Hyaluronic acid stimulation of stem cells for cardiac repair: a cell-free strategy for myocardial infarct.

BACKGROUND: Myocardial infarction (MI), a representative form of ischemic heart disease, remains a huge burden worldwide. This study aimed to explore whether extracellular vesicles (EVs) secreted from hyaluronic acid (HA)-primed induced mesenchymal stem cells (HA-iMSC-EVs) could enhance the cardiac repair after MI. RESULTS: HA-iMSC-EVs showed typical characteristics for EVs such as morphology, size, and marker proteins expression. Compared with iMSC-EVs, HA-iMSC-EVs showed enhanced tube formation and survival against oxidative stress in endothelial cells, while reduced reactive oxygen species (ROS) generation in cardiomyocytes. In THP-1 macrophages, both types of EVs markedly reduced the expression of pro-inflammatory signaling players, whereas HA-iMSC-EVs were more potent in augmenting anti-inflammatory markers. A significant decrease of inflammasome proteins was observed in HA-iMSC-EV-treated THP-1. Further, phospho-SMAD2 as well as fibrosis markers in TGF-ß1-stimulated cardiomyocytes were reduced in HA-iMSC-EVs treatment. Proteomic data showed that HA-iMSC-EVs were enriched with multiple pathways including immunity, extracellular matrix organization, angiogenesis, and cell cycle. The localization of HA-iMSC-EVs in myocardium was confirmed after delivery by either intravenous or intramyocardial route, with the latter increased intensity. Echocardiography revealed that intramyocardial HA-iMSC-EVs injections improved cardiac function and reduced adverse cardiac remodeling and necrotic size in MI heart. Histologically, MI hearts receiving HA-iMSC-EVs had increased capillary density and viable myocardium, while showed reduced fibrosis. CONCLUSIONS: Our results suggest that HA-iMSC-EVs improve cardiac function by augmenting vessel growth, while reducing ROS generation, inflammation, and fibrosis in MI heart.

Gut Microbiota and Cognitive Function Among Women Living with HIV.

BACKGROUND: Altered gut microbiota has been associated with cognitive dysfunction and Alzheimer's disease, but little is known among people living with HIV. OBJECTIVE: To examine associations between gut microbiota and cognitive impairment among women with or without HIV. METHODS: This is a cross-sectional study of 446 women (302 HIV+) who had completed a neuropsychological test battery and stool sample collected within 1 year. Gut microbiota composition was quantified using 16SV4 rRNA gene sequencing and microbial functional pathways were predicted using PICRUSt. Cognitive domains included attention, executive function, learning, memory, fluency, processing speed, and motor function. Cognitive impairment was defined as two or more domains with T scores < 1 SD below mean. ANCOM-II was used to identify taxa and functional pathways associated with cognitive impairment, and the associations were further examined by multivariable logistic regression. RESULTS: In overall sample, adjusting for multiple covariates including HIV status, we found that higher abundance of Methanobrevibacter, Odoribacter, Pyramidobacter, Eubacterium, Ruminococcus, and Gemmiger, and lower abundance of Veillonella were associated with cognitive impairment. The associations between these taxa and cognitive impairment were more profound in HIV+ women compared to HIV- women. Most associations with bacterial taxa were observed for learning and memory. We found accompanying microbial functional differences associated with cognitive impairment, including twelve enriched pathways and three depleted pathways. CONCLUSIONS: In women with or without HIV infection, this study identified multiple altered gut bacterial taxa and functional pathways associated with cognitive impairment, supporting the potential role of gut microbiota in cognitive dysfunction and Alzheimer's disease.

Role of Artificial Intelligence in Global Surgery: A Review of Opportunities and Challenges.

