The influence of COVID-19 infection-associated immune response on the female reproductive system†.

Coronavirus disease 2019 (COVID-19) is a multi-system disease that has led to a pandemic with unprecedented ramifications. The pandemic has challenged scientists for the past 2 years and brought back previously abandoned research topics. COVID-19 infection causes a myriad of symptoms ranging from mild flu-like symptoms to severe illness requiring hospitalization. Case reports showed multiple systemic effects of COVID-19 infection, including acute respiratory distress syndrome, fibrosis, colitis, thyroiditis, demyelinating syndromes, and mania, indicating that COVID-19 can affect most human body systems. Unsurprisingly, a major concern for women all over the globe is whether a COVID-19 infection has any long-term effects on their menstrual cycle, fertility, or pregnancy. Published data have suggested an effect on the reproductive health, and we hypothesize that the reported reproductive adverse effects are due to the robust immune reaction against COVID-19 and the associated cytokine storm. While the COVID-19 receptor (angiotensin converting enzyme, ACE2) is expressed in the ovaries, uterus, vagina, and placenta, we hypothesize that it plays a less important role in the adverse effects on the reproductive system. Cytokines and glucocorticoids act on the hypothalamo-pituitary gonadal axis, arachidonic acid pathways, and the uterus, which leads to menstrual disturbances and pregnancy-related adverse events such as preterm labor and miscarriages. This hypothesis is further supported by the apparent lack of long-term effects on the reproductive health in females, indicating that when the cytokine storm and its effects are dampened, the reproductive health of women is no longer affected.

Incidence of pacing-induced cardiomyopathy in pacemaker-dependent patients is lower with leadless pacemakers compared to transvenous pacemakers.

INTRODUCTION: Frequent right AQ4ventricular pacing (≥40%) with a transvenous pacemaker (TVP) is associated with the risk of pacing-induced cardiomyopathy (PICM). Leadless pacemakers (LPs) have distinct physical and mechanical differences from TVP. The risk of PICM with LP is not known. To identify incidence, predictors, and long-term outcomes of PICM in LP and TVP patients. METHODS: The study comprised all pacemaker-dependent patients with LP or TVP who had left ventricular ejection fraction (LVEF) of ≥50 from 2014 to 2019. The incidence of PICM (≥10% LVEF drop) was assessed with an echocardiogram. Predictors for PICM were identified using multivariate analysis. Long-term outcomes after cardiac resynchronization (CRT) were assessed in both groups. RESULTS: A total of 131 patients with TVP and 67 with LP comprised the study. All patients in the TVP group and the majority in the LP group underwent atrioventricular node ablation. The mean follow-up duration in TVP and LP groups was 592 ± 549 and 817 ± 600 days, respectively. A total of 18 (13.7%) patients in TVP and 2 (3%) in LP developed PICM after a median duration of 254 (interquartile range: 470) days. The incidence of PICM was significantly higher with TVP compared with LP (p = .02). TVP as pacing modality was a positive (odds ratio [OR]: 1.07) while age was negative (OR: 0.94) predictor for PICM on multivariable analysis. Both patients in LP and all except two in the TVP group responded to CRT. CONCLUSION: Incidence of PICM is significantly lower with LP compared with TVP in pacemaker-dependent patients. Age and TVP as pacing modality were predictors for PICM.

Establishing a point-of-care additive manufacturing workflow for clinical use.

Additive manufacturing, or 3-Dimensional (3-D) Printing, is built with technology that utilizes layering techniques to build 3-D structures. Today, its use in medicine includes tissue and organ engineering, creation of prosthetics, the manufacturing of anatomical models for preoperative planning, education with high-fidelity simulations, and the production of surgical guides. Traditionally, these 3-D prints have been manufactured by commercial vendors. However, there are various limitations in the adaptability of these vendors to program-specific needs. Therefore, the implementation of a point-of-care in-house 3-D modeling and printing workflow that allows for customization of 3-D model production is desired. In this manuscript, we detail the process of additive manufacturing within the scope of medicine, focusing on the individual components to create a centralized in-house point-of-care manufacturing workflow. Finally, we highlight a myriad of clinical examples to demonstrate the impact that additive manufacturing brings to the field of medicine.

Defining new mechanistic roles for αII spectrin in cardiac function.

