Abatacept: A Promising Repurposed Solution for Myocardial Infarction-Induced Inflammation in Rat Models.

Myocardial infarction (MI) is irreversible damage to the myocardial tissue caused by prolonged ischemia/hypoxia, subsequently leading to loss of contractile function and myocardial damage. However, after a perilous period, ischemia-reperfusion (IR) itself causes the generation of oxygen free radicals, disturbance in cation homeostasis, depletion of cellular energy stores, and activation of innate and adaptive immune responses. The present study employed Abatacept (ABT), which is an anti-inflammatory drug, originally used as an antirheumatic response agent. To investigate the cardioprotective potential of ABT, primarily, the dose was optimized in a chemically induced model of myocardial necrosis. Thereafter, ABT optimized the dose of 5 mg/kg s.c. OD was investigated for its cardioprotective potential in a surgical model of myocardial IR injury, where animals (n = 30) were randomized into five groups: Sham, IR-C, Telmi10 + IR (Telmisartan, 10 mg/kg oral OD), ABT5 + IR, ABT perse. ABT and telmisartan were administered for 21 days. On the 21st day, animals were subjected to LAD coronary artery occlusion for 60 min, followed by reperfusion for 45 min. Further, the cardioprotective potential was assessed through hemodynamic parameters, oxidant-antioxidant biochemical enzymatic parameters, cardiac injury, inflammatory markers, histopathological analysis, TUNEL assay, and immunohistochemical evaluation, followed by immunoblotting to explore signaling pathways. The statistics were performed by one-way analysis of variance, followed by the Tukey comparison post hoc tests. Noteworthy, 21 days of ABT pretreatment amended the hemodynamic and ventricular functions in the rat models of MI. The cardioprotective potential of ABT is accompanied by inhibiting MAP kinase signaling and modulating Nrf-2/HO-1 proteins downstream signaling cascade. Overall, the present work bolsters the previously known anti-inflammatory role of ABT in MI and contributes a mechanistic insight and application of clinically approved drugs in averting the activation of inflammatory response.

A novel strategy to elicit enduring anti-morphine immunity and relief from addiction by targeting Acr1 protein nano vaccine through TLR-2 to dendritic cells.

Morphine addiction poses a significant challenge to global healthcare. Current opioid substitution therapies, such as buprenorphine, naloxone and methadone are effective but often lead to dependence. Thus, exploring alternative treatments for opioid addiction is crucial. We have developed a novel vaccine that presents morphine and Pam3Cys (a TLR-2 agonist) on the surface of Acr1 nanoparticles. This vaccine has self-adjuvant properties and targets TLR-2 receptors on antigen-presenting cells, particularly dendritic cells. Our vaccination strategy promotes the proliferation and differentiation of morphine-specific B-cells and Acr1-reactive CD4 T-cells. Additionally, the vaccine elicited the production of high-affinity anti-morphine antibodies, effectively eliminating morphine from the bloodstream and brain in mice. It also reduced the expression of addiction-associated µ-opioid receptor and dopamine genes. The significant increase in memory CD4 T-cells and B-cells indicates the vaccine's ability to induce long-lasting immunity against morphine. This vaccine holds promise as a prophylactic measure against morphine addiction.

Unveiling parental perspectives: COVID-19 vaccination for children in India.

