Photochemical Uncaging of Aldehydes and Ketones via Photocyclization/Fragmentation Cascades of Enyne Alcohols: An Unusual Application for a Cycloaromatization Process.

We utilized a cycloaromatization reaction driven by relief of excited state antiaromaticity to photouncage aldehydes and ketones. We developed several synthetic routes towards the synthesis of photocaged carbonyls as allylically substituted 3-(2-(arylethynyl)phenyl)prop-2-en-1-ols. A library of photocaged aryl aldehydes and ketones containing donors and acceptors, as well as several photocaged fragrance aldehydes and the steroid 5α-cholestan- 3 -one, were synthesized and demonstrated photouncaging in good to excellent yields.

Leveraging a Safety Event Management System to Improve Organizational Learning and Safety Culture.

BACKGROUND AND OBJECTIVES: Safety event management systems (SEMS) are rich sources of patient safety information, which can be used to improve organizational safety culture. An ideal SEMS can accomplish this when the system is improved with the intention of increasing learning and engagement across the organization. To support a global aim of improving overall patient safety and becoming a highly reliable learning health system, focus was directed toward increasing event review and follow-up completion and using this information to drive resource allocation and improvement efforts. METHODS: A new integrated SEMS was customized, tested, and implemented based on identified organizational need. Revised policies were developed to define expectations for event review and follow-up. The new SEMS incorporated a closed-loop communication process which ensured information from events was shared with the event submitters and facilitated shared learning. The expected impacts, improved event reporting, and follow-up were studied and guided ongoing improvements. RESULTS: After transitioning to a new SEMS, we experienced increased overall reporting by 8.6% and improved event follow-up, demonstrated by documentation on specified system forms, by 53.7%. CONCLUSIONS: By implementing a new, efficient, and standardized SEMS, which decentralized event management processes, the organization saw increased reporting and better engagement with patient safety event review and follow-up. Overall, these results demonstrated a stronger reporting culture, which allowed for local problem solving and improved learning from every event reported. A robust reporting culture positively impacted the overall organizational culture of safety.

Antiaromaticity Gain Activates Tropone and Nonbenzenoid Aromatics as Normal-Electron-Demand Diels-Alder Dienes.

We propose a carbonyl umpolung strategy for activating tropone as a normal-electron-demand Diels-Alder diene. Tropone has low reactivity for Diels-Alder reactions because of its [4n+2] π-aromaticity. Conversion of the carbonyl group into a hydrazone ion (═N-NR-) reverses the polarity of the exocyclic double bond, increases the [4n] ring π-antiaromaticity, and raises the HOMO energy. Computed gas-phase activation free energies for a Diels-Alder reaction with maleimide suggest a billion-fold rate increase when the tropone C═O is replaced by ═N-NR- (R = H or SO2CH3). Other nonbenzenoid aromatics can be activated as normal-electron-demand Diels-Alder dienes in the same way.

Photochemical Activation of Enediyne Warheads: A Potential Tool for Targeted Antitumor Therapy.

Spatial and temporal control over DNA cleavage by photoactivated enediynes can be complemented by additional factors such as the release of internal strain, chelation, pH changes, intramolecular H-bonds, and substituent effects. This review presents design and reactivity of photoactivated enediynes/enynes and analyses the chemical, biological, and photophysical challenges in their applications.

The reduction of gunshot noise and auditory risk through the use of firearm suppressors and low-velocity ammunition.

OBJECTIVE: This research assessed the reduction of peak levels, equivalent energy and sound power of firearm suppressors. DESIGN: The first study evaluated the effect of three suppressors at four microphone positions around four firearms. The second study assessed the suppressor-related reduction of sound power with a 3 m hemispherical microphone array for two firearms. RESULTS: The suppressors reduced exposures at the ear between 17 and 24 dB peak sound pressure level and reduced the 8 h equivalent A-weighted energy between 9 and 21 dB depending upon the firearm and ammunition. Noise reductions observed for the instructor's position about a metre behind the shooter were between 20 and 28 dB peak sound pressure level and between 11 and 26 dB LAeq,8h. Firearm suppressors reduced the measured sound power levels between 2 and 23 dB. Sound power reductions were greater for the low-velocity ammunition than for the same firearms fired with high-velocity ammunition due to the effect of N-waves produced by a supersonic bullet. CONCLUSIONS: Firearm suppressors may reduce noise exposure, and the cumulative exposures of suppressed firearms can still present a significant hearing risk. Therefore, firearm users should always wear hearing protection whenever target shooting or hunting.

