The Impact of Hypoglossal Nerve Stimulation on Secondary Health Outcomes.

Objectives: Obstructive sleep apnea (OSA) is a prevalent sleep disorder that can increase the risk of hypertension, diabetes, obesity, and cardiovascular diseases. Hypoglossal nerve stimulation (HGNS) is an alternative therapy for OSA in patients who cannot tolerate continuous positive airway pressure. Understanding the impact of HGNS on blood pressure, hemoglobin A1C (A1C), and body mass index (BMI) currently remains limited. Methods: A retrospective review study of HGNS outcomes at a single practice from January 2020 to November 2022 was conducted. Inclusion/exclusion criteria were based on HGNS eligibility and postoperative titration study. Statistical analysis and data management were performed using statistical software, R (v.4.2.1; R Core Team). Paired Student's T test, Fisher's exact test, and McNemar's exact test were utilized for statistical analysis. P values less than .05 were considered statistically significant. Results: Sixty-three patients were included in this study. A significant decrease in mean apnea-hypopnea index was noted following HGNS (mean change -28; P < .0001). Similar significant decreases were also seen in mean arterial pressures (mean change -8.4, P < .0001). There was a significant change in overall antihypertensive medication requirements and in requirements ≥3 medications (P < .0005, P = .03). There was a trend toward reduction in A1C; however, there was no change in BMI or number of diabetes medications taken. Conclusions: Our results reinforce previous findings that HGNS is an effective treatment option for carefully selected patients with OSA. In addition, our findings suggest that HGNS may improve patients' quality of life while minimizing OSA associated morbidity.

Antibiotic cement nails manufactured with threaded rods or cannulated intramedullary nails are better than those made with guidewires and do not debond.

Purpose: The purpose of this study was to comparatively evaluate cement debonding at the time of removal of antibiotic cemented coated nails (ABNs) with cores made with a guidewire ($120), a regular intramedullary nail ($1100) or a threaded rod from a circular frame external fixator set ($60). Methods: A retrospective study was performed on 32 ABNs that had been implanted for long bone infections after intramedullary nailing. All ABNs were manufactured intraoperatively by the treating surgeon using 2 grams of vancomycin and single package of Tobramycin Simplex Cement (Stryker, Kalamazoo, MI). The powder, antibiotics, and polymer were mixed and then injected into an ABN cement mold (Bonesetter Holdings USA). Debonding was assessed at time of removal by the operating surgeon. Rates of cement debonding between the 3 groups were statistically compared. Results: Debonding occurred in 0/12 of the cement nails manufactured with an intramedullary nail, 0/7 threaded rod ABNs, and 6/13 guidewire ABNs. There was a significant difference in the rate of debonding between the 3 groups (P < 0.01). Removal of the remnant cement was accomplished with thin osteotomes, long pituitary rongeurs, or reamers. The canal was visualized using an arthroscope to ensure complete removal of the cement. Conclusion: ABNs fabricated with standard intramedullary nails or threaded rods did not lead to any debonding. Debonding of the cement from the inner core of an antibiotic nail often requires significant effort to remove the remnant cement. Given that threaded rods are often cheaper than guidewires, we recommend that ABNs be fabricated with either threaded rods or interlocking nails, but not guidewires, depending on the level of stability required.

Vertical transmission of African-lineage Zika virus through the fetal membranes in a rhesus macaque (Macaca mulatta) model.

Zika virus (ZIKV) can be transmitted vertically from mother to fetus during pregnancy, resulting in a range of outcomes including severe birth defects and fetal/infant death. Potential pathways of vertical transmission in utero have been proposed but remain undefined. Identifying the timing and routes of vertical transmission of ZIKV may help us identify when interventions would be most effective. Furthermore, understanding what barriers ZIKV overcomes to effect vertical transmission may help improve models for evaluating infection by other pathogens during pregnancy. To determine the pathways of vertical transmission, we inoculated 12 pregnant rhesus macaques with an African-lineage ZIKV at gestational day 30 (term is 165 days). Eight pregnancies were surgically terminated at either seven or 14 days post-maternal infection. Maternal-fetal interface and fetal tissues and fluids were collected and evaluated for ZIKV using RT-qPCR, in situ hybridization, immunohistochemistry, and plaque assays. Four additional pregnant macaques were inoculated and terminally perfused with 4% paraformaldehyde at three, six, nine, or ten days post-maternal inoculation. For these four cases, the entire fixed pregnant uterus was evaluated with in situ hybridization for ZIKV RNA. We determined that ZIKV can reach the MFI by six days after infection and infect the fetus by ten days. Infection of the chorionic membrane and the extraembryonic coelomic fluid preceded infection of the fetus and the mesenchymal tissue of the placental villi. We did not find evidence to support a transplacental route of ZIKV vertical transmission via infection of syncytiotrophoblasts or villous cytotrophoblasts. The pattern of infection observed in the maternal-fetal interface provides evidence of paraplacental vertical ZIKV transmission through the chorionic membrane, the outer layer of the fetal membranes.