Background: Irrespective of the availability of a safe and effective COVID-19 vaccine and its success rate in adults, administering vaccines to children remains a challenge for healthcare workers. Children's vaccine hesitancy among parents remains substantial and is exacerbated due to misleading information. In the present study, we aimed to investigate the hesitancy of parents and their concern about the vaccination and clinical characteristics of COVID-19 in their children. Methods: A cross-sectional web-based and offline survey comprised of questions about the demographic of children, the status of COVID-19 infection, its severity, vaccination status, sources of information, willingness, concerns and attitude of parents to vaccinate their children against the COVID-19 virus, was conducted. Overall, 846 responses from parents fulfilling the inclusion criteria were analysed by GraphPad Prism 5. Results: Out of the 846 responses, 51.2% (n = 433) of children were vaccinated against COVID-19. Out of vaccinated children (51.2%), 60.3% (n = 261) had experienced adverse events. Around 21% (n = 98) of children had a history of exposure to the SARS-CoV-2 virus. Among the infected children, 14.3% were asymptomatic and 85.7% had symptoms. Approximately 8% of children had comorbidities, with chronic lung diseases and asthma being the most common. Among the 846 participating parents, 59.5% were mothers and the remaining 40.5% were fathers. A total of 2.7% and 22.2% of parents were found hesitant to administer the COVID-19 vaccine to their children aged 15-18 years and below 15 years, respectively. Among hesitant parents, mothers were found slightly more hesitant as compared to fathers. Also, 35.5% of parents were found hesitant about their own COVID-19 vaccination. Furthermore, the concern for COVID-19 vaccine unwillingness among parents is that a child has already achieved natural immunity after COVID-19 infections (76.8%) followed by vaccine safety and its side effects. The motivating factors to convince parents for their children's COVID-19 vaccination were if their doctors recommend it, followed by detailed information on vaccine side effects and efficacy in children. The most trusted source of information for the parents was found to be the healthcare workers. Conclusion: These results suggest that data and reviews regarding the safety and efficacy of the COVID-19 vaccine readily available in the public domain could serve as a highly effective strategy for promoting and implementing widespread vaccination among children. By providing easily accessible and comprehensive information, public health authorities can address parental concerns, dispel misconceptions and foster a greater sense of trust in the vaccination process.

Overexpression of human DNA polymerase theta is a biomarker of aggressive and DNA repair-deficient papillary thyroid cancers.

BACKGROUND: DNA polymerase theta (POLQ) is an enzyme that repairs double-strand DNA breaks. POLQ is overexpressed in several cancer types, and increased expression is associated with a poor prognosis. Ablating POLQ function in vitro increases drug sensitivity to agents that cause double-strand DNA breaks, including chemotherapies and ionizing radiation. POLQ's role in thyroid cancer remains poorly understood. METHODS: Expression of POLQ and other genes of interest were analyzed in 513 papillary thyroid cancers (505 primary tumors and 8 metastatic lesions) and 59 normal thyroid samples available in the Cancer Genome Atlas. The Cancer Genome Atlas RNA and DNA sequencing data were queried with the Xena platform. The Recombination Proficiency Score was calculated to assess DNA repair efficiency. Other signaling events associated with thyroid tumorigenesis and clinical outcomes were analyzed. Univariate and multivariate analyses were performed. Treatment with the POLQ inhibitors ART558 and Novobiocin tested the effect of POLQ inhibition on in vitro thyroid cancer growth. RESULTS: POLQ expression was increased in papillary thyroid cancers compared to normal thyroid tissue (P < .05). POLQ expression levels were inversely correlated with Recombination Proficiency Score levels (P < .05). POLQ expression was highest in tall cell papillary thyroid cancers and in metastases. Higher POLQ expression was also associated with dedifferentiation, BRAF signaling, and shorter progression-free intervals (P < .05). Treatment with POLQ inhibitors decreased in vitro thyroid cancer growth (P < .05). CONCLUSION: These findings suggest that increased POLQ expression could serve as a valuable clinical marker and a potential therapeutic target in the treatment of thyroid cancer.

Toxicological profile using mass spectrometry in sudden cardiac arrest survivors admitted to a tertiary centre.

BACKGROUND: There has been no previous thorough toxicological examination of a cohort of patients with resuscitated sudden cardiac arrest. We aimed to determine the qualitative and quantitative drug composition in a resuscitated sudden cardiac arrest population, using forensic toxicology, with focus on prescribed, non-prescribed, and commonly abused drugs. METHODS: Individuals aged 18-90 years with resuscitated sudden cardiac arrest of presumed cardiac causes were prospectively included from a single tertiary center. Data from the sudden cardiac arrest hospitalization was collected from medical reports. Drugs used during resuscitation or before the blood sampling were identified and excluded in each patient. Mass spectrometry-based toxicology was performed to determine the absence or presence of most drugs and to quantify the findings. RESULTS: Among 186 consecutively enrolled resuscitated sudden cardiac arrest patients (median age 62 years, 83% male), 90% had a shockable rhythm, and were primarily caused by ischemic heart disease (66%). In total, 90 different drugs (excluding metabolites) were identified, and 82% of patients had at least one drug detected (median of 2 detected drugs (IQR:1-4)) (polypharmacy). Commonly abused drugs were present in 16%, and QT-prolonging drugs were present in 12%. Polypharmacy (≥5drugs) were found in 19% of patients. Importantly, none had potentially lethal concentrations of any drugs. CONCLUSION: In resuscitated sudden cardiac arrest patients with cardiac arrest of presumed cardiac cause, routine toxicological screening provides limited extra information. However, the role of polypharmacy in sudden cardiac arrest requires further investigation. No occult overdose-related cardiac arrests were identified.

