Sickle Cell Disease Related Vasculopathies and Early Evaluation in a Pediatric Population.

BACKGROUND/AIM: Cardiovascular pathologies are ubiquitous in sickle cell disease (SCD). A targeted literature review was conducted to compare the overall epidemiology of selected vasculopathies seen in SCD (SCDVs) compared to the general population. Since many SCDV may originate in childhood, the study also focused on the retrospective investigation of SCDVs in a pediatric cohort at the Harbor-UCLA Medical Center. PATIENTS AND METHODS: SCDVs were studied along patient age, ß-globin genotypes, and fetal hemoglobin (HbF). Urine microalbumin/creatinine ratios (UM/Cr), trans-cranial doppler (TCD) and tricuspid regurgitant jet velocities (TRJV) were analyzed as well. Retinographies and overt vasculopathies were presented descriptively. RESULTS: Among 20 females and 20 males [average 8.3 years (2.3-19 years)], 70% had HbSS/Sß0, 22.5% HbSC and 7.5%-HbSß+. The mean(±SD) HbF% was 17.4±12.7% (30% higher in <10 vs. ≥10 y/o, and 3 times higher in SS/Sß0). Twenty-six patients received hydroxyurea and 13/26, L-glutamine. Thirty-six patients had TCDs within 1.4±0.9 years and all laboratory values were obtained within the last 12 months. TCDs showed low-normal velocities, but 2 were higher for HbSS/Sß0 vs. HbSC/Sß+ (MCA-96 vs. 86 cm/s, p=0.03; and PCA-50 vs. 41, p<0.001). Nineteen of 28 patients with echocardiograms had measurable TRJV (2.46±0.19 m/s); 9 had TRJV ≥2.5-2.8 m/s, but BNP ≤80 pg/ml. SS/Sß0 was associated with higher UM/Cr. There were 2 cases with silent infarcts, 1-Moyamoya, 2-persistent macroalbuminuria, and 1-hematuria/renal papillary necrosis. Most ≥9 y/o patients had retinographies without SCD-related changes. There was no correlation among TCD (MCA), TRJV, and UM/Cr (n=17); thus, in this subpopulation, pathologies of cerebral, cardiopulmonary, and renal vasculatures evolved independently. Patients with higher TRJV and/or overt vasculopathy (n=14) were older than ones without (12.5±4.7 vs. 6.1±3.1 y/o, p<0.001), and had lower HbF (11.4±7.6 vs. 20.6±13.8%, p=0.026). CONCLUSION: While overt SCDVs are less frequent in children, age-dependent trends/surrogate markers suggest their early origination in youth, justifying intense screening to prevent their progression with disease-modifying measures.

The Effect of Testosterone Replacement Therapy on Nonalcoholic Fatty Liver Disease in Older Hypogonadal Men.

CONTEXT: Male hypogonadism is associated with visceral obesity and the metabolic syndrome: factors important for the development of nonalcoholic fatty liver disease (NAFLD). The Testosterone Trials (The T Trials) showed testosterone (T) treatment compared with placebo in older hypogonadal men was associated with decreases in cholesterol and insulin levels suggesting that T treatment may improve NAFLD. OBJECTIVE: Compare effects of T vs placebo treatment on NAFLD scores and liver scans in elderly hypogonadal men. METHODS: Secondary data analyses from 479 older hypogonadal men with total T < 275 ng/dL from The T Trials were performed. Three clinical liver fat scores-lipid accumulation product index, hepatic steatosis index, nonalcoholic fatty liver disease-metabolic syndrome score-and liver computed tomography (CT) Hounsfield units and liver to spleen ratio were evaluated at baseline and 12 months after treatment. RESULTS: There were no statistically significant differences of change in lipid accumulation product index (P = .98), hepatic steatosis index (P = .67), and nonalcoholic fatty liver disease-metabolic syndrome (P = .52) in 246 men treated with T compared with 233 treated with placebo for 12 months. Liver CT showed no statistically significant difference of change in Hounsfield units (P = .24; n = 71 for T, n = 69 for placebo) and liver to spleen ratio (P = .74; n = 55 for T, n = 62 for placebo) between the 2 groups. CONCLUSIONS: Our study did not show improvement of NAFLD in older hypogonadal men after 12 months of T vs placebo treatment, as assessed by 3 clinical scores and liver CT for hepatic steatosis. Future studies with longer treatment duration and additional NAFLD diagnostic modalities as primary outcome are warranted.