Association between Asthma and Chronic Rhinosinusitis Severity in the Context of Asthma Control.

Objective Comorbid asthma is associated with decreased quality of life (QOL) in chronic rhinosinusitis (CRS). It is unclear whether this association is independent of the patients' clinical asthma status. We therefore sought to determine if asthma is associated with lower QOL in CRS, independent of asthma control. Study Design Cross-sectional cohort study of 350 patients with CRS. Setting Tertiary academic rhinology clinic. Subjects and Methods In total, 350 participants with CRS were recruited and 28.3% were asthmatic. CRS-specific QOL was measured using the 22-item Sinonasal Outcome Test (SNOT-22). Asthma control was assessed with the Asthma Control Test (ACT). General health-related QOL was assessed with the EuroQoL 5-dimensional general health-related quality of life survey visual analog scale (EQ-5D VAS). Associations were sought between SNOT-22 and EQ-5D VAS (dependent variables) and asthma (independent variable), while controlling for ACT. ACT score for patients with CRS without asthma was set at 25 (indicating completely controlled, asymptomatic asthma). Results Comorbid asthma was associated with SNOT-22 (ß = 11.8; 95% confidence interval [CI], 6.2-17.3; P < .001) and EQ-5D VAS (ß = -6.2; 95% CI, -11.2 to -1.3; P = .014). After controlling for ACT, asthma was no longer associated with SNOT-22 ( P = .147) or EQ-5D VAS ( P = .994). Instead, ACT score was associated with SNOT-22 (ß = -2.1; 95% CI, -3.2 to -1.1; P < .001) and EQ-5D VAS (ß = 2.1; 95% CI, 1.1 to 3.0; P < .001). ACT score completely drove the association between asthma and worse QOL. Conclusion Comorbid asthma is not necessarily reflective of decreased QOL in CRS. The association of comorbid asthma with lower QOL in CRS is related to the clinical status (eg, control) of asthma.

Periostin as a Biomarker for Nasal Polyps in Chronic Rhinosinusitis.

Objective Periostin is an extracellular matrix protein that is elevated in the sinonasal tissues of patients with chronic rhinosinusitis (CRS). The purpose of this study was to determine whether serum periostin could serve as a molecular biomarker of nasal polyp burden in sinonasal disease. Study Design Prospective cohort study. Setting Academic medical center. Subjects and Methods Serum periostin levels were measured by ELISA on blood samples collected from patients undergoing sinus surgery for CRS (n = 71), further stratified by phenotype as defined by nasal polyps and asthma. Results were compared with assays performed on control subjects (n = 62). Results Mean serum periostin levels were markedly elevated in patients with CRS versus controls (66.1 ng/mL [95% CI, 51.6-80.6] vs 38.7 ng/mL [95% CI, 34.4-42.9], respectively, P = .004). In addition, mean periostin levels were significantly higher in CRS patients with nasal polyps as compared with those without polyps (94.8 ng/mL [95% CI, 67.3-122.4] vs 41.1 ng/mL [95% CI, 35.2-47.0], respectively, P < .001). Periostin levels did not correlate with sex ( P = .473), smoking history ( P = .748), aspirin-exacerbated respiratory disease status ( P = .136), oral steroid use within 1 month of surgery ( P = .281), use of topical steroid nasal spray ( P = .864), or number of prior sinus operations ( P = .973). Conclusion Serum periostin appears to be a novel molecular biomarker for the presence of nasal polyps and may serve as an indicator of CRS endotypes.

Association between systemic antibiotic and corticosteroid use for chronic rhinosinusitis and quality of life.

