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Background In-hospital respiratory outcomes of non-surgical patients with undiagnosed obstructive sleep apnea (OSA), particularly those with significant comorbidities are not well defined. Undiagnosed and untreated OSA may be associated with increased cardiopulmonary morbidity. Study objectives Evaluate respiratory failure outcomes in patients identified as at-risk for OSA by the Berlin Questionnaire (BQ). Methods This was a retrospective study conducted using electronic health records at a large health system. The BQ was administered at admission to screen for OSA to medical-service patients under the age of 80 years old meeting the following health system criteria: (1) BMI greater than 30; (2) any of the following comorbid diagnoses: hypertension, heart failure, acute coronary syndrome, pulmonary hypertension, arrhythmia, cerebrovascular event/stroke, or diabetes. Patients with known OSA or undergoing surgery were excluded. Patients were classified as high-risk or low-risk for OSA based on the BQ score as follows: low-risk (0 or 1 category with a positive score on the BQ); high-risk (2 or more categories with a positive score on BQ). The primary outcome was respiratory failure during index hospital stay defined by any of the following: orders for conventional ventilation or intubation; at least two instances of oxygen saturation less than 88% by pulse oximetry; at least two instances of respiratory rate over 30 breaths per minute; and any orders placed for non-invasive mechanical ventilation without a previous diagnosis of sleep apnea. Propensity scores were used to control for patient characteristics. Results Records of 15,253 patients were assessed. There were no significant differences in the composite outcome of respiratory failure by risk of OSA (high risk: 11%, low risk: 10%, p = 0.55). When respiratory failure was defined as need for ventilation, more patients in the low-risk group experienced invasive mechanical ventilation (high-risk: 1.8% vs. low-risk: 2.3%, p = 0.041). Mortality was decreased in patients at high-risk for OSA (0.86%) vs. low risk for OSA (1.53%, p Conclusions Further prospective studies are needed to understand the contribution of undiagnosed OSA to in-hospital respiratory outcomes.

Sleep tracker data have not been utilized routinely in sleep-related disorders and their management. Sleep-related disorders are common in primary care practice and incorporating sleep tracker data may help in improving patient care. We conducted a pilot study to assess the feasibility of a sleep program using the Fitbit Charge 2™ device and SleepLifeA prospective, randomized, parallel group, observational pilot study was conducted in 20 primary care clinics in Indianapolis, IN from June 2018 to February 2019. Inclusion criteria included patients over the age of 18, have a diagnosis of insomnia identified by electronic medical record and/or a validated questionnaire, and were on a prescription sleep aid. The study was not specific to any sleep aid prescription, branded or generic, and was not designed to evaluate a drug or drug class. Each primary care clinic was randomized to either the SleepLifeForty-nine physicians and 75 patients were enrolled in the study. Patients had a mean age of 57 (SD 12.8) years and 61% were female. Mean age of physicians was 47 (SD 10.6) years. Patients showed high rates of involvement in the program with 83% completing all survey questions. Physician survey completion rate was 55%. Only one physician logged into the SleepLife portal to check their patients' sleep status. At the end of the 6-week intervention, patients' composite general satisfaction scores with sleep health management decreased significantly in the intervention arm when compared to controls (p = 0.03). Patients' satisfaction with communication also decreased significantly in the intervention group (p = 0.01). The sleep outcomes, which were calculated on the basis of study questionnaire answers, improved significantly in the intervention group as compared to the control group (p = 0.04). Physician communication satisfaction scores remained unchanged (p = 0.12).SleepLife

