High-Throughput Transcriptomics Screen of ToxCast Chemicals in U-2 OS Cells.

New approach methodologies (NAMs) aim to accelerate the pace of chemical risk assessment while simultaneously reducing cost and dependency on animal studies. High Throughput Transcriptomics (HTTr) is an emerging NAM in the field of chemical hazard evaluation for establishing in vitro points-of-departure and providing mechanistic insight. In the current study, 1201 test chemicals were screened for bioactivity at eight concentrations using a 24-h exposure duration in the human- derived U-2 OS osteosarcoma cell line with HTTr. Assay reproducibility was assessed using three reference chemicals that were screened on every assay plate. The resulting transcriptomics data were analyzed by aggregating signal from genes into signature scores using gene set enrichment analysis, followed by concentration-response modeling of signatures scores. Signature scores were used to predict putative mechanisms of action, and to identify biological pathway altering concentrations (BPACs). BPACs were consistent across replicates for each reference chemical, with replicate BPAC standard deviations as low as 5.6 × 10-3 µM, demonstrating the internal reproducibility of HTTr-derived potency estimates. BPACs of test chemicals showed modest agreement (R2 = 0.55) with existing phenotype altering concentrations from high throughput phenotypic profiling using Cell Painting of the same chemicals in the same cell line. Altogether, this HTTr based chemical screen contributes to an accumulating pool of publicly available transcriptomic data relevant for chemical hazard evaluation and reinforces the utility of cell based molecular profiling methods in estimating chemical potency and predicting mechanism of action across a diverse set of chemicals.

Superior Ophthalmic Vein Thrombosis Associated With Asymptomatic COVID-19 Infection.

Superior ophthalmic vein thrombosis is a rare condition scarcely described in clinical literature with potentially severe consequences including permanent vision loss. This report details the case of a 70-year-old woman who presented with acute binocular horizontal diplopia, relative proptosis of the OD by 4 mm, and pain OD. On exam, visual acuity was 20/20 OD and 20/30 OS with full extraocular movements. CT revealed proptosis OD with a thrombosed superior ophthalmic varix. Evaluation for etiology of hypercoagulability was unremarkable, although the patient did have an asymptomatic COVID-19 infection 1 month prior. To the authors' knowledge, this is the first reported case of superior ophthalmic vein thrombosis secondary to an asymptomatic COVID-19 infection.

Isolated Ocular Relapse of Acute Myeloid Leukaemia Post Allogeneic Stem Cell Transplant.

We present a rare case of a 39-year-old female with extramedullary relapse of acute myeloid leukaemia (AML) isolated to the left eye 2 months post allogeneic haematopoietic stem cell transplant. She initially presented with painless left eye erythema, swelling, and visual impairment. Initial ophthalmology review revealed conjunctival chemosis, raised intraocular pressure, and serous retinal detachments. She was initially treated for suspected orbital cellulitis with intravenous antibiotic and antifungal therapy but clinically progressed so was then treated with intravenous corticosteroids. One week later, she progressed to angle-closure glaucoma with development of a hypopyon and an enlarging subconjunctival mass. She proceeded to urgent subconjunctival biopsy and drainage of subretinal fluid which confirmed extramedullary relapse of AML. Notably, further investigation found no evidence of bone marrow or central nervous system relapse. She proceeded to localized radiotherapy with gradual resolution of the subconjunctival mass and serous retinal detachment and was for consideration of donor lymphocyte infusions and azacitidine therapy; unfortunately, she developed respiratory sepsis and passed away despite maximal efforts. This case represents a rare and unusual presentation of isolated ocular extramedullary relapse of AML and emphasises the importance of early ophthalmology involvement and tissue biopsy when there is high clinical suspicion of the disease.

Ophthalmic manifestations and management considerations for emerging chemical threats.