Global surgery broadly refers to a rapidly expanding multidisciplinary field concerned with providing better and equitable surgical care across international health systems. Global surgery initiatives primarily focus on capacity building, advocacy, education, research, and policy development in low- and middle-income countries (LMICs). The inadequate surgical, anesthetic, and obstetric care currently contributes to 18 million preventable deaths each year. Hence, there is a growing interest in the rapid growth of artificial intelligence (AI) that provides a distinctive opportunity to enhance surgical services in LMICs. AI modalities have been used for personalizing surgical education, automating administrative tasks, and developing realistic and cost-effective simulation-training programs with provisions for people with special needs. Furthermore, AI may assist with providing insights for governance, infrastructure development, and monitoring/predicting stock take or logistics failure that can help in strengthening global surgery pillars. Numerous AI-assisted telemedicine-based platforms have allowed healthcare professionals to virtually assist in complex surgeries that may help to improve surgical accessibility across LMICs. Challenges in implementing AI technology include the misrepresentation of minority populations in the datasets leading to discriminatory bias. Human hesitancy, employment uncertainty, automation bias, and role of confounding factors need to be further studied for equitable utilization of AI. With a focused and evidence-based approach, AI could help several LMICs overcome bureaucratic inefficiency and develop more efficient surgical systems.

Adults with immune thrombocytopenia who switched to avatrombopag following prior treatment with eltrombopag or romiplostim: A multicentre US study.

Patients with immune thrombocytopenia (ITP) may respond to one thrombopoietin receptor agonist (TPO-RA) but not another. Limited data are available describing outcomes in patients who switched from romiplostim or eltrombopag to avatrombopag, a newer oral TPO-RA. We performed a retrospective observational study of adults with ITP who switched from eltrombopag or romiplostim to avatrombopag at four US tertiary ITP referral centres. Forty-four patients were included, with a mean ITP duration of 8.3 years and a median (range) of four prior ITP treatments. On avatrombopag, 41/44 patients (93%) achieved a platelet response (≥50 × 109 /l) and 38/44 patients (86%) achieved a complete response (≥100 × 109 /l). In all patients, the median platelet count on eltrombopag or romiplostim was 45 × 109 /l vs 114 × 109 /l on avatrombopag (p < 0.0001); in patients switched for ineffectiveness of romiplostim/eltrombopag, it was 28 × 109 /l on romiplostim/eltrombopag vs 88 × 109 /l on avatrombopag (p = 0.025). Fifty-seven percent of patients receiving concomitant ITP medications before switching discontinued them after switching, including 63% of patients receiving chronic corticosteroids. In a heavily pretreated chronic ITP population, avatrombopag was effective following therapy with romiplostim or eltrombopag, with high response rates even in patients with inadequate response to a prior TPO-RA.

Cultivating a Culture of Reflection Among Pharmacy Students Through Storytelling.

Objective. To hold a storytelling event and assess its effect on Doctor of Pharmacy (PharmD) students' perspectives on and attitudes toward reflection. Methods. Story Slam, a four-hour storytelling competition, was incorporated into the spring semester of the first professional year of a PharmD program. The event featured short first-person stories told by faculty members as well as students. Students were invited to participate in a pre- and post-intervention survey and focus group. An inductive qualitative analysis of the resulting data was conducted using textual and audio artifacts. Results. All 136 first professional year (P1) students participated in the 2019 Story Slam. Eleven students submitted qualitative pre- and post-intervention survey instruments and participated in a semi-structured recorded focus group. Thematic analysis revealed nine themes. Students' perspectives regarding the importance of self-reflection changed after participating in Story Slam, with students expressing a greater willingness to engage in self-reflection in the context of professional practice following the event. Students believed Story Slam created an environment conducive to reflection and engagement, resulting in strengthened relationships with peers and faculty members. Students expressed feeling a wide range of emotions as they shared their story and listened to the stories of others. Conclusion. Story Slam is an effective strategy for introducing P1 students to reflection, while also strengthening the school's reflective culture. Additionally, sharing stories may foster positive relationships and cultivate trust and respect between students and faculty members.

Physical Activity and Risk of Postoperative Delirium.