Background Sleep disturbances in critically ill patients are associated with poorer long-term clinical outcomes and quality of life. Studies are needed to better characterize associations and risk factors for persistent sleep disturbances after intensive care unit (ICU) discharge. Psychiatric disorders are frequently associated with sleep disturbances, but the role of psychiatric symptoms in sleep disturbances in ICU survivors has not been well-studied. Objective To examine the association between psychiatric symptoms and sleep disturbances in ICU survivors. Methods 112 adult ICU survivors seen from July 2011 to August 2016 in the Critical Care Recovery Center, an ICU survivor clinic at the Eskenazi Hospital in Indianapolis, IN, USA, were assessed for sleep disturbances (insomnia, hypersomnia, difficulty with sleep onset, difficulty with sleep maintenance, and excessive daytime sleepiness) and psychiatric symptoms (trauma-related symptoms and moderate to severe depressive symptoms) 3 months after ICU discharge. A multivariate logistic regression model was performed to examine the association between psychiatric symptoms and sleep disturbances. Analyses were controlled for age, hypertension, history of depression, and respiratory failure. Results ICU survivors with both trauma-related and depression symptoms (OR 16.66, 95% CI 2.89-96.00) and trauma-related symptoms alone (OR 4.59, 95% CI 1.11-18.88) had a higher likelihood of sleep disturbances. Depression symptoms alone were no longer significantly associated with sleep disturbances when analysis was controlled for trauma-related symptoms. Conclusion Trauma-related symptoms and trauma-related plus moderate to severe depressive symptoms were associated with a higher likelihood of sleep disturbances. Future studies are needed to determine whether psychiatric symptoms are associated with objective changes on polysomnography and actigraphy and whether adequate treatment of psychiatric symptoms can improve sleep disturbances.

Background Obstructive sleep apnea (OSA) is associated with higher rates of postoperative delirium. The relationship between preoperative OSA risk and postoperative delirium and coma in thoracic surgery patients hospitalized in the intensive care unit (ICU) is not well understood. This study tests the hypothesis that thoracic surgery patients hospitalized in ICU with a higher preoperative risk for OSA are more likely to develop postoperative delirium and coma, resulting in longer hospital stays. Methods Preoperative OSA risk was measured using the STOP-BANG questionnaire. STOP-BANG scores of greater than or equal to 3 were defined as intermediate-high risk for OSA; 128 patients who underwent major thoracic surgery completed the STOP-BANG questionnaire preoperatively. The Richmond Agitation and Sedation Scale was used to assess level of consciousness. The Confusion Assessment Method for the ICU was used to assess for delirium. Linear regression was used to assess the relationship between risk of OSA and outcome measures. Results were adjusted for age, sex, body mass index, Charlson Comorbidity Index, instrumental activities of daily living, and surgery type. Results A total of 96 of 128 patients (76%) were in the intermediate–high-risk OSA group. Adjusted analyses showed that the intermediate–high-risk OSA group had a longer duration of postoperative ICU delirium and coma compared with the low-risk OSA group (1.4 ± 1.3 days versus 0.9 ± 1.4 days; P = 0.04). Total number of hospital days was not significantly different. Conclusions Higher preoperative risk for OSA in thoracic surgery patients was associated with a longer duration of postoperative delirium and coma.

Background Sleep disturbances in critically ill patients are associated with poorer long-term clinical outcomes and quality of life. Studies are needed to better characterize associations and risk factors for persistent sleep disturbances after intensive care unit (ICU) discharge. Psychiatric disorders are frequently associated with sleep disturbances, but the role of psychiatric symptoms in sleep disturbances in ICU survivors has not been well-studied. Objective To examine the association between psychiatric symptoms and sleep disturbances in ICU survivors. Methods 112 adult ICU survivors seen from July 2011 to August 2016 in the Critical Care Recovery Center, an ICU survivor clinic at the Eskenazi Hospital in Indianapolis, IN, USA, were assessed for sleep disturbances (insomnia, hypersomnia, difficulty with sleep onset, difficulty with sleep maintenance, and excessive daytime sleepiness) and psychiatric symptoms (trauma-related symptoms and moderate to severe depressive symptoms) 3 months after ICU discharge. A multivariate logistic regression model was performed to examine the association between psychiatric symptoms and sleep disturbances. Analyses were controlled for age, hypertension, history of depression, and respiratory failure. Results ICU survivors with both trauma-related and depression symptoms (OR 16.66, 95% CI 2.89–96.00) and trauma-related symptoms alone (OR 4.59, 95% CI 1.11–18.88) had a higher likelihood of sleep disturbances. Depression symptoms alone were no longer significantly associated with sleep disturbances when analysis was controlled for trauma-related symptoms. Conclusion Trauma-related symptoms and trauma-related plus moderate to severe depressive symptoms were associated with a higher likelihood of sleep disturbances. Future studies are needed to determine whether psychiatric symptoms are associated with objective changes on polysomnography and actigraphy and whether adequate treatment of psychiatric symptoms can improve sleep disturbances.

