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Background: In patients with idiopathic pulmonary fibrosis (IPF), our objectives were to identify predictors of abnormal heart rate recovery (HRR) at 1 min after completion of a 6-min walk test (6MWT) [HRR1] and 2 min after completion of a 6MWT (HRR2), and to determine whether abnormal HRR predicts mortality.Methods: From 2003 to 2008, we identified IPF patients who had been evaluated at our center (n = 76) with a pulmonary physiologic examination and the 6MWT. We used logistic regression to identify predictors of abnormal HRR, the product-limit method to compare survival in the sample stratified on HRR, and Cox proportional hazards analysis to estimate the prognostic capability of abnormal HRR.Results: Cutoff values were 13 beats for abnormal HRR1 and 22 beats for HRR2. In a multivariable model, predictors of abnormal HRR1 were diffusing capacity of the lung for carbon monoxide (odds ratio [OR], 0.4 per 10% predicted; 95% confidence interval [CI], 0.2 to 0.7; p = 0.003), change in heart rate from baseline to maximum (OR, 0.9; 95% CI, 0.8 to 0.97; p = 0.01), and having a right ventricular systolic pressure > 35 mm Hg as determined by transthoracic echocardiogram (OR, 12.7; 95% CI, 2.0 to 79.7; p = 0.01). Subjects with an abnormal HRR had significantly worse survival than subjects with a normal HRR (for HRR1, p = 0.0007 [log-rank test]; for HRR2, p = 0.03 [log-rank test]); these results held for the subgroup of 30 subjects without resting pulmonary hypertension (HRR1, p = 0.04 [log-rank test]). Among several candidate variables, abnormal HRR1 appeared to be the most potent predictor of mortality (hazard ratio, 5.2; 95% CI, 1.8 to 15.2; p = 0.004).Conclusion: Abnormal HRR after 6MWT predicts mortality in IPF patients. Research is needed to confirm these findings prospectively and to examine the mechanisms of HRR in IPF patients. [ABSTRACT FROM AUTHOR]

Aim We report four cases of acquired severe encephalopathy with massive hyperkinesia, marked neurological and cognitive regression, sleep disturbance, prolonged mutism, and a remarkably delayed recovery (time to full recovery between 5 and 18mo) with an overall good outcome, and its association with anti-N-methyl-d-aspartate (anti-NMDA) receptor antibodies. Method We reviewed the four cases retrospectively and we also reviewed the literature. Results Anti-NMDA receptor antibodies (without ovarian teratoma detected so far) were found in the two children tested in this study. Interpretation The clinical features are similar to those first reported in 1992 by Sebire et al.,(1) and rarely recognized since. Sleep disturbance was not emphasized as part of the disorder, but appears to be an important feature, whereas coma is less certain and difficult to evaluate in this setting. The combination of symptoms, evolution (mainly seizures at onset), severity, paucity of abnormal laboratory findings, very slow recovery, and difficult management justify its recognition as a specific entity. The neuropathological substrate may be anatomically close to that involved in encephalitis lethargica, in which the same target functions (sleep and movement) are affected but in reverse, with hypersomnolence and bradykinesia. This syndrome closely resembles anti-NMDA receptor encephalitis, which has been reported in adults and is often paraneoplastic. [ABSTRACT FROM AUTHOR]

Objective: To compare the rate of device failure for those cochlear implants (CIs) involved in the 2020 Food and Drug Administration (FDA) voluntary field corrective action (VFCA)., Databases Reviewed: Medline, Embase, and Scopus., Methods: A systematic review was performed according to the PRISMA guidelines. Publications reporting institutional experiences with implants affected by the VFCA were included. Outcomes assessed included etiology of, rate of, and time to failure and pre-/post-device failure speech perception testing. All outcomes reported in at least two independent studies were included in a meta-analysis., Results: Six studies met criteria for analysis. The overall pooled failure rate was 23.7% (95% CI, 11.6-38.4%). The pooled device, inconclusive, and medical failure rates were 21.5%, 0.2%, and 0.7%, respectively. Pediatric failure rates were higher than those of adults (46.9% [95% CI, 11.2-84.5%] versus 32.6% [95% CI, 8.2-63.7%]). WRS declined with primary implant failure (55.1% [95% CI, 48.0-62.1%] to 34.1% [95% CI, 30.2-38.0%]) but improved after reimplantation (34.1% [95% CI, 30.2-38.0%] to 50.1% [95% CI, 45.2-55.1%])., Conclusions: The rate of pooled reported failure for CIs falling under the 2020 VFCA in the literature thus far is 23.7%. The overwhelming majority of these failures were device related, the rates of which were higher in children. Speech perception improved significantly after reimplantation., (Copyright © 2024, Otology & Neurotology, Inc.)

Objective: To examine the role of lumbar drains (LDs) in the success of spontaneous temporal cerebrospinal fluid (CSF) leak and encephalocele repair., Study Design: Retrospective cohort study., Setting: Tertiary academic health system., Patients: Patients undergoing repair of spontaneous temporal lobe encephaloceles or middle fossa CSF leaks during years 2017 to 2023., Interventions: Transmastoid, middle fossa craniotomy, or combination approaches to CSF leak repair., Outcome Measures: Failure rate, complication rate, length of stay (LOS), readmission., Results: Sixty-nine patients were included, with a combination approach performed in 78.3%, transmastoid in 17.4%, and isolated middle fossa craniotomy in 4.3%. Mean body mass index was 33.2, mean bony defect size width was 6.51 mm, and defect locations included the epitympanum, antrum, mastoid, and petrous apex. Multilayer closure with three or more layers was performed in 87.0%. LD was used in 73.9% of cases for a mean duration 2.27 days and was associated with longer LOS (3.27 vs. 1.56 d, p = 0.006) but not with failure rate, complications, discharge destination, or readmission. Only one major complication occurred as a result of the drain, but low-pressure headache was anecdotally common., Conclusions: Use of LD in the repair of spontaneous CSF leaks and temporal lobe encephaloceles is associated with longer LOS but not failure rates or other admission-level outcomes., Competing Interests: Conflicts of interest: The authors disclose no conflicts of interest., (Copyright © 2024, Otology & Neurotology, Inc.)