BACKGROUND/OBJECTIVE: Regular physical activity (PA) has been associated with improved cognitive function, but its effect on postoperative delirium (POD) has not been established. Our objectives were to determine the effect of baseline PA on the incidence of POD in older patients undergoing elective orthopedic surgery and to determine whether these effects were independent of cognitive reserve. We hypothesize that PA protects against POD by bolstering physiologic reserve needed to withstand the stressors of surgery. DESIGN: Secondary analysis of a prospective, single-center, cohort study. SETTING: Urban academic hospital. PARTICIPANTS: A total of 132 nondemented, English-speaking adults older than 60 years undergoing elective orthopedic surgery. MEASUREMENTS: Subjects were screened for POD and delirium severity using the Confusion Assessment Method and the Memorial Delirium Assessment Scale. Baseline cognitive activities and PAs were assessed with a validated Leisure Activity Scale. Regular PA was categorized as 6 to 7 days per week. The association of regular PA with incidence of POD was assessed using multivariable logistic regression, adjusting for age, sex, Charlson Comorbidity Index, cognitive reserve, and cognitive function. Linear regression was used to assess the association of delirium severity with regular PA. RESULTS: Of 132 patients, 41 (31.1%) developed POD. Regular PA was associated with a 74% lower odds of developing POD (odds ratio [OR] = 0.26; 95% confidence interval [CI] = 0.08-0.82). There was no significant interaction between PA and cognitive reserve (P = .70). Of 85 women, 25 (29.4%), and of 47 men, 16 (34.0%) developed POD. In stratified analysis, women who engaged in regular PA had dramatically lower odds of POD (OR = 0.08; 95% CI = 0.01-0.63) compared with men (OR = 0.93; 95% CI = 0.18-4.97). CONCLUSIONS: Regular PA is associated with decreased incidence of POD, especially among women. Future studies should address the basis of sex differences in PA benefits on delirium. J Am Geriatr Soc 67:2260-2266, 2019.

Use of the Draeger Apollo to Deliver Bilevel Positive Pressure Ventilation During Awake Frontal Craniotomy for a Patient with Severe Chronic Obstructive Pulmonary Disease.

In this case report, we describe the use of the Draeger Apollo anesthesia machine to deliver bilevel positive airway pressure (BiPAP) to a patient with severe chronic obstructive pulmonary disease and a history of lung resection undergoing frontal craniotomy for the removal of a brain tumor under moderate to deep sedation. BiPAP in the perioperative period has been described for purposes of preoxygenation and postextubation recruitment. Although its utility as a mode of ventilation during moderate to deep sedation has been demonstrated, it has not come into widespread use. We describe the intraoperative use of pressure support mode on the anesthesia machine to deliver noninvasive positive pressure ventilation through a standard anesthesia mask. Given its ease of access and effectiveness, it is our belief that intraoperative BiPAP may reduce hypoxemia and/or hypercarbia in patients with chronic obstructive pulmonary disease and obstructive sleep apnea undergoing moderate to deep sedation.

Spiraeoside inhibits mast cells activation and IgE-mediated allergic responses by suppressing phospholipase C-γ-mediated signaling.

Mast cells are responsible for IgE-mediated allergic responses through the secretion of various inflammatory cytokines and mediators. Therefore, the pharmacological regulation of mast cell activation is an important goal in the development of novel anti-allergic drugs. In this study, we found that spiraeoside (SP) inhibits mast cell activation and allergic responses in vivo. SP dose-dependently inhibited the degranulation induced by IgE-antigen (Ag) stimulation in RBL-2H3 mast cells without cytotoxic effects. At the molecular level, SP reduced the Ag-induced phosphorylation and subsequent activation of phospholipase C-γ2 (PLC-γ2). Moreover, SP inhibited the phosphorylation of spleen tyrosine kinase (Syk), linker for activation of T cells (LAT), and downstream MAPKs, such as ERK1/2, p38, and JNK, eventually attenuating expression of TNF-α and IL-4. Finally, we found that SP significantly inhibited IgE-mediated passive cutaneous anaphylaxis (PCA) in mice. Taken together, our results strongly suggest that SP suppresses IgE-mediated mast cell activation and allergic responses by inhibiting Lyn-induced PLC-γ2/MAPK signaling in mast cells.

Human COL7A1-corrected induced pluripotent stem cells for the treatment of recessive dystrophic epidermolysis bullosa.