OBJECTIVE: We sought to establish the significance of querying chronic rhinosinusitis (CRS) patients about their past CRS-related oral antibiotic and corticosteroid usage by determining the association between these metrics and patients' quality of life (QoL). STUDY DESIGN: Cross-sectional study. METHODS: A total of 157 patients with CRS were prospectively recruited. CRS-specific QoL was measured using the 22-item Sinonasal Outcome Test (SNOT-22). General health-related QoL was measured using the EuroQoL five-dimensional questionnaire visual analog scale. Associations were sought between these measures of QoL and frequency of CRS-related oral antibiotic and corticosteroid usage reported by the participants in the prior 3 and 12 months. RESULTS: More frequent antibiotic and corticosteroid use was significantly associated with worse CRS-specific and general health-related QoL, whether querying medication use over the prior 3 months or over the prior 12 months (P < 0.001 in all cases). The effect size of CRS-related antibiotic use during the prior 3 months on CRS-specific QoL (SNOT-22 score) was significantly greater than for use during the prior 12 months. However, there was no other statistically significant difference in effect size for association between QoL and CRS-related antibiotic or corticosteroid use in the prior 3 months versus prior 12 months. These results were independent of the presence or absence of polyps. CONCLUSION: More frequent past CRS-related oral antibiotic and corticosteroid use, regardless of time period queried (3 months or 12 months) is associated with significant decrease in CRS-specific and general health-related QoL. CRS-related systemic medication use is an important indicator of CRS patients' QOL that easily can be queried and utilized in both clinical and research settings. LEVEL OF EVIDENCE: 2c. Laryngoscope, 128:37-42, 2018.

A validated model for the 22-item Sino-Nasal Outcome Test subdomain structure in chronic rhinosinusitis.

BACKGROUND: Previous studies have identified subdomains of the 22-item Sino-Nasal Outcome Test (SNOT-22), reflecting distinct and largely independent categories of chronic rhinosinusitis (CRS) symptoms. However, no study has validated the subdomain structure of the SNOT-22. This study aims to validate the existence of underlying symptom subdomains of the SNOT-22 using confirmatory factor analysis (CFA) and to develop a subdomain model that practitioners and researchers can use to describe CRS symptomatology. METHODS: A total of 800 patients with CRS were included into this cross-sectional study (400 CRS patients from Boston, MA, and 400 CRS patients from Reno, NV). Their SNOT-22 responses were analyzed using exploratory factor analysis (EFA) to determine the number of symptom subdomains. A CFA was performed to develop a validated measurement model for the underlying SNOT-22 subdomains along with various tests of validity and goodness of fit. RESULTS: EFA demonstrated 4 distinct factors reflecting: sleep, nasal, otologic/facial pain, and emotional symptoms (Cronbach's alpha, >0.7; Bartlett's test of sphericity, p < 0.001; Kaiser-Meyer-Olkin >0.90), independent of geographic locale. The corresponding CFA measurement model demonstrated excellent measures of fit (root mean square error of approximation, <0.06; standardized root mean square residual, <0.08; comparative fit index, >0.95; Tucker-Lewis index, >0.95) and measures of construct validity (heterotrait-monotrait [HTMT] ratio, <0.85; composite reliability, >0.7), again independent of geographic locale. CONCLUSION: The use of the 4-subdomain structure for SNOT-22 (reflecting sleep, nasal, otologic/facial pain, and emotional symptoms of CRS) was validated as the most appropriate to calculate SNOT-22 subdomain scores for patients from different geographic regions using CFA.

Association between Nasal Obstruction and Risk of Depression in Chronic Rhinosinusitis.

Objective Chronic rhinosinusitis (CRS) is associated with an increased risk for depression. Since nasal obstruction is a symptom of CRS that is treatable, we sought to characterize its impact on the risk for depression in CRS. Study Design Prospective cross-sectional cohort of 94 patients with CRS. Setting Academic tertiary care rhinology clinic. Subjects and Methods Patients with CRS without vasculitis, cystic fibrosis, sarcoidosis, immunodeficiency, or sinonasal malignancy. Risk for depression was assessed with the 2-item Patient Health Questionnaire (PHQ-2) while nasal obstruction was assessed with the Nasal Obstruction Symptom Evaluation (NOSE) instrument. Multivariate logistic regressions were performed to seek association between NOSE and PHQ-2 scores. Analysis of receiver operating characteristic (ROC) curves defined a NOSE threshold for detecting participants with PHQ-2 greater than 1. Results Of the 94 participants, the mean NOSE score was 47.3, and 29.8% of patients had a PHQ-2 score greater than 1. We found an elevated NOSE score was associated with having a PHQ-2 score greater than 1 (adjusted odds ratio, 1.03; 95% CI, 1.01-1.05; P = .001). Alternatively, a 23-point increase in NOSE score was associated with a 1.5-fold increase in PHQ-2 score (adjusted relative risk, 1.02; 95% CI, 1.01-1.03; P < .001). ROC analysis identified an optimal NOSE threshold of 42.5 for detecting participants with PHQ-2 greater than 1, with 82.1% sensitivity and 50.0% specificity. Conclusions The impact of nasal obstruction is associated with an increased risk for depression in patients with CRS. Assessing for severe nasal obstruction may help to identify those patients with CRS with the highest risk for depression.