Chemical agents have been utilized for centuries in warfare and pose a health threat to civilians and military personnel during armed conflict. Despite treaties and regulations against their use, chemical agent exposure remains a threat and measures to understand their effects and countermeasures for systemic and organ-specific health are needed. Many of these agents have ocular complications, both acute and chronic. This mini-review focuses on key chemical agents including vesicants (mustards, lewisite), nerve agents (sarin, VX), knockdown gasses (hydrogen cyanide), and caustics (hydrofluoric acid). Their ophthalmic manifestations and appropriate treatment are emphasized. Acute interventions include removal of the source and meticulous decontamination, as well as normalization of pH to 7.2-7.4 if alteration of the ocular pH is observed. Besides vigorous lavage, acute therapies may include topical corticosteroids and non-steroid anti-inflammatory therapies. Appropriate personal protective equipment (PPE) and strict donning and doffing protocols to avoid healthcare provider exposure are also paramount in the acute setting. For more severe disease, corneal transplantation, amniotic membrane graft, and limbal stem cell transplantation may be needed. Orbital surgery may be required in patients in whom cicatricial changes of the ocular surface have developed, leading to eyelid malposition. Multidisciplinary care teams are often required to handle the full spectrum of findings and consequences associated with emerging chemical threats.

The Effects of Smoking on the Diagnostic Characteristics of Metabolic Syndrome: A Review.

Metabolic syndrome is a growing epidemic that increases the risk for cardiovascular disease, diabetes, stroke, and mortality. It is diagnosed by the presence of three or more of the following risk factors: 1) obesity, with an emphasis on central adiposity, 2) high blood pressure, 3) hyperglycemia, 4) dyslipidemia, with regard to reduced high-density lipoprotein concentrations, and 5) dyslipidemia, with regard to elevated triglycerides. Smoking is one lifestyle factor that can increase the risk for metabolic syndrome as it has been shown to exert negative effects on abdominal obesity, blood pressure, blood glucose concentrations, and blood lipid profiles. Smoking may also negatively affect other factors that influence glucose and lipid metabolism including lipoprotein lipase, adiponectin, peroxisome proliferator-activated receptors, and tumor necrosis factor-alpha. Some of these smoking-related outcomes may be reversed with smoking cessation, thus reducing the risk for metabolic disease; however, metabolic syndrome risk may initially increase post cessation, possibly due to weight gain. Therefore, these findings warrant the need for more research on the development and efficacy of smoking prevention and cessation programs.

Conditional Minimal Detectable Change for the Cochlear Implant Quality of Life-35 Profile Associated With Improved Functional Abilities 12 Months After Cochlear Implantation.

Importance: It is essential to measure an individual patient's baseline and follow-up abilities to demonstrate changes in clinical outcomes over time. Inherent in this strategy is interpreting whether the measured change is clinically significant and beyond measurement error. Conditional minimal detectable change (cMDC) values are widely used in many disciplines but have rarely been established for outcome measures in otolaryngology or hearing research, and never in cochlear implantation. Objective: To determine cMDC values for the Cochlear Implant Quality of Life-35 (CIQOL-35) Profile instrument to enhance our understanding of the initial and ongoing changes in functional abilities from cochlear implants (CIs). Design, Setting, and Participants: Item response theory analyses of responses from a multi-institutional cohort of 705 CI users at a tertiary CI center were used to derive standard error (SE) values for each possible CIQOL-35 domain score. Using an iterative approach, these SE values were used to calculate cMDC values for every possible pre-CI and post-CI domain score combination. We then compared pre-CI to 12-month post-CI CIQOL-35 domains scores in an independent cohort of 65 adult CI users to determine whether the measured change exceeded error to be clinically significant. The analysis took place on December 14, 2022. Interventions: The CIQOL-35 Profile instrument and cochlear implantation. Results: The cMDC values were smaller for the communication domain, and global measure and cMDC values for all domains were larger at the extremes of the measurement scale. Overall, 60 CI users (92.3%) demonstrated improvement beyond cMDC at 12 months post-CI for at least 1 CIQOL-35 domain, and no patients' scores declined beyond cMDC for any domain. The percentage of CI users demonstrating improvement beyond cMDC varied by domain, with communication (53 [81.5%]) showing the largest number of CI users improving, followed by global (42 [64.6%]) and entertainment (40 [60.9%]). In general, CI users who demonstrated improvement in CIQOL-35 domains had greater improvement in speech recognition scores than patients who did not, but the strength and significance of these associations greatly varied by domain and speech material. Conclusions and Relevance: This multistep cohort study found that cMDC values for the CIQOL-35 Profile provided personalized thresholds for detecting real changes in patient self-reported functional abilities over time across multiple domains, which may inform clinical decision-making. Moreover, these longitudinal results reveal the domains with more or less improvement, which may aid in patient counseling.