Spectrins are cytoskeletal proteins essential for membrane biogenesis and regulation and serve critical roles in protein targeting and cellular signaling. αII spectrin (SPTAN1) is one of two α spectrin genes and αII spectrin dysfunction is linked to alterations in axon initial segment formation, cortical lamination, and neuronal excitability. Furthermore, human αII spectrin loss-of-function variants cause neurological disease. As global αII spectrin knockout mice are embryonic lethal, the in vivo roles of αII spectrin in adult heart are unknown and untested. Here, based on pronounced alterations in αII spectrin regulation in human heart failure we tested the in vivo roles of αII spectrin in the vertebrate heart. We created a mouse model of cardiomyocyte-selective αII spectrin-deficiency (cKO) and used this model to define the roles of αII spectrin in cardiac function. αII spectrin cKO mice displayed significant structural, cellular, and electrical phenotypes that resulted in accelerated structural remodeling, fibrosis, arrhythmia, and mortality in response to stress. At the molecular level, we demonstrate that αII spectrin plays a nodal role for global cardiac spectrin regulation, as αII spectrin cKO hearts exhibited remodeling of αI spectrin and altered ß-spectrin expression and localization. At the cellular level, αII spectrin deficiency resulted in altered expression, targeting, and regulation of cardiac ion channels NaV1.5 and KV4.3. In summary, our findings define critical and unexpected roles for the multifunctional αII spectrin protein in the heart. Furthermore, our work provides a new in vivo animal model to study the roles of αII spectrin in the cardiomyocyte.

SuPAR, an emerging biomarker in kidney and inflammatory diseases.

Soluble urokinase plasminogen activator receptor (suPAR) is a circulating form of a physiological and pathophysiological important cell surface receptor, implicated in inflammation. Recent studies showed that suPAR is a promising biomarker, useful for diagnosis, assessment and prognosis of several diseases. This review summarises the majority of preliminary studies and analyses the significance and the clinical application of suPAR in various clinical conditions. SuPAR seems to have a significant value in the diagnosis as well as prognosis of many diseases; nonetheless, it merits large-scale studies to set cut-off values that help physicians in following up their patients and accordingly tailor their treatment plans.

BMP-mediated induction of GATA4/5/6 blocks somitic responsiveness to SHH.

The relative timing of SHH and BMP signals controls whether presomitic mesoderm (PSM) cells will adopt either a chondrogenic or lateral plate mesoderm fate. Here we document that SHH-mediated induction of Nkx3.2 maintains the competence of somitic cells to initiate chondrogenesis in response to subsequent BMP signals by repressing BMP-dependent induction of GATA genes. Conversely, administration of BMP signals to PSM or forced expression of GATA family members in chick PSM explants blocks induction of hedgehog-dependent gene expression. We demonstrate that GATA factors can interact with Gli factors and can recruit the transcriptional co-factor FOG1 (ZFPM1) to the regulatory region of the mouse Gli1 gene, repressing the induction of Gli1 by SHH by binding to both GATA and Gli binding sites. Knockdown of FOG1 reverses the ability of GATA factors to repress Gli1 expression. Our findings uncover a novel role for GATA transcription factors as repressors of hedgehog signaling, and document that NKX3.2 maintains the ability of sclerotomal cells to express SHH transcriptional targets in the presence of BMP signals by repressing the induction of Gata4/5/6.

Nanotheragnostic applications for ischemic and hemorrhagic strokes: improved delivery for a better prognosis.

Stroke is the second leading cause of death worldwide and a major cause of long-term severe disability representing a global health burden and one of the highly researched medical conditions. Nanostructured material synthesis and engineering have been recently developed and have been largely integrated into many fields including medicine. Recent studies have shown that nanoparticles might be a valuable tool in stroke. Different types, shapes, and sizes of nanoparticles have been used for molecular/biomarker profiling and imaging to help in early diagnosis and prevention of stroke and for drug/RNA delivery for improved treatment and neuroprotection. However, these promising applications have limitations, including cytotoxicity, which hindered their adoption into clinical use. Future research is warranted to fully develop and effectively and safely translate nanoparticles for stroke diagnosis and treatment into the clinic. This work will discuss the emerging role of nanotheragnostics in stroke diagnosis and treatment applications.

Salivary Mucinous Adenocarcinoma Masquerading as Chronic Submandibular Sialolithiasis.

A patient with chronic submandibular sialolithiasis underwent conservative treatment with appropriate imaging and multiple biopsies that continually revealed chronic inflammation. Due to continued symptoms, the patient underwent eventual excision and finaly pathology revealed salivary mucinous adenocarcinoma, which is a rare and poorly understood salivary malignancy. Persistent diagnostic workup and a high suspicion for salivary gland lesions is important for appropriate diagnosis and treatment. More attention and research on this specific entity can help future clinicians better diagnose and treat patients with a similar presentation. Laryngoscope, 134:2258-2261, 2024.