Decentralized, Integrated Treatment of RR/MDR-TB and HIV Using a Bedaquiline-Based, Short-Course Regimen Is Effective and Associated With Improved HIV Disease Control.

BACKGROUND: In decentralized sites, with fewer resources and a high prevalence of advanced HIV, the effectiveness of the new short-course, bedaquiline-based regimen for rifampicin-resistant and multidrug-resistant tuberculosis (RR/MDR-TB) is not well-described. SETTING: Adults with pulmonary RR/MDR-TB initiating the short-course regimen in KwaZulu-Natal, South Africa were prospectively enrolled at a decentralized program that integrated person-centered TB care. METHODS: In addition to standard of care monitoring, study visits occurred at enrollment and months 1, 2, 4, 6, and 9. Favorable RR/MDR-TB outcome was defined as cure or treatment completion without loss to follow-up, death, or failure by treatment. In patients with HIV, we assessed antiretroviral therapy (ART) uptake, virologic and immunologic outcomes. RESULTS: Among 57 patients, HIV was present in 73.7% (95% CI: 60.3-84.5), with a median CD4 count of 170 cells/mm 3 (intraquartile range 49-314). A favorable RR/MDR-TB outcome was achieved in 78.9% (CI: 67.1-87.9). Three deaths occurred, all in the setting of baseline advanced HIV and elevated viral load. Overall, 21.1% (95% CI: 12.1-32.9) experienced a severe or life-threatening adverse event, the most common of which was anemia. Among patients with HIV, enrollment resulted in increased ART uptake by 24% (95% CI: 12.1%-39.4%), a significant improvement from baseline ( P = 0.004); virologic suppression during concomitant treatment was observed in 71.4% (n = 30, 95% CI: 55.4-84.3). CONCLUSION: Decentralized, person-centered care for RR/MDR-TB in patients with HIV using the short-course, bedaquiline-based regimen is effective and safe. In patients with HIV, enrollment led to improved ART use and reassuring virologic outcomes.

Male contraception development: monitoring effective spermatogenesis suppression utilizing a user-controlled sperm concentration test compared with standard semen analysis.

OBJECTIVE: To determine whether a user-controlled sperm concentration test compared with standard semen analysis can effectively monitor spermatogenesis suppression for male contraception. DESIGN: Single center, prospective sub study of the ongoing clinical trial: "Study of daily application of Nestorone and testosterone combination gel for male contraception." SETTING: Research institute at an academic medical center. PARTICIPANT(S): Couples participating in the male contraceptive clinical trial. INTERVENTIONS: None. MAIN OUTCOME MEASURE(S): The ability by participants to monitor sperm suppression to a threshold compatible with contraceptive efficacy utilizing a user-controlled test verified by sperm concentration determined by standard laboratory methods. RESULT(S): Thirty-eight men participating in a hormonal male contraceptive clinical trial provided multiple samples during spermatogenesis suppression for this substudy. Participants, employing a user-controlled test, correctly identified the absence of sperm (a negative test) in 100% of their laboratory-confirmed azoospermic samples (n = 122). Participants also identified 100% of samples (n = 73) with sperm >0.2 million/mL as positive. Sperm counts between 0.01 and 0.2 million/mL were identified as negative in 96% of samples. Trial participants noted the overall ease of using the test with respect to sample preparation, test timing, and result interpretation, and that they could accurately use this test at home without difficulty. CONCLUSION(S): Participants undergoing spermatogenesis suppression in a hormonal male contraceptive trial performed user-controlled test to determine whether their semen sperm concentration was ≤ or >0.2 million/mL. Compared with standard semen analyses, participants correctly identified 100% of samples with sperm counts >0.2 million/mL as positive (Sensitivity 100%). A positive result when the couple is using a male contraceptive method triggers the need for semen analysis by a laboratory while the couple uses another method of contraception. Participants correctly diagnosed samples ≤0.2 million sperm/mL as negative in 99% of samples (specificity 99%). A negative result indicates a sperm concentration ≤0.2 million/mL, well below the threshold of ≤1 million/mL offering contraceptive efficacy demonstrated by prior studies. At-home sperm concentration test would minimize the need for users to return to the clinic to monitor suppression of spermatogenesis, decreasing cost and burden of male contraception trials and increasing practicality of the method. CLINICAL TRIAL REGISTRATION NUMBER: NCT: 03452111.

