Outcomes with use of extra-corporeal membrane oxygenation in high-risk pulmonary embolism: a national database perspective.

High-risk pulmonary embolism (PE) patients can be managed with systemic lysis, catheter-based therapies, or surgical embolectomy. Despite the advent of newer therapies, patients with high-risk PE remain with a 50-60% short-term mortality risk. In such patients, extracorporeal membrane oxygenation (ECMO) is increasingly utilized for hemodynamic support. To evaluate the outcomes of the use of ECMO in patients with high-risk PE. Using the National Inpatient Sample (NIS) database, we identified patients with high-risk PE using ICD 10 codes and compared in-hospital outcomes of patients with and without ECMO support. We identified 38,035 patients with high-risk PE, of whom 820 had undergone ECMO placement. Most patients who underwent ECMO were male (54%), white (65%), and with a mean age of 53.7 years. ECMO use was not associated with a meaningful difference in patient mortality when comparing treatment groups (OR, 1.32 ± 0.39; 0.74-2.35; p = 0.35). Rather, ECMO use was associated with a higher frequency of inpatient complications. ECMO use was not associated with a significant difference in patient mortality in patients with high-risk PE.

Transcriptional Landscape of Repetitive Elements in Psoriatic Skin from Large Cohort Studies: Relevance to Psoriasis Pathophysiology.

While studies demonstrating the expression of repetitive elements (REs) in psoriatic skin using RNA-seq have been published before, not many studies have focused on the genome-wide expression patterns using larger cohorts. This study investigated the transcriptional landscape of differentially expressed REs in lesional and non-lesional skin from two previously published large datasets. We observed significant differential expression of REs in lesional psoriatic skin as well as the skin of healthy controls. Significant downregulation of several ERVs, HERVs (including HERV-K) and LINEs was observed in lesional psoriatic skin from both datasets. The upregulation of a small subset of HERV-Ks and Alus in lesional psoriatic skin was also reported. An interesting finding from this expression data was the significant upregulation and overlapping of tRNA repetitive elements in lesional and non-lesional psoriatic skin. The data from this study indicate the potential role of REs in the immunopathogenesis of psoriasis. The expression data from the two independent large study cohorts are powerful enough to confidently verify the differential expression of REs in relation to psoriatic skin pathology. Further studies are warranted to understand the functional impact of these repetitive elements in psoriasis pathogenesis, thereby expanding their significance as a potential targeting pathway for the disease treatment of psoriasis and other inflammatory diseases.

Transcriptional Basis of Psoriasis from Large Scale Gene Expression Studies: The Importance of Moving towards a Precision Medicine Approach.

Transcriptome profiling techniques, such as microarrays and RNA sequencing (RNA-seq), are valuable tools for deciphering the regulatory network underlying psoriasis and have revealed large number of differentially expressed genes in lesional and non-lesional skin. Such approaches provide a more precise measurement of transcript levels and their isoforms than any other methods. Large cohort transcriptomic analyses have greatly improved our understanding of the physiological and molecular mechanisms underlying disease pathogenesis and progression. Here, we mostly review the findings of some important large scale psoriatic transcriptomic studies, and the benefits of such studies in elucidating potential therapeutic targets and biomarkers for psoriasis treatment. We also emphasised the importance of looking into the alternatively spliced RNA isoforms/transcripts in psoriasis, rather than focussing only on the gene-level annotation. The neutrophil and blood transcriptome signature in psoriasis is also briefly reviewed, as it provides the immune status information of patients and is a less invasive platform. The application of precision medicine in current management of psoriasis, by combining transcriptomic data, improves the clinical response outcome in individual patients. Drugs tailored to individual patient's genetic profile will greatly improve patient outcome and cost savings for the healthcare system.

Implications of increased S100ß and Tau5 proteins in dystrophic nerves of two mdx mouse models for Duchenne muscular dystrophy.

