Transoral robotic surgery in HPV+ oropharyngeal cancer of unknown primary.

PURPOSE: This study was designed to assess trends in and outcomes associated with TORS-treated HNCUP using a large national database. MATERIALS AND METHODS: HPV+ oropharyngeal HNCUPs were isolated from the 2004-2017 National Cancer Database. Overall survival (OS) was assessed, with patients stratified by 1) use of TORS and 2) whether the occult tumor was ultimately located. Demographic and oncologic predictors of survival were evaluated on regression. RESULTS: The cohort contained 284,734 cases, of which 8336 were HNCUPs. HNCUPs represented 2.49 % of all HNSCC in 2010 versus 3.13 % in 2017. 3897 (46.7 %) of these unknown primaries were ultimately identified. The proportion of cases treated with TORS increased from 6.9 % in 2010 to 18.1 % in 2017 (p < 0.001). Kaplan-Meier analysis of 2991 HPV+ oropharyngeal HNCUPs demonstrated higher 5-year overall survival (OS) for patients treated with robotic surgery versus no robotic surgery (95.4 % ± 1.7 % standard error [SE] versus 84.0 % ± 0.9 % SE; p < 0.001). Patients with primary tumors identified during treatment had improved OS compared to those whose tumors were not located (5-year OS was 90.5 % ± 0.9 % SE and 77.3 % ± 1.5 % SE, respectively; p < 0.001). For patients in which the primary tumor was found, those who received robotic surgery survived longer than those who did not (96.5 % ± 1.4 % SE versus 89.1 % ± 1.0 % SE 5-year OS; p < 0.001). The relationship between TORS and OS remained significant on Cox regression controlling for confounders. CONCLUSIONS: Use of TORS in the workup for HPV+ HNCUP is associated with higher rates of tumor identification and improved OS.

Conventional clinical signs and symptoms are poor predictors of postoperative cerebrospinal fluid leak: A single-centre cohort perspective.

BACKGROUND: Postoperative cerebrospinal fluid (CSF) leak remains a concerning complication of the endoscopic endonasal approach (EEA) for skull base pathology. Signs and symptoms suggesting CSF leak often trigger additional workup during the postoperative course. We systematically evaluate associations between subjectively reported clinical signs/symptoms noted during the immediate postoperative period and incidence of postoperative CSF leaks. METHODS: Retrospective chart review was conducted at a tertiary academic medical centre including 137 consecutive patients with intraoperative CSF leak during EEA with primary repair between July 2018 and August 2022. Postoperative CSF leak associations with clinical signs and symptoms were evaluated using positive (PPV) and negative predictive values (NPV), sensitivity, specificity and odds ratio (OR) via univariate logistic regression. RESULTS: Seventy-nine patients (57.7%) had high-flow leaks repaired and 5 (3.6%) developed CSF leaks postoperatively. Of reported symptoms, rhinorrhea was most common (n = 52, 38.0%; PPV [95% CI] = 7.6% [4.8%, 11.9%]), followed by severe headache (n = 47, 34.3%; 6.3% [3.1%, 12.5%]), dizziness (n = 43, 31.4%; 2.3% [0.4%, 12.1%]), salty or metallic taste (n = 20, 14.6%; 9.9% [3.3%, 25.8%]), and throat drainage (n = 10, 7.3%; 9.9% [1.7%, 41.4%]). Nausea or vomiting constituted the most reported sign concerning for CSF leak (n = 73, 53.3%; PPV [95% CI] = 4.1% [2.0%, 8.1%]). On univariate regression, no sign or symptom, including rhinorrhea (OR [95% CI] = 7.00 [0.76-64.44]), throat drainage (3.42 [0.35-33.86]), salty/metallic taste (4.22 [0.66-27.04]), severe headache (3.00 [0.48-18.62]), dizziness (0.54 [0.06-4.94]), fever (3.16 [0.50-19.99]), and nausea/vomiting (1.33 [0.22-8.21]), associated with postoperative CSF leak. CONCLUSIONS: A range of subjectively reported symptoms and signs failed to predict postoperative CSF leak. Further investigation is warranted to inform appropriate attention and response.