Anesthesia for Global General Thoracic Surgery.

Anesthesia in low-to-middle income countries (LMICs) is often provided by nonphysician anesthetists. The training and resources for anesthesia in LMICs are limited, and this must be evaluated when starting or expanding a thoracic surgery program in LMICs. The ability to access a patient's baseline pulmonary and cardiovascular status is often based on rudimentary studies and a thorough history and physical. Advance studies, such as echocardiograms, cardiovascular stress test, cardiac catherizations, pulmonary function tests, and MRIs, are often not available. Careful assessment of both preoperative patient selection, intraoperative ability to provide one-lung ventilation, and postoperative critical care management must be considered when surgical planning is occurring.

Anesthetic Management for Combined Anterior Cervical Spinal Decompression and Fusion and Cesarean Delivery: A Case Report.

A 31-year-old G2P1 (gravida 2 para 1) woman at 34 weeks of gestation presented after a motor vehicle collision with an incomplete cervical spinal cord injury. The patient underwent emergent anterior cervical decompression and fusion (ACDF), immediately followed by cesarean delivery. We discuss the clinical decision making to perform ACDF first, weighing risks and benefits to both mother and baby. We also address important anesthetic considerations for this pregnant patient having emergent spine surgery, including positioning with left uterine displacement, rapid sequence intubation to minimize aspiration risk, choice of vasopressor, implications of total intravenous maintenance anesthetic, and the medical teams involved in this care.

Do oropharyngeal throat packs prevent fluid ingestion during orthognathic surgery?

The oropharyngeal throat pack is commonly used in oral and maxillofacial surgery despite debated evidence regarding its barrier function. The study objectives were to investigate whether the oropharyngeal pack reduces blood ingestion and to evaluate its relationship with postoperative nausea and vomiting (PONV) and throat pain. This was a single-center, parallel group, single-blind randomized controlled trial. Participants undergoing orthognathic surgery, age ≥16 years, were included in the study. After intubation and prior to surgery start, the treatment group received oropharyngeal packing; the control group received no packing. Outcome variables were the quality of gastric contents aspirated by nasogastric tube (bloody or not bloody), PONV, and throat pain (visual analog scale). Thirty patients (treatment n = 15; control n = 15) were randomized and analyzed. There was no difference between the groups in quality of gastric contents (P = 1.00) or incidence of PONV at 2 hours and 24 hours (P = 1.00). Throat pain incidence and severity at 2 hours were both higher in the treatment group, but this was not statistically significant (P = 0.128, P = 0.223). The results indicate that the oropharyngeal pack is not an effective barrier against blood ingestion. Oropharyngeal packs do not improve or worsen PONV, but may increase throat pain.

Cardiac transplantation outcomes in patients with amyloid cardiomyopathy.