This study investigates changes with respect to increasing protein levels in dystrophic nerves of two mdx mouse models of Duchenne muscular dystrophy (DMD). We propose that these nerve changes result from progressive ongoing damage to neuromuscular junctions (NMJs) due to repeated intrinsic bouts of necrosis in dystrophic muscles. We compared sciatic nerves from classic mdx mice aged 13, 15 and 18 months (M), with D2.mdx mice (on DBA2 background) aged 9 and 13 M, using immunoblotting to quantify levels of 7 proteins. The neuronal proteins S100ß and Tau5 were increased by 13 M in mdx nerves (compared with WT), indicating ongoing myonecrosis in this strain. In striking contrast there was no difference in levels of these neuronal proteins for D2.mdx and D2.WT sciatic nerves at 13 M, indicating reduced myonecrosis over this time in D2.mdx mice compared with mdx. These novel changes in mdx sciatic nerves by 13 M, suggest early denervation or neurodegeneration of dystrophic nerves that is likely irreversible and progressive. This neuronal readout of persistent myonecrosis may provide a useful new long-term biomarker for preclinical studies that aim to reduce myonecrosis, plus such neuronal changes present potential new drug targets to help maintain the function of DMD muscles.

Dystrophic Dmdmdx rats show early neuronal changes (increased S100ß and Tau5) at 8 months, supporting severe dystropathology in this rodent model of Duchenne muscular dystrophy.

The intrinsic necrosis of skeletal muscles in animal models of Duchenne muscular dystrophy (DMD) damages neuromuscular junctions (NMJs) with progressively altered NMJs associated with denervation and premature changes in dystrophic nerves. In the mdx mouse model of DMD, the proteins S100ß and Tau5 are significantly increased in sciatic nerves by 13 months (M) of age, far earlier (by 9 M) than in normal wildtype (WT) nerves. Since dystrophic Dmdmdx rats are reported to have a more severe dystropathology than mdx mice, we hypothesised that Dmdmdx rat nerves would show earlier neuronal changes compared with mdx nerves. We quantified levels of 8 proteins (by immunoblotting) in sciatic and radial nerves from young adult Dmdmdx rats (aged 8 M) and mdx mice (9 M), plus levels of 7 mRNAs (by qPCR) in rat nerves only. Sciatic nerves of 8 M Dmdmdx rats had more consistently increased levels of S100ß and Tau5 proteins, compared with 9 M mdx mice, supporting pronounced dystropathology in the rat model. There were no differences for mRNA levels, apart from higher gelsolin mRNA in Dmdmdx sciatic nerves. The pronounced protein changes in Dmdmdx nerves indicate a severe ongoing myonecrosis, and likely consequent myofibre denervation, for the dystrophic rat model. These data support increased neuronal proteins in dystrophic nerves as a novel pre-clinical readout of ongoing myonecrosis for DMD research. In older DMD boys, such progressive neuronal changes over many years are likely to contribute to loss of muscle function, and may complicate evaluation of late-onset clinical therapies.

Age-related loss of VGLUT1 excitatory, but not VGAT inhibitory, immunoreactive terminals on motor neurons in spinal cords of old sarcopenic male mice.

Age-related changes in ventral lumbar spinal cord (L3-L5) were compared in young [3 month, (M)] and old (27 M) C57BL/6J male mice. The aged mice had previously been shown to exhibit sarcopenia and changes to peripheral nerve morphology. The putative connectivity of ß-III tubulin positive α-motor neurons was compared in immunostained transverse sections using excitatory and inhibitory terminal markers vesicular glutamate transporter-1 (VGLUT1) and vesicular GABA transporter (VGAT). Glial fibrillary acidic protein (GFAP) and ionized calcium binding adaptor molecule 1 (Iba1) immunostaining was used to monitor changes in astrocyte and microglial phenotype respectively. For a given motor neuron, the neuronal perimeter was outlined and terminals immunoreactive for VGLUT1 or VGAT in close apposition to the soma were identified. By 27 M, the percentage coverage and total number of VGLUT1 immunoreactive terminals immediately adjacent to the soma of α-motor neurons was significantly decreased compared with young mice. However, percentage coverage of immunoreactive VGAT inhibitory terminals did not change significantly with age. The gray matter of 27 M spinal cords showed increased astrocytic and microglial activity. The loss of VGLUT1 terminals on α-motor neurons, terminals known to be derived from proprioceptive muscle afferents, may further impair sensorimotor control of hind limb skeletal muscle function in old mice.