Evaluation of a patient specific, targeted-intensity pharmacologic thromboprophylaxis protocol in hospitalized patients with COVID-19.

Patients with COVID-19 are at higher risk of thrombosis due to the inflammatory nature of their disease. A higher-intensity approach to pharmacologic thromboprophylaxis may be warranted. The objective of this retrospective cohort study was to determine if a patient specific, targeted-intensity pharmacologic thromboprophylaxis protocol incorporating severity of illness, weight, and biomarkers decreased incidence of thrombosis in hospitalized patients with COVID-19. Included patients were hospitalized with COVID-19 and received thromboprophylaxis within 48 h of admission. Exclusion criteria included receipt of therapeutic anticoagulation prior to or within 24 h of admission, history of heparin-induced thrombocytopenia, extracorporeal membrane oxygenation, pregnancy, or incarceration. Per-protocol patients received thromboprophylaxis according to institutional protocol involving escalated doses of anticoagulants based upon severity of illness, total body weight, and biomarker thresholds. The primary outcome was thrombosis. Secondary outcomes included major bleeding, mortality, and identification of risk factors for thrombosis. Of 1189 patients screened, 803 were included in the final analysis. The median age was 54 (42-65) and 446 (55.5%) were male. Patients in the per-protocol group experienced significantly fewer thrombotic events (4.4% vs. 10.7%, p = 0.002), less major bleeding (3.1% vs. 9.6%, p < 0.001), and lower mortality (6.3% vs. 11.8%, p = 0.02) when compared to patients treated off-protocol. Significant predictors of thrombosis included mechanical ventilation and male sex. Post-hoc regression analysis identified mechanical ventilation, major bleeding, and D-dimer ≥ 1500 ng/mL FEU as significant predictors of mortality. A targeted pharmacologic thromboprophylaxis protocol incorporating severity of illness, body weight, and biomarkers appears effective and safe for preventing thrombosis in patients with COVID-19.

The Effect of Cyclic Strain on Human Fibroblasts With Lamin A/C Mutations and Its Relation to Heart Disease.

Although mutations in the Lamin A/C gene (LMNA) cause a variety of devastating diseases, the pathological mechanism is often unknown. Lamin A/C proteins play a crucial role in forming a meshwork under the nuclear membrane, providing the nucleus with mechanical integrity and interacting with other proteins for gene regulation. Most LMNA mutations result in heart diseases, including some types that primarily have heart disease as the main pathology. In this study, we used cells from patients with different LMNA mutations that primarily lead to heart disease. Indeed, it is a mystery why a mutation to the protein in every nucleus of the body manifests as a disease of primarily the heart in these patients. Here, we aimed to investigate if strains mimicking those within the myocardial environment are sufficient to cause differences in cells with and without the LMNA mutation. To test this, a stretcher device was used to induce cyclic strain upon cells, and viability/proliferation, cytoskeleton and extracellular matrix organization, and nuclear morphology were quantified. The properties of cells with Hutchinson-Gilford progeria syndrome (HGPS) were found to be significantly different from all other cell lines and were mostly in line with previous findings. However, the properties of cells from patients who primarily had heart diseases were not drastically different when compared to individuals without the LMNA mutation. Our results indicated that cyclic strain alone was insufficient to cause any significant differences that could explain the mechanisms that lead to heart diseases in these patients with LMNA mutations.

Is starting with the feet out of the water faster in backstroke swimming?

This study aimed to determine if starting with the feet above the water (FAW) in male backstroke swimming resulted in faster start times (15-m time) than when the feet were underwater (FUW). It was hypothesised that setting higher on the wall would generate increased horizontal force and velocity, resulting in quicker starts. Twelve high-level male backstrokers performed three trials of the FAW and FUW techniques. A biomechanical swimming testing system comprising one force plate (1,000 Hz), four lateral-view (100Hz), and five overhead (50Hz) video cameras captured the swimmers' performance. Data for each participant's fastest trial for each technique were collated, grouped, and statistically analysed. Analysis included Wilcoxon, Spearman Rho correlation, and regression analysis. Wilcoxon results revealed a significantly faster start time for the FAW technique (p < 0.01). Peak horizontal force was significantly smaller for FAW (p = 0.02), while take-off horizontal velocity was significantly greater (p = 0.01). Regression analysis indicated take-off horizontal velocity to be a good predictor of start time for both techniques, and the horizontal displacement of the centre of mass for the FAW start.