Year-Over-Year Ventral Hernia Recurrence Rates and Risk Factors.

Importance: Recurrence is one of the most challenging adverse events after ventral hernia repair as it impacts quality of life, utilization of resources, and subsequent need for re-repair. Rates of recurrence range from 30% to 80% after ventral hernia repair. Objective: To determine the contemporary ventral hernia recurrence rate over time in patients with previous hernia repair and to determine risk factors associated with recurrence. Design, Setting, and Participants: This retrospective, population-based study used the Abdominal Core Health Quality Collaborative registry to evaluate year-over-year recurrence rates in patients with prior ventral hernia repair between January 2012 and August 2022. Patients who underwent at least 1 prior ventral hernia repair were included and categorized into 2 groups based on mesh or no-mesh use. There were 43 960 eligible patients; after exclusion criteria (patients with concurrent inguinal hernias as the primary diagnosis, nonstandard hernia procedure categories, American Society of Anesthesiologists class unassigned, or no follow-up), 29 834 patients were analyzed in the mesh group and 5599 in the no-mesh group. Main Outcomes and Measures: Ventral hernia recurrence rates. Risk factors analyzed include age, body mass index, sex, race, insurance type, medical comorbidities, American Society of Anesthesiologists class, smoking, indication for surgery, concomitant procedure, hernia procedure type, myofascial release, fascial closure, fixation type, number of prior repairs, hernia width, hernia length, mesh width, mesh length, operative approach, prior mesh placement, prior mesh infection, mesh location, mesh type, postoperative surgical site occurrence, postoperative surgical site infection, postoperative seroma, use of drains, and reoperation. Results: Among 29 834 patients with mesh, the mean (SD) age was 57.17 (13.36) years, and 14 331 participants (48.0%) were female. Among 5599 patients without mesh, the mean (SD) age was 51.9 (15.31) years, and 2458 participants (43.9%) were female. When comparing year-over-year hernia recurrence rates in patients with and without prior mesh repair, respectively, the Kaplan Meier analysis showed a recurrence rate of 201 cumulative events with 13 872 at risk (2.8%) vs 104 cumulative events with 1707 at risk (4.0%) at 6 months; 411 cumulative events with 4732 at risk (8.0%) vs 184 cumulative events with 427 at risk (32.6%) at 1 year; 640 cumulative events with 1518 at risk (19.7%) vs 243 cumulative events with 146 at risk (52.4%) at 2 years; 731 cumulative events with 670 at risk (29.3%) vs 258 cumulative events with 73 at risk (61.4%) at 3 years; 777 cumulative events with 337 at risk (38.5%) vs 267 cumulative events with 29 at risk (71.2%) at 4 years; and 798 cumulative events with 171 at risk (44.9%) vs 269 cumulative events with 19 at risk (73.7%) at 5 years. Higher body mass index; immunosuppressants; incisional and parastomal hernias; a robotic approach; greater hernia width; use of a biologic or resorbable synthetic mesh; and complications, such as surgical site infections and reoperation, were associated with higher odds of hernia recurrence. Conversely, greater mesh width, myofascial release, and fascial closure had lower odds of recurrence. Hernia type was the most important variable associated with recurrence. Conclusions and Relevance: In this study, the 5-year recurrence rate after ventral hernia repair was greater than 40% and 70% in patients with and without mesh, respectively. Rates of ventral hernia recurrence increased over time, underscoring the importance of close, long-term follow up in this population.

Supramolecular Organo/hydrogel-Fabricated Long Alkyl Chain α-Amidoamides as a Smart Soft Material for pH-Responsive Curcumin Release.