Smoking: An independent risk factor for lost productivity in chronic rhinosinusitis.

OBJECTIVES/HYPOTHESIS: Chronic rhinosinusitis (CRS) is associated with a significant loss of patient productivity that costs billions of dollars every year. Smoking is associated with worsening sinonasal symptoms, but its effect on lost productivity in CRS patients has yet to be described. Therefore, we sought to determine the association between smoking and productivity in patients with CRS. STUDY DESIGN: Prospective cross-sectional cohort study of 140 patients with CRS. METHODS: Sinonasal symptom severity was measured using the 22-item Sino-Nasal Outcomes Test. Lost productivity was assessed by asking participants how many days of work and/or school they missed in the last 3 months due to CRS. Associations were sought between lost productivity and smoking. RESULTS: Participants missed a mean of 3.0 days (standard deviation = 12.8 days) of work or school due to CRS. Having any history of smoking was associated with 6 days of lost productivity due to CRS (adjusted ß = 6.20, 95% confidence interval [CI]: 0.64 to 11.77, P = .031). Although the number of active smokers in our study cohort was very small (N = 6), we performed a univariate association between smoking status, considering former smokers and active smokers separately, and found that active smoking (ß = 11.75, 95% CI: 2.11 to 21.40, P = .018) had a much larger impact on CRS-related productivity loss than that experienced by former smokers (ß = 4.45, 95% CI: -0.32 to 9.23, P = .070). CONCLUSIONS: Smoking (likely driven by active smoking) is independently associated with missed days of work or school in patients with CRS. Further study is needed to determine whether interventions directed at smoking may impact CRS-related productivity loss. LEVEL OF EVIDENCE: 2c Laryngoscope, 127:1742-1745, 2017.

Depression symptoms and lost productivity in chronic rhinosinusitis.

BACKGROUND: Chronic rhinosinusitis (CRS) is associated with significant losses of patient productivity that cost billions of dollars every year. The causative factors for decreases in productivity in patients with CRS have yet to be determined. OBJECTIVE: To determine which patterns of CRS symptoms drive lost productivity. METHODS: Prospective, cross-sectional cohort study of 107 patients with CRS. Sinonasal symptom severity was measured using the 22-item Sinonasal Outcomes Test, from which sleep, nasal, otologic or facial pain, and emotional function subdomain scores were calculated using principal component analysis. Depression risk was assessed with the 2-item Patient Health Questionnaire (PHQ-2), whereas nasal obstruction was assessed with the Nasal Obstruction Symptom Evaluation (NOSE) instrument. Lost productivity was assessed by asking participants how many days of work and/or school they missed in the last 3 months because of CRS. Associations were sought between lost productivity and CRS symptoms. RESULTS: A total of 107 patients were recruited. Patients missed a mean (SD) of 3.1 (12.9) days of work or school because of CRS. Lost productivity was most strongly associated with the emotional function subdomain (ß = 7.48; 95% confidence interval [CI], 5.71-9.25; P < .001). Reinforcing this finding, lost productivity was associated with PHQ-2 score (ß = 4.72; 95% CI, 2.62-6.83; P < .001). Lost productivity was less strongly associated with the nasal symptom subdomain score (ß = 2.65; 95% CI, 0.77-4.52; P = .007), and there was no association between lost productivity and NOSE score (ß = 0.01; 95% CI, -0.12 to 0.13; P = .91). CONCLUSION: Symptoms associated with depression are most strongly associated with missed days of work or school because of CRS. Further treatment focusing on depression-associated symptoms in patients with CRS may reduce losses in productivity.

Nitric oxide coupling to generate N2O promoted by a single-heme system as examined by density functional theory.