Necrotizing epiglottitis treated with early surgical debridement: A case report.

OBJECTIVE: Necrotizing supraglottitis is a rare but potentially morbid infection most often seen in immunocompromised patients. All reported cases have utilized intravenous antibiotic therapy as the mainstay of treatment and many have had associated morbidities. METHODS: We describe a case of a 50-year-old previously healthy female who presented with necrotizing epiglottis and was treated with immediate surgical debridement followed by directed antibiotic therapy. RESULTS: Our patient rapidly recovered with no further invasive interventions. On follow up she had no further complications or functional deficits. CONCLUSIONS: Although uncommon, providers should be aware of the potential benefits of early debridement when treating patients with similar pathology. Early surgical intervention should be considered to avoid local tissue loss, airway interventions, and long-term sequelae.

Resistance wheel exercise from mid-life has minimal effect on sciatic nerves from old mice in which sarcopenia was prevented.

The ability of resistance exercise, initiated from mid-life, to prevent age-related changes in old sciatic nerves, was investigated in male and female C57BL/6J mice. Aging is associated with cellular changes in old sciatic nerves and also loss of skeletal muscle mass and function (sarcopenia). Mature adult mice aged 15 months (M) were subjected to increasing voluntary resistance wheel exercise (RWE) over a period of 8 M until 23 M of age. This prevented sarcopenia in the old 23 M aged male and female mice. Nerves of control sedentary (SED) males at 3, 15 and 23 M of age, showed a decrease in the myelinated axon numbers at 15 and 23 M, a decreased g-ratio and a significantly increased proportion of myelinated nerves containing electron-dense aggregates at 23 M. Myelinated axon and nerve diameter, and axonal area, were increased at 15 M compared with 3 and 23 M. Exercise increased myelinated nerve profiles containing aggregates at 23 M. S100 protein, detected with immunoblotting was increased in sciatic nerves of 23 M old SED females, but not males, compared with 15 M, with no effect of exercise. Other neuronal proteins showed no significant alterations with age, gender or exercise. Overall the RWE had no cellular impact on the aging nerves, apart from an increased number of old nerves containing aggregates. Thus the relationship between cellular changes in aging nerves, and their sustained capacity for stimulation of old skeletal muscles to help maintain healthy muscle mass in response to exercise remains unclear.

Nurses' Perceptions of Intensive Care Unit Orientation Patient Education Pamphlet.

Background: Critical illness is a stressful time for patients and their support networks. Although patient-directed educational material to improve the understanding of critical illness exists, both patients and staff members are often unaware of these resources or how to find them. Objectives: We aimed to evaluate the impact of the implementation of the American Thoracic Society's (ATS) "Managing the Intensive Care Unity (ICU) Experience: A Proactive Guide for Patients and Families", an ICU orientation pamphlet, on nurses' perceptions of the availability and effectiveness of patient and family educational resources. Methods: In a safety-net urban institution, we surveyed medical ICU (MICU) nurses in February 2021 regarding their perceptions of the availability of patient and family educational materials and the time and quality of communication with families of critically ill patients. We then introduced the MICU nurses to the ATS ICU orientation pamphlet to complement patient and family education. Quick response (QR) codes were created, linking to the online versions of the ICU pamphlet, and made available in waiting rooms. Printed copies of the pamphlet were provided to families in the ICU introductory packet upon patient MICU admission. We informed nurses regarding the pamphlet content, website, and QR codes. A postintervention survey was administered 11 months after the initial survey. Changes between pre and postintervention responses were analyzed for significant differences. Debriefing sessions with the MICU nurses were conducted, and subsequent discussions identified opportunities to improve the available educational resources. Results: At baseline, 28 of 67 (42%) MICU nurses responded to the survey. Although all nurses provided verbal education to patients and families, only 18% reported knowing about and using additional resources to supplement this education. The postintervention survey was completed by 39% of nurses; 39% of them reported using additional materials to supplement patient and family education. Reported awareness of the ATS ICU pamphlet increased from 4% before implementation to 23% after implementation (P = 0.04). MICU nurses offered suggestions to improve the pamphlet, which thematically fell into three categories: 1) opportunities to alter the ICU pamphlet, 2) opportunities to provide the pamphlet in varied formats, and 3) opportunities to add additional education topics. Conclusions: Informing nurses about the ICU pamphlet improved the acceptance and use of the materials, but it was still not accepted by many nurses. Barriers to ICU nurses using patient education resources should be explored to facilitate quality materials reaching patients and complementing patient communication. QR codes may have offered a way to disseminate educational materials to patients and families in a manner not previously considered. The process of evaluating the ICU pamphlet for our institution led to a broader discussion of additional needs for patient and family educational materials for our patient population. We encourage institutions to evaluate the sufficiency of their patient and family educational materials for similar local benefits.