Introduction: Endoscopic ossicular chain reconstruction (OCR) in adults has demonstrated equivalent outcomes to the traditional microscopic approach. Less data exist on endoscopic OCR outcomes in children, who have unique considerations including a smaller transcanal corridor and variable pathology. The purpose of this study was to investigate surgical and audiometric outcomes in children undergoing fully endoscopic and endoscopic-assisted OCR in both the short and long-term., Methods: Retrospective review of all children (<17 years) who underwent endoscopic OCR at one tertiary care center between 2017 and 2021. Children undergoing primary and revision endoscopic OCR with either partial (PORP) and total ossicular reconstruction prostheses (TORP) were included. Children undergoing surgery for juvenile otosclerosis or congenital stapes fixation, or any child receiving a stapes prosthesis were excluded. Primary outcome measures were post-operative change in 4 frequency (500 Hz, 1, 2, 4 KHz) air conduction pure tone average (AC PTA) and change in air-bone gap (ABG). Secondary measures included need for readmission and/or revision surgery, complication rate, and surgery duration., Results: Seventeen patients met inclusion criteria. Average age was 11.3 years (range, 5-17 years); 14 were male. A variety of fixed length, titanium total and partial prostheses were used. The most common prosthesis length was 2 mm (range 2-5 mm), and there were no intra- or perioperative complications. Mean long-term follow-up was 2.6 years. Most common pathology was congenital cholesteatoma (11/17, 64%), followed by chronic otitis media with tympanic membrane perforation (5/17, 29.4%), and extruded prosthesis (1/17, 5.9%). Intraoperatively, the most common finding was incus erosion (10/17, 58.8%), followed by malleus erosion (6/17, 35.3%), stapes erosion (4/17, 23.5%), and stapes absence (4/17, 23.5%). Eight children (47%) were reconstructed with PORPs, and 9 children (52.9%) were reconstructed with TORPs. Average ABG improved from 36.8 dB preoperatively to 19.9 dB postoperatively in the short-term and remained stable at 19.5 dB in the long-term. Average short-term ABG improvement was 4.2 dB for PORPs and 18 dB for TORPs. In the long-term, average ABG improved by 2.3 dB in PORPs and 13.4 dB in TORPs. PORPs had higher rates of ABG closure and lower AC PTAs than TORPs in the long-term., Discussion: Endoscopic ossiculoplasty is a viable option in children presenting with ossicular erosion from various causes. Audiometric improvement following endoscopic partial and total ossicular reconstruction remains stable over time, with a preference towards partial in the long-term, and mirrors published outcomes for microscopic surgery., Competing Interests: Declaration of competing interest Dr. Cosetti is a member of the advisory board of Cochlear Americas. She participates in sponsored research with Cochlear Americas and MedEL. Dr. Cosetti and Dr. Perez are research consultants with Acclarent., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: To determine whether surgeon use of a soft cervical collar during endoscopic and microscopic otologic surgery is feasible and impacts surgeon ergonomics as measured by inertial sensors., Study Design: Prospective crossover trial., Setting: US-based otolaryngology training program., Patients: Otolaryngology residents and fellows., Interventions: Therapeutic-use of a soft cervical collar during simulated otologic surgery., Main Outcome Measures: Time spent in high-risk angles of neck and back flexion and extension; average angle of neck flexion, extension, rotation, and lateral bending; validated assessment of neck pain; average daily phone use., Results: Fifteen subjects met criteria for inclusion. Ten of 15 (67%) were male. Seven of 15 (47%) were postgraduate year 1-2. Seven of 15 (47%) reported a history of neck pain. None reported prior spinal steroid injections or surgery. Across all subjects, use of the soft cervical collar significantly reduced time spent in high-risk angles of neck flexion/extension during both endoscopic (56% vs. 35%, p < 0.05) and microscopic (60% vs. 32%, p < 0.05) otologic surgery. There was no effect on back flexion or extension. There was no difference in time spent in high-risk neck or back angles between endoscopic and microscopic surgery. Average angles of neck or back flexion, extension, lateral bending, and rotation were not significantly different for subgroups with more operative experience, increased phone use, perception of good posture, or history of neck pain., Conclusions: Use of a soft cervical collar during simulated otologic surgery significantly reduced time spent in high-risk neck positions. These data support feasibility of soft collar use during otologic surgery and hold promise for reduction in the high rates of neck pain reported by neurotologists., Professional Practice Gap and Educational Need: Improving surgeon ergonomics for otologic surgery., Learning Objective: To identify a therapeutic intervention to mitigate neck pain in surgeons caused by assumption of high-risk cervical neck flexion and extension., Desired Result: To demonstrate that use of a readily available soft cervical collar reduces risk of neck pain in otologic surgeons., Level of Evidence: II., Indicate Irb or Iacuc: Exempt., Competing Interests: Conflicts of interest: None., (Copyright © 2024, Otology & Neurotology, Inc.)

Background: /Aims: Epidemiological data show that there is an important relationship between respiratory and intestinal diseases. To improve our understanding on the interconnectedness between the lung and intestinal mucosa and the overlap between respiratory and intestinal diseases, our aim was to investigate the influence of ovalbumin (OVA)-induced allergic airway inflammation on gut homeostasis., Methods: A/J mice were sensitized and challenged with OVA. The animals were euthanized 24 h after the last challenge, lung inflammation was determined by evaluating cells in Bronchoalveolar lavage fluid, serum anti-OVA IgG titers and colon morphology, inflammation and integrity of the intestinal mucosa were investigated. IL-4 and IL-13 levels and myeloperoxidase activity were determined in the colon samples. The expression of genes involved in inflammation and mucin production at the gut mucosa was also evaluated., Results: OVA challenge resulted not only in lung inflammation but also in macroscopic alterations in the gut such as colon shortening, increased myeloperoxidase activity and loss of integrity in the colonic mucosal. Neutral mucin intensity was lower in the OVA group, which was followed by down-regulation of transcription of ATOH1 and up-regulation of TJP1 and MUC2 . In addition, the OVA group had higher levels of IL-13 and IL-4 in the colon. Ova-specific IgG1 and OVA-specific IgG2a titers were higher in the serum of the OVA group than in controls., Conclusions: Our data using the OVA experimental model suggested that challenges in the respiratory system may result not only in allergic airway inflammation but also in the loss of gut homeostasis., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Purpose: Musculoskeletal disorders are prevalent among otolaryngologists and otologists with symptoms starting during residency. Prior data suggested that high-risk joint angles were often adopted at procedure onset, suggesting a detrimental "natural" operating position. Despite its importance, dedicated ergonomic teaching is not systematically introduced into residency training. The objective of this study was to compare initial ergonomic positioning during microscopic temporal bone surgery between those who receive "Just in Time" ergonomic teaching prior to starting dissection with those who did not., Materials and Methods: This was a pilot, prospective trial in which otolaryngology residents at an urban, multicenter tertiary care academic institution (n = 14) wore ergonomic sensors (inertial measurement units) during microscopic temporal bone lab drilling. Prior to recording, participants were randomized to receive an instructional presentation on ergonomic principles (n = 8, intervention group) or not (n = 6, control group). The inertial measurement units analyzed neck and back angles for the initial 5 min of drilling., Results: Of 14 trainees, 78.6 % had prior experience with otologic microscopic cases and 14.3 % reported prior surgical ergonomic training or instruction. The groups were matched in trainee height (P = 0.54), handedness (P = 0.83), stage of otolaryngology training (P = 0.64), prior otologic microscopic surgery experience (P = 0.35), prior temporal bone drilling experience (P = 0.35), and prior teaching in ergonomic principles (P = 0.47). Junior trainees (PGY 1-3) who did not receive "Just in Time" teaching adopted a posture with significantly higher risk back flexion compared to junior trainees who received the training (25.3° vs. 5.7°, P = 0.04). There was no difference in back positioning among senior trainees (12.6° vs. -5.7°, P = 0.13). While there was a trend towards those in the intervention group adopting safer procedural posture, there was no significant difference in the overall cohort between the intervention and control groups in both neck positioning (-11.0° vs. -19.1°, P = 0.17) and back positioning (8.6° vs. 19.1°, P = 0.18)., Conclusions: Musculoskeletal related pain is prevalent among otolaryngologists and otologists with data suggesting that symptoms begin during residency. Targeted "Just in Time" teaching of ergonomic principles is feasible and may be effective for development of healthy postural habits, especially among junior trainees., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to report., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: Acute mastoiditis is commonly attributed to infection. Rarely do clinicians encounter cases that do not respond to traditional antibiotics or surgical management. The goal of this study was to systematically review the literature to characterize diseases masquerading as acute infectious mastoiditis., Data Sources: PubMed, Embase, and Scopus., Review Methods: A systematic review was performed to identify all publications that reported on diseases with presentations mimicking acute mastoiditis, defined as postauricular redness, swelling, and tenderness. We included clinical prospective studies, retrospective studies, and case series/reports. Exclusion criteria included non-English articles, letters/commentaries, abstracts, and review articles., Results: Out of 3339 results, 35 studies met final inclusion criteria. In children, 11 diseases were reported to mimic mastoiditis, including solid tumors, hematologic diseases, and autoimmune/inflammatory diseases. The most common disease in children was Langerhans cell histiocytosis, followed by rhabdomyosarcoma and acute myelogenous leukemia. In adults, 8 additional diseases were reported. The most common disease in adults was squamous cell carcinoma, followed by nasopharyngeal carcinoma and Langerhans cell histiocytosis. Presenting symptoms are reviewed, as well as characteristic radiographic, laboratory, and intraoperative features that may assist with diagnosis. A diagnostic algorithm for atypical cases of acute mastoiditis is proposed., Conclusion: A small but significant group of diseases in children and adults can mimic acute mastoiditis. In such cases, history and examination alone may be insufficient to reach a diagnosis, and further investigation may be necessary. Otolaryngologists should always be mindful of the possibility that noninfectious pathologies may present with a constellation of symptoms similar to mastoiditis.

