Objectives/Hypothesis
Adjuvant medications including proton pump inhibitors (PPI), antibiotics (trimethoprim/sulfamethoxazole TMP‐SMX), and inhaled corticosteroids (ICS) may be prescribed for ...patients with idiopathic subglottic stenosis (iSGS). We describe medication use with endoscopic dilation (ED) or endoscopic resection with medical treatment (ERMT) and evaluate impact on outcomes.
Study Design
International, prospective, 3‐year multicenter cohort study of 810 patients with untreated, newly diagnosed, or previously treated iSGS.
Methods
Post hoc secondary analysis of prospectively collected North American Airway Collaborative data on outcomes linked with adjuvant medication utilization. Primary outcome was time to recurrent operation, evaluated using Kaplan–Meier curves and Cox regression analysis. Secondary outcomes of change in peak expiratory flow (PEF) and clinical chronic obstructive pulmonary disease questionnaire (CCQ) score over 12 months were compared.
Results
Sixty‐one of 129 patients undergoing ED received PPI (47%), and 10/143 patients undergoing ED received ICS (7%). TMP‐SMX was used by 87/115 patients (76%) undergoing EMRT. PPI use in the ED group did not affect time to recurrence (hazard ratio HR = 1.00, 95% confidence interval CI: 0.53–1.88; P = .99) or 12‐month change in PEF (L/min) (median interquartile range, 12.0 10.7–12.2 vs. 8.7 −5.1 to 24.9; P = .59), but was associated with 12‐month change in CCQ (−0.05 −0.97 to 0.75 vs. −0.50 −1.60 to 0.20; P = .04). ICS did not affect outcome measures. TMP‐SMX use in ERMT did not affect time to recurrence (HR = 0.842, 95% CI: 0.2345–3.023; P = .79), PEF at 12 months (75 68–89 vs. 81 68–89; P = .92), or 12‐month change in CCQ (0.20 −1.05 to 0.47 vs. −0.30 −1.00 to 0.10; P = .45).
Conclusion
There is no standard practice for prescribing adjuvant medications. These data do not support that adjuvant medications prolong time to recurrence or increase PEF. Patients with iSGS and gastroesophageal reflux disease may experience some symptom benefit with PPI.
Level of Evidence
3 Laryngoscope, 131:E2880–E2886, 2021
The North American Airway Collaborative (NoAAC) previously published a 3-year multi-institutional prospective cohort study showing variation in treatment effectiveness between 3 primary surgical ...techniques for idiopathic subglottic stenosis (iSGS). In this report, we update these findings to include 5 years of data evaluating treatment effectiveness. Patients in the NoAAC cohort were re-enrolled for 2 additional years and followed using the prespecified published protocol. Consistent with prior data, prospective observation of 487 iSGS patients for 5 years showed treatment effectiveness differed by modality. Cricotracheal resection maintained the lowest rate of recurrent operation (5%), followed by endoscopic resection with adjuvant medical therapy (30%) and endoscopic dilation (50%). These data support the initial observations and continue to provide value to providers and patients navigating longitudinal decision-making. Level of evidence: 2-prospective cohort study.
Age-related maculopathy (ARM), or age-related macular degeneration, is one of the most common causes of visual impairment in the elderly population of developed nations. In a combined analysis of two ...previous genomewide scans that included 391 families, containing up to 452 affected sib pairs, we found linkage evidence in four regions: 1q31, 9p13, 10q26, and 17q25. We now have added a third set of families and have performed an integrated analysis incorporating 530 families and up to 736 affected sib pairs. Under three diagnostic models, we have conducted linkage analyses using parametric (heterogeneity LOD HLOD scores under an autosomal dominant model) and nonparametric (
S
all statistic) methods. There is ongoing evidence of susceptibility loci within the 1q31, 10q26, and 17q25 regions. If we treat the third set of families as a replication set, then two regions (10q26 and 17q25) are replicated, with LOD scores >1.0. If we pool all our data together, then four regions (1q31, 2q14.3, 10q26, and 17q25) show HLOD or
S
all scores ⩾2.0. Within the 1q31 region, we observed an HLOD of 2.72 (genomewide
P=.061) under our least stringent diagnostic model, whereas the 17q25 region contained a maximal HLOD of 3.53 (genomewide
P=.007) under our intermediate diagnostic model. We have evaluated our results with respect to the findings from several new independent genomewide linkage studies and also have completed ordered subset analyses (OSAs) with apolipoprotein E alleles, smoking history, and age at onset as stratifying covariates. The OSAs generate the interesting hypothesis that the effect of smoking on the risk of ARM is accentuated by a gene in the 10q26 region—a region implicated by four other studies.