Cost analysis of robotic assisted general surgery cases in a single academic institution.

Laparoscopy is currently the standard approach for minimally invasive general surgery procedures. However, robotic surgery is now increasingly being used in general surgery. Robotic surgery provides several advantages such as 3D-visualization, articulated instruments, improved ergonomics, and increased dexterity, but is also associated with an increased overall cost which limits its widespread use. In our institution, the robotic assisted approach is frequently used for the performance of general surgery cases including inguinal hernias, cholecystectomies and paraesophageal hernia (PEH) repairs. The primary aim of the study was to evaluate the differences in cost between a robotic and laparoscopic approach for the above-mentioned cases. With IRB approval, we conducted a retrospective cost analysis of patients undergoing inguinal hernia repairs, cholecystectomies and PEH repairs between June 2018 and November 2020. Patients who had a concomitant procedure, a revisional surgery, or bilateral inguinal hernia repair were excluded from the study. Cost analysis was performed using a micro-costing approach. Statistical significance was denoted by p < 0.05. There were no differences among the different groups in relation to age, gender, ethnicity, and BMI. The overall cost of the robotic (R-) approach compared to a laparoscopic (L-) approach was significantly lower for cholecystectomy ($3,199.96 vs $4019.89, p < 0.05). For inguinal hernia repairs and PEH repairs without mesh, we found no significant difference in overall costs between the R- and L- approach (R- $3835.06 vs L- $3783.50, p = 0.69) and (R- $6852.41 vs L- $6819.69, p = 0.97), respectively. However, the overall cost of PEH with mesh was significantly higher for the R- group compared to the L- group (R- $7,511.09 vs L- $6,443.32, p < 0.05). Based on our institutional cost data, use of a robotic approach when performing certain general surgery cases does not seem to be cost prohibitive.

Maternal, placental and fetal response to a non-viral, polymeric nanoparticle gene therapy in nonhuman primates.

Background: Currently, there are no placenta-targeted treatments to alter the in utero environment. Water-soluble polymers have a distinguished record of clinical relevance outside of pregnancy. We have demonstrated the effective delivery of polymer-based nanoparticles containing a non-viral human insulin-like 1 growth factor ( IGF1 ) transgene to correct placental insufficiency in small animal models of fetal growth restriction (FGR). Our goal was to extend these studies to the pregnant nonhuman primate (NHP) and assess maternal, placental and fetal responses to nanoparticle-mediated IGF1 treatment. Methods: Pregnant macaques underwent ultrasound-guided intraplacental injections of nanoparticles ( GFP- or IGF1- expressing plasmid under the control of the trophoblast-specific PLAC1 promoter complexed with a HPMA-DMEAMA co-polymer) at approximately gestational day 100 (term = 165 days). Fetectomy was performed 24 h ( GFP ; n =1), 48 h ( IGF1 ; n = 3) or 10 days ( IGF1 ; n = 3) after nanoparticle delivery. Routine pathological assessment was performed on biopsied maternal tissues, and placental and fetal tissues. Maternal blood was analyzed for complete blood count (CBC), immunomodulatory proteins and growth factors, progesterone (P4) and estradiol (E2). Placental ERK/AKT/mTOR signaling was assessed using western blot and qPCR. Findings: Fluorescent microscopy and in situ hybridization confirmed placental uptake and transgene expression in villous syncytiotrophoblast. No off-target expression was observed in maternal and fetal tissues. Histopathological assessment of the placenta recorded observations not necessarily related to the IGF1 nanoparticle treatment. In maternal blood, CBCs, P4 and E2 remained within the normal range for pregnant macaques across the treatment period. Changes to placental ERK and AKT signaling at 48 h and 10 d after IGF1 nanoparticle treatment indicated an upregulation in placental homeostatic mechanisms to prevent over activity in the normal pregnancy environment. Interpretation: Maternal toxicity profile analysis and lack of adverse reaction to nanoparticle-mediated IGF1 treatment, combined with changes in placental signaling to maintain homeostasis indicates no deleterious impact of treatment. Funding: National Institutes of Health, and Wisconsin National Primate Research Center.

The X-linked histone demethylase Kdm6a in CD4+ T lymphocytes modulates autoimmunity.