Abdominal Wall Reconstruction with Retrorectus Self-Adhering Mesh: A Single-Center Long-Term Follow-Up.

BACKGROUND: Mesh repair has been demonstrated to be superior to suture alone in ventral hernia repair. In a previous short-term pilot study, the authors found lower postoperative narcotic requirements with self-adhering mesh. The aim of this study was to follow-up on that pilot study, using long-term data. METHODS: This is a retrospective review of a prospectively collected database. All patients who underwent ventral hernia repair with retrorectus mesh and who had at least a 12-month follow-up were reviewed. Comparisons were performed between patients who received self-adhering mesh and those who received transfascially sutured mesh, using matched-pair analysis, examining perioperative outcomes, surgical-site occurrences, and hernia recurrence/bulge. RESULTS: Forty-two patients were included in the study, with 21 patients undergoing repair with transfascially sutured mesh and 21 patients receiving self-adhering mesh. Average length of follow-up was 1078 days. There were no significant differences between the two groups in baseline characteristics. Patients receiving self-adhering mesh had significantly shorter surgery, and a shorter hospital length of stay. They also had a tendency toward lower narcotic requirements. There were no significant differences in the rate of surgical-site occurrences, hernia recurrences, or bulge between the two groups. CONCLUSIONS: This long-term study shows that self-adhering mesh in ventral hernia repair results in similar long-term outcomes to transfascially sutured mesh, with shorter surgery, shorter length of stay, and a tendency toward improved pain control. These findings mirror the known advantages of self-adhering mesh in inguinal hernia repair. Further research is needed to study the incidence of chronic pain and the cost-effectiveness of self-adhering mesh. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

The Larry Tube: Customized 3D Printed Laryngectomy Tubes Following Total Laryngectomy.

OBJECTIVE: To determine whether a custom laryngectomy tube can improve airway symptoms in total laryngectomy patients with atypical anatomy who are unable to use commercial laryngectomy tubes. Furthermore, to exemplify the power of customizable 3D printed medical devices when combined with the expanded access pathway through the FDA. METHODS: A custom-fabricated laryngectomy tube, manufactured at in-house clinical engineering labs, was utilized for each patient following typical laryngectomy tube protocols. All participants had previously undergone a total laryngectomy. Patients were selected based on critical airway obstruction posing potentially life-threatening scenarios while using commercially available laryngectomy tubes. RESULTS: For all patients involved, there were no further airway obstruction complications or events, and they reported a subjective, significant improvement in comfort after placement of the custom laryngectomy tube. CONCLUSION: Custom laryngectomy tubes can provide patients with atypical anatomy relief from airway obstructions and improve comfort when commercial options fail to address the anatomic restriction. The process used to develop custom laryngectomy tubes may be relevant for other diseases and patients with atypical anatomies through the expanded access pathway.

Promotion of avian endothelial cell differentiation by GATA transcription factors.

In the avian embryo, endothelial cells originate from several sources, including the lateral plate and somite mesoderm. In this study, we show that Gata transcription factors are expressed in the lateral plate and in vasculogenic regions of the avian somite and are able to promote a vascular endothelial fate when ectopically expressed in somite precursors. A fusion of GATA4 to the transcriptional activator VP16 promoted endothelium formation, indicating that GATA transcription factors promote vasculogenesis via activation of downstream targets, while a fusion of GATA4 to the transcriptional repressor engrailed repressed expression of Vascular Endothelial Growth Factor Receptor 2, a marker of endothelial precursors. These findings indicate a role for GATA transcription factors in the differentiation of the endothelium.

mRNA vaccines: Past, present, future.

mRNA vaccines have emerged as promising alternative platforms to conventional vaccines. Their ease of production, low cost, safety profile and high potency render them ideal candidates for prevention and treatment of infectious diseases, especially in the midst of pandemics. The challenges that face in vitro transcribed RNA were partially amended by addition of tethered adjuvants or co-delivery of naked mRNA with an adjuvant-tethered RNA. However, it wasn't until recently that the progress made in nanotechnology helped enhance mRNA stability and delivery by entrapment in novel delivery systems of which, lipid nanoparticles. The continuous advancement in the fields of nanotechnology and tissue engineering provided novel carriers for mRNA vaccines such as polymeric nanoparticles and scaffolds. Various studies have shown the advantages of adopting mRNA vaccines for viral diseases and cancer in animal and human studies. Self-amplifying mRNA is considered today the next generation of mRNA vaccines and current studies reveal promising outcomes. This review provides a comprehensive overview of mRNA vaccines used in past and present studies, and discusses future directions and challenges in advancing this vaccine platform to widespread clinical use.