Low-molecular-mass gelators, due to their excellent biocompatibility, low toxicological profile, innate biodegradability and ease of fabrication have garnered significant interest as they self-assemble through non-covalent interactions. In this study, we have designed and synthesized a series of six α-amidoamides by varying the hydrophobic alkyl chain length (C12-C22), which were well characterized using different spectral techniques. These α-amidoamides formed self-assembled aggregates in a DMSO/water solvent system affording organo/hydrogels at 0.66% w/v, which is the minimum gelation concentration (MGC) making them as remarkable supergelators. The various functionalities present in these gelators such as amides and alkyl chain length pave the way toward excellent gelation mechanism through hydrogen bonding and van der Waals interaction as evidenced from FTIR spectroscopy. Notably, as the chain length increased, organo/hydrogels became more thermally stable. Rheological results showed that the stability and strength of these gelators were considerably impacted by variations in chain length. The SEM morphology revealed dense sheet architectures of the organo/hydrogel samples. Organo/hydrogels have a significant impact on the advancement of innovative drug delivery systems that respond to various stimuli, ushering in a new era in pharmaceutical technology. Inspired by this, we encapsulated curcumin, a chemopreventive medication, into the gel core and further released via gel-to-sol transition induced by pH variation at 37 °C, without any alteration in structure-activity relationship. The drug release behavior was observed by UV-vis spectroscopy. Moreover, cell viability and cell invasion experiments demonstrate that the gel formulations exhibit high biocompatibility and low cytotoxicity. Among the tested formulations, 5e+Cur exhibited remarkable efficacy in controlling A549 cell migration, suggesting significant potential for applications in the pharmaceutical industry.

New and Recurrent Ulcerations after Free Tissue Transfer with Partial Bony Resection in Chronic Foot Wounds within a Comorbid Population.

BACKGROUND: Chronic foot wounds often require bony resection; however, altering the tripod of the foot carries a risk of new ulcer development nearing 70%. Resulting defects often require free tissue transfer (FTT) reconstruction; outcomes data for various bony resection and FTT options may guide clinical decision-making regarding bone and soft-tissue management. The authors hypothesized that alteration of the bony tripod will increase risk of new lesion development after FTT reconstruction. METHODS: A single-center retrospective cohort analysis of patients undergoing FTT from 2011 through 2019 with bony resection and soft-tissue defects of the foot was performed. Data collected included demographics, comorbidities, wound locations, and FTT characteristics. Primary outcomes were recurrent lesion (RL) and new lesion (NL) development. Multivariate logistic regression and Cox hazards regression were used to produce adjusted odds ratios and hazard ratios. RESULTS: Sixty-four patients (mean age, 55.9 years) who underwent bony resection and FTT were included. Mean Charlson Comorbidity Index was 4.1 (SD 2.0), and median follow-up was 14.6 months (range, 7.5 to 34.6 months). Wounds developed after FTT in 42 (67.1%) (RL, 39.1%; NL, 40.6%). Median time to NL development was 3.7 months (range, 0.47 to 9.1 months). First-metatarsal defect (OR, 4.8; 95% CI, 1.5 to 15.7) and flap with cutaneous component (OR, 0.24; 95% CI, 0.07 to 0.8) increased and decreased odds of NL development, respectively. CONCLUSIONS: First-metatarsal defects significantly increase NL risk after FTT. The majority of ulcerations heal with minor procedures but require long-term follow-up. Soft-tissue reconstruction with FTT achieves success in the short term, but NL and RL occur at high rates in the months to years after initial healing. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

Breast adipose tissue-derived extracellular vesicles from obese women alter tumor cell metabolism.

Breast adipose tissue is an important contributor to the obesity-breast cancer link. Extracellular vesicles (EVs) are nanosized particles containing selective cargo, such as miRNAs, that act locally or circulate to distant sites to modulate target cell functions. Here, we find that long-term education of breast cancer cells with EVs obtained from breast adipose tissue of women who are overweight or obese (O-EVs) results in increased proliferation. RNA-seq analysis of O-EV-educated cells demonstrates increased expression of genes involved in oxidative phosphorylation, such as ATP synthase and NADH: ubiquinone oxidoreductase. O-EVs increase respiratory complex protein expression, mitochondrial density, and mitochondrial respiration in tumor cells. The mitochondrial complex I inhibitor metformin reverses O-EV-induced cell proliferation. Several miRNAs-miR-155-5p, miR-10a-3p, and miR-30a-3p-which promote mitochondrial respiration and proliferation, are enriched in O-EVs relative to EVs from lean women. O-EV-induced proliferation and mitochondrial activity are associated with stimulation of the Akt/mTOR/P70S6K pathway, and are reversed upon silencing of P70S6K. This study reveals a new facet of the obesity-breast cancer link with human breast adipose tissue-derived EVs causing metabolic reprogramming of breast cancer cells.