Evaluating Barriers to Opioid Use Disorder Treatment From Patients' Perspectives.

Introduction: Utilizing medications to treat opioid use disorder (MOUD) is both highly effective and unfortunately underutilized in the US health care system. Stigma surrounding substance use disorders, insufficient provider knowledge about substance use disorders and MOUD, and historical lack of physicians with X-waivers to prescribe buprenorphine contribute to this underutilization. Our study aimed to elucidate barriers to accessing MOUD in Milwaukee, Wisconsin. Methods: We conducted semistructured interviews with patients receiving MOUD at a family medicine residency program in Milwaukee, Wisconsin. Interviews were audio-recorded, transcribed verbatim, and analyzed using the qualitative analysis Framework Method. Researchers in our team reviewed transcripts, coding for specific topics of discussion. Coded transcript data were then sorted into a matrix to identify common themes. Results: Interviews with 30 participants showed that motivations to seek treatment appeared self-driven and/or for loved ones. Eighteen patients noted concerns with treatment including treatment denial and efficacy of treatment. Housing instability, experiences with incarceration, insurance, and transportation were common structural barriers to treatment. Conclusions: Primary drivers to seek treatment were patients themselves and/or loved ones. Barriers to care include lack of effective transportation, previous experience with the carceral system, and relative scarcity of clinicians offering MOUD. Future studies may further explore effects of structural inadequacies and biases on MOUD access and quality.

Supplemental oxygen requirement after tonsillectomy in children >3 years of age.

INTRODUCTION: The indications for postoperative admission after tonsillectomy in children >3 years of age are less well defined than for children <3 years old, and typically include severe obstructive sleep apnea (OSA), obesity, comorbidities, or behavioral factors. Inpatient care after tonsillectomy typically consists of respiratory monitoring and support, as respiratory compromise is the most common complication after pediatric tonsillectomy. We aim to evaluate risk factors associated with postoperative oxygen supplementation and to identify high risk populations within the admitted population who use additional resources or require additional interventions. METHODS: Retrospective chart review of patients between the ages of 3 and 18 years old who underwent tonsillectomy by four surgeons at a tertiary care children's hospital was performed. Data including demographics, comorbidities, surgical intervention, pre- and postoperative AHI, admission, postoperative oxygen requirement, and postoperative complications was collected and analyzed. RESULTS: There were 401 patients included in the analysis. Of the patients in this study, 65.59% were male, 43.39% were Latino, and 53.87% were ages 3 to 7. Of the 397 patients with a record for supplemental oxygen, 36 (9.07%) received supplemental oxygen. The LASSO regression odds ratios (OR) found to be important for modeling supplemental oxygen use (in decreasing order of magnitude) are BMI ≥35 (OR = 2.30), pre-op AHI >30 (OR = 2.28), gastrointestinal comorbidities (OR = 2.20), musculoskeletal comorbidities (OR = 1.91), cardiac comorbidities (OR = 1.20), pulmonary comorbidities (OR = 1.14), and BMI 30 to <35 (OR = 1.07). Female gender was found to be negatively associated with risk of supplemental oxygen use (OR = 0.84). Age, race, AHI ≥15-30, neurologic comorbidities, syndromic patients, admission reason, and undergoing other procedures concomitantly were not found to be associated with increased postoperative oxygen requirement. CONCLUSION: BMI ≥30, pre-op AHI >30, male gender, and gastrointestinal, musculoskeletal, cardiac, and pulmonary comorbidities are all associated with postoperative supplemental oxygen use. Age, race, AHI ≥15-30, neurologic comorbidities, syndromic patients, admission reason, and undergoing other procedures concomitantly were not found to be associated with increased postoperative oxygen requirement.

Anatomic Relationship Between the Head of the Middle Turbinate and First Olfactory Filum: A Radiographic Assessment.