Physical Activity Counseling and Documentation by Pediatric Residents in Primary Care: Before and After Introduction of the FITT Principle.

Physician training on physical activity (PA) counseling in patient care is highly variable. The objective of this study was to improve PA counseling by pediatric residents through introduction of the four components of PA, called the FITT principle (frequency, intensity, time, type). Pediatric residents (n=30) received lectures, curriculum content, and an electronic smart-phrase addressing PA in obesity, including the FITT principle. Surveys assessed resident attitudes, and chart reviews (n = 423 over 16 months) identified evidence of PA counseling including FITT principle components preintervention and postintervention. Survey results showed positive attitudes and confidence regarding primary care provider roles in counseling on PA, with no differences postintervention. Chart reviews demonstrated increased documentation on PA frequency postintervention (pre 31.9% vs post 50.9%, P=.00006), but no significant changes in intensity, time or type. In conclusion, a focused PA curriculum promoted PA counseling by pediatric residents, with increased documentation of one component of the FITT principle.

Pediatric Patients With Sickle Cell Disease at a Public Hospital: Nutrition, Compliance and Early Experience With L-Glutamine Therapy.

BACKGROUND/AIM: Hydration and hydroxyurea (HU) can modify sickle cell disease (SCD) severity. Optimal nutrition and L-glutamine (Gln) may provide further amelioration. PATIENTS AND METHODS: Reviews of medical records and nutrition surveys were used to investigate severity of pediatric patients with SCD in relation to nutrition, growth, hematologic parameters, and diseasemodifying agents. RESULTS: Among 25 females and 25 males (9.1±7 years), beta-globin genotypes were: HbSS/Sß°, 60%; HbSC, 32%; HbSß+, 8%. The mean number of annual pain crises (APC) was 0.97±1.1. APCs increased ≥2-fold as HbF dropped to <10% with age. Proper hydration and nutrition correlated with younger ages and fewer APCs. Height and weight Z-scores were ≤-1SD in 20% of 35 surveyed patients (12±7.8 years), who had more APCs (2.5±2.5 vs. 1±1.3, p=0.03). Prealbumin levels were overall low. Twenty-two of 28 patients on HU reported ≥90% adherence - with higher mean corpuscular volume (92±9.6 vs. 74±10 f/l, p<0.01). Seventy percent of Gln prescriptions were filled. Compliance over 23 months was ≥70% in 12 patients, including 2 on chronic transfusion. Of 10 evaluable patients, 6 (8.8±2.2 years) had fewer APCs with Gln (mean 0.2 vs. 0.9, p=0.016), with increasing prealbumin levels (14.1 to 15.8 mg/dl, p=0.1). CONCLUSION: Younger, and well-nourished, well-hydrated patients have a milder clinic course. Disease severity was the worse in undernourished teenagers with suboptimal compliance. L-Glutamine with prealbumin monitoring should be considered for further evaluation in pediatric SCD.