Breast Cancer Macrophage Heterogeneity and Self-renewal are Determined by Spatial Localization.

Tumor-infiltrating macrophages support critical steps in tumor progression, and their accumulation in the tumor microenvironment (TME) is associated with adverse outcomes and therapeutic resistance across human cancers. In the TME, macrophages adopt diverse phenotypic alterations, giving rise to heterogeneous immune activation states and induction of cell cycle. While the transcriptional profiles of these activation states are well-annotated across human cancers, the underlying signals that regulate macrophage heterogeneity and accumulation remain incompletely understood. Here, we leveraged a novel ex vivo organotypic TME (oTME) model of breast cancer, in vivo murine models, and human samples to map the determinants of functional heterogeneity of TME macrophages. We identified a subset of F4/80highSca-1+ self-renewing macrophages maintained by type-I interferon (IFN) signaling and requiring physical contact with cancer-associated fibroblasts. We discovered that the contact-dependent self-renewal of TME macrophages is mediated via Notch4, and its inhibition abrogated tumor growth of breast and ovarian carcinomas in vivo, as well as lung dissemination in a PDX model of triple-negative breast cancer (TNBC). Through spatial multi-omic profiling of protein markers and transcriptomes, we found that the localization of macrophages further dictates functionally distinct but reversible phenotypes, regardless of their ontogeny. Whereas immune-stimulatory macrophages (CD11C+CD86+) populated the tumor epithelial nests, the stroma-associated macrophages (SAMs) were proliferative, immunosuppressive (Sca-1+CD206+PD-L1+), resistant to CSF-1R depletion, and associated with worse patient outcomes. Notably, following cessation of CSF-1R depletion, macrophages rebounded primarily to the SAM phenotype, which was associated with accelerated growth of mammary tumors. Our work reveals the spatial determinants of macrophage heterogeneity in breast cancer and highlights the disruption of macrophage self-renewal as a potential new therapeutic strategy.

Facile one-pot multicomponent synthesis of peptoid based gelators as novel scaffolds for drug incorporation and pH-sensitive release.

Infections caused by bacteria are the primary cause of illness and death globally, and antibiotics are the most commonly used medications to treat them. However, there are certain inherent problems in administering these drugs without any changes to their effectiveness. In order to sustain the targeted dosage over time, the use of a biocompatible local drug delivery system using low molecular mass gelators is preferred as a potential approach to reduce its side effects. Low molecular weight organic gelators (LMWOGs) have drawn a lot of attention due to their numerous and varied applications in multiple fields. But nowadays its quite a challenging task to synthesize new types of LMWOGs that can fill the significant gap towards potential applications. In this work, we have explored a multicomponent pathway for the synthesis of a small repertoire of peptoids from simple building blocks by a one-pot Ugi reaction. A variety of novel effective low molecular weight organic gelators have been synthesized, leading to the formation of stable self-assembled aggregates in various solvents such as DMSO, aqueous DMSO, and methanol. Consequently, these aggregates give rise to the creation of organogels and organo/hydrogels. The gels have a minimum gelation concentration (MGC) of 1-2% w/v with high thermal stability. Furthermore, successful encapsulation and release of metronidazole (MZ) were achieved within the gel matrix under physiological pH conditions at 37 °C, ensuring the preservation of its structural and functional properties. The results demonstrated that the release rate of MZ from the organo/hydrogels is contingent on pH, exhibiting a gradual and regulated release in mild alkaline environments. Moreover, the devised system displayed noteworthy antimicrobial efficacy against E. coli, underscoring the potential of these novel low molecular weight organic gels (LMWOGs) as effective drug delivery systems in the pharmaceutical industry. The gel formulations exhibit biocompatibility and negligible cytotoxicity, as evidenced by cell viability studies conducted using the MTT assay.

