous stent initially placed (28% vs. 2%; P = 0.0001). The rate of intervention with balloon expansion was not significantly different between the Vici and Venovo systems (6% vs. 2%; P = 0.08). CONCLUSIONS: While 2 venous stent systems were recalled simultaneously, significant differences exist between reported device issues in MAUDE and whether patient injury was involved and well described. Our data suggest that despite recent improvements to MAUDE reporting, additional standardization with specificity regarding patient issues and interventions is needed to assist vascular surgeons monitoring real-time adverse event trends for vascular devices.

Elabela Peptide: An Emerging Target in Therapeutics.

Elabela, a bioactive micropeptide, is recognized as the second endogenous ligand for the Apelin receptor and is widely distributed in different tissues and organs. Elabela plays an important role in various physiological processes, such as blood pressure control, heart morphogenesis, apoptosis, angiogenesis, cell proliferation, migration, etc. Elabela is also implicated in pathological conditions, like cardiac dysfunctions, heart failure, hypertension, kidney diseases, cancer and CNS disorders. The association of Elabela with these disease conditions makes it a potential target for their therapy. This review summarizes the physiological role of Elabela peptide as well as its implication in various disease conditions.

Liver X receptor: a potential target in the treatment of atherosclerosis.

INTRODUCTION: Liver X receptors (LXRs) are master regulators of atherogenesis. Their anti-atherogenic potential has been attributed to their role in the inhibition of macrophage-mediated inflammation and promotion of reverse cholesterol transport. Owing to the significance of their anti-atherogenic potential, it is essential to develop and test new-generation LXR agonists, both synthetic and natural, to identify potential LXR-targeted therapeutics for the future. AREAS COVERED: This review describes the role of LXRs in atherosclerotic development, and provides a summary of LXR agonists and future directions for atherosclerosis research. We searched PubMed, Scopus, and Google Scholar for relevant reports, from last 10 years, using atherosclerosis, liver X receptor, and LXR agonist as keywords. EXPERT OPINION: LXRα has gained widespread recognition as a regulator of cholesterol homeostasis and expression of inflammatory genes. Further research using models of cell type-specific knockout and specific agonist-targeted LXR isoforms is warranted. Enthusiasm for therapeutic value of LXR agonists has been tempered due to LXRα-mediated induction of hepatic lipogenesis. LXRα agonism and LXRß targeting, gut-specific inverse LXR agonists, investigations combining LXR agonists with other lipogenesis-mitigating agents, like IDOL antagonists and synthetic HDL, and targeting ABCA1, M2 macrophages, and LXRα phosphorylation remain as promising possibilities.

Medical optimization of the peripheral artery disease patient.

Peripheral artery disease (PAD) impacts an estimated 230 million adults worldwide, including more than 9.5 million adults older than 40 years in the United States. PAD remains more underdiagnosed and undertreated than manifestations of atherosclerosis elsewhere in the body, such as coronary artery disease and cerebrovascular disease. Medical therapies benefit all patients with PAD, including those who are asymptomatic, as well as those with symptoms and advanced disease requiring intervention. Comprehensive medical management of PAD is based on tempering atherosclerotic disease processes and should include smoking cessation, exercise therapy, cholesterol reduction, antiplatelet, and/or anticoagulation therapy, as well as the application of peripheral vasodilators and blood pressure control, when indicated. For patients with intermittent claudication, supervised exercise therapy has been shown to provide similar or superior benefit compared with intervention and is recommended by major society guidelines as first-line therapy. In patients with advanced PAD requiring endovascular or surgical intervention, continued adherence to optimal medical therapy has been found to improve functional outcomes and decrease post-interventional mortality. Optimal medical management provides crucial benefits to patients with early, moderate, and advanced PAD and, once started, should be continued for life.

Emerging targets signaling for inflammation in Parkinson's disease drug discovery.

Parkinson's disease (PD) patients not only show motor features such as bradykinesia, tremor, and rigidity but also non-motor features such as anxiety, depression, psychosis, memory loss, attention deficits, fatigue, sexual dysfunction, gastrointestinal issues, and pain. Many pharmacological treatments are available for PD patients; however, these treatments are partially or transiently effective since they only decrease the symptoms. As these therapies are unable to restore dopaminergic neurons and stop the development of Parkinson's disease, therefore, the need for an effective therapeutic approach is required. The current review summarizes novel targets for PD, that can be utilized to identify disease-modifying treatments.

Change in Patients' Perceived Cognition Following Chimeric Antigen Receptor T-Cell Therapy for Lymphoma.