Patients with recessive dystrophic epidermolysis bullosa (RDEB) lack functional type VII collagen owing to mutations in the gene COL7A1 and suffer severe blistering and chronic wounds that ultimately lead to infection and development of lethal squamous cell carcinoma. The discovery of induced pluripotent stem cells (iPSCs) and the ability to edit the genome bring the possibility to provide definitive genetic therapy through corrected autologous tissues. We generated patient-derived COL7A1-corrected epithelial keratinocyte sheets for autologous grafting. We demonstrate the utility of sequential reprogramming and adenovirus-associated viral genome editing to generate corrected iPSC banks. iPSC-derived keratinocytes were produced with minimal heterogeneity, and these cells secreted wild-type type VII collagen, resulting in stratified epidermis in vitro in organotypic cultures and in vivo in mice. Sequencing of corrected cell lines before tissue formation revealed heterogeneity of cancer-predisposing mutations, allowing us to select COL7A1-corrected banks with minimal mutational burden for downstream epidermis production. Our results provide a clinical platform to use iPSCs in the treatment of debilitating genodermatoses, such as RDEB.

Surgical debriefing: a reliable roadmap to completing the patient safety cycle.

Morbidity and mortality due to preventable medical errors are a disastrous reality in medicine. Debriefing, a process that allows individuals to discuss team performance in a constructive, supportive environment, has been linked to improved performance in various medical and surgical fields, including improvements in specific procedures, teamwork and communication, and error identification. However, the neurosurgical literature on this topic is limited. The authors review the debriefing literature in the field of medicine, with a specific emphasis on the operating room, and they report their own institutional experience with a debriefing module, from invention to pilot implementation, at Vanderbilt University Medical Center. The authors share the challenges and lessons learned from their quality improvement project. The field of neurosurgery would undoubtedly benefit from embracing debriefing, as its potential has been established in other medical specialties and can serve as a valuable role in immediately learning from mistakes. The authors hope that their colleagues can learn from this experience and improve their own.

Inactivation of Spry2 accelerates AKT-driven hepatocarcinogenesis via activation of MAPK and PKM2 pathways.

BACKGROUND & AIMS: Aberrant activation of the AKT oncogenic pathway and downregulation of the Sprouty 2 (Spry2) tumor suppressor gene are frequently observed molecular events in human hepatocarcinogenesis. The goal of the present study was to investigate the eventual biochemical and genetic crosstalk between activated AKT and inactivation of Spry2 during liver cancer development by using in vivo and in vitro approaches. METHODS: Activated AKT and/or Spry2Y55F, a dominant negative form of Spry2, were overexpressed in the mouse liver via hydrodynamic gene delivery. Histological and biochemical assays were applied to characterize the molecular features of AKT and AKT/Spry2Y55F liver tumors. The human HLE hepatocellular carcinoma (HCC) cell line, stably overexpressing AKT, was transfected with Spry2Y55F to study the molecular mechanisms underlying hepatocarcinogenesis driven by Spry2 loss. RESULTS: Spry2Y55F overexpression significantly accelerated AKT-induced hepatocarcinogenesis in the mouse. AKT/Spry2Y55F liver lesions had increased proliferation and glycolysis and decreased lipogenesis when compared with AKT corresponding lesions. At the molecular level, AKT/Spry2Y55F HCCs exhibited a significantly stronger induction of activated mitogen-activated protein kinase (MAPK) and pyruvate kinase M2 (PKM2) pathways than in AKT corresponding lesions. This phenotype was reproduced in HLE cells overexpressing AKT following transfection with Spry2Y55F. Furthermore, we found that concomitant suppression of the MAPK cascade and PKM2 strongly inhibited the growth induced by Spry2Y55F in AKT-overexpressing cells. CONCLUSIONS: Inactivation of Spry2 accelerates AKT-induced hepatocarcinogenesis via activation of MAPK and PKM2 pathways.

Novel use of electronic whiteboard in the operating room increases surgical team compliance with pre-incision safety practices.