A transition to the American Academy of Sleep Medicine-recommended hypopnea definition in adults: initiatives of the Hypopnea Scoring Rule Task Force.

The American Academy of Sleep Medicine (AASM) recommends that hypopneas be identified using a definition that is based on a ≥ 30% decrease in airflow associated with a ≥ 3% reduction in the oxygen saturation or an arousal (H3A) for diagnosis of obstructive sleep apnea (OSA) in adults. This conflicts with the Centers for Medicare & Medicaid Services definition, which requires a ≥ 4% decrease in the oxygen saturation to identify a hypopnea (H4) and does not acknowledge arousals. In 2018, the AASM Board of Directors constituted a Hypopnea Scoring Rule Task Force with a mandate to "create a strategy for adoption and implementation of the AASM recommended adult hypopnea scoring criteria among members, payers and device manufacturers." The task force initiated several activities including a survey of AASM-accredited sleep facilities and discussions with polysomnography software vendors. Survey results indicated that most sleep facilities scored polysomnograms using only the Centers for Medicare & Medicaid Services definition. Vendors indicated that they could easily support dual scoring. Informal testing among task force members' sleep facilities confirmed there would be little additional work if dual scoring was performed. The task force convened several meetings of a working group of OSA content experts and interested parties, with the purpose of creating research recommendations to study the impact on relevant clinical outcomes using the different definitions of hypopnea. Several possible prospective and retrospective approaches were discussed with emphasis on the group of patients diagnosed with OSA based on an apnea-hypopnea index using H3A but not H4. Based on the deliberations of the working group, the Hypopnea Scoring Rule Task Force submitted recommendations to the AASM Foundation concerning research project strategies for potential grant funding. Further discussions within the Hypopnea Scoring Rule Task Force focused on developing advocacy initiatives among patient stakeholder groups to change payer policy. CITATION: Berry RB, Abreu AR, Krishnan V, Quan SF, Strollo PJ Jr, Malhotra RK. A transition to the American Academy of Sleep Medicine-recommended hypopnea definition in adults: initiatives of the Hypopnea Scoring Rule Task Force. J Clin Sleep Med. 2022;18(5):1419-1425.

Assessing the prioritization of primary care referrals for polysomnograms.