Chimeric antigen receptor (CAR) T-cell therapy can lead to durable responses in patients with relapsed/refractory hematologic malignancies. Immune effector cell-associated neurotoxicity syndrome (ICANS) and cytokine release syndrome (CRS) are common and may place patients at risk for longer-term cognitive impairment. This study examined changes in cognition in the first year after CD19-directed CAR T-cell therapy for lymphoma, as well as CAR T-cell therapy-specific risk-factors (e.g., ICANS, CRS) and nonspecific risk factors (e.g., baseline quality of life, frailty) for worsening cognition. Patients' perceived cognition was assessed at baseline and at days 90 and 360. Clinical variables were abstracted from medical records. Piecewise mixed models were used to examine acute change (i.e., within 90 days) and longer-term change (i.e., from 90 days to 360 days) in cognition, as well as to explore risk factors for worsening cognition. Among 118 participants (mean age 61, 59% male), mean levels of perceived cognition did not change from baseline to day 90 (P> .05) but worsened from day 90 to day 360 in global cognition and in the domains of memory, language, organization, and divided attention (P< .05). Although statistically significant, changes were small (d values 0.15-0.28). Greater baseline fatigue, anxiety, and depression were associated with worse global cognition at day 90 (P< .01). Patients with more severe ICANS post-CART reported worse global cognition at day 360 (P< .05), although there were no differences in perceived cognition by severity of CRS (P> .05). Other putative risk factors were not associated with acute or longer-term changes in perceived cognition (P> .05). CAR T-cell therapy recipients reported delayed deterioration in several cognitive domains, although changes were small. These findings may be useful when educating future patients on what to expect when receiving CAR T-cell therapy.

Assessing Resident Impact on Surgical Outcomes in Below-the-Knee Amputations Based on Operative Autonomy.

BACKGROUND: Gradual increases in resident autonomy with attending physician oversight is crucial to developing safe and competent surgeons1. The Veterans Affairs Surgical Quality Improvement Program (VASQIP) follows surgical outcomes within the VA. We set forth to examine the VASQIP database to compare outcomes between resident independent cases and nonindependent cases during below-the-knee amputations (BKA). METHODS: All VASQIP records for BKA from 2000 to 2020 were examined and categorized based on whether the attending was scrubbed during the case. Case matching was performed based on preoperative comorbidities; 30-day postoperative outcomes, including a return to the operating room, wound infection, and mortality, were assessed in addition to operative time, hospital length of stay, and transfusion requirements. Student's t-test and Fisher's Exact Test were utilized. RESULTS: A total of 13,208 BKA VASQIP records were obtained. After case control matching, 2,688 cases remained. Cases were identified with the attending surgeon noted as being scrubbed during the case (n = 1,344), or not scrubbed (n = 1,344). Patients were similar in comorbidities across both groups. No statistically significant difference in operative time (1.52 hr ± 0.78 vs. 1.47 hr ± 0.75, P = 0.08), 30-day mortality (3.3% vs. 4.8%, P = 0.05), or complication rate (19.5% vs. 21.3%, P = 0.25). Resident independent cases were noted to have slightly longer postop length of stay (12.47 days ± 12.69 vs. 15.33 days ± 20.56, P < 0.01) and operative bleeding requiring more than 4 units transfused (0.3% vs. 1.3%, P ≤ 0.01). CONCLUSIONS: Resident independent operating during below-the-knee amputation at VA hospitals is associated with an increased length of stay and blood transfusion. There was no statistically significant increase in operative time, 30-day mortality, or total complication rate. Further research is required to assess the risks associated with surgical training, resident supervision, and resident preparedness for independent practice.

Elevated Risk Analysis Index (RAI) Frailty Scores Are Independently Associated with Adverse Outcomes in Lower Extremity Surgical Revascularizations Similarly Across Genders.

BACKGROUND: The Risk Analysis Index (RAI) frailty scoring system has recently undergone revision and external validation using the National Surgical Quality Improvement Program (NSQIP) database. We set forth to evaluate the association of RAI-rev ranges with outcomes following lower extremity surgical revascularization and verify equivalent applicability across genders. METHODS: All elective NSQIP Targeted Lower Extremity Open cases from 2015-2019 were divided by EMR-recorded gender. Aggregate demographics, perioperative factors, and 30-day outcomes were compared using unpaired t-test and Fisher's exact test. Adjusted odds-ratios (aOR) for each outcome were generated by applying a multivariate binary logistic regression model (IBM SPSSTM) for five-point RAI-rev score increments from 25-45 and a most-frail group with scores >45 with a non-frail reference of <25. Covariates included surgical indication, prior ipsilateral revascularization, graft utilization, dirty/infected wound, smoking, hypertension, diabetes, and steroid use. RESULTS: 8,155 cases included 2,498 (31%) performed in women who demonstrated slightly lower RAI-rev scores than men (22.1 ± 5.8 vs. 24.2 ± 5.1; P = 0.0001). Univariate trends demonstrated dose-dependent increases in frequency of most outcomes with rising frailty score ranges, most substantially regarding mortality (0.4% non-frail to 14.7% most-frail), disposition to skilled nursing facility (8% non-frail to 27% most-frail), and extended length of stay (16% non-frail to 44% most-frail). After adjusting for co-variates, patients with RAI-rev scores of 26-30 had aOR of 1.4 (95% CI: 1.2-1.6; P < 0.001), 1.9 (95% CI: 1.6-2.2; P < 0.001), and 2.4 (95% CI:1.3-4.4; P < 0.001) for extended stay, disposition to skilled nursing, and mortality respectively. Trends were similar across genders in both univariate and multivariate analyses. CONCLUSIONS: Mortality, extended stay, and increased rehabilitation needs after surgical revascularization were associated with higher RAI-rev score ranges in a dose dependent manner similarly across genders.