Immune checkpoint inhibitors and diabetes: Mechanisms and predictors.

The emergence of immune checkpoint inhibitors in the arsenal of cancer immunotherapy was a breakthrough which provided hope to many cancer patients. However, not long has passed since their discovery that some adverse effects were associated with these promising therapeutic agents. Immune checkpoint inhibitors dysregulate host immunity and may precipitate autoimmune diseases including diabetes mellitus. In this review, we go beyond the case reports towards understanding the underlying mechanisms by which Programmed cell death 1 (PD-1) and Programmed death ligand-1 (PD-L1) inhibitors precipitate diabetes. We discuss the role of PD-1/PD-L1 in autoimmunity and the use of mice models to describe their involvement in diabetes. We also reviewed the genetic anomalies in PD-1/PD-L1genes and their link to diabetes. Finally, we present the studies conducted to identify patients at risk of developing autoimmune diseases as an adverse effect for PD-1/PD-L1 use. Understanding these issues can guide researchers to find a way to circumvent the autoimmune adverse reactions seen with PD-1/PD-L1 inhibitors without affecting their antitumor activity.

Tideglusib attenuates growth of neuroblastoma cancer stem/progenitor cells in vitro and in vivo by specifically targeting GSK-3ß.

BACKGROUND: Neuroblastoma (NB) is the most frequently diagnosed extracranial solid tumor among the pediatric population. It is an embryonic tumor with high relapse rates pertaining to the presence of dormant slowly dividing cancer stem cells (CSC) within the tumor bulk that are responsible for therapy resistance. Therefore, there is a dire need to develop new therapeutic approaches that specifically target NB CSCs. Glycogen synthase kinase (GSK)-3ß is a serine/threonine kinase that represents a common signaling node at the intersection of many pathways implicated in NB CSCs. GSK-3ß sustains the survival and maintenance of CSCs and renders them insensitive to chemotherapeutic agents and radiation. METHODS: In our study, we aimed at evaluating the potential anti-tumor effect of Tideglusib (TDG), an irreversible GSK-3ß inhibitor drug, on three human NB cell lines, SK-N-SH, SH-SY5Y, and IMR-32. RESULTS: Our results showed that TDG significantly reduced cell proliferation, viability, and migration of the NB cells, in a dose- and time-dependent manner, and also significantly hindered the neurospheres formation eradicating the self-renewal ability of highly resistant CSCs. Besides, TDG potently reduced CD133 cancer stem cell marker expression in both SH-SY5Y cells and G1 spheres. Lastly, TDG inhibited NB tumor growth and progression in vivo. CONCLUSION: Collectively, we concluded that TDG could serve as an effective treatment capable of targeting the NB CSCs and hence overcoming therapy resistance. Yet, future studies are warranted to further investigate its potential role in NB and decipher the subcellular and molecular mechanisms underlying this role.

HTR-8/SVneo: A model for epithelial to mesenchymal transition in the human placenta.

INTRODUCTION: The placenta is a transitory organ essential for proper fetal maturation and growth. Trophoblasts, the main cell type of the placenta, differentiate along the villous or extravillous pathways. The ability of villous cytotrophoblasts to undergo an epithelial-to-mesenchymal transition to form the invasive extravillous trophoblasts is vital for a successful pregnancy outcome. Many trophoblastic cell lines, including HTR-8/SVneo, have been widely used to investigate extravillous trophoblast biology and functions. We have previously reported that HTR-8/SVneo cell line contains a mixed populations of epithelial and mesenchymal cells. Uncovering the mechanisms underlying this heterogeneity is essential for the proper study of normal and pathological placental function. METHODS: HTR-8/SVneo was subjected to monoclonal isolation, spheroid formation assay and cell sorting to isolate pure epithelial and mesenchymal populations. These fractions were maintained in culture and assessed for expression of epithelial and mesenchymal markers using quantitative real-time PCR and immunofluorescence. In addition, the implication of TGFß in the EMT process was investigated using a selective inhibitor of TGF-ßR1 (A83-01). RESULTS: Passaging of the pure epithelial population maintained under normal culture condition resulted in a shift to a mesenchymal phenotype. This transition was reduced upon inhibiting TGF-ßR1. Similarly, E-cadherin positive HTR-8/SVneo spheroids plated in 2D culture resulted in the emergence of streams of invading mesenchymal cells. DISCUSSION: HTR-8/SVneo cell line is undergoing EMT under normal culture condition and TGFß is a key mediator of this process. Our results raise the possibility of using HTR-8/SVneo cell line as a model to investigate EMT in extravillous trophoblast cells.