Objective: To analyze our institutional experience with two active transcutaneous bone-anchored hearing aids., Study Design: Retrospective cohort study., Setting: Tertiary academic otology-neurotology practice., Patients: Patients with conductive or mixed hearing losses meeting criteria to receive active transcutaneous bone-anchored hearing aids., Interventions: Implantation with one of two active transcutaneous bone-anchored hearing aids., Outcome Measures: Operative time, dural exposure and decompression, use of lifts, implant position, ease of use, qualitative patient satisfaction, complication rates., Results: Ten patients received Implant 1 and 11 patients received Implant 2. The most common underlying etiologies of hearing loss were chronic suppurative otitis media in 33.3%, atresia/microtia in 23.8%, and cholesteatoma in 23.8%. Average operative times were 99.3 minutes for Implant 1 and 80.9 minutes for Implant 2 ( p = 0.263). Implant 1 required lifts in 60%, dural exposure in 50%, and dural compression in 30%. Overall, placement was difficult in 47.6% of cases. There were no intraoperative complications. There were higher rates of issues with sound quality (27.3% versus 0.0%, p = 0.123) and poor cosmesis (36.4% versus 10.0%, p = 0.360) with Implant 2. Functional gain was not recorded, but all patients derived qualitative benefit from their implant. Three patients had local wound complications that self-resolved or were treated with antibiotics. One patient implanted at an outside institution required explant because of multiple infections., Conclusions: There were no statistically significant differences in outcomes comparing Implants 1 and 2; however, Implant 2 had much higher rates of issues with audio quality and poor cosmesis. Placing Implant 1 often required special techniques., Competing Interests: G.W. was previously on the surgical advisory board for Oticon and Med-El. He consulted for Med-El, cochlear, and Advanced Bionics. M.C. has received travel grants from Med-El, Cochlear, Stryker, educational research grants from Advanced Bionics, and has done clinical research with Advanced Bionics, Cochlear, and Otonomy. She is on the surgical advisory board for Cochlear. The remaining authors disclose no conflicts of interest, (Copyright © 2022, Otology & Neurotology, Inc.)

Objective: Evaluate the impact of sharing otoendoscopy exams on patient satisfaction in the outpatient clinical setting., Methods: Randomized, prospective cohort study. Consecutive adults presenting to otology clinic at one tertiary referral center were randomized into two groups: standard microscopy (SM) and video otoendoscopy (VO). The SM group had ears examined using a standard, otomicroscope; the VO group had ears examined using a 0° rigid endoscope connected to a video tower. All subjects were counseled on their exam findings in a routine manner; the VO group was concurrently shown a recording of their ear exam. All subjects completed the 18-item Patient Satisfaction Questionnaire (PSQ-18) at the conclusion of their clinic visit., Results: The SM group consisted of 27 patients and VO group consisted of 23 patients. VO subjects reported higher PSQ-18 scores compared to SM subjects within the domains of communication (p = 0.04) and technical quality (p = 0.005). On linear regression models, demographic factors and positive exam findings were not predictive of patient satisfaction., Conclusions: Sharing otoendoscopy recordings may be a valuable tool that can improve patient satisfaction., Practice Implications: Clinicians should consider sharing recordings of otoscopic exams with patients, particularly when faced with the possibility of surgery., Competing Interests: Declarations of interest None., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Introduction: Debate is ongoing regarding the best service model for achieving a prompt recanalization in LVO ischemic stroke with an indication for thrombectomy. We aim to assess differences between two of the existing models within our region., Methods: We work in a cluster of three public hospitals (one hub and two spokes) forming a single functional neurology service in Madrid (Spain). Upon a LVO case out of regular hours, the interventional neuroradiologist drives to the hub hospital following the drive-the-doctor paradigm (DD). For any of the spokes, the patient is transferred to the nearest endovascular-capable hospital (drip-and-ship-DS) following the Madrid Stroke Plan. We compared times to endovascular procedures between cases managed under each model., Results: Thirty-eight patients in the period April 2014-March 2021 meet the inclusion criteria (DD 27; DS 11). While baseline characteristics are comparable between groups, we observed a notable difference in the time delays favoring those managed under the DD model; with differences between median times of 105 min for hospital arrival-groin puncture (DD 140 [110-181]; DS 245 [222-310], p 0.0004); 122 min for CT-groin puncture (DD 100 [85-144]; DS 222 [200-255], p = 0.0001); and 98 min for hospital arrival-recanalization (DD 180 [140-209]; DS 278 [241-360], p = 0.0014). No differences were observed for NIHSS or mRS on discharge., Conclusions: Compared to the drip-and-ship, the drive-the-doctor triage model for patients with LVO ischemic stroke in primary centers seems to guarantee a shorter time to the start of the endovascular procedure and to recanalization in our region., (© 2022. Fondazione Società Italiana di Neurologia.)

Infection with the flavivirus Zika virus (ZIKV) can result in tissue tropism, disease outcome, and route of transmission distinct from those of other flaviviruses; therefore, we aimed to identify host machinery that exclusively promotes the ZIKV replication cycle, which can inform on differences at the organismal level. We previously reported that deletion of the host antiviral ribonuclease L (RNase L) protein decreases ZIKV production. Canonical RNase L catalytic activity typically restricts viral infection, including that of the flavivirus dengue virus (DENV), suggesting an unconventional, proviral RNase L function during ZIKV infection. In this study, we reveal that an inactive form of RNase L supports assembly of ZIKV replication factories (RFs) to enhance infectious virus production. Compared with the densely concentrated ZIKV RFs generated with RNase L present, deletion of RNase L induced broader subcellular distribution of ZIKV replication intermediate double-stranded RNA (dsRNA) and NS3 protease, two constituents of ZIKV RFs. An inactive form of RNase L was sufficient to contain ZIKV genome and dsRNA within a smaller RF area, which subsequently increased infectious ZIKV release from the cell. Inactive RNase L can interact with cytoskeleton, and flaviviruses remodel cytoskeleton to construct RFs. Thus, we used the microtubule-stabilization drug paclitaxel to demonstrate that ZIKV repurposes RNase L to facilitate the cytoskeleton rearrangements required for proper generation of RFs. During infection with flaviviruses DENV or West Nile Kunjin virus, inactive RNase L did not improve virus production, suggesting that a proviral RNase L role is not a general feature of all flavivirus infections., Competing Interests: Competing interest statement: S.R.W. is on the scientific advisory board of Immunome, Inc. and Ocugen, Inc. R.H.S. is a consultant to Inception Therapeutics, Inc.

