Definition of system suitability and proficiency testing acceptance criteria for the standardization of quality control methodologies of botanical bioactives: A case study for the development of AOAC Official Method of Analysis 2020.05 flavanols and procyanidins.

Flavanols and procyanidins are bioactives found in many foods including cocoa. The characterization of cocoa flavanols and procyanidins (CF) has historically been challenged by the lack of commercially available standards and weak chromatographic separation performances. The recent release of a reference material and the final authorization of an AOAC Official Method of Analysis (AOAC 2020.05) technically enables the standardization of CF testing. However, the practical implementation of CF testing for routine testing remains challenging for new laboratories, highlighting the need to define guidelines and acceptance criteria to verify normal method performance and user proficiency. This study leveraged the data generated from the recent multi-laboratory validation to define normal method performances. While the challenges associated with HILIC separation can be alleviated through a thorough system equilibration, monitoring system performances remains critical to routine operation and a laboratory's ability to generate reliable data. Guidelines for routine analysis were developed for system precision and bracketing standard recovery, as well as acceptance criteria for the analysis of the reference material. These guidelines not only complete a body of work that provide accessible, reliable, and robust CF analysis solution to research and quality laboratories, but also provide an example to facilitate the establishment and implementation of future international testing standards for botanical bioactives.

Periodontal Disease Treatment After Stroke or Transient Ischemic Attack: The PREMIERS Study, a Randomized Clinical Trial.

BACKGROUND: Patients with stroke/transient ischemic attack and periodontal disease (PD) are at increased risk for cardiovascular events. PD treatments that can improve stroke risk factors were tested if they might assist patients with cerebrovascular disease. METHODS: In this multicenter phase II trial, patients with stroke/transient ischemic attack and moderately severe PD were randomly assigned to intensive or standard PD treatment arms. The primary outcome measure was a composite of death, myocardial infarction, and recurrent stroke, as well as adverse events. Secondary outcome included changes in stroke risk factors. RESULTS: A total of 1209 patients with stroke/transient ischemic attack were screened, of whom 481 met the PD eligibility criteria; 280 patients were randomized to intensive arm (n=140) and standard arm (n=140). In 12-month period, primary outcome occurred in 11 (8%) in the intensive arm and 17 (12%) in the standard arm. The intensive arm was nonsuperior to the standard arm (hazard ratio, 0.65 [95% CI, 0.30-1.38]) with similar rates of adverse events (sepsis 2.1% versus 0.7%; dental bleeding 1.4% versus 0%; and infective endocarditis 0.7% versus 0%). Secondary-outcome improvements were noted in both arms with diastolic blood pressure and high-density lipoprotein cholesterol (P<0.05). CONCLUSIONS: In patients with recent stroke/transient ischemic attack and PD, intensive PD treatment was not superior to standard PD treatment in prevention of stroke/myocardial infarction/death. Fewer events were noted in the intensive arm and the 2 arms were comparable in the safety outcomes. Secondary-outcome measures showed a trend toward improvement, with significant changes noted in diastolic blood pressure and high-density lipoprotein in both the treatment arms.

Concurrent Validity of the IOPI and Tongueometer Orofacial Strength Measurement Devices.