BACKGROUND: The endoscopic modified Lothrop procedure (EMLP) has become a frequently utilized procedure in rhinologic surgery. One of the most serious complications of the procedure is cerebrospinal fluid leak, which may occur due to lack of recognition of the anterior skull base in the region of the first olfactory filum (FOF), or direct injury to the FOF itself. OBJECTIVES: To evaluate the position of the head of the middle turbinate (MT) relative to the FOF, which is an important landmark in the EMLP. METHODS: A series of previously obtained patient computed tomography scans of the sinus were reviewed. A reproducible process was implemented to obtain the measurements. First, the FOF was identified on an axial series. Using a localization feature of the radiographic software, this anteroposterior (AP) position could be visualized in a coronal plane. Subsequently, the MT was viewed in a sagittal plane, where a measurement between the head of the MT and the AP position of the FOF could be performed. RESULTS: The AP distance between the head of the MT and the FOF was measured in 92 patients. The head of the MT was either at or anterior to the FOF in all measured subjects. The mean anterior distance of the head of the MT to FOF was 3.6 mm (±2.4 mm) on the right, and 3.8 mm (±2.2 mm) on the left. The range in AP distance was 0 to 12 mm. There was no significant difference in AP distance between the head of the MT and FOF based on gender (P = .413) or diagnosis (P = .254). CONCLUSIONS: In our study, the head of the MT was reliably at or anterior to the FOF in all subjects, suggesting its utility as a fixed landmark in endoscopic sinus surgery, particularly in the EMLP. LEVEL OF EVIDENCE: N/A.

Severe unilateral refractory epistaxis arising from the septal branch of the anterior ethmoid artery.

KEY POINTS: The septal branch of the anterior ethmoid artery (sbAEA) is an underrecognized source of severe refractory epistaxis. Herein, we describe the presentation, predisposing factors, treatment strategies, and outcomes of a series of patients with this condition.

Tissue Sealant Impact on Skull Base Reconstruction Outcomes: A Systematic Review and Meta-Analysis.

OBJECTIVE: Despite significant advances in understanding of skull base reconstruction principles, the role of tissue sealants in modifying postoperative cerebrospinal fluid (CSF) leak outcomes remains controversial. We evaluate postoperative CSF leak incidence associated with tissue sealant use in skull base defect repair during endoscopic skull base surgery (ESBS). DATA SOURCES: Web of Science, PubMed/MEDLINE, Scopus, and Cochrane Library. REVIEW METHODS: Systematic review and meta-analysis of risk differences (RD). A search strategy identified original studies reporting CSF leakage following ESBS with disaggregation by tissue sealant use and/or type. RESULTS: 27 non-randomized studies (n = 2,403) were included for qualitative and meta-analysis. Reconstruction with a tissue sealant did not significantly reduce postoperative CSF leak risk compared with reconstruction without sealant (RD[95% CI] = 0.02[-0.01, 0.05]). Sub-analyses of dural sealant (-0.02[-0.11, 0.07]) and fibrin glue (0.00[-0.07, 0.07]) compared with no sealant were similarly unremarkable. Postoperative CSF leakage was not significantly modulated in further sub-analyses of DuraSeal (0.02[-0.02, 0.05]), Adherus (-0.03[-0.08, 0.03]), or Bioglue (-0.06[-0.23, 0.12]) versus no dural sealant use, or Tisseel/Tissucol versus fibrin glue nonuse (0.00[-0.05, 0.05]). No significant association was seen comparing dural sealant use versus fibrin glue use on pairwise (0.01[-0.03, 0.05]) or network meta-analysis (-0.01[-0.05, 0.04]). Limitations in source literature prevented sub-analyses stratified by leak characteristics, defect size and location, and accompanying reconstruction materials. CONCLUSION: Tissue sealant use did not appear to impact postoperative CSF leak incidence when compared with nonuse. Higher quality studies are warranted to thoroughly elucidate the clinical value of adjunct sealant use in endoscopic skull base reconstruction. LEVEL OF EVIDENCE: N/A Laryngoscope, 2024.

Comparison of patient-reported outcomes and clinical characteristics among patients with pituitary macroadenomas and giant adenomas.