Bacteria utilize a heme/non-heme enzyme system to detoxify nitric oxide (NO) to N2O. In order to probe the capacity of a single-heme system to mediate this NO-to-N2O transformation, various scenarios for addition of electrons, protons, and a second NO molecule to a heme nitrosyl to generate N2O were explored by density functional theory calculations. We describe, utilizing this single-heme system, several stepwise intermediates along pathways that enable the critical N-N bond formation step yielding the desired Fe-N2O product. We also report a hitherto unreported directional second protonation that results in either productive N2O formation with loss of water, or formation of a non-productive hyponitrous acid adduct Fe{HONNOH}.

Long-term glycemic control with hepatic insulin gene therapy in streptozotocin-diabetic mice.

BACKGROUND: Insulin self-administration is burdensome and can produce dangerous hypoglycemia. Insulin gene therapy may improve and simplify the treatment of diabetes mellitus. In rats, metabolically responsive hepatic insulin gene therapy (HIGT) delivered by adenovirus normalizes random blood sugars but with a limited duration. To prolong glycemic control, we delivered a metabolically regulated insulin transgene by adeno-associated virus (AAV). METHODS: We administered increasing doses of self-complementary (SC), pseudotyped AAV8 expressing the (GlRE)3 BP1-2xfur insulin transgene to streptozotocin-diabetic CD-1 mice, and monitored blood sugar and body weight. We also compared responses to intraperitoneal glucose and chow withdrawal, assessed for viral genomes in liver by Southern blotting, and measured hepatic glycogen. RESULTS: Glucose lowering required the combination of SC genomes and AAV capsid pseudotyping. HIGT controlled glycemia in diabetic mice (DM) for > 1 year. However, glycemic responses were variable. Approximately 30% of mice succumbed to hypoglycemia, and approximately 30% of mice again became hyperglycemic. During an intraperitoneal glucose tolerance test, blood sugars declined to normal within 180 min in HIGT-treated DM compared to 90 min in control mice. Hypoglycemia was common among HIGT-treated mice during a 24-h fast. However, HIGT mice lost less weight than either diabetic or nondiabetic controls as a result of increased water intake. HIGT treatment reduced the hepatic glycogen content of fed mice. CONCLUSIONS: Our studies demonstrate the possibility for long-term glycemic correction following AAV-mediated HIGT in mice. However, the dose-response relationship is irregular, and metabolic responsiveness may be less than that observed in rats.

The Relationship Between Cochleovestibular Orientation, Age, and Sensorineural Hearing Loss: Implications for Cochlear Implantation.

OBJECTIVES: To determine if spatial orientation of the cochlea within the temporal bone is related to age or sensorineural hearing loss (SNHL) and describe the implications for cochlear implantation. METHODS: Five angles of cochlear orientation were determined from computed tomography (CT) imaging of the temporal bones in adults with (n = 55) and without (n = 27) sensorineural hearing loss (SNHL) and children with (n = 45) and without (n = 12) SNHL: facial recess versus basal turn, posterior semicircular canal versus basal turn, round window versus basal turn (axial view), round window versus basal turn (coronal view), and the cochlear axis versus the mastoid facial nerve. RESULTS: All angles showed substantial variation between subjects and between ears. The angles between the round window and basal turn (coronal view) and the posterior semicircular canal and basal turn were significantly correlated with age for all subjects with SNHL (r = 0.22, P = .002 and r = 0.15, P = .03, respectively). Patients with SNHL had significantly more acute angles (46.6° vs 55.8°) between the round window versus basal turn (axial orientation) compared to controls (P < .001). CONCLUSIONS: Cochlear orientation within the temporal bone changes with age and the degree of SNHL. These results suggest that the approach to the round window for electrode insertion might differ between children and adults.

New Zealand land search and rescue operations: an analysis of medical and traumatic conditions.