Chemotherapy Can Synergize With Adoptive Immunotherapy to Inhibit Medulloblastoma Growth.

BACKGROUND/AIM: In the age of ever-increasing developments in targeted cancer treatments, new immune-based approaches for brain tumor therapy represent an attractive avenue. Despite encouraging pre-clinical data, results in patients have been sub-optimal, likely due to tumor-induced immune suppression and intrinsic resistance to immune attack. Chemotherapy and biologic agents may be able to disrupt these mechanisms and restore tumor sensitivity to immune attack. In this study, we explore whether a combination of gemcitabine and rapamycin can sensitize medulloblastoma cells to immunotherapy in vitro and in vivo. MATERIALS AND METHODS: With the commercial medulloblastoma cell line, Daoy, we explored the concentrations of combinations of Gemcitabine with rapamycin needed to induce cytotoxicity. Next, we used flow cytometry to assess the cytotoxicity of chemotherapy-treated Daoy cells with the addition of anti-tumor T-cells, generated from naive T-cells stimulated in the presence of Daoy lysate-pulsed dendritic cells. Then, we examined the efficacy of chemotherapy alone versus chemotherapy plus immunotherapy in tumor growth inhibition of subcutaneous medulloblastoma xenografts. RESULTS: Rapamycin alone at <1,000 nM had moderate activity against Daoy cells in vitro and IC50 was >1,000 nM. Gemcitabine had a 3-day IC50 alone of 10 nM but in combination with 100 nM rapamycin, it decreased to 1 nM, suggesting increased cytotoxicity with combined therapy. Stimulated T-cells mediated in-vitro cytotoxicity, although background cytotoxicity of unstimulated "naïve" T-cells was also significant. Finally, established subcutaneous Daoy cell xenografts in SCID mice were treated with chemotherapy alone or chemotherapy plus adoptive immunotherapy (stimulated and non-stimulated). Gemcitabine and rapamycin alone significantly slowed tumor growth, but the addition of immunotherapy further augmented inhibition. CONCLUSION: Combining immunotherapy and chemo-biologic therapy inhibit medulloblastoma cell and xenograft growth, and may offer an effective treatment for patients with medulloblastoma.

A Combined Phenotypic-Genotypic Predictive Algorithm for In Vitro Detection of Bicarbonate: ß-Lactam Sensitization among Methicillin-Resistant Staphylococcus aureus (MRSA).

Antimicrobial susceptibility testing (AST) is routinely used to establish predictive antibiotic resistance metrics to guide the treatment of bacterial pathogens. Recently, a novel phenotype termed "bicarbonate (NaHCO3)-responsiveness" was identified in a relatively high frequency of clinical MRSA strains, wherein isolates demonstrate in vitro "susceptibility" to standard ß-lactams (oxacillin [OXA]; cefazolin [CFZ]) in the presence of NaHCO3, and in vivo susceptibility to these ß-lactams in experimental endocarditis models. We investigated whether a targeted phenotypic-genotypic screening of MRSA could rule in or rule out NaHCO3 susceptibility upfront. We studied 30 well-characterized clinical MRSA bloodstream isolates, including 15 MIC-susceptible to CFZ and OXA in NaHCO3-supplemented Mueller-Hinton Broth (MHB); and 15 MIC-resistant to both ß-lactams in this media. Using a two-tiered strategy, isolates were first screened by standard disk diffusion for susceptibility to a combination of amoxicillin-clavulanate [AMC]. Isolates then underwent genomic sequence typing: MLST (clonal complex [CC]); agr; SCCmec; and mecA promoter and coding region. The combination of AMC disk susceptibility testing plus mecA and spa genotyping was able to predict MRSA strains that were more or less likely to be NaHCO3-responsive in vitro, with a high degree of sensitivity and specificity. Validation of this screening algorithm was performed in six strains from the overall cohort using an ex vivo model of endocarditis. This ex vivo model recapitulated the in vitro predictions of NaHCO3-responsiveness vs. nonresponsiveness above in five of the six strains.