Myocardial scarring and recurrence of ventricular arrhythmia in patients surviving an out-of-hospital cardiac arrest.

INTRODUCTION: Prediction of recurrent ventricular arrhythmia (VA) in survivors of an out-of-hospital cardiac arrest (OHCA) is important, but currently difficult. Risk of recurrence may be related to presence of myocardial scarring assessed with late gadolinium enhancement cardiac magnetic resonance (LGE-CMR). Our study aims to characterize myocardial scarring as defined by LGE-CMR in survivors of a VA-OHCA and investigate its potential role in the risk of new VA events. METHODS: Between 2015 and 2022, a total of 230 VA-OHCA patients without ST-segment elevation myocardial infarction had CMR before implantable cardioverter-defibrillator implantation for secondary prevention at Copenhagen University Hospital, Rigshospitalet, and Hospital Clínic, University of Barcelona, of which n = 170 patients had a conventional (no LGE protocol) CMR and n = 60 patients had LGE-CMR (including LGE protocol). Scar tissue including core, border zone (BZ) and BZ channels were automatically detected by specialized investigational software in patients with LGE-CMR. The primary endpoint was recurrent VA. RESULTS: After exclusion, n = 52 VA-OHCA patients with LGE-CMR and a mean left ventricular ejection fraction of 49 ± 16% were included, of which 18 (32%) patients reached the primary endpoint of VA. Patients with recurrent VA in exhibited greater scar mass, core mass, BZ mass, and presence of BZ channels compared with patients without recurrent VA. The presence of BZ channels identified patients with recurrent VA with 67% sensitivity and 85% specificity (area under the ROC curve (AUC) 0.76; 95% CI: 0.63-0.89; p < .001) and was the strongest predictor of the primary endpoint. CONCLUSIONS: The presence of BZ channels was the strongest predictor of recurrent VA in patients with an out of-hospital cardiac arrest and LGE-CMR.

Metal-organic framework based drug delivery systems as smart carriers for release of poorly soluble drugs hydrochlorothiazide and dapsone.

Drug delivery systems (DDSs) that are derived from biocompatible carriers are attractive platforms for sustained release of drugs. In particular, sustained and controlled release of poorly soluble BCS (Biopharmaceutics Classification System) class IV drugs is important and this requires the development of new DDSs. In this work, we exploit two porous metal-organic frameworks (MOFs) MIL-100(Fe) and MIL-53(Fe) as carriers/DDSs for the release of two BCS class IV drugs hydrochlorothiazide (HCT) and dapsone (DAP). The chosen MOFs are known to possess good physicochemical stability and we realized high drug loading capacity that is attributed to the high porosity of the MOFs. The drug-encapsulated MOFs were characterized thoroughly and our results show ∼23.1% loading of HCT in MIL-100(Fe) and ∼27.6% loading of DAP in MIL-Fe(53), respectively. The release study of these drugs was carried out under simulated physiological conditions that shows sustained release of the drug molecules from the MOFs up to 72 h. Cell viability studies through MTT assays show insignificant cytotoxicity signalling biocompatibility of the proposed DDSs. Our investigations suggest MIL-100(Fe) and MIL-53(Fe) are potential DDSs for enhancing the performance of poorly soluble drugs HCT and DAP.

Biocompatible Drug Delivery System Based on a MOF Platform for a Sustained and Controlled Release of the Poorly Soluble Drug Norfloxacin.

Norfloxacin (NFX), an important antibacterial fluoroquinolone, is a class IV drug according to the biopharmaceutics classification system (BCS) and has low solubility and permeability issues. Such poor physicochemical properties of drug molecules lead to poor delivery and are of serious concern to the pharmaceutical industry for clinical development. We present here a conceptually new approach to deliver NFX, by loading the drug molecule on the porous platform of a biocompatible metal-organic framework (MOF), MIL-100(Fe). The loading of the drug on the MOF leading to NFX@MIL-100(Fe) was characterized by Fourier transform infrared (FTIR), UV-visible spectroscopy, thermogravimetric analyses (TGA), and nitrogen adsorption studies. Controlled experiments resulted in the high loading of the drug molecule (∼20 wt %) along with the desired sustained release. We could further control the release of norfloxacin by coating drug-loaded MIL-100(Fe) with PEG, PEG{NFX@MIL-100(Fe)}. Both drug delivery systems (DDSs), NFX@MIL-100(Fe) and PEG{NFX@MIL-100(Fe)}, were tested for their biocompatibility through toxicity studies. The DDSs are biocompatible and show insignificant cytotoxicity, as revealed by cell viability studies through the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay.