OBJECTIVE: The aim of this study was to describe the range and types of medical and traumatic conditions encountered in land search and rescue operations in New Zealand. METHODS: Twenty months (May 2010 to December 2011) of land search and rescue operations were analyzed. Data on medical and traumatic conditions were extracted from the New Zealand Police search and rescue database. RESULTS: During the period audited, New Zealand Police coordinated 1490 land-based search and rescue operations, from which 611 persons fulfilled the study inclusion criteria. Males accounted for 60.5% of the subjects, and a trauma-related injury was the most commonly encountered condition (37.3% of all). The lower limb was the most commonly injured body site, and most injuries occurred as the result of a slip or fall. Medical conditions were recorded in 11.6% of operations and included a wide spread of conditions, with cardiovascular events being seen most frequently. Hypothermia was diagnosed in 9.3% of all operations, and fatalities made up 5.6% of the sample. Thirty percent of all operations were for persons with cognitive impairment who had wandered away from their usual place of residence. These were almost entirely urban searches and concentrated in districts with large populations. CONCLUSIONS: Search and rescue personnel are exposed to a broad range of medical and traumatic conditions. In New Zealand, they include preexisting cognitive impairment that results in persons lost in urban environments. Notwithstanding this, many subjects will also need to be managed in remote, resource-limited environments for extended periods. First aid training and field equipment should reflect these demands.

Kinetic approach to hyper-doped optical quality thin films.

Efficient and benign doping of thin films is key for materials applications and sensor development. Herein, an alternative method of doping is presented where R6G is loaded to an evolving silica thin film. Dopant loading is markedly enhanced and doping can be carried out under relatively benign conditions. The film exhibits outstanding optical quality while its mechanical strength is well-preserved. Early results show diffusion and encapsulation can be tunable.

Intracochlear electrocochleography during cochlear implantation.

OBJECTIVE: Electrophysiologic responses to acoustic stimuli are present in nearly all cochlear implant recipients when measured at the round window (RW). Intracochlear recording sites might provide an even larger signal and improve the sensitivity and the potential clinical utility of electrocochleography (ECoG). Thus, the goal of this study is to compare RW to intracochlear recording sites and to determine if such recordings can be used to monitor cochlear function during insertion of a cochlear implant. METHODS: Intraoperative ECoG recordings were obtained in subjects receiving a cochlear implant from the RW and from just inside scala tympani (n = 26). Stimuli were tones at high levels (80-100 dB HL). Further recordings were obtained during insertions of a temporary lateral cochlear wall electrode (n = 8). Response magnitudes were determined as the sum of the first and second harmonics amplitudes. RESULTS: All subjects had measurable extracochlear responses at the RW. Twenty cases (78%) showed a larger intracochlear response, compared with three (11%) that had a smaller response and three that were unchanged. On average, signal amplitudes increased with increasing electrode insertion depths, with the largest increase between 15 and 20 mm from the RW. CONCLUSION: ECoG to acoustic stimuli via an intracochlear electrode is feasible in standard cochlear implant recipients. The increased signal can improve the speed and efficiency of data collection. The growth of response magnitudes with deeper intrascalar electrode positions could be explained by closer proximity or favorable geometry with respect to residual apical signal generators. Reductions in magnitude may represent unfavorable geometry or cochlear trauma.

The experience of having psoriasis through the lens of the International Classification of Functioning, Disability and Health (ICF).

BACKGROUND/OBJECTIVE: The International Classification of Functioning, Disability and Health (ICF) was developed by the World Health Organization to comprehensively describe the ways that health conditions can affect people. The identification of ICF categories of most relevance to people with a particular disease can increase the usefulness of the ICF and create a reference for outcome studies. This study aimed to ascertain, through focus group interviews with psoriasis patients and an online Delphi survey with health professionals, the impacts of psoriasis as categorised by the ICF. METHODS: We conducted and transcribed verbatim focus group interviews with 32 outpatients with psoriasis from two New Zealand cities. The interview transcripts were analysed to yield meaning units and concepts contained in the meaning units were extracted. These concepts were linked to ICF categories. An online Delphi survey among 23 health professionals was conducted to obtain similar information. The ICF categories were rated for their perceived relevance to psoriasis by health professionals over three iterations. RESULTS: In total, 32 patients participated in six focus groups. Interview saturation was reached after five focus groups. The concepts were linked to 83 ICF categories and two separate health conditions. Among health professionals, 167 ICF categories were rated, mostly in the moderately relevant (four to six) range. CONCLUSION: Applying the established method of meaning condensation to focus group interview transcripts allowed the accurate linking of concepts to ICF categories. This will be of use to researchers developing the first ICF core set for psoriasis in the future.