OBJECTIVE: Amyloid cardiomyopathy (ACM) is a progressive and life-threatening disease caused by abnormal protein deposits within cardiac tissue. The most common forms of ACM are caused by immunoglobulin derived light chains (AL) and transthyretin (TTR). Orthotopic heart transplantation (OHT) remains the definitive treatment for patients with end stage heart failure. In this study, we perform a contemporary multicenter analysis evaluating post OHT survival in patients with ACM. METHODS: We conducted a multicenter analysis of 40,044 adult OHT recipients captured in the United Network for Organ Sharing (UNOS) registry from 1987-2018. Patients were characterized as ACM or non-ACM. Baseline characteristics were obtained, and summary characteristics were calculated. Outcomes of interest included post-transplant survival, infection, treated rejection, and the ability to return to work. Racial differences in OHT survival were also analyzed. Unadjusted associations between ACM and non-ACM survival were determined using the Kaplan-Meier estimations and confounding was addressed using multivariable Cox proportional hazards models. RESULTS: Three hundred ninety-eight patients with a diagnosis of ACM were identified of which 313 underwent heart only OHT. ACM patients were older (61 vs 53; P < .0001) and had a higher proportion of African Americans (30.7% vs 17.6%; P < .0001). Median survival for ACM was 10.2 years vs 12.5 years in non-ACM (P = .01). After adjusting for confounding, ACM patients had a higher likelihood of death post-OHT (HR 1.39 CI: 1.14, 1.70; P = .001). African American ACM patients had a higher likelihood of survival compared to White ACM patients (HR 0.51 CI 0.31-0.85; P = .01). No difference was observed in episodes of treated rejection (OR 0.63 CI 0.23, 1.78; P = .39), hospitalizations for infections (OR 1.24 CI: 0.85, 1.81; P = .26), or likelihood of returning to work for income (OR 1.23 CI: 0.84, 1.80; P = .30). CONCLUSIONS: In this analysis of OHT in ACM, ACM was associated with a higher likelihood of post-OHT mortality. Racial differences in post-OHT were observed with African American patients with ACM having higher likelihood of survival compared to White patients with ACM. No differences were observed in episodes of treated rejection, hospitalization for infection, or likelihood to return to work for income.

History of cigarette smoking and heart transplant outcomes.

Background : Active cigarette smoking (CS) is a contraindication for Orthotopic Heart Transplantation (OHT) with a recommendation that HT candidates be free from CS for at minimum 6 months prior to HT. Animal studies have shown that a history of CS is associated with increased risk of allograft rejection, but few studies have examined the association of past CS and HT outcomes. Methods : Data were analyzed from HT recipients captured in the United Network for Organ Sharing (UNOS) transplant registry. Adults aged 18-79 who underwent HT from 1987 to 2018 and with data for all covariates (N = 32,260) were included in this study. The cohort was categorized by past smoking history (CS vs non-CS). Post-transplant outcomes of interest included survival, graft failure, treated rejection, malignancy and hospitalization for infection. Baseline characteristics were compared between the two groups using the chi-squared analysis. Unadjusted associations between CS and patient survival were determined using the Kaplan-Meier estimations and confounding was addressed using multivariable Cox proportional hazards models. Results : HT recipients with a history of CS were older (55 vs 50, p = <0.0001), more likely to be Caucasian (75.7 vs 62.3, p = <0.0001), male (81.7 vs 68.2, p =< 0.0001), and diabetic (27.4 vs 24.4, p =< 0.0001). CS was associated with significantly worse survival (HR: 1.23, p < 0.0001). A history of CS was also associated with increased risk of acute rejection (OR: 1.20, p < 0.0001), hospitalization for infection (OR:1.24, p < 0.0001), graft failure (OR:1.23, p < 0.0001) and post-transplant malignancy (OR:1.43, p < 0.0001). Conclusion : A history of CS is associated with increased risk of adverse events post OHT.

Histological Analysis of the Effect of ATX-101 (Deoxycholic Acid Injection) on Subcutaneous Fat: Results From a Phase 1 Open-Label Study.

BACKGROUND: ATX-101 is approved for submental fat reduction. OBJECTIVE: To characterize the histological effect of ATX-101 injection into subcutaneous fat. METHODS: This Phase 1 open-label study enrolled 14 adults to receive injections of ATX-101 into abdominal fat at varying concentrations (0.5%, 1.0%, 2.0%, or 4.0%), volumes (0.2 or 0.4 mL), spacing (0.7, 1.0, or 1.5 cm), and time points before scheduled abdominoplasty (1, 3, 7, or 28 days). During abdominoplasty, tissue was excised and preserved for histology. RESULTS: All injection paradigms resulted in histological changes confined to the subcutaneous layer, which were more prominent at higher concentrations and independent of volume and spacing. Key features at Day 1 after injection were adipocytolysis, blood vessel injury, neutrophilic inflammation, and lysis of locally present neutrophils. At Day 3, inflammation was reduced versus Day 1, and hemorrhage and lipid lake formation (at higher concentrations) were observed. Day 7 samples exhibited prominent adipocytolysis, mild inflammation, lipid-laden macrophages in the septae, and repair of vascular injury. At Day 28, inflammation was largely resolved and prominent features were septal thickening, neovascularization, and atrophy of fat lobules. CONCLUSION: Subcutaneous injection of ATX-101 induces adipocytolysis and local inflammation with septal thickening and resolution of inflammation by 28 days after injection.