Sinonasal undifferentiated carcinoma: Institutional trend toward induction chemotherapy followed by definitive chemoradiation.

BACKGROUND: Recent reports have investigated the nascent role of induction chemotherapy for sinonasal undifferentiated carcinoma (SNUC). The goal of this study was to ascertain trends in treatment pattern changes for SNUC at a single institution and design a treatment algorithm utilized at our institution. METHODS: Retrospective chart analysis of 21 cases of SNUC from 2010 to 2018. RESULTS: Of 21 patients in this cohort, 18 (85.7%) presented with T4 disease, 7 (33.3%) presented with nodal disease, and 3 (14.3%) presented with distant metastasis. Since 2016, patients have been managed by induction chemotherapy followed by concurrent chemoradiation. To this point, patients treated with TPF induction chemotherapy followed by concurrent chemoradiation show no evidence of disease; however, the average follow up time is 16.8 months. CONCLUSIONS: The multimodality treatment for SNUC continues to evolve, as highlighted by this study, toward increased use of induction chemotherapy followed by chemoradiotherapy.

Current state of leadless pacemakers: state of the art review.

Introduction: Leadless pacemakers (LPs) are the latest advancement in the field of pacing. Experience from pivotal trials and post-marketing studies has proven the feasibility and safety of these devices. The LPs obviate the need of pulse generator pocket and leads, which translates into lower incidence of lead related complications and pocket related infections. This review will summarize the existing literature on the LPs, specifically indications; implant procedure, unique situations and long- term follow up.Areas covered: This review will summarize the results of published pivotal trials. Several multicenter studies where LP was used in the unique situations such as during concomitant AV node ablation and across bioprosthetic valve will also be discussed. An extensive search using PUBMED was performed to identify the relevant articles.Expert commentary: The use of LPs is expanding and the published results a preferential use of such devices for patients who need single ventricle pacing. Additionally, the use of these devices in several unique situations such as patients with inferior vena cava filters, bioprosthetic tricuspid valves and concomitant atrio-ventricular nodal (AV) ablation has also been shown to be safe.

Separating the agony from ecstasy: R(-)-3,4-methylenedioxymethamphetamine has prosocial and therapeutic-like effects without signs of neurotoxicity in mice.

S,R(+/-)-3,4-methylenedioxymethamphetamine (SR-MDMA) is an amphetamine derivative with prosocial and putative therapeutic effects. Ongoing clinical trials are investigating it as a treatment for post-traumatic stress disorder (PTSD) and other conditions. However, its potential for adverse effects such as hyperthermia and neurotoxicity may limit its clinical viability. We investigated the hypothesis that one of the two enantiomers of SR-MDMA, R-MDMA, would retain the prosocial and therapeutic effects but with fewer adverse effects. Using male Swiss Webster and C57BL/6 mice, the prosocial effects of R-MDMA were measured using a social interaction test, and the therapeutic-like effects were assessed using a Pavlovian fear conditioning and extinction paradigm relevant to PTSD. Locomotor activity and body temperature were tracked after administration, and neurotoxicity was evaluated post-mortem. R-MDMA significantly increased murine social interaction and facilitated extinction of conditioned freezing. Yet, unlike racemic MDMA, it did not increase locomotor activity, produce signs of neurotoxicity, or increase body temperature. A key pharmacological difference between R-MDMA and racemic MDMA is that R-MDMA has much lower potency as a dopamine releaser. Pretreatment with a selective dopamine D1 receptor antagonist prevented SR-MDMA-induced hyperthermia, suggesting that differential dopamine signaling may explain some of the observed differences between the treatments. Together, these results indicate that the prosocial and therapeutic effects of SR-MDMA may be separable from the stimulant, thermogenic, and potential neurotoxic effects. To what extent these findings translate to humans will require further investigation, but these data suggest that R-MDMA could be a more viable therapeutic option for the treatment of PTSD and other disorders for which SR-MDMA is currently being investigated.