Patients with rotator cuff tears have varying degrees of symptom expression. Our purpose was to evaluate the differential firing patterns of the rotator cuff, deltoid, and scapular stabilizer muscle ...groups in normal control subjects and in patients with symptomatic and asymptomatic 2-tendon rotator cuff tears. Eighteen subjects were evaluated: six normal subjects and twelve with 2-tendon cuff tears (six asymptomatic and six symptomatic). All cuff tear patients had magnetic resonance imaging (MRI) scans documenting superoposterior tear configurations involving the supraspinatus and infraspinatus tendons; all normal subjects had an ultrasound examination confirming the absence of cuff pathology. Subjects were grouped based on shoulder examination and outcomes questionnaires. Asymptomatic patients had minimal pain (<3 on the visual analog scale and no loss of active range of motion compared with the contralateral side); symptomatic patients had pain greater than 3 on the visual analog scale and decreased range of motion compared with the contralateral side (>10° of motion loss). Electromyographic activity from 12 muscles and kinematic data were collected simultaneously during 10 functional tasks. Both symptomatic and asymptomatic cuff subjects demonstrated a trend toward increased muscle activation during all tasks compared with normal subjects. During the internal rotation tasks, asymptomatic patients had significantly greater (P < .05) subscapularis activity than symptomatic patients (65% maximal voluntary contraction MVC vs 42% MVC). During the carrying task, asymptomatic patients demonstrated significantly less (P < .03) upper trapezius muscle activation than symptomatic patients (16% MVC vs 50% MVC). During shoulder elevation tasks, symptomatic patients had significantly greater supraspinatus (52% MVC vs 28% MVC, P < .03), infraspinatus (32% MVC vs 16% MVC, P < .05), and upper trapezius (39% MVC vs 20% MVC, P < .04) muscle activation compared with asymptomatic patients. During heavy elevation (8 lb), asymptomatic patients showed a trend toward increased activation (P < .06) of the subscapularis compared with symptomatic patients (34% MVC vs 21% MVC). Differential shoulder muscle firing patterns in patients with rotator cuff pathology may play a role in the presence or absence of symptoms. Asymptomatic subjects demonstrated increased firing of the intact subscapularis, whereas symptomatic subjects continued to rely on torn rotator cuff tendons and periscapular muscle substitution, resulting in compromised function.
Objectives/Hypothesis
We sought to establish normative peak expiratory flow (PEF) data for patients with idiopathic subglottic stenosis (iSGS), evaluate whether immediate changes in PEF after a ...procedure predict long‐term treatment response, and test if a decline in longitudinal PEF is associated with disease recurrence.
Study Design
International, prospective, 3‐year multicenter cohort study of 810 patients with untreated, newly diagnosed, or previously treated iSGS.
Methods
iSGS patients consented and enrolled in the North American Airway Collaborative (NoAAC) iSGS1000 cohort recorded PEF data on a mobile smartphone app. Cox regression tested the associations between the magnitude of postoperative PEF improvement and longitudinal 90‐day PEF decline with the risk of disease recurrence.
Results
Within the NoAAC iSGS1000 cohort, 810 patients participated in a 3‐year prospective study comparing surgical treatment efficacy and 385 had appropriate PEF measurements and follow‐up data. Of those patients, 42% (161/385) required at least one operation during study follow‐up. The mean PEF preceding operative intervention was 241 L/min (95% confidence interval CI: 120–380) corresponding to a predicted PEF of 52%. The mean increase in PEF following a procedure was 111 L/min (95% CI: 96–125 L/min). Interestingly, the magnitude of immediate PEF improvement was not predictive of disease recurrence (hazard ratio HR for 100 L/min increase = 0.90, 95% CI: 0.60–1.00). However, recurrence was associated with the magnitude of PEF decline over 90 days (30% vs. 10% decline, HR = 2.2, 95% CI: 1.5–3.0).