Cigarette Smoking: An Accessory to the Development of Insulin Resistance.

Insulin resistance is a condition characterized by decreased sensitivity of a skeletal or adipose cell to insulin, resulting in decreased glucose uptake by the cell. This can lead to hyperinsulinemia and further reduce insulin sensitivity. Insulin resistance is one of the primary factors contributing to metabolic syndrome (MetS), causing elevated glucose and fatty acid concentrations in the blood. Smoking is associated with insulin resistance in a dose-dependent manner. It directly increases the risk for insulin resistance, mainly via hormone activation, and may indirectly cause insulin resistance due to its effects on abdominal obesity. Nicotine may be the factor underlying these potential mechanisms. With the prevalence of prediabetes and diabetes on the rise, and considering the role of smoking and its relationship to insulin resistance, smoking reduction or cessation may be a viable option for those who are at risk or already identified as insulin resistant. Therefore, smoking cessation or reduction would serve as a beneficial component in any diabetes prevention or treatment plan.

Triple-Plane Augmentation Mastopexy.

Dual-plane augmentation mammaplasty has gained wide popularity in treating breast ptosis. However, in our experience, dual-plane augmentation mastopexy fails to treat severe cases of ptosis (grade 3) and glandular ptosis. Therefore, we conceived a method to manage these cases effectively. The aim was to achieve harmonious, natural fullness, better projection, and appropriate size with limited scarring. We named this technique triple-plane augmentation mastopexy as three planes are used: the first plane is the subfascial plane, the second is the subglandular plane, and the third is the subpectoral plane. METHODS: A retrospective review was performed of 75 consecutive cases of grade 3 or glandular ptosis treated in a single clinic by three separate surgeons adopting the same technique from January 2010 to January 2017. Triple-plane augmentation mastopexy begins by undermining the breast tissue through a tunnel until the second rib is in the prepectoral plane. Then, the subpectoral pocket for the implant is dissected with release of the lower border of the pectoralis major and avoiding release of the sternal border. Subsequently, the breast tissue is suspended at the lower border of the second rib, followed by subpectoral insertion of the implant and skin envelope excision. RESULTS: Surgical follow-up varied from a minimum of 6 months to a maximum of 6 years, with an average of 3 years. Among a total of 75 patients, 64 patients (85.3%) complied with follow-up and 49 (76.5%) of these patients were satisfied. Complications varied from early complications (14.6%) to late complications (21.5%). CONCLUSIONS: Grade 3 and glandular ptosis represent a challenge to plastic surgeons. Traditional techniques may fail to achieve optimized results. Triple-plane augmentation mastopexy is a safe, reliable procedure that ensures long-term desired aesthetic outcomes with limited scarring.

Dysphagia Requiring Nasogastric Feeding Following Orthognathic Surgery: An Unusual Complication, Case Report, Literature Review, and Recommendations.

PURPOSE: To report on dysphagia following orthognathic surgery, to review the literature on this topic, and to make recommendations for the management of this highly unusual problem. PATIENTS AND METHODS: Two cases of dysphagia requiring nasogastric feeding tubes following two-jaw surgery are presented adding to the two already reported in the English language. Similarities and possible causes are discussed and the management of this entity is proposed. RESULTS: Both of our patients required nasogastric feeding tubes be placed to facilitate enteral nutrition. Similar to cases reported in the literature, none of the patients had neurological deficits other than to the second and third division of the trigeminal nerve. All patients recovered the ability to swallow. CONCLUSIONS: While less than 2% of patients undergoing orthognathic surgery may report difficulty with swallowing following jaw surgery, most will recover in a short period of time. For those with prolonged dysphagia, a neurologic examination, a swallow study, and a nasogastric feeding may be required until normal swallowing returns.