Background: Salivary fistulas remain a significant problem in patients undergoing major head and neck reconstructive surgery. Surgical sealants have become increasingly used in cutaneous and non-cutaneous wound closure, providing a barrier to fluids/gases and promoting healing. The purpose of this study was to determine the efficacy of a common surgical sealant, 2-Octyl Cyanoacrylate (2-OCA, Dermabond®), in the prevention of salivary fistulas following free flap reconstruction of the oral cavity., Methods: In this non-randomized, single arm prospective trial, patients undergoing free flap reconstruction of gravity-dependent oral cavity defects were recruited. Application of 2-OCA was performed along flap inset suture lines at the time of surgery. Prospectively collected trial data were propensity score matched to a control cohort to compare outcomes. Data collected include demographics, medical co-morbidities, previous treatments, primary tumor site, and subsites reconstructed. The primary outcome measure was rate of salivary fistula formation. Secondary outcomes were time to development of leak and percentage of patients tolerating oral feeding at one month post-operatively., Results: In the 46 propensity score matched pairs, eight (17.4%) out of 46 patients in the 2-OCA prospective cohort and seven (15.2%) out of 46 patients in the control cohort developed postoperative salivary fistulas within the one-month study interval (p = 1.00). The average time to postoperative leak in the 2-OCA group was 12.5 days versus 7.1 days in the control cohort (p = 0.10). In the 2-OCA group, 30 (65.2%) patients were tolerating regular diet at one month post-operatively compared to 33 (71.7%) in the control cohort (p = 0.65)., Conclusion: Salivary fistula rates after application of a 2-OCA surgical sealant were not improved compared to a control cohort in this single institutional trial. There are several surgical sealants available, each with varying elasticity and adhesiveness. Future studies are needed to identify surgical sealants that are able to provide sufficient strength and adhesion to seal closures and combat corrosive saliva, but elastic enough to handle motion related tension during swallowing and post-operative movements in the head and neck., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Disparities in exposure to occupational hazards may be linked to social position as well as the type of job a person holds. This study aimed to describe the prevalence of exposure to workplace hazards among three migrant worker groups and to assess whether social disparities in exposure for these groups remain after adjusting for occupational characteristics., Methods: Data were collected in 2017/2018 from 1630 Australian workers born in New Zealand, India, and the Philippines. Weighted estimated prevalence of exposure to 10 carcinogens and four psychosocial hazards (discrimination, job strain, vulnerability, and insecurity) was calculated for sociodemographics and occupation. Regression estimated the likelihood of exposure by sociodemographics after adjustment for occupational characteristics., Results: Exposure to workplace hazards ranged from 11.7% (discrimination) to 61.2% (exposed to at least one carcinogen). Compared with workers born in India, New Zealand born workers were over twice as likely to be exposed to diesel engine exhaust (adjusted odds ratio [aOR] = 2.60) and 60% more likely to be exposed to at least one carcinogen (aOR = 1.60) but less likely to be exposed to any psychosocial hazard. Social disparities by country of birth, sex, age, education, and number of years in Australia, as well as company size, employment type, and hours, worked remained associated with greater likelihood of reporting one or more workplace hazards after adjusting for occupational characteristics., Conclusion: Examining sociodemographic as well as occupational characteristics helps to clarify groups most likely to be exposed to workplace hazards who can be hidden when examining occupational characteristics alone., (© 2020 Wiley Periodicals LLC.)

Objective: To determine the diagnostic efficacy and clinical value of preoperative computed tomography (CT) and magnetic resonance imaging (MRI) among patients with suspected temporal bone encephaloceles (TBE)., Study Design: Retrospective chart review from 2006 to 2018., Setting: Tertiary referral center., Subjects and Methods: The subjects underwent surgery for a clinically suspected TBE or cerebrospinal fluid (CSF) leak. Preoperative imaging test characteristics of CT and MRI, including sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), were calculated for TBE scans and compared with intraoperative findings., Results: Fifty-seven subjects with otorrhea, middle ear effusion, hearing loss, and/or meningitis with suspected TBE or CSF leak were identified. All had preoperative CT scans, and 61% (35/57) had preoperative MRI scans. Intraoperatively, 37 of 57 patients (65%) were found to have a TBE. CT scans (17% sensitivity, 100% specificity, 100% PPV, 46% NPV) were less sensitive than MRI (58% sensitivity, 100% specificity, 100% PPV, 24% NPV) for detecting TBEs. Furthermore, the time from initial scan to operative repair was significantly longer in those who had a CT followed by MRI scan compared with CT alone or a fused CT-MRI scan (mean = 68 vs 15 days, respectively; P = .004)., Conclusion: CT and MRI provide complementary information that may aid surgical planning. However, imaging cannot always rule out TBE. In cases with high clinical suspicion, surgical confirmation is often required for definitive diagnosis and treatment. The cost of an additional preoperative study should be considered before its use.

Hypothesis: Merlin-deficient Schwann cells (MD-SC) and primary human vestibular schwannoma (VS) cells exhibit selective uptake of sodium-fluorescein (SF), allowing for fluorescent detection and improved visualization of tumor cells, when compared with Schwann cells (SC)., Background: SF is a fluorescent compound used for fluorescence-guided resection of gliomas. The utility of SF for VS surgery has not been assessed., Methods: Mouse MD-SCs and rat SCs were cultured on 96-well plates at different cell densities and treated with SF at several drug concentrations and durations. Relative fluorescence units (RFU) were measured using a fluorometer to determine optimal treatment parameters in vitro. Subsequently, a four-point Likert scale for fluorescence visualization of pelleted cells was created and validated. Blinded observers rated SF-treated primary human VS and SC cultures, which were developed from deidentified specimens obtained from live and cadaveric donors, respectively., Results: In contrast to SCs that showed low levels of fluorescence, MD-SCs demonstrated dose-dependent increases in RFUs when treated with incremental dosages of SF as well as longer treatment and fluorescent excitation times. In addition, RFUs were higher at greater MD-SC densities. The Likert scale for fluorescence visualization was validated using nine blinded observers and there were excellent inter- and intrarater reliabilities (intraclass coefficients of 0.989 and >0.858, respectively). Using the Likert scale, human VS treated with SF received higher scores than human SCs (p < 0.001)., Conclusion: Mouse MD-SC and human VS cells demonstrate preferential uptake of SF when compared with normal primary SCs. Observers detected differences in fluorescence using the validated Likert scale. Further investigations into the utility of SF-guidance in VS surgery are warranted.