Comparison of metabolic effects of the progestational androgens dimethandrolone undecanoate and 11ß-MNTDC in healthy men.

BACKGROUND: Dimethandrolone (DMA) and 11ß-methyl-19-nortestosterone (11ß-MNT) are two novel compounds with both androgenic and progestational activity that are under investigation as potential male hormonal contraceptives. Their metabolic effects have never been compared in men. OBJECTIVE: Assess for changes in insulin sensitivity and adiponectin and compare the metabolic effects of these two novel androgens. MATERIALS/METHODS: In two clinical trials of DMA undecanoate (DMAU) and 11ß-MNT dodecylcarbonate (11ß-MNTDC), oral prodrugs of DMA and 11ß-MNT, healthy men received drug, or placebo for 28 days. Insulin and adiponectin assays were performed on stored samples. Mixed model analyses were performed to compare the effects of the two drugs. Student's t test, or the non-parametric Kruskal-Wallis test as appropriate, was used to evaluate for an effect of active drug versus placebo. RESULTS: Class effects were seen, with decrease in HDL-C and SHBG, and increase in weight and hematocrit, with no statistically significant differences between the two compounds. No changes in fasting glucose, fasting insulin, or HOMA-IR were seen with either compound. There was a slight decrease in adiponectin with DMAU that was not seen with 11ß-MNTDC. An increase in LDL-C was seen with 11ß-MNTDC but not with DMAU. DISCUSSION: There were no significant changes in insulin resistance after 28 days of oral administration of these novel androgens despite a mild increase in weight. There may be subtle differences in their metabolic impacts that should be explored in future studies. CONCLUSION: Changes in metabolic parameters should be carefully monitored when investigating androgenic compounds.

Investigating the Impact of Intensive Care Unit Interruptions on Patient Safety Events and Electronic Health Records Use: An Observational Study.

BACKGROUND: Constant interruptions and continual data flow result in information overload for clinicians and become barriers to identification and extraction of relevant patient data and its correct interpretation. The aim of the study was to describe the types, frequencies, and impact of intensive care unit (ICU) interruptions on patient safety event occurrences and electronic health records (EHR) use. METHODS: We conducted a live observational study for 6 weeks, observing critical care physicians' and other providers' communication while recording interruptions, patient safety events, and EHR use. RESULTS: Across 55 hours, the researchers observed 7515 ICU tasks, 15.7% of which were interrupted. We found that technological interruptions directly influences the occurrence of patient safety events: an increase in technological interruptions directly contributes to patient safety event occurrence (P = 0.004). Technological interruptions had a direct effect on human interruptions, as the frequency of technological interruptions increase, human interruptions also increase (P = 0.02). CONCLUSIONS: A prospective, observational study was conducted to understand the relationship between interruptions and patient safety events and EHR use, in a time-sensitive, activity-based study in a large academic medical center with a certified EHR system. We found that technological interruptions were statistically correlated to the occurrence of patient safety events, and human interruptions significantly affected the level of EHR use. This study recommends that ICUs adopt a safety culture that promotes minimizing unnecessary interruptions, such as side conversations during rounds, for improved quality of care.

Effect of the Lysin Exebacase on Cardiac Vegetation Progression in a Rabbit Model of Methicillin-Resistant Staphylococcus aureus Endocarditis as Determined by Echocardiography.