Effect of frailty on resource use and cost for Medicare patients.

Aim: The effects of frailty and multiple chronic conditions (MCCs) on cost of care are rarely disentangled in archival data studies. We identify the marginal contribution of frailty to medical care cost estimates using Medicare data. Materials & methods: Use of the Faurot frailty score to identify differences in acute medical events and cost of care for patients, controlling for MCCs and medication use. Results: Estimated marginal cost of frailty was US$10,690 after controlling for demographics, comorbid conditions, polypharmacy and use of potentially inappropriate medications. Conclusion: Frailty contributes greatly to cost of care, but while often correlated, is not synonymous with MCCs. Thus, it is important to control separately for frailty in studies that compare medical care use and cost.

Human gestation-associated tissues express functional cytosolic nucleic acid sensing pattern recognition receptors.

The role of viral infections in adverse pregnancy outcomes has gained interest in recent years. Innate immune pattern recognition receptors (PRRs) and their signalling pathways, that yield a cytokine output in response to pathogenic stimuli, have been postulated to link infection at the maternal-fetal interface and adverse pregnancy outcomes. The objective of this study was to investigate the expression and functional response of nucleic acid ligand responsive Toll-like receptors (TLR-3, -7, -8 and -9), and retinoic acid-inducible gene 1 (RIG-I)-like receptors [RIG-I, melanoma differentiation-associated protein 5 (MDA5) and Laboratory of Genetics and Physiology 2(LGP2)] in human term gestation-associated tissues (placenta, choriodecidua and amnion) using an explant model. Immunohistochemistry revealed that these PRRs were expressed by the term placenta, choriodecidua and amnion. A statistically significant increase in interleukin (IL)-6 and/or IL-8 production in response to specific agonists for TLR-3 (Poly(I:C); low and high molecular weight), TLR-7 (imiquimod), TLR-8 (ssRNA40) and RIG-I/MDA5 (Poly(I:C)LyoVec) was observed; there was no response to a TLR-9 (ODN21798) agonist. A hierarchical clustering approach was used to compare the response of each tissue type to the ligands studied and revealed that the placenta and choriodecidua generate a more similar IL-8 response, while the choriodecidua and amnion generate a more similar IL-6 response to nucleic acid ligands. These findings demonstrate that responsiveness via TLR-3, TLR-7, TLR-8 and RIG-1/MDA5 is a broad feature of human term gestation-associated tissues with differential responses by tissue that might underpin adverse obstetric outcomes.

Validating Facial Aesthetic Surgery Results with the FACE-Q.

BACKGROUND: In aesthetic clinical practice, surgical outcome is best measured by patient satisfaction and quality of life. For many years, there has been a lack of validated questionnaires. Recently, the FACE-Q was introduced, and the authors present the largest series of face-lift patients evaluated by the FACE-Q with the longest follow-up to date. METHODS: Two hundred consecutive patients were identified who underwent high-superficial musculoaponeurotic system face lifts, with or without additional facial rejuvenation procedures, between January of 2005 and January of 2015. Patients were sent eight FACE-Q scales and were asked to answer questions with regard to their satisfaction. Rank analysis of covariance was used to compare different subgroups. RESULTS: The response rate was 38 percent. Combination of face lift with other procedures resulted in higher satisfaction than face lift alone (p < 0.05). Patients who underwent lipofilling as part of their face lift showed higher satisfaction than patients without lipofilling in three subscales (p < 0.05). CONCLUSIONS: Facial rejuvenation surgery, combining a high-superficial musculoaponeurotic system face lift with lipofilling and/or other facial rejuvenation procedures, resulted in a high level of patient satisfaction. The authors recommend the implementation of the FACE-Q by physicians involved in aesthetic facial surgery, to validate their clinical outcomes from a patient's perspective.