A 44-year-old woman was referred by her primary care physician for a polysomnogram for further workup of excessive daytime sleepiness. She reported a 6-month history of uncontrollably falling asleep. She frequently dozed off while watching television, sitting inactive in public places, and talking to people. She had dozed off while driving, but had not had any driving accidents. Her Epworth Sleepiness Scale score was 21 of 24. She admitted to snoring, but no apneas were witnessed by her bed partner. She denied symptoms of morning headaches, gasping for air, leg jerking during sleep, cataplexy, sleep paralysis, hypnagogic hallucinations, gastroesophageal reflux during sleep, or insomnia. She usually went to bed at 10:00 pm and woke up at 9:00 am . She reported three to four nocturnal awakenings per night. She denied taking naps. Medical history included chronic pain from cervical spinal stenosis, hypothyroidism, hyperlipidemia, depression, restless legs, migraines, and gastroesophageal reflux disease. She had no known cardiac illnesses. Medications included levothyroxine, 50 μg daily; duloxetine, 60 mg daily; cyclobenzaprine, 10 mg tid; omeprazole, 20 mg daily; trazodone, 50 mg daily; gabapentin, 600 mg daily; tolterodine, 2 mg bid; cetirizine, 10 mg daily; extended-release oral morphine sulfate, 15 mg bid; and immediate-release oral morphine sulfate, 15 mg qid as needed for pain.

Pulmonary emphysema is a disease characterized by alveolar cellular loss and inflammation. Recently, excessive apoptosis of structural alveolar cells has emerged as a major mechanism in the development of emphysema. Here, we investigated the proapoptotic and monocyte chemoattractant cytokine endothelial monocyte-activating protein 2 (EMAPII). Lung-specific overexpression of EMAPII in mice caused simplification of alveolar structures, apoptosis, and macrophage accumulation, compared with that in control transgenic mice. Additionally, in a mouse model of cigarette smoke-induced (CS-induced) emphysema, EMAPII levels were significantly increased in murine lungs. This upregulation was necessary for emphysema development, as neutralizing antibodies to EMAPII resulted in reduced alveolar cell apoptosis, inflammation, and emphysema-associated structural changes in alveoli and small airways and improved lung function. The mechanism of EMAPII upregulation involved an apoptosis-dependent feed-forward loop, since caspase-3 instillation in the lung markedly increased EMAPII expression, while caspase inhibition decreased its production, even in transgenic EMAPII mice. These findings may have clinical significance, as both current smokers and ex-smoker chronic obstructive pulmonary disease (COPD) patients had increased levels of secreted EMAPII in the bronchoalveolar lavage fluid compared with that of nonsmokers. In conclusion, we suggest that EMAPII perpetuates the mechanism of CS-induced lung emphysema in mice and, given its secretory nature, is a suitable target for neutralization antibody therapy.

The synthesis of accurate, full-length cDNA from low-abundance RNA and the subsequent PCR amplification under conditions which provide amplicon that contains minimal mutations remain a difficult molecular biological process. Many of the challenges associated with performing sensitive, long RT/PCR have been alleviated by using a mixture of DNA polymerases. These mixtures have typically contained a DNA polymerase devoid of 3'-5' exonuclease, or "proofreading", activity blended with a small amount of an Archaea DNA polymerase possessing 3'-5' exonuclease activity, since reverse transcriptases lack 3'-5' exonuclease activity and generally have low fidelity. To create a DNA polymerase with efficient reverse transcriptase and 3'-5' exonuclease activity, a family of mutant DNA polymerases with a range of attenuated 3'-5' exonuclease activities was constructed from a chimeric DNA polymerase derived from Thermus species Z05 and Thermotoga maritima DNA polymerases. These "designer" DNA polymerases were fashioned using structure-based tools to identify amino acid residues involved in the substrate-binding site of the exonuclease domain of a thermostable DNA polymerase. Mutation of some of these residues resulted in proteins in which DNA polymerase activity was unaffected, while proofreading activity ranged from 60% of the wild-type level to undetectable levels. Kinetic characterization of the exonuclease activity indicated that the mutations affected catalysis much more than binding. On the basis of their specificity constants (kcat/KM), the mutant enzymes have a 5-15-fold stronger preference for a double-stranded mismatched substrate over a single-stranded substrate than the wild-type DNA polymerase, a desirable attribute for RT/PCR. The utility of these enzymes was evaluated in a RT/PCR assay to generate a 1.7 kb amplicon from HIV-1 RNA.