OBJECTIVE(S): This study examined the concurrent validity of two orofacial strength manometers: (1) the Iowa Oral Performance Instrument (IOPI) - the current, gold standard orofacial manometer; and (2) the Tongueometer - a newly-available, lower cost, orofacial manometer. METHODS: This study compared IOPI and Tongueometer pressure readings across three experimental conditions. Experiment 1 compared full setup (manometer + tongue bulb) pressure readings between the IOPI and Tongueometer. Experiment 2 compared IOPI tongue bulb and Tongueometer tongue bulb pressure readings, while controlling for manometer. Experiment 3 compared IOPI manometer and Tongueometer manometer pressure readings, while controlling for tongue bulb. Pressures were applied manually within a laboratory setting. Lin's concordance correlation (ρc ) was used to calculate level of agreement, with ρc interpreted as 'poor' if <0.90, 'moderate' if 0.90 to <0.95, 'substantial' if 0.95 to <0.99, and 'excellent' if ≥0.99. RESULTS: 539 trials were analyzed. There was a median absolute difference of 2.4 kPa in pressure readings between the IOPI and Tongueometer full setups (manometer + tongue bulb). Correlations revealed substantial agreement between IOPI and Tongueometer full setups (experiment 1: n = 292; ρc = 0.986), tongue bulbs (experiment 2: n = 146; ρc = 0.987-0.992), and manometers (experiment 3: n = 101; ρc = 0.970). CONCLUSIONS: Differences in pressures were consistently observed between the Tongueometer and IOPI. Despite these differences, substantial agreement was present. These data suggest the Tongueometer may be a valid, lower cost alternative to the IOPI for objectively assessing orofacial strength in clinical practice. LEVEL OF EVIDENCE: Level 2 Laryngoscope, 133:3123-3131, 2023.

The Role of Vocal Fold Bowing on Cough and Swallowing Dysfunction in Progressive Supranuclear Palsy.

OBJECTIVES: Progressive supranuclear palsy (PSP) is a neurodegenerative disease which results in cough and swallowing dysfunction and aspiration pneumonia. Relationships among vocal fold atrophy, cough, and swallowing have been identified in related diseases, but remain unknown in PSP. This study examined: 1) the prevalence of vocal fold bowing in PSP, and 2) the influence of vocal fold bowing on cough and swallowing in PSP. STUDY DESIGN: Prospective Cohort Study. METHODS: Twenty-three participants with PSP completed instrumental assessments of cough and swallowing. Vocal fold bowing (BI) and swallowing safety (PAS) was assessed using flexible laryngoscopy. Measures of cough effectiveness were obtained using spirometry. Statistical analyses were used to determine the frequency of mild-moderate (BI > 0) and severe (BI > 12.2) bowing, and to assess the influence of BI on PAS and cough effectiveness in PSP. RESULTS: Fifty-two percent (n = 12) of participants exhibited severe bowing while 48% (n = 11) exhibited mild-to-moderate bowing. Voluntary cough peak expiratory flow rate (P = .01), as well as reflex (P = .02) and voluntary (P = .005) cough volume acceleration were lower for participants with severe BI when compared to mild-to-moderate BI. However, BI did not influence PAS (P > .05). CONCLUSIONS: Findings from this study suggest that vocal fold bowing is highly prevalent in PSP and associated with reduced reflex and voluntary cough effectiveness. These findings provide insight into the pathophysiology of compromised airway protection in this patient population. Future studies should examine vocal fold atrophy as a treatment target for behavioral and medical intervention in PSP. LEVEL OF EVIDENCE: 3 (Prospective Observational Study) Laryngoscope, 131:1217-1222, 2021.

Detection of Aspiration, Penetration, and Pharyngeal Residue During Flexible Endoscopic Evaluation of Swallowing (FEES): Comparing the Effects of Color, Coating, and Opacity.

The aim of this study was to assess the effects of color, coating, and opacity on the detection of aspiration, penetration, and residue during flexible endoscopic evaluations of swallowing (FEES). Thirty dysphagic adults underwent FEES while swallowing five 5 mL thin liquid boluses (1 × each, randomized): white water, blue water, white milk, blue milk, and barium water. To assess the effects of color, blue milk was compared to white milk. To assess the effects of coating, barium, white water, and white milk were compared to each other. To assess the effects of opacity, blue milk was compared to blue water. Videos were blindly analyzed and judged for the presence of pharyngeal residue, penetration, and aspiration. Repeated measures analyses were used to assess differences in the frequency of detection across bolus types. Pharyngeal residue was detected more frequently for liquids that were blue, had a coating effect, or were opaque (p < 0.05) when compared to liquids that were white, did not have a coating effect, or were translucent, respectively. Penetration and aspiration were detected more frequently for liquids that had a coating effect (p < 0.05), but not for liquids that were colored blue or opaque (p > 0.05). Coating appears to be the most important factor detecting thin liquid residue, penetration, and aspiration during FEES. Given these findings, standardized use of boluses that possess a coating effect (e.g., white-dyed water or barium) is highly recommended to enhance the sensitivity of identifying impairments in swallowing safety and efficiency during FEES.

Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy.

BACKGROUND: CCAAT enhancer-binding protein epsilon (C/EBPε) is a transcription factor involved in late myeloid lineage differentiation and cellular function. The only previously known disorder linked to C/EBPε is autosomal recessive neutrophil-specific granule deficiency leading to severely impaired neutrophil function and early mortality. OBJECTIVE: The aim of this study was to molecularly characterize the effects of C/EBPε transcription factor Arg219His mutation identified in a Finnish family with previously genetically uncharacterized autoinflammatory and immunodeficiency syndrome. METHODS: Genetic analysis, proteomics, genome-wide transcriptional profiling by means of RNA-sequencing, chromatin immunoprecipitation (ChIP) sequencing, and assessment of the inflammasome function of primary macrophages were performed. RESULTS: Studies revealed a novel mechanism of genome-wide gain-of-function that dysregulated transcription of 464 genes. Mechanisms involved dysregulated noncanonical inflammasome activation caused by decreased association with transcriptional repressors, leading to increased chromatin occupancy and considerable changes in transcriptional activity, including increased expression of NLR family, pyrin domain-containing 3 protein (NLRP3) and constitutively expressed caspase-5 in macrophages. CONCLUSION: We describe a novel autoinflammatory disease with defective neutrophil function caused by a homozygous Arg219His mutation in the transcription factor C/EBPε. Mutated C/EBPε acts as a regulator of both the inflammasome and interferome, and the Arg219His mutation causes the first human monogenic neomorphic and noncanonical inflammasomopathy/immunodeficiency. The mechanism, including widely dysregulated transcription, is likely not unique for C/EBPε. Similar multiomics approaches should also be used in studying other transcription factor-associated diseases.

Detection of Airway Invasion During Flexible Endoscopic Evaluations of Swallowing: Comparing Barium, Blue Dye, and Green Dye.

Purpose The aim of this study was to assess the effects of barium, blue dye, and green dye on the frequency and reliability of detecting airway invasion (penetration and aspiration) seen during flexible endoscopic evaluations of swallowing (FEES). Method Thirty patients with neurodegenerative disease and suspected dysphagia underwent an FEES. Patients were presented with 10-cc boluses of water colored with blue dye, green dye, and barium, within the same examination, in a randomized order. Airway protection outcomes were blindly analyzed by a panel of expert raters. Outcomes included the presence of residue on airway structures (epiglottis, laryngeal vestibule, vocal folds, subglottis) and abnormal Penetration-Aspiration Scale (PAS; Rosenbek, Robbins, Roecker, Coyle, & Wood, 1996 ) scores (PAS ≥ 3). Statistical analyses were performed to determine group differences in the frequency of airway residue and abnormal PAS scores, as well as reliability. Results Airway residue was observed most frequently with barium when compared to blue dye ( p < .05) or green dye ( p < .05). Abnormal PAS scores were also observed most frequently with barium when compared to blue dye ( p < .0005) and green dye ( p < .0005). There were no significant differences in the observed frequency of airway residue nor abnormal PAS scores when comparing blue and green dye ( p > .05). Intrapanel reliability scores for airway residue and PAS scores, respectively, were very good ( k = .83) and good ( k = .67) for barium, very good ( k = 1.00) and moderate ( k = .50) for green dye, and moderate ( k = .47) and fair ( k = .33) for blue dye. Conclusion Airway invasion was detected significantly more frequently and with greater reliability with barium when compared to blue and green dye. Given these findings, standardized use of barium is recommended at some point during FEES, especially when attempting to detect subtle signs of airway invasion.

Novel IL2RG Mutation Causes Leaky TLOWB+NK+ SCID With Nodular Regenerative Hyperplasia and Normal IL-15 STAT5 Phosphorylation.