Multiple sclerosis (MS) is a putative T cell-mediated autoimmune disease. As with many autoimmune diseases, females are more susceptible than males. Sexual dimorphisms may be due to differences in sex hormones, sex chromosomes, or both. Regarding sex chromosome genes, a small percentage of X chromosome genes escape X inactivation and have higher expression in females (XX) compared with males (XY). Here, high-throughput gene expression analysis in CD4+ T cells showed that the top sexually dimorphic gene was Kdm6a, a histone demethylase on the X chromosome. There was higher expression of Kdm6a in females compared with males in humans and mice, and the four core genotypes (FCG) mouse model showed higher expression in XX compared with XY. Deletion of Kdm6a in CD4+ T cells ameliorated clinical disease and reduced neuropathology in the classic CD4+ T cell-mediated autoimmune disease experimental autoimmune encephalomyelitis (EAE). Global transcriptome analysis in CD4+ T cells from EAE mice with a specific deletion of Kdm6a showed upregulation of Th2 and Th1 activation pathways and downregulation of neuroinflammation signaling pathways. Together, these data demonstrate that the X escapee Kdm6a regulates multiple immune response genes, providing a mechanism for sex differences in autoimmune disease susceptibility.

Gene expression in oligodendrocytes during remyelination reveals cholesterol homeostasis as a therapeutic target in multiple sclerosis.

Regional differences in neurons, astrocytes, oligodendrocytes, and microglia exist in the brain during health, and regional differences in the transcriptome may occur for each cell type during neurodegeneration. Multiple sclerosis (MS) is multifocal, and regional differences in the astrocyte transcriptome occur in experimental autoimmune encephalomyelitis (EAE), an MS model. MS and EAE are characterized by inflammation, demyelination, and axonal damage, with minimal remyelination. Here, RNA-sequencing analysis of MS tissues from six brain regions suggested a focus on oligodendrocyte lineage cells (OLCs) in corpus callosum. Olig1-RiboTag mice were used to determine the translatome of OLCs in vivo in corpus callosum during the remyelination phase of a chronic cuprizone model with axonal damage. Cholesterol-synthesis gene pathways dominated as the top up-regulated pathways in OLCs during remyelination. In EAE, remyelination was induced with estrogen receptor-ß (ERß) ligand treatment, and up-regulation of cholesterol-synthesis gene expression was again observed in OLCs. ERß-ligand treatment in the cuprizone model further increased cholesterol synthesis gene expression and enhanced remyelination. Conditional KOs of ERß in OLCs demonstrated that increased cholesterol-synthesis gene expression in OLCs was mediated by direct effects in both models. To address this direct effect, ChIP assays showed binding of ERß to the putative estrogen-response element of a key cholesterol-synthesis gene (Fdps). As fetal OLCs are exposed in utero to high levels of estrogens in maternal blood, we discuss how remyelinating properties of estrogen treatment in adults during injury may recapitulate normal developmental myelination through targeting cholesterol homeostasis in OLCs.

Cell-specific and region-specific transcriptomics in the multiple sclerosis model: Focus on astrocytes.

Changes in gene expression that occur across the central nervous system (CNS) during neurological diseases do not address the heterogeneity of cell types from one CNS region to another and are complicated by alterations in cellular composition during disease. Multiple sclerosis (MS) is multifocal by definition. Here, a cell-specific and region-specific transcriptomics approach was used to determine gene expression changes in astrocytes in the most widely used MS model, experimental autoimmune encephalomyelitis (EAE). Astrocyte-specific RNAs from various neuroanatomic regions were attained using RiboTag technology. Sequencing and bioinformatics analyses showed that EAE-induced gene expression changes differed between neuroanatomic regions when comparing astrocytes from spinal cord, cerebellum, cerebral cortex, and hippocampus. The top gene pathways that were changed in astrocytes from spinal cord during chronic EAE involved decreases in expression of cholesterol synthesis genes while immune pathway gene expression in astrocytes was increased. Optic nerve from EAE and optic chiasm from MS also showed decreased cholesterol synthesis gene expression. The potential role of cholesterol synthesized by astrocytes during EAE and MS is discussed. Together, this provides proof-of-concept that a cell-specific and region-specific gene expression approach can provide potential treatment targets in distinct neuroanatomic regions during multifocal neurological diseases.

Postoperative pain management after spinal fusion surgery: an analysis of the efficacy of continuous infusion of local anesthetics.

Spinal fusion surgery is a major surgery that results in severe postoperative pain, therefore pain reduction is a primary concern. New strategies for pain management are currently under investigation and include multimodal treatment. A 3-year retrospective analysis of patients with idiopathic scoliosis undergoing spinal fusion surgery was performed at our hospital, assessing patient pain scores, opioid use, and recovery. We evaluated the effect of adding continuous infusion of local anesthetics (CILA) to a postoperative pain management protocol that includes intraoperative intrathecal morphine, as well as postoperative patient-controlled analgesia and oral opioid/acetaminophen combination. The study compared 25 patients treated according to the standard protocol, with 62 patients treated with CILA in addition to the pain management protocol. Patients in the CILA group used nearly 0.5 mg/kg less opioid analgesics during the first 24 hours after surgery.