KEY POINTS: Patients with giant adenomas are more likely to have tumor extension into the paranasal sinuses. Compared to macroadenomas, giant adenomas are not associated with worse preoperative SNOT-22 scores.

Head and neck solitary fibrous tumors: A review of the National Cancer Database.

BACKGROUND: Head and neck solitary fibrous tumors (SFTs) are rare neoplasms, with few large-scale studies describing this entity. We evaluated the demographics and correlates of survival in a large series of SFT patients. METHODS: The 2004-2017 National Cancer Database was queried for head and neck SFT patients receiving definitive surgery. Cox proportional-hazards and Kaplan-Meier analyses assessed overall survival (OS). RESULTS: Of 135 patients, sinonasal (33.1%) and orbital (25.9%) SFTs were most common. Approximately 93% of SFTs were invasive and 64% were classified as hemangiopericytomas. The 5-year OS of skull base SFTs (84.5%) was lower than sinonasal (98.7%) and orbital (90.7%) SFTs (all p < 0.05). Government insurance exhibited higher mortality (HR 5.116; p < 0.001) and lower OS (p = 0.001). CONCLUSION: Head and neck SFTs presented with distinct prognoses based on anatomical origin. Overall survival was particularly worse in patients with skull base SFTs or government insurance. Prognostically, hemangiopericytomas were indistinct from other SFTs.

Endothelin-1, the unfolded protein response, and persistent inflammation: role of pulmonary artery smooth muscle cells.

Endothelin-1 is a potent vasoactive peptide that occurs in chronically high levels in humans with pulmonary hypertension and in animal models of the disease. Recently, the unfolded protein response was implicated in a variety of diseases, including pulmonary hypertension. In addition, evidence is increasing for pathological, persistent inflammation in the pathobiology of this disease. We investigated whether endothelin-1 might engage the unfolded protein response and thus link inflammation and the production of hyaluronic acid by pulmonary artery smooth muscle cells. Using immunoblot, real-time PCR, immunofluorescence, and luciferase assays, we found that endothelin-1 induces both a transcriptional and posttranslational activation of the three major arms of the unfolded protein response. The pharmacologic blockade of endothelin A receptors, but not endothelin B receptors, attenuated the observed release, as did a pharmacologic blockade of extracellular signal-regulated kinases 1 and 2 (ERK-1/2) signaling. Using short hairpin RNA and ELISA, we observed that the release by pulmonary artery smooth muscle cells of inflammatory modulators, including hyaluronic acid, is associated with endothelin-1-induced ERK-1/2 phosphorylation and the unfolded protein response. Furthermore, the synthesis of hyaluronic acid induced by endothelin-1 is permissive for persistent THP-1 monocyte binding. These results suggest that endothelin-1, in part because it induces the unfolded protein response in pulmonary artery smooth muscle cells, triggers proinflammatory processes that likely contribute to vascular remodeling in pulmonary hypertension.

Tympanostomy tube placement for pressure-sensitive vertigo.

Objective: To evaluate tympanostomy tube placement in patients with pressure-sensitive vertigo. Methods: Retrospective case series. Results: Six patients with pressure-sensitive vertigo reported resolution of their vertigo and other vestibular symptoms after placement of the tympanostomy tubes. All recurrences of symptoms were due to either extrusion or plugging of the tubes. All patients fulfilled the criteria for vestibular migraine. None of the patients had superior canal dehiscence on imaging or precedent event that triggered the problem, and all had a negative fistula test. Conclusion: Tympanostomy tube placement should be considered in selected patients with vertigo exacerbated by seemingly small changes in atmospheric pressure (e.g., just prior to thunderstorms, air travel, or travel to the mountains). By eliminating the capability of the tympanic membrane to sense changes in pressure with a tube, patients with pressure-induced vertigo (in the absence of perilymph fistula or superior canal dehiscence) may have relief of their symptoms.

Allowable room temperature excursions for refrigerated medications: A 20-year review.