The paper deals with the screen boundary value problem for vector Helmholtz equation in the three-dimensional space. Using the method of boundary integral equations and the theory of elliptic pseudodifferential operators on manifolds with boundary we prove uniqueness and existence theorems in Bessel-potential and Besov spaces and establish Cα-smoothness (with α < 1/2) of solutions up to the boundary.

α-1 Antitrypsin (A1AT) is a serpin with a major protective effect against cigarette smoke-induced emphysema development, and patients with mutations of the A1AT gene display a markedly increased risk for developing emphysema. We reported that A1AT protects lung endothelial cells from apoptosis and inhibits caspase-3 activity. It is not clear if cigarette smoking or A1AT mutations alter the caspase-3 inhibitory activity of A1AT and if this serpin alters the function of other caspases. We tested the hypothesis that the caspase-3 inhibitory activity of A1AT is impaired by cigarette smoking and that the A1AT RCL, the key antiprotease domain of the serpin, is required for its interaction with the caspase. We examined the caspase-3 inhibitory activity of human A1AT purified from plasma of actively smoking and nonsmoking individuals, either affected or unaffected with chronic obstructive pulmonary disease. We also tested the caspase inhibitory activity of two mutant forms of A1AT, the recombinant human piZZ and the RCL-deleted (RCL-null) A1AT forms. A1AT purified from the blood of active smokers exhibited marked attenuation in its caspase-3 inhibitory activity, independent of disease status. In vitro exposure of the normal (MM) form of A1AT to cigarette smoke extract reduced its ability to interact with caspase-3, measured by isothermal titration calorimetry, as did the deletion of the RCL, but not the ZZ point mutation. In cell-free assays A1AT was capable of inhibiting all executioner caspases, -3, -7 and especially -6, but not the initiator or inflammatory caspases. The inhibitory effect of A1AT against caspase-6 was tested in vivo, where overexpression of both human MM and ZZ-A1AT via adeno-associated virus transduction significantly protected against apoptosis and against airspace damage induced by intratracheal instillation of caspase-6 in mice. These data indicate a specific inhibitory effect of A1AT on executioner caspases, which is profoundly attenuated by active exposure to cigarette smoking and is dependent on the protein RCL, but is not affected by the PiZZ mutation.

Responsiveness to hepatitis C virus (HCV) therapy depends on viral and host factors. Our aim was to assess sustained virologic response (SVR)-associated early gene expression in patients with HCV receiving pegylated interferon-alpha2a (PEG-IFN-α2a) or PEG-IFN-α2b and ribavirin with the duration based on genotypes. Blood samples were collected into PAXgene tubes prior to treatment as well as 1, 7, 28, and 56 days after treatment. From the peripheral blood cells, total RNA was extracted, quantified, and used for one-step reverse transcription polymerase chain reaction to profile 154 messenger RNAs. Expression levels of messenger RNAs were normalized with six “housekeeping” genes and a reference RNA. Multiple regression and stepwise selection were performed to assess differences in gene expression at different time points, and predictive performance was evaluated for each model. A total of 68 patients were enrolled in the study and treated with combination therapy. The results of gene expression showed that SVR could be predicted by the gene expression of signal transducer and activator of transcription-6 (STAT-6) and suppressor of cytokine signaling-1 in the pretreatment samples. After 24 hours, SVR was predicted by the expression of interferon-dependent genes, and this dependence continued to be prominent throughout the treatment. Conclusion: Early gene expression during anti-HCV therapy may elucidate important molecular pathways that may be influencing the probability of achieving virologic response. (HEPATOLOGY 2009.)