BACKGROUND: Despite evidence that use of a checklist during the pre-incision time out improves patient morbidity and mortality, compliance with performing the required elements of the checklist has been low. In an effort to improve compliance, a standardized time out interactive Electronic Checklist System [iECS] was implemented in all hospital operating room (OR) suites at 1 institution. The purpose of this 12-month prospective observational study was to assess whether an iECS in the OR improves and sustains improved surgical team compliance with the pre-incision time out. METHODS: Direct observational analyses of preprocedural time outs were performed on 80 cases 1 month before, and 1 and 9 months after implementation of the iECS, for a total of 240 observed cases. Three observers, who achieved high interrater reliability (kappa = 0.83), recorded a compliance score (yes, 1; no, 0) on each element of the time out. An element was scored as compliant if it was clearly verbalized by the surgical team. RESULTS: Pre-intervention observations indicated that surgical staff verbally communicated the core elements of the time out procedure 49.7 ± 12.9% of the time. After implementation of the iECS, direct observation of 80 surgical cases at 1 and 9 months indicated that surgical staff verbally communicated the core elements of the time out procedure 81.6 ± 11.4% and 85.8 ± 6.8% of the time, respectively, resulting in a statistically significant (P < .0001) increase in time out procedural compliance. CONCLUSION: Implementation of a standardized, iECS can dramatically increase compliance with preprocedural time outs in the OR, an important and necessary step in improving patient outcomes and reducing preventable complications and deaths.

AKT (v-akt murine thymoma viral oncogene homolog 1) and N-Ras (neuroblastoma ras viral oncogene homolog) coactivation in the mouse liver promotes rapid carcinogenesis by way of mTOR (mammalian target of rapamycin complex 1), FOXM1 (forkhead box M1)/SKP2, and c-Myc pathways.

UNLABELLED: Activation of v-akt murine thymoma viral oncogene homolog (AKT) and Ras pathways is often implicated in carcinogenesis. However, the oncogenic cooperation between these two cascades in relationship to hepatocellular carcinoma (HCC) development remains undetermined. To investigate this issue, we generated a mouse model characterized by combined overexpression of activated forms of AKT and neuroblastoma Ras viral oncogene homolog (N-Ras) protooncogenes in the liver by way of hydrodynamic gene transfer. The molecular mechanisms underlying crosstalk between AKT and N-Ras were assessed in the mouse model and further evaluated in human and murine HCC cell lines. We found that coexpression of AKT and N-Ras resulted in a dramatic acceleration of liver tumor development when compared with mice overexpressing AKT alone, whereas N-Ras alone did not lead to tumor formation. At the cellular level, concomitant up-regulation of AKT and N-Ras resulted in increased proliferation and microvascularization when compared with AKT-injected mice. Mechanistic studies suggested that accelerated hepatocarcinogenesis driven by AKT and N-Ras resulted from a strong activation of mammalian target of rapamycin complex 1 (mTORC1). Furthermore, elevated expression of FOXM1/SKP2 and c-Myc also contributed to rapid tumor growth in AKT/Ras mice, yet by way of mTORC1-independent mechanisms. The biological effects of coactivation of AKT and N-Ras were then recapitulated in vitro using HCC cell lines, which supports the functional significance of mTORC1, FOXM1/SKP2, and c-Myc signaling cascades in mediating AKT and N-Ras-induced liver tumor development. CONCLUSION: Our data demonstrate the in vivo crosstalk between the AKT and Ras pathways in promoting liver tumor development, and the pivotal role of mTORC1-dependent and independent pathways in mediating AKT and Ras induced hepatocarcinogenesis.

Increased prevalence of celiac disease in patients with unexplained infertility in the United States.

OBJECTIVE: To determine whether there might be an increased prevalence of undiagnosed celiac disease among a population of infertile women using serologic screening. STUDY DESIGN: A prospective cohort study was performed at an academic infertility clinic in the United States. RESULTS: The overall prevalence of celiac disease in this population was 2.1% (4/188). There was a significantly increased prevalence (5.9%) of undiagnosed celiac disease among women presenting with unexplained infertility (n = 51). CONCLUSION: Women with unexplained infertility are at increased risk for having undiagnosed celiac disease, which may be a potentially modifiable (and treatable) risk factor.

Increased lipogenesis, induced by AKT-mTORC1-RPS6 signaling, promotes development of human hepatocellular carcinoma.