X-linked severe combined immunodeficiency disease (SCID) is caused by mutations in the interleukin (IL)-2 receptor γ (IL2RG) gene and patients usually present with a TBNK SCID phenotype. Nevertheless, a minority of these patients present with a TBNK phenotype, similar to the IL-7R-deficient patients. We report a patient with a novel missense p.Glu297Gly mutation in the IL2RG gene presenting with a leaky TBNK SCID with delayed onset, moderate susceptibility to infections, and nodular regenerative hyperplasia. He presents with preserved STAT5 tyrosine phosphorylation in response to IL-15 stimulation but not in response to IL-2 and IL-7, resulting in the NK phenotype.

Biallelic RIPK1 mutations in humans cause severe immunodeficiency, arthritis, and intestinal inflammation.

RIPK1 (receptor-interacting serine/threonine kinase 1) is a master regulator of signaling pathways leading to inflammation and cell death and is of medical interest as a drug target. We report four patients from three unrelated families with complete RIPK1 deficiency caused by rare homozygous mutations. The patients suffered from recurrent infections, early-onset inflammatory bowel disease, and progressive polyarthritis. They had immunodeficiency with lymphopenia and altered production of various cytokines revealed by whole-blood assays. In vitro, RIPK1-deficient cells showed impaired mitogen-activated protein kinase activation and cytokine secretion and were prone to necroptosis. Hematopoietic stem cell transplantation reversed cytokine production defects and resolved clinical symptoms in one patient. Thus, RIPK1 plays a critical role in the human immune system.

Outcomes of medialization laryngoplasty with and without arytenoid adduction.

OBJECTIVES/HYPOTHESIS: To evaluate the effect of medialization laryngoplasty (ML) performed alone compared to ML with arytenoid adduction (AA) on glottic gap and voice quality in unilateral vocal fold paralysis (UVFP) patients. STUDY DESIGN: Retrospective case series. METHODS: UVFP patients treated with ML alone and ML with AA at the University of California San Francisco Voice and Swallowing Center were identified. Demographic information and history of laryngeal procedures were collected. Preoperative and postoperative examinations were digitally analyzed using ImageJ for normalized anterior and posterior glottic gap and voice samples graded with CAPE-V scores. RESULTS: Forty-seven patients underwent ML and 27 patients underwent ML with AA. Normalized anterior gap (AG) improved in both ML (preop: 4.4 pixel units (u), postop: 0.8 u; P < 0.001) and ML with AA groups (preop: 3.3 u, postop 0.6 u; P < 0.001). There was no statistically significant difference in normalized AG values between treatment groups. Postoperative normalized posterior gap (PG) improved in the ML with AA group only (preop: 1.8 u, postop: 0.5 u; P = 0.01). Overall severity, roughness, and strain voice parameters had acceptable reliability for analysis. Overall severity improved in ML (preop: 54, postop: 27; P < 0.001) and ML with AA (preop: 44, postop: 24; P = 0.005). There was no statistically significant difference in any voice parameter between treatment groups. CONCLUSION: UVFP patients undergoing ML may benefit from addition of AA when a large posterior glottic gap is present. In this study, ML with AA but not ML alone resulted in statistically significant improvement in PG. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:2591-2595, 2017.

Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: A large patient cohort study.

BACKGROUND: Activated phosphoinositide 3-kinase δ syndrome (APDS) is a recently described combined immunodeficiency resulting from gain-of-function mutations in PIK3CD, the gene encoding the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ). OBJECTIVE: We sought to review the clinical, immunologic, histopathologic, and radiologic features of APDS in a large genetically defined international cohort. METHODS: We applied a clinical questionnaire and performed review of medical notes, radiology, histopathology, and laboratory investigations of 53 patients with APDS. RESULTS: Recurrent sinopulmonary infections (98%) and nonneoplastic lymphoproliferation (75%) were common, often from childhood. Other significant complications included herpesvirus infections (49%), autoinflammatory disease (34%), and lymphoma (13%). Unexpectedly, neurodevelopmental delay occurred in 19% of the cohort, suggesting a role for PI3Kδ in the central nervous system; consistent with this, PI3Kδ is broadly expressed in the developing murine central nervous system. Thoracic imaging revealed high rates of mosaic attenuation (90%) and bronchiectasis (60%). Increased IgM levels (78%), IgG deficiency (43%), and CD4 lymphopenia (84%) were significant immunologic features. No immunologic marker reliably predicted clinical severity, which ranged from asymptomatic to death in early childhood. The majority of patients received immunoglobulin replacement and antibiotic prophylaxis, and 5 patients underwent hematopoietic stem cell transplantation. Five patients died from complications of APDS. CONCLUSION: APDS is a combined immunodeficiency with multiple clinical manifestations, many with incomplete penetrance and others with variable expressivity. The severity of complications in some patients supports consideration of hematopoietic stem cell transplantation for severe childhood disease. Clinical trials of selective PI3Kδ inhibitors offer new prospects for APDS treatment.