Objective: Endothelial Monocyte-Activating Polypeptide II (EMAP II) is a monocyte attracting, anti-angiogenic and endothelial cells apoptosis inducing pro-inflammatory cytokine. Based on our previo...

The quasar 3C279 was the target of an extensive multiwavelength monitoring campaign from January through April 2006, including an optical-IR-radio monitoring campaign by the Whole Earth Blazar Telescope (WEBT) collaboration. In this paper we focus on the results of the WEBT campaign. The source exhibited substantial variability of optical flux and spectral shape, with a characteristic time scale of a few days. The variability patterns throughout the optical BVRI bands were very closely correlated with each other. In intriguing contrast to other (in particular, BL Lac type) blazars, we find a lag of shorter- behind longer-wavelength variability throughout the RVB ranges, with a time delay increasing with increasing frequency. Spectral hardening during flares appears delayed with respect to a rising optical flux. This, in combination with the very steep IR-optical continuum spectral index of ~ 1.5 - 2.0, may indicate a highly oblique magnetic field configuration near the base of the jet. An alternative explanation through a slow (time scale of several days) acceleration mechanism would require an unusually low magnetic field of < 0.2 G, about an order of magnitude lower than inferred from previous analyses of simultaneous SEDs of 3C279 and other FSRQs with similar properties., Accepted for publication in ApJ

anatomic evaluation with CT scan showed the anterior, apico-posterior and posterior segments, and two lingular subsegments arising directly from the LUL bronchus ( fig. 2 ). The patient had no other congenital anomalies. Cough resolved with treatment of gastroesophageal reflux disease. Tracheobronchial anatomic variations arise from embryogenic anomalies of supernumerary lung buds or lung buds arising from atypical sites. Congenital lobar and segmental bronchial variations are more common than tracheal or main bronchial anomalies, and they are A 55-year old female was seen in clinic for 6 weeks of nonproductive cough. Significant medical history included recurrent esophageal adenocarcinoma despite esophagectomy, chemotherapy and radiotherapy. Chest CT revealed recurrent esophageal tumor at the gastric pull-through site. Flexible bronchoscopy was performed to evaluate for possible tracheoesophageal fistula, however, none was found. Interestingly, an incidental finding of a five-orifice left upper lobe (LUL) bronchus was seen ( fig. 1 ). Bronchoscopic exploration of the five LUL segments revealed patent bronchi without atresia. Further Published online: November 24, 2009

Aim Design PCR and sequencing primers for subsequent use in the development of an assay prototype that enables the full length sequencing of HLA-DRB1 Exons 2 and 3. Methods AlleleSEQR® HLA-DRB1 reagents currently include primers for amplifying and sequencing Exon 2. For the present HLA-DRB1 reagents, the 5’ PCR primers are located in intron 1 and the 3’ PCR primers span the Exon 2 and intron 2 boundary. We have designed and developed a new set of HLA-DRB1 Exon 2 PCR and sequencing primers where the 5’ and the 3’ PCR primers are located in intron 1 and intron 2 respectively to amplify the entire Exon 2 followed by sequencing for complete Exon 2 coverage. We follow a similar approach where the PCR and sequencing primers are placed in the intronic regions (introns 2 and 3) to amplify and sequence the entire Exon 3. Sequencing reactions were standardized for the 3100 and the 3500xL (Life Technologies, CA) genetic analyzers. We tested 500 HLA typed DNA samples from UCLA and IHWG registries and compared the HLA typing results with our newly designed set of reagents for Exon 2 and Exon 3 to the results generated with the existing current AlleleSEQR® HLA-DRB1 set of reagents. Results All DNA amplified and sequenced for Exon 2 and Exon 3. All sequences were 100% concordant with the published HLA-DRB1 typing results for the 500 DNA samples obtained from UCLA and IHWG registries. Conclusions Some HLA-DRB1 alleles can only be identified by specific nucleotide base calls that are located in the last few bases of Exon 2. Sequencing the entire Exon 2 could potentially resolve such ambiguities and in addition some alleles are further confirmed based on the ambiguities typed in these last few bases. The ability to sequence through Exon 3 allows the typing of additional alleles that have identical base sequences in Exon 2. Sequencing additional HLA-DRB1 gene regions upfront may avoid the need to use alternative HLA typing test methods and ambiguity resolution primers thus conserving sample DNA, reagents and labor. Wadia: Celera / Quest Diagnostics: Employee; Stockholder. Drews: Celera / Quest Diagnostics: Employee. Sigua: Celera / Quest Diagnostics: Employee. Jiang: Celera / Quest Diagnostics: Employee. Bost: Celera / Quest Diagnostics: Employee.