Purpose: Interstitial lung disease is a common extra-articular manifestation of rheumatoid arthritis (RA-ILD) and is associated with significant morbidity and mortality. However, limited data exist regarding predictors of mortality. We sought to examine the prognostic value of the high-resolution computed tomography (HRCT) patterns in patients with RA-ILD., Materials and Methods: RA-ILD patients with HRCT patterns of usual interstitial pneumonia (UIP) or nonspecific interstitial pneumonia (NSIP) were identified among a longitudinal cohort of individuals evaluated at National Jewish Health. A total of 158 subjects were included in the study. For each subject, the earliest available HRCT was reviewed independently by two expert thoracic radiologists blinded to clinical data. HRCT patterns were classified as demonstrating definite UIP, possible UIP, or NSIP. Kaplan-Meier curves were generated and survival was compared among the three patterns using a log rank test for trend., Results: One hundred subjects (63%) had HRCT findings classified as definite UIP, 23 (15%) as possible UIP and 35 (22%) as NSIP. No difference in survival was seen between subjects with definite UIP versus those with possible UIP. The combined group of subjects with either definite- or possible UIP had significantly worse survival than those with NSIP (log-rank p = 0.03)., Conclusions: In patients with RA-ILD, patients with either definite UIP or possible UIP have equally poor survival when compared to those with an NSIP pattern., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Liquid chromatography-tandem mass spectrometry (LC-MS-MS) offers specific advantages over gas chromatography-mass spectrometry (GC-MS) such as the ability to identify and measure a broader range of compounds with minimal sample preparation. Comparative analysis of LC-MS-MS versus GC-MS was performed for urinalysis detection of five benzodiazepine compounds currently part of the Department of Defense (DoD) Drug Demand Reduction Program (DDRP) testing panel; alpha-hydroxyalprazolam, oxazepam, lorazepam, nordiazepam and temazepam. In the analyses of internally prepared control urine samples at concentrations around the DDRP administrative decision point for benzodiazepines (100 ng/mL), both technologies produced comparable results with average accuracies between 99.7 and 107.3% and average coefficients of variation (%CV) <9%. Analysis of service member specimens that screened positive for benzodiazepines using both technologies produced comparable results for all analytes. Different degrees of matrix effect were observed for all analytes in the LC-MS-MS analysis. However, the effects were controlled by using deuterated internal standards (ISTDs). Additionally, there was a 39% increase in nordiazepam mean concentration analyzed by LC-MS-MS due to suppression of the ISTD ion by the flurazepam metabolite 2-hydroxyethylflurazepam. The ease and speed of sample extraction, the broader range of compounds that can be analyzed and shorter run time make the LC-MS-MS technology a suitable and expedient alternative confirmation technology for benzodiazepine testing., (Published by Oxford University Press 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Herein, we report the synthesis and mass spectrometry studies of several N-alkylbenzenesulfonamides structurally related to sulfanilic acid. The compounds were synthesized using a modified Schotten-Baumann reaction coupled with Meisenheimer arylation. Sequential mass spectrometry by negative mode electrospray ionization (ESI(-)-MS/MS) showed the formation of sulfoxylate anion (m/z 65) observed in the mass spectrum of p-chloro-N-alkylbenzenesulfonamides. Investigation of the unexpected loss of two water molecules, as observed by electron ionization mass spectrometry (EI-MS) analysis of p-(N-alkyl)lactam sulfonamides, led to the proposal of corresponding fragmentation pathways. These compounds showed loss of neutral iminosulfane dioxide molecule (M-79) with formation of ions observed at m/z 344 and 377. These ions were formed by rearrangement on ESI(+)-MS/MS analysis. Some of the molecules showed antagonistic activity against Kv3.1 voltage-gated potassium channels.

Interstitial lung disease (ILD) is a common pulmonary manifestation of rheumatoid arthritis. There is lack of clarity around predictors of mortality and disease behaviour over time in these patients.We identified rheumatoid arthritis-related interstitial lung disease (RA-ILD) patients evaluated at National Jewish Health (Denver, CO, USA) from 1995 to 2013 whose baseline high-resolution computed tomography (HRCT) scans showed either a nonspecific interstitial pneumonia (NSIP) or a "definite" or "possible" usual interstitial pneumonia (UIP) pattern. We used univariate, multivariate and longitudinal analytical methods to identify clinical predictors of mortality and to model disease behaviour over time.The cohort included 137 subjects; 108 had UIP on HRCT (RA-UIP) and 29 had NSIP on HRCT (RA-NSIP). Those with RA-UIP had a shorter survival time than those with RA-NSIP (log rank p=0.02). In a model controlling for age, sex, smoking and HRCT pattern, a lower baseline % predicted forced vital capacity (FVC % pred) (HR 1.46; p<0.0001) and a 10% decline in FVC % pred from baseline to any time during follow up (HR 2.57; p<0.0001) were independently associated with an increased risk of death.Data from this study suggest that in RA-ILD, disease progression and survival differ between subgroups defined by HRCT pattern; however, when controlling for potentially influential variables, pulmonary physiology, but not HRCT pattern, independently predicts mortality., (Copyright ©ERS 2016.)

The last 2 years have seen exciting advances in the genetics of Landau-Kleffner syndrome and related disorders, encompassed within the epilepsy-aphasia spectrum (EAS). The striking finding of mutations in the N-methyl-D-aspartate (NMDA) receptor subunit gene GRIN2A as the first monogenic cause in up to 20% of patients with EAS suggests that excitatory glutamate receptors play a key role in these disorders. Patients with GRIN2A mutations have a recognizable speech and language phenotype that may assist with diagnosis. Other molecules involved in RNA binding and cell adhesion have been implicated in EAS; copy number variations are also found. The emerging picture highlights the overlap between the genetic determinants of EAS with speech and language disorders, intellectual disability, autism spectrum disorders and more complex developmental phenotypes.

Background: The usual interstitial pneumonia (UIP) pattern of lung injury may occur in the setting of connective tissue disease (CTD), but it is most commonly found in the absence of a known cause, in the clinical context of idiopathic pulmonary fibrosis (IPF). Our objective was to observe and compare longitudinal changes in pulmonary function and survival between patients with biopsy-proven UIP found in the clinical context of either CTD or IPF., Methods: We used longitudinal data analytic models to compare groups (IPF [n = 321] and CTD-UIP [n = 56]) on % predicted FVC (FVC %) or % predicted diffusing capacity of the lung for carbon monoxide (Dlco %), and we used both unadjusted and multivariable techniques to compare survival between these groups., Results: There were no significant differences between groups in longitudinal changes in FVC % or Dlco % up to diagnosis, or from diagnosis to 10 years beyond (over which time, the mean decrease in FVC % per year [95% CI] was 4.1 [3.4, 4.9] for IPF and 3.5 [1.8, 5.1] for CTD-UIP, P = .49 for difference; and the mean decrease in Dlco % per year was 4.7 [4.0, 5.3] for IPF and 4.3 [3.0, 5.6] for CTD-UIP, P = .60 for difference). Despite the lack of differences in pulmonary function, subjects with IPF had worse survival in unadjusted (log-rank P = .003) and certain multivariable analyses., Conclusions: Despite no significant differences in changes in pulmonary function over time, patients with CTD-UIP (at least those with certain classifiable CTDs) live longer than patients with IPF--an observation that we suspect is due to an increased rate of mortal acute exacerbations in patients with IPF.

The Fistula First Breakthrough Initiative (FFBI) has been one of the most important national programs to help achieve considerable improvements in the care of patients on chronic hemodialysis. FFBI has helped place guidelines to push practitioners to reduce the use of tunneled central venous catheters and to increase the rate of arteriovenous fistula use in patients requiring chronic hemodialysis access. However, despite current guidelines, no specific protocols exist for the creation and management of autogenous arteriovenous fistulas and outcomes at most centers are below national benchmarks. In this study, we examine the effectiveness of a standard protocol used at our institution for the creation of autogenous upper extremity fistulas for hemodialysis access in achieving early cannulation and early removal of tunneled dialysis catheters. Our review encompasses 855 consecutive autogenous fistulas created over a 10-year period. Our findings suggest that the use of a standard protocol for creation and management of autogenous fistulas can help increase the rate of functional accesses over national benchmarks. Additionally, extension/conversion of malfunctioning fistulas to grafts appears to be an excellent method to expedite removal of a tunneled dialysis catheter with concomitant preservation of a fistula.