Biallelic JAK1 mutations in immunodeficient patient with mycobacterial infection.

Mutations in genes encoding components of the immune system cause primary immunodeficiencies. Here, we study a patient with recurrent atypical mycobacterial infection and early-onset metastatic bladder carcinoma. Exome sequencing identified two homozygous missense germline mutations, P733L and P832S, in the JAK1 protein that mediates signalling from multiple cytokine receptors. Cells from this patient exhibit reduced JAK1 and STAT phosphorylation following cytokine stimulations, reduced induction of expression of interferon-regulated genes and dysregulated cytokine production; which are indicative of signalling defects in multiple immune response pathways including Interferon-γ production. Reconstitution experiments in the JAK1-deficient cells demonstrate that the impaired JAK1 function is mainly attributable to the effect of the P733L mutation. Further analyses of the mutant protein reveal a phosphorylation-independent role of JAK1 in signal transduction. These findings clarify JAK1 signalling mechanisms and demonstrate a critical function of JAK1 in protection against mycobacterial infection and possibly the immunological surveillance of cancer.

Clinical and immunologic phenotype associated with activated phosphoinositide 3-kinase δ syndrome 2: A cohort study.

BACKGROUND: Activated phosphoinositide 3-kinase δ syndrome (APDS) 2 (p110δ-activating mutations causing senescent T cells, lymphadenopathy, and immunodeficiency [PASLI]-R1), a recently described primary immunodeficiency, results from autosomal dominant mutations in PIK3R1, the gene encoding the regulatory subunit (p85α, p55α, and p50α) of class IA phosphoinositide 3-kinases. OBJECTIVES: We sought to review the clinical, immunologic, and histopathologic phenotypes of APDS2 in a genetically defined international patient cohort. METHODS: The medical and biological records of 36 patients with genetically diagnosed APDS2 were collected and reviewed. RESULTS: Mutations within splice acceptor and donor sites of exon 11 of the PIK3R1 gene lead to APDS2. Recurrent upper respiratory tract infections (100%), pneumonitis (71%), and chronic lymphoproliferation (89%, including adenopathy [75%], splenomegaly [43%], and upper respiratory tract lymphoid hyperplasia [48%]) were the most common features. Growth retardation was frequently noticed (45%). Other complications were mild neurodevelopmental delay (31%); malignant diseases (28%), most of them being B-cell lymphomas; autoimmunity (17%); bronchiectasis (18%); and chronic diarrhea (24%). Decreased serum IgA and IgG levels (87%), increased IgM levels (58%), B-cell lymphopenia (88%) associated with an increased frequency of transitional B cells (93%), and decreased numbers of naive CD4 and naive CD8 cells but increased numbers of CD8 effector/memory T cells were predominant immunologic features. The majority of patients (89%) received immunoglobulin replacement; 3 patients were treated with rituximab, and 6 were treated with rapamycin initiated after diagnosis of APDS2. Five patients died from APDS2-related complications. CONCLUSION: APDS2 is a combined immunodeficiency with a variable clinical phenotype. Complications are frequent, such as severe bacterial and viral infections, lymphoproliferation, and lymphoma similar to APDS1/PASLI-CD. Immunoglobulin replacement therapy, rapamycin, and, likely in the near future, selective phosphoinositide 3-kinase δ inhibitors are possible treatment options.