BACKGROUND & AIMS: De novo lipogenesis is believed to be involved in oncogenesis. We investigated the role of aberrant lipid biosynthesis in the pathogenesis of human hepatocellular carcinoma (HCC). METHODS: We evaluated expression of enzymes that regulate lipogenesis in human normal liver tissues and HCC and surrounding, nontumor, liver tissues from patients using real-time reverse transcription polymerase chain reaction, immunoblotting, immunohistochemistry, and biochemical assays. Effects of lipogenic enzymes on human HCC cell lines were evaluated using inhibitors and overexpression experiments. The lipogenic role of the proto-oncogene AKT was assessed in vitro and in vivo. RESULTS: In human liver samples, de novo lipogenesis was progressively induced from nontumorous liver tissue toward the HCC. Extent of aberrant lipogenesis correlated with clinical aggressiveness, activation of the AKT-mammalian target of rapamycin signaling pathway, and suppression of adenosine monophosphate-activated protein kinases. In HCC cell lines, the AKT-mammalian target of rapamycin complex 1-ribosomal protein S6 pathway promoted lipogenesis via transcriptional and post-transcriptional mechanisms that included inhibition of fatty acid synthase ubiquitination by the USP2a de-ubiquitinase and disruption of the SREBP1 and SREBP2 degradation complexes. Suppression of the genes adenosine triphosphate citrate lyase, acetyl-CoA carboxylase, fatty acid synthase, stearoyl-CoA desaturase 1, or sterol regulatory element-binding protein 1, which are involved in lipogenesis, reduced proliferation, and survival of HCC cell lines and AKT-dependent cell proliferation. Overexpression of an activated form of AKT in livers of mice induced lipogenesis and tumor development. CONCLUSIONS: De novo lipogenesis has pathogenic and prognostic significance for HCC. Inhibitors of lipogenic signaling, including those that inhibit the AKT pathway, might be useful as therapeutics for patients with liver cancer.

RNA interference as therapeutics for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC), a major form of primary liver cancer, is one of the leading causes of cancer related deaths worldwide. Hepatitis B and C infections are major risk factors for the development of HCC. Currently, the treatment options are rather limited, and the prognosis for this malignancy is poor for most of these patients. RNA interference has emerged as an innovative technology for gene silencing and as a potential therapeutic for various diseases, including cancer. HCC has been widely chosen as a model system for the development of RNAi therapy due to the convenience and availability of effective delivery of RNA molecules into liver tissues. Targets for HCC treatment include HBV and HCV viruses, oncogenes, as well as cellular genes mediating angiogenesis, tumor growth and metastasis. Here, we summarized the progress of RNAi therapeutics in HCC treatment, relevant patents, potential challenges and prospects in the future.

Synergistic role of Sprouty2 inactivation and c-Met up-regulation in mouse and human hepatocarcinogenesis.

UNLABELLED: Sprouty2 (Spry2), a negative feedback regulator of the Ras/mitogen-activated protein kinase (MAPK) pathway, is frequently down-regulated in human hepatocellular carcinoma (HCC). We tested the hypothesis that loss of Spry2 cooperates with unconstrained activation of the c-Met protooncogene to induce hepatocarcinogenesis via in vitro and in vivo approaches. We found coordinated down-regulation of Spry2 protein expression and activation of c-Met as well as its downstream effectors extracellular signal-regulated kinase (ERK) and v-akt murine thymoma viral oncogene homolog (AKT) in a subset of human HCC samples with poor outcome. Mechanistic studies revealed that Spry2 function is disrupted in human HCC via multiple mechanisms at both transcriptional and post-transcriptional level, including promoter hypermethylation, loss of heterozygosity, and proteosomal degradation by neural precursor cell expressed, developmentally down-regulated 4 (NEDD4). In HCC cell lines, Spry2 overexpression inhibits c-Met-induced cell proliferation as well as ERK and AKT activation, whereas loss of Spry2 potentiates c-Met signaling. Most importantly, we show that blocking Spry2 activity via a dominant negative form of Spry2 cooperates with c-Met to promote hepatocarcinogenesis in the mouse liver by sustaining proliferation and angiogenesis. The tumors exhibited high levels of activated ERK and AKT, recapitulating the subgroup of human HCC with a clinically aggressive phenotype. CONCLUSION: The occurrence of frequent genetic, epigenetic, and biochemical events leading to Spry2 inactivation provides solid evidence that Spry2 functions as a tumor suppressor gene in liver cancer. Coordinated deregulation of Spry2 and c-Met signaling may be a pivotal oncogenic mechanism responsible for unrestrained activation of ERK and AKT pathways in human hepatocarcinogenesis.