Objective: Small series suggest mycophenolate mofetil (MMF) is well tolerated and may be an effective therapy for connective tissue disease-associated interstitial lung disease (CTD-ILD). We examined the tolerability and longitudinal changes in pulmonary physiology in a large and diverse cohort of patients with CTD-ILD treated with MMF., Methods: We identified consecutive patients evaluated at our center between January 2008 and January 2011 and prescribed MMF for CTD-ILD. We assessed safety and tolerability of MMF and used longitudinal data analyses to examine changes in pulmonary physiology over time, before and after initiation of MMF., Results: We identified 125 subjects treated with MMF for a median 897 days. MMF was discontinued in 13 subjects. MMF was associated with significant improvements in estimated percentage of predicted forced vital capacity (FVC%) from MMF initiation to 52, 104, and 156 weeks (4.9% ± 1.9%, p = 0.01; 6.1% ± 1.8%, p = 0.0008; and 7.3% ± 2.6%, p = 0.004, respectively); and in estimated percentage predicted diffusing capacity (DLCO%) from MMF initiation to 52 and 104 weeks (6.3% ± 2.8%, p = 0.02; 7.1% ± 2.8%, p = 0.01). In the subgroup without usual interstitial pneumonia (UIP)-pattern injury, MMF significantly improved FVC% and DLCO%, and in the subgroup with UIP-pattern injury, MMF was associated with stability in FVC% and DLCO%., Conclusion: In a large diverse cohort of CTD-ILD, MMF was well tolerated and had a low rate of discontinuation. Treatment with MMF was associated with either stable or improved pulmonary physiology over a median 2.5 years of followup. MMF appears to be a promising therapy for the spectrum of CTD-ILD.

Objective: We sought to characterize a novel cohort of patients with lung disease, anti-cyclic citrullinated peptide (CCP) antibody positivity, without rheumatoid arthritis (RA) or other connective tissue disease (CTD)., Methods: The study sample included 74 subjects with respiratory symptoms, evaluated January 2008-January 2010 and found to have a positive anti-CCP antibody but no evidence for RA or other CTD. Each underwent serologic testing, pulmonary physiology testing, and thoracic high-resolution computed tomography (HRCT) scan as part of routine clinical evaluation., Results: The majority of subjects were women, and most were former cigarette smokers. Four distinct radiographic phenotypes were identified: isolated airways disease (54%), isolated interstitial lung disease (ILD) (14%), mixed airways disease and ILD (26%), and combined pulmonary fibrosis with emphysema (7%). This cohort had a predominance of airways disease, either in isolation or along with a usual interstitial pneumonia-pattern of ILD. Among subjects with high-titer anti-CCP positivity (n=33), three developed the articular manifestations of RA during a median follow-up of 449 days., Conclusion: We have described a unique cohort of patients with anti-CCP antibody positivity and lung disease in the absence of existing RA or other CTD. The lung phenotypic characteristics of this cohort resemble those of established RA and a few of these patients have developed articular RA within a short period of follow-up. The implications of a positive anti-CCP antibody among patients with lung disease but not RA are not yet known, but we believe requires further investigation., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: In patients with fibrosing interstitial lung disease (fILD), gastroesophageal reflux (GER) is highly prevalent, perhaps because of the effects of lung fibrosis on altering intrathoracic pressure, diaphragm morphology and lower esophageal sphincter (LES) function. For unclear reasons, obstructive sleep apnea (OSA) is also highly prevalent among patients with fILD. We conducted this study to test our hypothesis that, in patients with fILD, OSA would exacerbate diaphragm/LES dysfunction and increase the propensity for-and severity of - GER., Methods: We identified patients with fILD who underwent screening polysomnogram and pH or pH/impedence probe at our center during the same week. We examined the association between OSA and GER and used logistic regression to determine independent predictors of OSA or GER., Results: In 54 included subjects, neither OSA (dichotomous) nor apnea hypopnea index (continuous) predicted the presence of GER. Regardless of body position (upright, recumbent), GER was no more frequent or severe among subjects with OSA vs. those without OSA. Subjects with idiopathic pulmonary fibrosis (IPF) had an odds of GER nearly seven-fold greater than subjects with other forms of fILD (odds ratio = 6.84, 95% confidence interval 1.36-34.43, p = 0.02). For the entire cohort and the subgroup with IPF, there was no correlation between pulmonary physiology and GER., Conclusions: In fILD, OSA does not appear to promote GER. Research is needed to determine if compensatory mechanisms emanating from the crural diaphragm prevent GER in fILD patients with OSA and to sort out whether GER has a role in the pathogenesis of certain forms of fILD., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: In studies of idiopathic pulmonary fibrosis (IPF), whites makeup the vast majority of subjects. Whether ethnic/racial differences in idiopathic pulmonary fibrosis occur in the general population is unknown., Methods: To compare the presence of IPF between ethnic/racial groups of U.S. decedents from 1989 to 2007 by using the National Center for Health Statistics database., Results: There were 251,058 U.S. decedents with IPF; 87.2% were non-Hispanic whites (White), 5.1% were non-Hispanic African American (black), 5.4% were Hispanic, and 2.2% were from other ethnic/racial groups (other). Whites coded with IPF died older than those in the other groups (77.9 years vs. 72.1 years for blacks, 75.3 years for Hispanics, and 75.6 years for others; p < 0.0001 for all pairwise comparisons). When controlling for age and for sex, compared with whites, both Hispanics and Others were more likely to be coded with IPF (OR = 1.47, 95% CI 1.44-1.49, p < 0.0001 and OR = 1.29, 95% CI 1.26-1.36, p < 0.0001 respectively), while blacks were significantly less likely to be coded with IPF (OR = 0.48, 95% CI 0.47-0.49, p < 0.0001). Among decedents with IPF, Hispanics were more likely, and blacks were less likely, than whites to die from IPF (OR = 1.24, 95% CI 1.20-1.29, p < 0.0001 and OR = 0.91, 95% CI 0.87-0.94, p < 0.0001)., Conclusion: From 1989 to 2007, black decedents were less-and Hispanics were more-likely than whites to die of/with IPF. Research is needed to determine if genetic differences between ethnic/racial groups explain these findings., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Recent epidemiological studies have suggested an increased risk of venous thromboembolism (VTE) in lung fibrosis. Large-scale epidemiological data regarding the risk of VTE in pulmonary fibrosis-associated mortality have not been published. Using data from the National Center for Health Statistics from 1988-2007, we determined the risk of VTE in decedents with pulmonary fibrosis in the USA. We analysed 46,450,489 records, of which 218,991 met our criteria for idiopathic pulmonary fibrosis. Among these, 3,815 (1.74%) records also contained a diagnostic code for VTE. The risk of VTE in pulmonary fibrosis decedents was 34% higher than in the background population, and 44% and 54% greater than among decedents with chronic obstructive pulmonary disease and lung cancer, respectively. Those with VTE and pulmonary fibrosis died at a younger age than those with pulmonary fibrosis alone (females: 74.3 versus 77.4 yrs (p<0.0001); males: 72.0 versus 74.4 yrs (p<0.0001)). Decedents with pulmonary fibrosis had a significantly greater risk of VTE. Those with VTE and pulmonary fibrosis died at a younger age than those with pulmonary fibrosis alone. These data suggest a link between a pro-fibrotic and a pro-coagulant state.

Background: A recently published report from the United Kingdom suggested an association between sarcoidosis and pulmonary embolism (PE). We sought to examine whether this association was present among US decedents with sarcoidosis., Methods: We used data from the National Center for Health Statistics to investigate the association between sarcoidosis and PE among US decedents from 1988 to 2007., Results: From 1988 to 2007, there were 46,450,489 deaths in the United States and 23,679 decedents with sarcoidosis mentioned on their death certificates. Among these, 602 (2.54%) had PE mentioned on their death certificates, compared with only 1.13% of the background population (P < .0001 for comparison). The association between sarcoidosis and PE was significant regardless of gender (OR, 2.07; 95% CI, 1.80-2.39; P < .0001 for men and OR, 1.76; 95% CI, 1.59-1.96; P ≤ .0001 for women) or race (OR, 1.57; 95% CI, 1.41-1.76; P < .0001 for blacks and OR, 1.87; 95% CI, 1.63-2.14; P < .0001 for whites). Among decedents with sarcoidosis, there was no difference in risk of PE between men and women (2.30% vs 2.54%, χ(2) = 1.32, P = .25) or between blacks and whites (2.60% vs 2.23%, χ(2) = 3.09, P = .08). The association between sarcoidosis and PE held regardless of age., Conclusions: Using death certificate data from 1988 to 2007, we detected an association between sarcoidosis and PE regardless of gender, race, or age. Further investigation is needed to decipher the mechanisms of this apparent association.