Conclusions
We provide normative PEF data on a large iSGS patient cohort. The degree of PEF improvement immediately after surgery was not associated with a longer procedure‐free interval. However, a 30% decline in PEF over 90 days was associated with elevated risk of disease recurrence.
Level of Evidence
2 Laryngoscope, 131:E2841–E2848, 2021
Objectives:
To examine whether social determinants of health (SDH) factors are associated with time to diagnosis, treatment selection, and time to recurrent surgical intervention in idiopathic ...subglottic stenosis (iSGS) patients.
Methods:
Adult patients with diagnosed iSGS were recruited prospectively (2015-2017) via clinical providers as part of the North American Airway Collaborative (NoAAC) and via an online iSGS support community on Facebook. Patient-specific SDH factors included highest educational attainment (self-reported), median household income (matched from home zip code via U.S. Census data), and number of close friends (self-reported) as a measure of social support. Main outcomes of interest were time to disease diagnosis (years from symptom onset), treatment selection (endoscopic dilation ED vs cricotracheal resection CTR vs endoscopic resection with adjuvant medical therapy ERMT), and time to recurrent surgical intervention (number of days from initial surgical procedure) as a surrogate for disease recurrence.
Results:
The total 810 participants were 98.5% female, 97.2% Caucasian, and had a median age of 50 years (IQR, 43-58). The cohort had a median household income of $62 307 (IQR, $50 345-$79 773), a median of 7 close friends (IQR, 4-10), and 64.7% of patients completed college or graduate school. Education, income, and number of friends were not associated with time to diagnosis via multivariable linear regression modeling. Univariable multinominal logistic regression demonstrated an association between education and income for selecting ED versus ERMT, but no associations were noted for CTR. No associations were noted for time to recurrent surgical procedure via Kaplan Meier modeling and Cox proportional hazards regression.
Conclusions:
Patient education, income, and social support were not associated with time to diagnosis or time to disease recurrence. This suggests additional patient, procedure, or disease-specific factors contribute to the observed variations in iSGS surgical outcomes.
The U.S. District Court for the Southern District of Florida held that there was no negligence by the employer as a matter of law because the employer's directions were not inherently unsafe, the ...condition was open and obvious, and the employer did not cause the dangerous condition.2 The court held that although the Jones Act relaxes an employee's burden of proof on the causation element of a negligence claim, it does not abolish it entirely.3 A Jones Act employer is not an insurer of employee safety, but is liable only for its own negligence.4 Nevor v. Moneypenny Holdings, LLC involved a bench trial on a seaman's claims against his employer for injuries sustained on board a racing sailboat.5 The U.S. District Court for the District of Rhode Island found in the seaman's favor on all counts and awarded judgment in favor of a seaman.6 The case was notable for the court's determination that the appropriate pre-judgment interest rate to apply was the twelve percent adopted by the Rhode Island General Assembly.'' "16 However, the court denied the motion with respect to the Jones Act claim because there were factual issues as to whether spotlights could have illuminated the dock area, whether the plaintiff's crewmates knew about and failed to warn him of the hazardous condition of the dock, and whether the plaintiff was properly trained.17 The U.S. District Court for the Southern District of New York in In re MAT MSC Flaminia addressed the application of remedies under U.S. law to foreign crewmembers.18 The mater involved a cargo ship that exploded while sailing from the United States to Belgium.19 Its German owner and operator commenced a Limitation of Liability action in the United States.20 The estate of a crewmember killed by the explosion and fire filed a claim seeking damages pursuant to the Jones Act, the Death on the High Seas Act, and U.S. general maritime law.21 The owner and operator filed a motion for summary judgment seeking to dismiss the estate's claim on the grounds that it was exclusively subject to German law.22 The court applied the federal choice of law principles set forth in Lauritzen v. Larsen and Hellenic Lines Ltd. v. Rhoditis to determine whether the Jones Act was applicable.23 Although the operator had a permanent office in the United States, forty percent of the operator's vessels sailed to and from the United States, and the operator carried passengers on voyages that began, visited, or ended in the United States, those facts did not, when taken together, amount to substantial contacts with the United States.24 Further, the estate was already receiving full benefits pursuant to German law.\n Notable for tankers fitted with exhaust gas inerting systems, the application of inert gas must be carried out during loading and unloading, on passage, tank cleaning, and purging prior to gas freeing.