Static endoscopic evaluation of swallowing: Transoral endoscopy during clinical swallow evaluations.

OBJECTIVES/HYPOTHESIS: To determine the sensitivity and specificity for assessing pharyngeal residue, laryngeal penetration, and tracheal aspiration when comparing findings from the Static Endoscopic Evaluation of Swallowing (SEES) with findings from the Videofluoroscopic Swallow Study (VFSS). METHODS: Retrospective study at a tertiary academic medical center. Records were reviewed consecutive outpatients who underwent both SEES and VFSS evaluations. Video segments from SEES and VFSS examinations were blindly judged by experienced clinicians on a categorical/ordinal rating form for the absence, quantitative presence, and location of postswallow residue, penetration, and aspiration. Statistical analysis was performed to identify intra- and interrater reliability and correlation between SEES and VFSS findings. RESULTS: Thirty-nine patients were identified who met the above inclusion criteria, for a total of 206 video segments. Inter- and intrarater reliability was judged by Cronbach's alpha to be good to excellent. SEES findings revealed statistically significant correlations with VFSS findings (P < 0.001) with the absence, quantitative presence, and location of thin liquid and solid swallow residue, penetration, and aspiration. In addition, SEES was more sensitive to the presence of liquid residue, penetration, and aspiration than VFSS. CONCLUSION: SEES is an endoscopic screening procedure that strengthens the clinical swallowing evaluation by documenting the presence or absence of postswallow residue, penetration, and aspiration. Accurate identification of a patient's risk for aspiration helps to direct further workup. It is an expedient, repeatable, and clinical relevant procedure that can be easily incorporated into a clinician's practice. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:2291-2294, 2016.

Immunodeficiency and severe susceptibility to bacterial infection associated with a loss-of-function homozygous mutation of MKL1.

Megakaryoblastic leukemia 1 (MKL1), also known as MAL or myocardin-related transcription factor A (MRTF-A), is a coactivator of serum response factor, which regulates transcription of actin and actin cytoskeleton-related genes. MKL1 is known to be important for megakaryocyte differentiation and function in mice, but its role in immune cells is unexplored. Here we report a patient with a homozygous nonsense mutation in the MKL1 gene resulting in immunodeficiency characterized predominantly by susceptibility to severe bacterial infection. We show that loss of MKL1 protein expression causes a dramatic loss of filamentous actin (F-actin) content in lymphoid and myeloid lineage immune cells and widespread cytoskeletal dysfunction. MKL1-deficient neutrophils displayed reduced phagocytosis and almost complete abrogation of migration in vitro. Similarly, primary dendritic cells were unable to spread normally or to form podosomes. Silencing of MKL1 in myeloid cell lines revealed that F-actin assembly was abrogated through reduction of globular actin (G-actin) levels and disturbed expression of multiple actin-regulating genes. Impaired migration of these cells was associated with failure of uropod retraction likely due to altered contractility and adhesion, evidenced by reduced expression of the myosin light chain 9 (MYL9) component of myosin II complex and overexpression of CD11b integrin. Together, our results show that MKL1 is a nonredundant regulator of cytoskeleton-associated functions in immune cells and fibroblasts and that its depletion underlies a novel human primary immunodeficiency.

Phosphoinositide 3-kinase δ gene mutation predisposes to respiratory infection and airway damage.

Genetic mutations cause primary immunodeficiencies (PIDs) that predispose to infections. Here, we describe activated PI3K-δ syndrome (APDS), a PID associated with a dominant gain-of-function mutation in which lysine replaced glutamic acid at residue 1021 (E1021K) in the p110δ protein, the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ), encoded by the PIK3CD gene. We found E1021K in 17 patients from seven unrelated families, but not among 3346 healthy subjects. APDS was characterized by recurrent respiratory infections, progressive airway damage, lymphopenia, increased circulating transitional B cells, increased immunoglobulin M, and reduced immunoglobulin G2 levels in serum and impaired vaccine responses. The E1021K mutation enhanced membrane association and kinase activity of p110δ. Patient-derived lymphocytes had increased levels of phosphatidylinositol 3,4,5-trisphosphate and phosphorylated AKT protein and were prone to activation-induced cell death. Selective p110δ inhibitors IC87114 and GS-1101 reduced the activity of the mutant enzyme in vitro, which suggested a therapeutic approach for patients with APDS.