Rationale: It has been nearly 20 years since sarcoidosis mortality was examined at the population level in the United States., Objectives: To examine mortality rates and underlying causes of death among United States decedents with sarcoidosis from 1988-2007., Methods: We used data from the National Center for Health Statistics to (1) calculate age-adjusted sarcoidosis-associated mortality rates; (2) examine how those rates differ by age, sex, and race and ethnicity; and (3) determine underlying causes of death among sarcoidosis decedents., Measurements and Main Results: From 1988-2007, there were 46,450,489 deaths in the United States and 23,679 decedents with sarcoidosis mentioned on their death certificates. Over this time, the age-adjusted, sarcoidosis-related mortality rate increased 50.5% in women and 30.1% in men. The greatest absolute increase in death rates was among non-Hispanic black females. Regardless of sex or race, mortality rates climbed most in decedents 55 years or older. The most common cause of death was sarcoidosis itself. Younger sarcoidosis decedents with pulmonary fibrosis were more likely to be black than white, and younger sarcoidosis decedents were more likely than similarly aged decedents in the general population to have a cardiac cause contribute to death., Conclusions: From 1988-2007, sarcoidosis-related mortality rates increased significantly, particularly in non-Hispanic black females aged 55 years or older. The underlying cause of death in most patients with sarcoidosis was the disease itself. Among young sarcoidosis decedents, those with pulmonary fibrosis or a cardiac cause contributing to death were more likely to be black than white.

Rationale: Mortality rates from rheumatoid arthritis-associated interstitial lung disease (RA-ILD) are largely unknown., Objectives: We sought to determine mortality rates from rheumatoid arthritis-associated interstitial lung disease in the United States from 1988 through 2004., Methods: Using data from the National Center for Health Statistics, we calculated age-adjusted mortality rates from the deaths of persons with rheumatoid arthritis-associated interstitial lung disease, determined the prevalence of interstitial lung disease in all decedents with rheumatoid arthritis, and compared the age and underlying cause of death in these two cohorts of decedents., Measurements and Main Results: From 1988 to 2004, there were 39,138,394 deaths in U.S. residents and 162,032 rheumatoid arthritis-associated deaths. Of these deaths, 10,725 (6.6%) met criteria for rheumatoid arthritis-associated interstitial lung. Mortality rates from rheumatoid arthritis fell over the course of this study in both women and men. However, mortality rates from rheumatoid arthritis-associated interstitial lung disease increased 28.3% in women (to 3.1 per million persons in 2004) and declined 12.5% in men (to 1.5 per million persons in 2004). Because the rate of decline in rheumatoid arthritis outpaced rheumatoid arthritis-associated interstitial lung disease in men, the prevalence of rheumatoid arthritis-associated interstitial lung disease increased in both sexes over time., Conclusions: Clinically significant RA-ILD occurs in nearly 10% of the RA population, and is associated with shortened survival and more severe underlying disease. Whereas overall mortality rates for RA have fallen, those associated with RA-ILD have increased significantly in older age groups.

Purpose: Cancer progression is mediated by processes that are also important in wound repair. As a result, cancers have been conceptualized as overhealing wounds or "wounds that do not heal," and gene expression signatures reflective of wound repair have shown value as predictors of breast cancer survival. Despite the widespread acknowledgment of commonalities between host responses to wounds and host responses to cancer, the gene expression responses of normal tissue adjacent to cancers have not been well characterized., Experimental Design: Using RNA extracted from histologically normal breast tissue from 107 patients, including 60 reduction mammoplasty patients and 47 cancer patients, we measured whole genome expression profiles and identified a gene expression signature that is induced in response to breast cancer., Results: This signature represents an in vivo "wound response" signature that is differentially expressed in the normal tissue of breast cancer patients compared with those without disease and is highly accurate (at least 92% sensitivity and 98% specificity) in distinguishing diseased and nondiseased. The in vivo wound response signature is highly prognostic of breast cancer survival, and there is a strong association between the groups identified by this signature and those identified using serum-treated fibroblasts and other microenvironment-derived or microenvironment-related signatures., Conclusions: The prevalence of the wound response signature in histologically normal tissue adjacent to breast cancer suggests that microenvironment response is an important variable in breast cancer progression and may be an important target for clinical interventions.

Objectives: To describe the clinical features of patients presenting with "idiopathic" interstitial pneumonia that were diagnosed with anti-synthetase syndrome based on clinical features and positive anti-PL-7 or PL-12 antibodies., Methods: Over a 24-month period, we evaluated 37 patients who presented with clinical features of anti-synthetase (AS) syndrome, negative anti-Jo-1 antibodies, and who were assessed for other anti-tRNA synthetase (anti-tRS) antibodies. All data were abstracted from the medical record., Results: Nine (24%) were confirmed to have non-anti-Jo-1 positive AS syndrome based on clinical features and the presence of other anti-tRS antibodies (seven with anti-PL-7, two with anti-PL-12 antibodies). All presented with dyspnea as the initial symptom and with ILD as the first manifestation. Elevated CPK was identified in three patients but only two had muscle weakness. Pulmonary physiology revealed restriction (forced vital capacity 60% of predicted) and impaired gas transfer (diffusing capacity for carbon monoxide 40% of predicted). All had similar findings on thoracic HRCT scans, with basilar predominance of abnormalities and patterns suggestive of non-specific interstitial pneumonia and organizing pneumonia. Immunomodulatory therapies were used to treat the ILD-responses were variable, but some subjects clearly improved., Conclusion: Anti-PL-7 and PL-12 antibodies may be more common among patients presenting with "idiopathic" interstitial pneumonia than formerly considered and should be checked in patients with features of AS syndrome despite a negative screen for anti-nuclear or anti-Jo-1 antibodies. Further research is needed to advance understanding of anti-PL-7 or anti-PL-12-positive AS syndrome, including its prognosis and optimal approaches to therapy.

We investigated the temporal and regional profile of blood-brain barrier (BBB) permeability to both large and small molecules after moderate fluid percussion (FP) brain injury in rats and determined the effects of post-traumatic modest hypothermia (33 degrees C/4 h) on these vascular perturbations. The visible tracers biotin-dextrin-amine 3000 (BDA-3K, 3 kDa) and horseradish peroxidase (HRP, 44 kDa) were injected intravenously at 4 h or 3 or 7 days post-TBI. At 30 min after the tracer infusion, both small and large molecular weight tracers were detected in the contusion area as well as remote regions adjacent to the injury epicenter in both cortical and hippocampal structures. In areas adjacent to the contusion site, increased permeability to the small molecular weight tracer (BDA-3K) was evident at 4 h post-TBI and remained visible after 7 days survival. In contrast, the larger tracer molecule (HRP) appeared in these remote areas at acute permeable sites but was not detected at later post-traumatic time periods. A regionally specific relationship was documented at 3 days between the late-occurring permeability changes observed with BDA-3K and the accumulation of CD68-positive macrophages. Mild hypothermia initiated 30 min after TBI reduced permeability to both large and small tracers and the infiltration of CD68-positive cells. These results indicate that moderate brain injury produces temperature-sensitive acute, as well as more long-lasting vascular perturbations associated with secondary injury mechanisms.