Alterations in lysosomal proteases have been implicated in many neurodegenerative diseases. The current study demonstrates a concentration-dependent decrease in PC12 cell viability and transient ...changes in cystatin C (CYSC), cathepsin B (CATB), cathepsin D (CATD) and caspase-3 following exposure to H2O2. Furthermore, activation of CATD occurred following exposure to H2O2 and cysteine protease suppression, while inhibition of CATD with pepstatin A significantly improved cell viability. Additionally, significant PARP cleavage, suggestive of caspase-3-like activity, was observed following H2O2 exposure, while inhibition of caspase-3 significantly increased cell viability compared to H2O2 administration alone. Collectively, our data suggest that H2O2 induced cell death is regulated at least in part by caspase-3 and CATD. Furthermore, cysteine protease suppression increases CATD expression and activity. These studies provide insight for alternate pathways and potential therapeutic targets of cell death associated with oxidative stress and lysosomal protease alterations.
Age-related macular degeneration or age-related maculopathy (ARM) is a major public health issue, as it is the leading cause of irreversible vision loss in the elderly in the Western world. Using ...three diagnostic models, we have genotyped markers in 16 plausible candidate regions and have carried out a genome-wide screen for ARM susceptibility loci. A panel of 225 ARM families comprising up to 212 affected sib pairs was genotyped for 386 markers. Under our most stringent diagnostic model, the regions with the strongest evidence of linkage were on chromosome 9 near D9S301 and on 10 near D10S1230, with peak multipoint heterogeneity LOD scores (HLOD) of 1.87 and 1. 42 and peak GeneHunter-Plus non-parametric LOD scores (GHP LOD) of 1. 69 and 1.83. After expanding our initial set of families to 364 ARM families with up to 329 affected sib pairs, the linkage signal on chromosome 9 vanished, while the chromosome 10 signal decreased to a GHP LOD of about 1.0, with a SimIBD P -value of 0.008 under the broadest diagnostic model with marker D10S1236. After error filtration, the GHP LOD increased to 1.27 under our most stringent model and 1.42 under our broadest model, peaking near D10S1236. This peak was seen consistently across all three diagnostic models. Our analyses also excluded up to nine different candidate regions and identified a few other regions of potential linkage, suitable for further studies. Of particular interest was the region on chromosome 5 near D5S1480, where a reasonable candidate gene, glutathione peroxidase 3, resides.
Mutation and loss of function in p53 are common features among human breast cancers. Here we use BALB/c- Trp53+/− mice as a model to examine the sequence of events leading to mammary tumors. Mammary ...gland proliferation rates were similar in both BALB/c- Trp53+/− mice and wild-type controls. In addition, sporadic mammary hyperplasias were rare in BALB/c- Trp53+/− mice and not detectably different from those of wild-type controls. Among the 28 mammary tumors collected from BALB/c- Trp53+/− mice, loss of heterozygosity for Trp53 was detected in more than 90% of invasive mammary tumors. Transplantation of Trp53+/− ductal hyperplasias also indicated an association between loss of the wild-type allele of Trp53 and progression to invasive carcinomas. Therefore, loss of p53 function seems to be a rate-limiting step in progression. Moreover, expression of biomarkers such as estrogen receptor α, progesterone receptor, Her2/Neu, and activated Notch1 varied among mammary tumors, suggesting that multiple oncogenic lesions collaborate with loss of p53 function. Expression of biomarkers was retained when tumor fragments were transplanted to syngeneic hosts. Tumors expressing solely luminal or basal keratins were also observed (27 and 11%, respectively), but the largest class of tumors expressed both luminal and basal keratins (62%). Overall, this panel of transplantable tumors provides a resource for detailed evaluation of the cell lineages undergoing transformation and preclinical testing of therapeutic agents targeting a variety of oncogenic pathways including cancer stem cells.
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