PURPOSE: The aim of this review was to build upon previous literature describing the maximum duration for which refrigerated medications can tolerate room temperature excursions while maintaining stability and potency. METHODS: During a 12-month period ending in June 2021, the prescribing information and published monographs from multiple pharmacy compendia were reviewed for all medications and biologic products approved by the US Food and Drug Administration (FDA) for human use since January 2000. Products that were subsequently withdrawn from the US market were excluded. When temperature excursion data was unavailable in published form, product manufacturers were surveyed via telephone and/or email. Acceptable storage information for all products for which storage is recommended at temperatures below room temperature (20-25 °C [68-77 °F]) was compiled and arranged in tabular format. RESULTS: Of the 705 products or formulations approved by FDA during the predefined time period, 246 were identified as requiring storage at temperatures below room temperature. After review of available prescribing information and manufacturer communications, if applicable, acceptable periods of excursion to temperatures at room temperature or higher were identified for 214 products (87%). CONCLUSION: Information related to acceptable periods of room temperature excursion was compiled for a total of 214 products approved for US distribution since 2000. The included tables may increase patient safety and decrease medication loss or related expenditures.

Barriers to Access to Hematopoietic Cell Transplantation among Patients with Acute Myeloid Leukemia in Virginia.

Allogeneic hematopoietic cell transplantation (HCT) is a standard therapy for patients with intermediate to high-risk acute myeloid leukemia (AML) and is associated with improved long-term disease-free survival. Disparity exists in access to HCT among different patient populations and requires further study. In this study, we compared HCT rates for AML among different regions in the state of Virginia and identified geographic and socioeconomic factors associated with the likelihood of receiving HCT. We conducted a retrospective, cohort study of patients 18 to 74 years of age diagnosed with AML in Virginia from 2013 to 2017 as reported to the Virginia Cancer Registry (VCR); the VCR was further linked with the Center for International Blood and Marrow Transplant Research database for identification of patients who had undergone HCT within 2 years of diagnosis. Socioeconomic data were generated from the VCR and the American Community Survey. Univariate and multivariable logistic regression models were used to examine selected socioeconomic factors of interest, including patient-level information such as sex, age, race, marital status, and primary insurance payer, as well as factors associated with geography, including the Social Vulnerability Index (SVI) and percentage of African Americans residing in the region. In Virginia, 818 patients were diagnosed with AML from 2013 to 2017, and, of these, 168 patients (21%) underwent HCT within 2 years of diagnosis. Median age was lower in the HCT cohort (55 years) versus the non-HCT cohort (64 years) (P < .001). There was a higher proportion of married patients in the HCT cohort (67%) versus the non-HCT cohort (53%) (P = .005). The rate of HCT varied by geographic region (P = .004). The multivariable analyses (without including SVI) showed decreased likelihood of HCT with increasing age (odds ratio [OR], .96; 95% confidence interval [CI], .95 to .98). Patients from regions that had a greater than 25% African American population were less likely to undergo HCT (OR, .58; 95% CI, .38 to .89). Patients who were not married were less likely to undergo HCT compared with married patients (OR, .56; 95% CI, .36 to .88). Patients with government-sponsored insurance as the primary payer were less likely to undergo HCT compared with patients with private insurance (OR, .49; 95% CI, .32 to .77). Patients living in Zip Code areas with a greater percentage of population with a bachelor's or graduate degree were more likely to undergo HCT (OR, 1.02; 95% CI, 1.00 to 1.03). In a separate multivariate model with SVI, patients residing in a Zip Code with higher SVI were less likely to undergo HCT (OR, .37; 95% CI, .16 to .82). From 2013 to 2017, we found that the likelihood of a patient undergoing HCT in Virginia for AML within 2 years of diagnosis was negatively associated with increasing age, percent of African Americans residing in the region, not-married relationship status, government-sponsored insurance as primary payer, higher SVI, and decreased percent of population with a bachelor's or graduate degree. Resources should be directed toward at-risk patient populations to remove barriers to improve access to HCT. The SVI can be used to identify communities at risk nationwide.

DNA methylation analysis reveals epimutation hotspots in patients with dilated cardiomyopathy-associated laminopathies.