Tumor necrosis factor (TNF) plays a critical role in pathomechanisms associated with secondary damage after traumatic brain injury (TBI). The TNF ligand-receptor system stimulates inflammation by activation of gene transcription through the IkappaB kinase (IKK)-NF-kappaB and c-Jun NH(2)-terminal kinase (JNK)-AP-1 signaling cascades. TNF signaling following TBI involves both cell survival and apoptotic pathways, but the mechanism that accounts for the dual role of TNF remains unclear. Multiple studies have reported hypothermia to be protective following TBI, but the precise mechanism has not been clearly defined. Here, TNFR1 signaling pathways were investigated in the cerebral cortex of adult male Sprague-Dawley rats subjected to moderate fluid-percussion TBI and of naïve controls. Another group was subjected to moderate TBI with 30 min of pre- and post-traumatic hypothermia (33 degrees C). Rapid and marked increases in protein expression of TNFR1 and signaling intermediates in both the IKK-NF-kappaB and JNK pathways were induced in traumatized cortices. Hypothermia decreased TNFR1 protein expression acutely in traumatized cortices and stimulated early activation of signaling intermediates in the JNK, but not the IKK-NF-kappaB, signaling pathways. Hypothermia promoted a rapid activation of caspase-3 acutely after injury but suppressed caspase-3 activation at later time points. Moreover, hypothermia treatment suppressed cleavage of X-linked inhibitor of apoptosis protein (XIAP) into fragments induced by TBI. These data suggest that hypothermia may regulate both the JNK signaling cascade via XIAP and the preconditioning pathways that activate caspases. Thus, hypothermia mediates TNFR1 responses via early activation of the JNK signaling pathway and caspase-3, leading to endogenous neuroprotective events.

Allergic reactions and systemic desensitization to corticosteroids have been documented rarely in English language literature. These reactions appear more often when the agent is applied topically and may lead to dangerous complications in patients if administered i.v. Therefore, the safety and efficacy of using an i.v. corticosteroid for desensitization in a patient who has a history of allergy to corticosteroid must be weighed carefully, especially when the aim of its use is to prevent an allergic reaction from a second drug. We report a case of successful systemic hydrocortisone desensitization in a patient with radiocontrast-induced anaphylactoid reaction and corticosteroid allergy. Sensitization to corticosteroids was determined through skin testing. The patient was desensitized to hydrocortisone and premedicated with hydrocortisone and diphenhydramine and subsequently underwent cardiac catheterization with radiocontrast without adverse reaction.

A male presenting with benign partial epilepsy with rolandic spikes from the age of 7 years was evaluated at age 11 years for worsening of his epilepsy associated with a specific regression of graphomotor skills. A longitudinal study over nearly 2 years showed an improvement in handwriting to an almost normal level under modified antiepileptic therapy. A detailed analysis with a computer-monitored graphics table showed at first a rapid improvement of skills followed by protracted slower progress. We argue that the initial rapid recovery of skills was directly linked to the improvement of his epilepsy. The slower late acquisition of motor programmes that had never been fully established was due to long-standing interference by his epilepsy. The specificity of the deficit within the graphomotor system and its possible neurobiological basis are also discussed. The analytical method and approach used in a single patient might provide an example for other patients in whom epilepsy can interfere in the acquisition, progress, and maintenance of new skills and can be responsible for selective deficits.

We describe two young children who presented with frequent falls and myoclonic jerks affecting the trunk and legs associated with a sharp and slow wave epileptic focus at the vertex. The initial neurological examination and brain magnetic resonance imaging were normal. Both patients had a persistent gait dysfunction, sometimes asymmetrical, fluctuating with the intensity of the epilepsy and the electroencephalogram abnormalities. The localization of the epileptic focus at the vertex, corresponding to the motor control of the legs and trunk, can explain this peculiar semiology. The seizures were difficult to treat, but one patient is currently in remission. Although epileptic falls are most often a feature of severe epilepsies of childhood, we think that these two patients present a variant of benign partial epilepsy of childhood.

Acquired epileptic aphasia (AEA, or Landau-Kleffner syndrome) is a unique condition in which children can lose oral language (OL) comprehension and expression for a prolonged period. These children can benefit from visual forms of language, mainly sign language (SL), but the quality of SL has never been analyzed. The case is reported here of a boy with AEA who lost speech comprehension and expression from 3 years 6 months to 7 years and was educated in SL from the age of 6 years. His SL was evaluated at the age of 13 years and 6 months and compared with a control child with congenital sensorineural deafness. It was found that: (1) our patient achieved the same proficiency in SL as the control child with deafness; (2) SL learning did not compete with, but perhaps even hastened, the recovery of OL. Intact ability to learn a new linguistic code such as SL suggests that higher-order language areas were preserved and received input from a separate visual route, as shown by neuropsychological and functional imaging research in deaf and hearing signers.

Spindle cell carcinoma of the breast, a variant of metaplastic carcinoma, includes a wide spectrum of lesions with histomorphologic and nuclear features ranging from overtly malignant to mildly atypical. Spindle cell carcinomas with mildly atypical features may resemble fasciitis, fibromatosis, or myofibroblastic tumors and therefore are often misinterpreted as such. A recent study has suggested that spindle cell carcinomas with a dominant fibromatosis-like phenotype, unlike spindle cell carcinomas in general, have no propensity for distant metastasis and should be termed "tumors" rather than "carcinomas." To investigate the question of fibromatosis-like spindle cell breast carcinoma (FLSpCCs) metastatic potential, we studied cases of FLSpCC seen at the University of Texas M.D. Anderson Cancer Center between 1987 and 2000. Clinical, pathologic, and immunophenotypic features were reviewed, with emphasis on biologic behavior and predictors of clinical outcome. Our series included 24 women who ranged in age from 55 to 85 years (mean 66 years). Tumor size ranged from 1.0 to 5 cm (mean 2.8 cm). Most tumors were grossly well defined but had microscopic infiltrative borders. Tumors showed a dominant fibromatosis-like or myofibroblastic-like growth pattern with prominent collagenization. Inflammatory infiltrate was noted in the majority of tumors. Cytokeratin-positive cells were seen in all cases and usually appeared as cords or sheets of polygonal cells; isolated cytokeratin-positive cells were rare. In most tumors immunoreactivity for smooth muscle actin (SMA) was confined to the cytokeratin-negative cells. In five cases intense co-expression of cytokeratin and SMA was noted. None of the tumors showed immunoreactivity for smooth muscle heavy chain myosin, estrogen receptors, progesterone receptors, or HER-2/neu. Ki-67 expression was noted in fewer than 5% of tumor cells. Treatment consisted of local excision (seven cases) or modified radical mastectomy (13 cases). Treatment was unknown in four cases. In patients who underwent axillary nodal dissection, no lymph node metastases were found. Two of the six patients who underwent local excision developed local recurrence. Two patients who underwent modified radical mastectomy developed lung metastases within 2 years after the initial diagnosis. The metastatic tumors were histologically similar to the primary tumors. Our findings indicate that FLSpCCs have the potential for local recurrence and distant metastasis and should be treated accordingly. Because FLSpCCs may be underdiagnosed as benign, the use of immunohistochemical studies, especially for cytokeratins and SMA, is essential in the evaluation of any spindle cell proliferations of the breast.

Two infants developed unilateral hippocampal swelling on magnetic resonance imaging after prolonged seizures of temporal origin. Subsequent images suggested hippocampal sclerosis. The first child had febrile status epilepticus with exanthem subitum and developed refractory complex partial seizures. Histological findings after temporal lobectomy confirmed hippocampal sclerosis but also revealed sequelae of a focal encephalitis and microdysgenesis of the hippocampus. The second child had signs of brain dysgenesis, but acquired hippocampal damage affecting each side successively was documented by serial magnetic resonance imaging. These cases illustrate that different clinical conditions combining preexisting and acquired pathological characteristics can lead to hippocampal sclerosis.