Differences among young unwitnessed sudden cardiac death, according to time from last seen alive: Insights from a 15-year nationwide study.

BACKGROUND: More than half of all sudden cardiac deaths (SCDs) are unwitnessed, but the composition of the unwitnessed SCD population is poorly described. OBJECTIVE: The purpose of this study was to compare clinical and autopsy characteristics of young unwitnessed SCD subjects, based on the time from last contact to being found dead. METHODS: All unwitnessed SCD subjects aged 1-35 years in Denmark from 2000-2014 identified through a multisource approach were included. Time from last seen alive to being found dead was dichotomized to <1 hour or 1-24 hours. Clinical characteristics and autopsy results were compared, and predictors of autopsy were assessed by logistic regression. RESULTS: Of 440 unwitnessed SCD subjects, 366 (83%) had not been seen alive within 1 hour of being found dead. Comorbidities differed between the groups, with more epilepsy (17% vs 5%) and psychiatric diseases (13% vs 7%) in the 24-hour group. Patients in the 24-hour group died more frequently during sleep (64% vs 23%), the autopsy rate was higher (75% vs 61%), and deaths were more often unexplained after autopsy (69% vs 53%). Having been seen within 1 hour of death independently decreased the chance of being autopsied (odds ratio 0.51; 95% confidence interval 0.27-1.00; P = .0497). CONCLUSION: The majority of unwitnessed SCD subjects had not been seen alive within 1 hour of being found dead. Clinical- and autopsy-related characteristics differed between the 2 groups. Differences were mainly attributable to death-related circumstances and comorbidities. Excluding SCD cases not seen alive within 1 hour of being found dead would severely underestimate the burden of SCD.

Severity of Brugada syndrome disease manifestation and risk of new-onset depression or anxiety: a Danish nationwide study.

AIMS: Reduced psychological health is associated with adverse patient outcomes and higher mortality. We aimed to examine if a Brugada syndrome (BrS) diagnosis and symptomatic disease presentation were associated with an increased risk of new-onset depression or anxiety and all-cause mortality. METHODS AND RESULTS: All Danish patients diagnosed with BrS (2006-2018) with no history of psychiatric disease and available for ≥6 months follow-up were identified using nationwide registries and followed for up to 5 years after diagnosis. The development of clinical depression or anxiety was evaluated using the prescription of medication and diagnosis codes. Factors associated with developing new-onset depression or anxiety were determined using a multivariate Cox proportional hazards regression model. Disease manifestation was categorized as symptomatic (aborted cardiac arrest, ventricular tachycardia, or syncope) or asymptomatic/unspecified at diagnosis. A total of 223 patients with BrS and no history of psychiatric disease were identified (72.6% male, median age at diagnosis 46 years, 45.3% symptomatic). Of these, 15.7% (35/223) developed new-onset depression or anxiety after BrS diagnosis (median follow-up 5.0 years). A greater proportion of symptomatic patients developed new-onset depression or anxiety compared with asymptomatic patients [21/101 (20.8%) and 14/122 (11.5%), respectively, P = 0.08]. Symptomatic disease presentation (HR 3.43, 1.46-8.05) and older age (lower vs. upper tertile: HR 4.41, 1.42-13.63) were significantly associated with new-onset depression or anxiety. All-cause mortality in this group of patients treated according to guidelines was low (n = 4, 1.8%); however, 3/4 developed depression or anxiety before death. CONCLUSION: Approximately, one-sixth of patients with BrS developed new-onset depression or anxiety following a diagnosis of BrS. Symptomatic BrS disease manifestation was significantly associated with new-onset depression or anxiety.

Heterotypic signaling of cancer-associated fibroblasts in shaping the cancer cell drug resistance.