Aim We have designed a system of RUO Quantitative PCR assays and software enabling highly sensitive, stem cell engraftment monitoring. Our approach allows for facile quantification of minute amounts of minor components in a mixture, while also reducing workflow and analysis burdens. This approach expands the linear dynamic range over which increasing mixed chimerism may be monitored, effectively increasing the probability of detecting adverse transplant events earlier. Methods We utilize a panel of 34 Quantitative PCR research assays to bi-allelic indels across the genome. Our system affords rapid pre-transplant marker identification and quantification of recipient levels post-transplant. It enables marker identification and quantification to occur within a few hours and without the need for capillary electrophoresis. In an effort to decrease our current sample volume requirements, increase throughput and enable multiple donor screening scenarios, we evaluated a multiplexed assay approach for marker identification. The Quantitative PCR assays are multiplexed, with 2-3 assays per well. The presence of alleles is scored in relation to amplification of an endogenous control assay. The results of samples within a group are compared against each other to identify informative markers for each sample. Up to eight samples can be evaluated in a single 96-well plate, with a variable number and configuration of samples within a group. Results The described multiplexed Quantitative PCR approach yielded results which were comparable to those generated when using the assays individually. When the single assay algorithms were applied to the samples tested in the multiplexed format, the same genotyping calls were made and informative alleles identified. Conclusions Use of this RUO, multiplexed Quantitative PCR system for screening of multiple specimens enabled rapid identification of informative markers for all samples without post-PCR processing, while dramatically decreasing sample volume requirements. Sigua: Celera/Quest Diagnostics: Employee. Wadia: Celera/Quest Diagnostics: Employee; Stockholder. Bost: Celera/Quest Diagnostics: Employee.

s / Biol Blood Marrow Transplant 19 (2013) S279eS312 S307 Medical Sciences, Tehran, Iran; 3 Immunology, Asthma, and Allergy Research Institute, Tehran University of Medical Sciences, Tehran, Iran; 4 Department of Pediatric Pathology, Mofid Children's Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran Backkground: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition characterized by prolonged fever, hepatosplenomegaly, cytopenia, and hemophagocytosis. Primary HLH is considered fatal unless treated by hematopoietic stem cell transplantation (HSCT). Method: Herein we report six Iranian patients as a case series with primary HLH and their outcome from a single tertiary-care center Between 2000-2012. Results: Griscelli syndrome type 2 (GS2) was diagnosed in 3 patients based on clinical, laboratory, and microscopic features of partial albinism and finding of RAB27Amutations in 2 patients tested. Two patients were on the HLH-2004 continuation therapy and waiting for HSCT, but no matched donor yet: The first case is in 2nd remission after 1.5 years; he had history of relapse in maintenance phase of HLH-2004 protocol which more immunosuppressive treatment was advised. The second case is in remission after 1 year. Two other patients died, while waiting for a suitable donor: case 3 had history of recurrent HLH and died after 6 months; and the case 4 had history of progression to T-cell ALL after 2 years and dead due to relapse of ALL, sepsis and DIC despite chemotherapy after 3 years. Two patients underwent HSCT; patient 5 had a HLA-identical sibling donor and patient 6 had a cord blood-, unrelated, one antigen mismatched donor. Both patients were treated according to the HLH-2004 treatment protocol and none had active disease at the time of HSCT. Patient 5 who were diagnosed with GS2 responded well and remained in remission through 24 months of follow-up, while another case died because of graft-versushost disease and infection on day 136 after HSCT. Conclusion: HSCT seems to be the only curative treatment for primary HLH which drastically improve survival of the patients. Making a definite diagnosis confirmed by gene mutation studies is helpful to provide genetic counseling and prenatal diagnosis and, more important, dictate the need for HSCT later in the patient's course.