BACKGROUND: Mutations in LMNA, encoding lamin A/C, lead to a variety of diseases known as laminopathies including dilated cardiomyopathy (DCM) and skeletal abnormalities. Though previous studies have investigated the dysregulation of gene expression in cells from patients with DCM, the role of epigenetic (gene regulatory) mechanisms, such as DNA methylation, has not been thoroughly investigated. Furthermore, the impact of family-specific LMNA mutations on DNA methylation is unknown. Here, we performed reduced representation bisulfite sequencing on ten pairs of fibroblasts and their induced pluripotent stem cell (iPSC) derivatives from two families with DCM due to distinct LMNA mutations, one of which also induces brachydactyly. RESULTS: Family-specific differentially methylated regions (DMRs) were identified by comparing the DNA methylation landscape of patient and control samples. Fibroblast DMRs were found to enrich for distal regulatory features and transcriptionally repressed chromatin and to associate with genes related to phenotypes found in tissues affected by laminopathies. These DMRs, in combination with transcriptome-wide expression data and lamina-associated domain (LAD) organization, revealed the presence of inter-family epimutation hotspots near differentially expressed genes, most of which were located outside LADs redistributed in LMNA-related DCM. Comparison of DMRs found in fibroblasts and iPSCs identified regions where epimutations were persistent across both cell types. Finally, a network of aberrantly methylated disease-associated genes revealed a potential molecular link between pathways involved in bone and heart development. CONCLUSIONS: Our results identified both shared and mutation-specific laminopathy epimutation landscapes that were consistent with lamin A/C mutation-mediated epigenetic aberrancies that arose in somatic and early developmental cell stages.

A Study of Gene Expression, Structure, and Contractility of iPSC-Derived Cardiac Myocytes from a Family with Heart Disease due to LMNA Mutation.

Genetic mutations to the Lamin A/C gene (LMNA) can cause heart disease, but the mechanisms making cardiac tissues uniquely vulnerable to the mutations remain largely unknown. Further, patients with LMNA mutations have highly variable presentation of heart disease progression and type. In vitro patient-specific experiments could provide a powerful platform for studying this phenomenon, but the use of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) introduces heterogeneity in maturity and function thus complicating the interpretation of the results of any single experiment. We hypothesized that integrating single cell RNA sequencing (scRNA-seq) with analysis of the tissue architecture and contractile function would elucidate some of the probable mechanisms. To test this, we investigated five iPSC-CM lines, three controls and two patients with a (c.357-2A>G) mutation. The patient iPSC-CM tissues had significantly weaker stress generation potential than control iPSC-CM tissues demonstrating the viability of our in vitro approach. Through scRNA-seq, differentially expressed genes between control and patient lines were identified. Some of these genes, linked to quantitative structural and functional changes, were cardiac specific, explaining the targeted nature of the disease progression seen in patients. The results of this work demonstrate the utility of combining in vitro tools in exploring heart disease mechanics.

Presidential Assassinations: Historical Review with Current Technology.

As many have studied in the past, the real question of a presidential assassination failure or completion of the attempt should focus on the medical outlook, albeit sometimes surgical in nature. In this article, injuries sustained by various assassination attempts will be examined thoroughly to ensure they received the most appropriate medical care possible at that time and, then in turn, evaluate the medical outcomes in light of contemporary medical knowledge. The five presidents include Abraham Lincoln, James Garfield, William McKinley, John Fitzgerald Kennedy, and Ronald Reagan. Although the advent of Advanced Trauma Life Support has dramatically altered the care of the critically ill patient, it was rehabilitated in response to the orthopedic surgeon listed in the following paragraph.

Multifocal abdominal endometriosis, a case report.

Multifocal endometriosis found outside of the pelvis is very rare. We present here a case of endometriosis found in the pelvis, appendix and umbilicus. A 52-year-old female had a previous umbilical hernia repair, and years later started to develop a recurrent umbilical mass. After a full work-up, it was decided the patient have a diagnostic laparoscopy with wide local excision of umbilical mass to rule out any underlying malignancy. Findings during the procedure included an umbilical mass, dilated appendix and ovoid mass abutting the appendix. Pathology of the umbilical mass was found to be consistent with endometriosis. Umbilical and pelvic endometriosis is a rare condition. Options for diagnosis prior to surgical interventions are limited in endometriosis. In this case, ruling out underlying malignancy took priority, and the mass was removed and she will have less chance of recurrence.