The context-dependent reciprocal interaction between the cancer cells and surrounding fibroblasts is imperative for regulating malignant potential, metabolic reprogramming, immunosuppression, and ECM deposition. However, recent evidence also suggests that cancer-associated fibroblasts induce chemoresistance in cancer cells to various anticancer regimens. Because of the protumorigenic function of cancer-associated fibroblasts, these stromal cell types have emerged as fascinating therapeutic targets for cancer. However, this notion was recently challenged by studies that targeted cancer-associated fibroblasts and highlighted the underlying heterogeneity by identifying a subset of these cells with tumor-restricting functions. Hence, it is imperative to understand the heterogeneity and heterotypic signaling of cancer-associated fibroblasts to target tumor-promoting signaling processes by sparing tumor-restricting ones. In this review, we discuss the heterogeneity and heterotypic signaling of cancer-associated fibroblasts in shaping drug resistance and also list the cancer-associated fibroblast-targeting therapeutics.

Bifunctionalized nanobioprobe based rapid color-shift assay for typhoid targeting Vi capsular polysaccharide.

Typhoid fever is an acute illness caused by Salmonella Typhi and the current diagnostic gap leads to inaccurate, over-diagnosis of typhoid leading to excessive use of antibiotics. Herein, to address the challenges we describe a new rapid color-shift assay based on a novel bifunctional nanobioprobe (Vi-AgNP probe) that is functionalized with specific biomarker Vi polysaccharide and also has the co-presence of Ag as urease inhibitor. The immunoreactions between the Vi with specific antibodies (Abs) present in typhoid patient sample forms a shielding barrier over Vi-AgNP probe rendering the urease to be active, generating colored output. Vi polysaccharide coating on the AgNP was visualized using HRTEM. TEM was performed to get insight into shielding barrier formation by the Abs. MST (microscale thermophoresis) data showed less binding Kd of 7.43 µM in presence of Abs whereas probe with urease showed efficient binding with Kd 437 nM. The assay was validated using 53 human sera samples and proven effective with 100% sensitivity. The assay showed relative standard deviation (RSD) of 4.3% estimated using rabbit anti-Vi Abs. The entire procedure could be completed within 15 min. Unlike lateral flow based assays, our assay does not require multiple combination of Abs for detection. The assay format was also found compatible in paper strip test that provides promising opportunities to develop low-cost on-spot assay for clinical diagnostics.

Use of Nonrecommended Drugs in Patients With Brugada Syndrome: A Danish Nationwide Cohort Study.

Background Patients with Brugada syndrome (BrS) are recommended to avoid drugs that may increase their risk of arrhythmic events. We examined treatment with such drugs in patients with BrS after their diagnosis. Methods and Results All Danish patients diagnosed with BrS (2006-2018) with >12 months of follow-up were identified from nationwide registries. Nonrecommended BrS drugs were grouped into drugs to "avoid" or "preferably avoid" according to http://www.brugadadrugs.org. Cox proportional hazards analyses were performed to identify factors associated with any nonrecommended BrS drug use, and logistic regression analyses were performed to examine associated risk of appropriate implantable cardioverter defibrillator therapy, mortality, and a combined end point indicating an arrhythmic event of delayed implantable cardioverter defibrillator implantation, appropriate implantable cardioverter defibrillator therapy, and mortality. During a median follow-up of 6.8 years, 93/270 (34.4%) patients with BrS (70.4% male, median age at diagnosis 46.1 years [interquartile range, 32.6-57.4]) were treated with ≥1 nonrecommended BrS drugs. No difference in any nonrecommended BrS drug use was identified comparing time before BrS diagnosis (12.6%) with each of the 5 years following BrS diagnosis (P>0.05). Factors associated with any nonrecommended BrS drug use after diagnosis were female sex (hazard ratio [HR]) 1.83 [95% CI, 1.15-2.90]), psychiatric disease (HR, 3.63 [1.89-6.99]), and prior use of any nonrecommended BrS drug (HR, 4.76 [2.45-9.25]). No significant association between any nonrecommended BrS drug use and implantable cardioverter defibrillator therapy (n=20/97, odds ratio [OR], 0.7 [0.2-2.4]), mortality (n=10/270, OR, 3.4 [0.7-19.6]), or the combined end point (n=38/270, OR, 1.7 [0.8-3.7]) was identified. Conclusions One in 3 patients with BrS were treated with a nonrecommended BrS drug after BrS diagnosis, and a BrS diagnosis did not change prescription patterns. More awareness of nonrecommended drug use among patients with BrS is needed.