STUDY OBJECTIVE: The mortality attributed to obstructive sleep apnea (OSA) is comparable to that of breast cancer and colon cancer. We sought to determine if patients at high risk for OSA were less likely to be referred by their primary care physician for polysomnograms (PSG) than mammograms or endoscopies. DESIGN: Prospective cohort study; patients were recruited between January 2007 and April 2007. SETTING: Academic public hospital system PATIENTS: 395 patients waiting for family or internal medicine primary care appointments were administered the Berlin questionnaire. Chart abstraction or interview determined demographics; insurance and employment status; body mass index (BMI); comorbidities; and prior PSG, mammography, or endoscopy referrals. RESULTS: Mean BMI was 30 +/- 7.4 kg/m2; 187 (47%) patients had high-risk Berlin scores. Overall, 19% of patients with high-risk Berlin scores were referred for PSG, compared to 63% of those eligible for mammograms and 80% of those eligible for endoscopies. Women (OR = 2.9, P = 0.02), COPD (OR = 4.6, P = 0.03), high-risk Berlin scores (OR = 3.4, P = 0.009), and higher BMI (OR = 1.1, P < 0.001) were positively associated with PSG referrals. Privately insured patients were less likely to be referred than uninsured patients (OR = 0.3, P = 0.04). There was no significant difference in referrals among those with other forms of insurance. Race was not associated with PSG referrals. CONCLUSION: In a public hospital, primary care patients were less likely to be referred for PSG compared to mammogram and endoscopy. Uninsured patients were more likely to be referred for PSG than those with private insurance. Further studies are needed to address the low PSG referral rates in high-risk populations.

Goat endometrial heat shock protein-90 (Hsp-90): development of an expedient method for its purification and observations on its intracellular movement.

An expedient method has been developed by which goat uterine Hsp-90 could be isolated and purified to homogeneity in less than 1day. The yield is roughly 1mg from 60g tissue. This method takes into advantage three of our earlier observation that (a) Hsp-90 gets linked to the non-activated estrogen receptor (naER) in the presence of 10mM sodium molybdate; (b) naER, but not Hsp-90 binds to phosphocellulose and (c) exposure to estradiol facilitates dissociation of Hsp-90 from naER through estradiol binding to naER and the possible change in naER conformation. Intracellular movement of Hsp-90 and naER was monitored in goat endometrial cells in culture following exposure of the cells to estradiol. Confocal microscopic analysis revealed a clear presence of both proteins within the nucleus within 3h after exposure to estradiol. Whether Hsp-90 has its own nuclear-transport machinery is debatable. Being an actin-binding protein, there is a distinct possibility that the nuclear entry of Hsp-90 is actin dependent. The functional significance of the nuclear entry of Hsp-90, along with naER, remains to be determined; it may, however, be speculated that the Hsp-90 might be directly involved in the naER to nER II transformation by functioning as a molecular chaperone and helping the protein in re-orienting its structural organization.

Regeneration of adult rat sensory and motor neuron axons through chimeric peroneal nerve grafts containing donor Schwann cells engineered to express different neurotrophic factors.

Large peripheral nerve (PN) defects require bridging substrates to restore tissue continuity and permit the regrowth of sensory and motor axons. We previously showed that cell-free PN segments repopulated ex vivo with Schwann cells (SCs) transduced with lentiviral vectors (LV) to express different growth factors (BDNF, CNTF or NT-3) supported the regeneration of axons across a 1 cm peroneal nerve defect (Godinho et al., 2013). Graft morphology, the number of regrown axons, the ratio of myelinated to unmyelinated axons, and hindlimb locomotor function differed depending on the growth factor engineered into SCs. Here we extend these observations, adding more LVs (expressing GDNF or NGF) and characterising regenerating sensory and motor neurons after injection of the retrograde tracer Fluorogold (FG) into peroneal nerve distal to grafts, 10 weeks after surgery. Counts were also made in rats with intact nerves and in animals receiving autografts, acellular grafts, or grafts containing LV-GFP transduced SCs. Counts and analysis of FG positive (+) DRG neurons were made from lumbar (L5) ganglia. Graft groups contained fewer labeled sensory neurons than non-operated controls, but this decrease was only significant in the LV-GDNF group. These grafts had a complex fascicular morphology that may have resulted in axon trapping. The proportion of FG+ sensory neurons immunopositive for calcitonin-gene related peptide (CGRP) varied between groups, there being a significantly higher percentage in autografts and most neurotrophic factor groups compared to the LV-CNTF, LV-GFP and acellular groups. Furthermore, the proportion of regenerating isolectin B4+ neurons was significantly greater in the LV-NT-3 group compared to other groups, including autografts and non-lesion controls. Immunohistochemical analysis of longitudinal graft sections revealed that all grafts contained a reduced number of choline acetyltransferase (ChAT) positive axons, but this decrease was significant only in the GDNF and NT-3 graft groups. We also assessed the number and phenotype of regrowing lumbar FG+ motor neurons in non-lesioned animals, and in rats with autografts, acellular grafts, or in grafts containing SCs expressing GFP, CNTF, NGF or NT-3. The overall number of FG+ motor neurons per section was similar in all groups; however in tissue immunostained for NeuN (expressed in α- but not γ-motor neurons) the proportion of NeuN negative FG+ neurons ranged from about 40-50% in all groups except the NT-3 group, where the percentage was 82%, significantly more than the SC-GFP group. Immunostaining for the vesicular glutamate transporter VGLUT-1 revealed occasional proprioceptive terminals in 'contact' with regenerating FG+ α-motor neurons in PN grafted animals, the acellular group having the lowest counts. In sum, while all graft types supported sensory and motor axon regrowth, there appeared to be axon trapping in SC-GDNF grafts, and data from the SC-NT-3 group revealed greater regeneration of sensory CGRP+ and IB4+ neurons, preferential regeneration of γ-motor neurons and perhaps partial restoration of monosynaptic sensorimotor relays.