Propofol-based versus dexmedetomidine-based sedation in cardiac surgery patients.

OBJECTIVES: To evaluate the effects of propofol-based and dexmedetomidine-based sedation regimens on achieving early extubation, length of stay (LOS), intensive care length of stay (ICU-LOS), total hospital costs, and mortality rates in cardiac surgery patients. DESIGN: Twenty-three-month retrospective analysis. SETTING: Single center, 907 bed community teaching hospital. PARTICIPANTS: Five hundred eighty-two patients ≥ 18 years of age who received propofol-based or dexmedetomidine-based sedation after cardiac valve or coronary artery bypass grafting (CABG) surgery and who did not undergo prolonged surgery (≤ 8 hours). INTERVENTION: Retrospective review of medical records. MEASUREMENTS AND MAIN RESULTS: Baseline characteristics (eg, age, sex, comorbidities) and outcomes (eg, achievement of early extubation, LOS, ICU-LOS, total hospital costs, pharmacy costs) were collected. Early extubation was achieved more frequently in the dexmedetomidine group when compared with the propofol group (68.7% v 58.1%, p = 0.008). The mean postoperative time to extubation and hospital LOS were shorter in the dexmedetomidine group when compared with the propofol group (8.8 v 12.8 hours, p = 0.026) and (181.9 v 221.3 hours, p = 0.001), respectively. There was a reduced ICU-LOS in the dexmedetomidine group compared with the propofol group that did not reach statistical significance (43.9 v 52.5 hours, p = 0.067). Average total hospital charges for the dexmedetomidine group were approximately $4000.00 less than the propofol group. CONCLUSIONS: Dexmedetomidine-based sedation resulted in achievement of early extubation more frequently than propofol-based sedation. Mean postoperative time to extubation and average hospital LOS were shorter with dexmedetomidine-based sedation and met a statistical level of significance. There was no difference in ICU-LOS or in-hospital mortality between the two groups. Total hospital charges were similar, although slightly higher in the propofol group.

Hemorrhagic gastritis with dabigatran in a patient with renal insufficiency.

BACKGROUND: Dabigatran etexilate is the first oral direct thrombin inhibitor approved in the United States. Unlike warfarin, dabigatran has no known antidote. Providers should be aware of patients that may be at risk for dabigatran coagulopathies and recognize potential treatment options. OBJECTIVE: To report a case of hemorrhagic gastritis in a patient with chronic renal insufficiency recently initiated on dabigatran etexilate. CASE SUMMARY: An 85-year-old white man with a known history of hypertension and stage III chronic kidney disease presented to the Emergency Department complaining of dark stools, shortness of breath, and abdominal pain. The patient recently started dabigatran 150mg twice daily for new-onset atrial fibrillation. An upper gastrointestinal endoscopy identified non-specific gastritis with hemorrhage. It was determined to be probable using the Naranjo Probability Scale that gastrointestinal hemorrhaging was a result of dabigatran therapy. Fresh frozen plasma was used to reverse the dabigatran-induced coagulopathy. CONCLUSION: This case highlights the challenges that providers may face when dealing with life-threatening bleeding in patients receiving dabigatran.

Common variants at 11p13 are associated with susceptibility to tuberculosis.

After imputation of data from the 1000 Genomes Project into a genome-wide dataset of Ghanaian individuals with tuberculosis and controls, we identified a resistance locus on chromosome 11p13 downstream of the WT1 gene (encoding Wilms tumor 1). The strongest signal was obtained at the rs2057178 SNP (P = 2.63 × 10(-9)). Replication in Gambian, Indonesian and Russian tuberculosis case-control study cohorts increased the significance level for the association with this SNP to P = 2.57 × 10(-11).