An evaluation of a titration strategy for prescription of oral appliances for obstructive sleep apnea.

BACKGROUND: Oral appliances (OAs) are first-line therapy for mild-to-moderate obstructive sleep apnea (OSA) and are being used with increasing frequency. Additionally, best practice of OA titration is unknown. We describe the experience of patients treated with an OA, identify factors that predict treatment success with an OA, and offer a protocol for OA titration. METHODS: We retrospectively studied patients seen in a dental sleep clinic between 2002 and 2006. Patients selected for OA treatment underwent baseline polysomnography, were individually fit with an OA, and were instructed to titrate it at home until symptom resolution or discomfort. During follow-up polysomnography, additional titration was performed as needed. Primary outcome was successful treatment, defined as apnea-hypopnea index (AHI) <10 events per hour and AHI decrease at least 50% from baseline. Logistic regression models were created to identify associations between patient characteristics and successful treatment. Overall differences in AHI at baseline, after home titration, and after final titration were compared using Kruskal-Wallis test, and post hoc comparisons were performed with sign tests, with Bonferroni corrections. RESULTS: Of 57 subjects treated with an OA, 37 subjects (64.9%) were successfully treated with OA therapy. Of the 49 subjects for whom data were available for AHI after home titration, 27 subjects (55%) achieved successful treatment of OSA by self-titration, without need for further titration during follow-up polysomnography. CONCLUSIONS: A majority of subjects, regardless of OSA severity, are successfully treated with an OA. Men and younger patients were found to be the best responders. The titration protocol for an OA offers a beneficial initial step in the treatment of OSA.

Sleep quality and health-related quality of life in idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive disorder resulting in irreversible scarring of the lung parenchyma. Although fatigue is a prominent symptom for patients with IPF, little is known about sleep quality in patients with IPF. METHODS: In this cross-sectional study of 41 patients with IPF from a prospectively designed cohort, we ascertained sleep quality by means of the Pittsburgh sleep quality index (PSQI) and the Epworth sleepiness scale. Health status, baseline demographics, and physiologic parameters were also assessed. RESULTS: Patients with IPF reported extremely poor sleep quality and high frequency of daytime sleepiness, which differs significantly from normal control populations. Further, poor sleep quality was not associated with body mass index, age, gender, or lung function. This population also demonstrated extremely poor health status in a number of domains, including physical function and vitality. Poor sleep quality (by the global PSQI) was significantly associated with decreased quality of life (QOL) in several domains, including role of physical function (r = - 0.58, p = 0.001), vitality (r = - 0.43, p = 0.015), and role of emotions (r = - 0.40, p = 0.023). CONCLUSIONS: Poor sleep quality is extremely common in patients with IPF and is not predicted by variables traditionally associated with sleep-disordered breathing. Further, poor sleep quality is associated with poor QOL. These findings suggest that systematic evaluation of the cause of poor sleep quality in IPF is merited.