Methicillin-resistant Staphylococcus aureus (MRSA) poses significant therapeutic challenges related to its frequency in clinical infections, innate virulence properties, and propensity for multiantibiotic resistance. MRSA is among the most common causes of endovascular infections, including infective endocarditis (IE). Our objective was to employ transthoracic echocardiography (TTE) to evaluate the effect of exebacase, a novel direct lytic agent, in experimental aortic valve MRSA IE. TTE was utilized to evaluate the in vivo effect of exebacase on MRSA-infected vegetation progression when combined with daptomycin (versus daptomycin alone). Primary intravegetation outcomes were maximum size, weights at sacrifice, and MRSA counts at infection baseline versus after 4 days of daptomycin treatment (alone or in addition to exebacase administered once on treatment day 1). A single dose of exebacase in addition to daptomycin cleared significantly more intravegetation MRSA than daptomycin alone. This was associated with a statistical trend toward reduced maximum vegetation size in the exebacase plus daptomycin versus the daptomycin alone therapy groups (P = 0.07). Also, mean vegetation weights in the exebacase-treated group were significantly lower than those of the daptomycin alone group (P < 0.0001). Maximum vegetation size by TTE correlated with vegetation weight (P = 0.005). In addition, intravegetation MRSA counts in the combination group were significantly lower than those of untreated controls (P < 0.0001) and the daptomycin alone group (P < 0.0001). This study suggests that exebacase has a salutary impact on MRSA-infected vegetation progression when combined with daptomycin, especially in terms of vegetation MRSA burden, size, and weight. Moreover, TTE appears to be an efficient noninvasive tool to assess therapeutic efficacies in experimental MRSA IE.

The De Novo Detection of Anti-Thyroglobulin Antibodies and Differentiated Thyroid Cancer Recurrence.

Background: The prevalence and clinical significance of de novo detection of anti-thyroglobulin antibodies (TgAbs) during the follow-up of patients with differentiated thyroid cancer (DTC) is unknown. Methods: We utilized the National Thyroid Cancer Treatment Cooperative Study registry (1987-2012). Patients registered after 1996 (n = 3318) were analyzed. We identified 1545 subjects who had available TgAb status (TgAb cohort) between years 1996 and 2012, of whom 1325 were TgAb negative at first postoperative follow-up testing. From this initial TgAb-negative group, we excluded 513 patients: 423 patients who had less than 3 years of follow-up and/or fewer than three follow-up visits, 86 patients with persistent disease after initial treatment, and 4 patients with data entry errors. The remaining 812 patients were included for analysis, comprising the TgAb persistently negative group (defined as TgAb negative for at least 3 consecutive follow-up visits and at least 3 years of follow-up) (n = 772) and the de novo TgAb-positive group in whom TgAbs became detectable (n = 40). We then assessed whether de novo appearance of TgAb was associated with DTC structural recurrence by using the Kaplan-Meier method. Results: The de novo detection of TgAb occurred in 5% of DTC patients. Recurrence of DTC in the TgAb persistently negative group compared with the de novo TgAb-positive group did not differ significantly (9.6% vs. 15.0%, p = 0.23). Baseline characteristics, histology, history of radiation exposure, staging, and median duration of follow-up were similar between the two groups. Interestingly, in all six patients who suffered a recurrence in the de novo TgAb-positive group, the TgAbs were negative at the time of recurrence detection and became positive at a median of 2.1 (0.7-8.7) years after the structural recurrence. Conclusions: Utilizing a large North American DTC registry, we found the prevalence of de novo TgAb detection to be 5% among initially TgAb-negative patients. We did not find a statistically significant association between de novo TgAb development and DTC structural recurrence. Larger prospective studies are required to confirm these findings and further assess the significance of de novo TgAb detection in the follow-up of DTC.

Scope and Predictive Genetic/Phenotypic Signatures of Bicarbonate (NaHCO3) Responsiveness and ß-Lactam Sensitization in Methicillin-Resistant Staphylococcus aureus.

Addition of sodium bicarbonate (NaHCO3) to standard antimicrobial susceptibility testing medium reveals certain methicillin-resistant Staphylococcus aureus (MRSA) strains to be highly susceptible to ß-lactams. We investigated the prevalence of this phenotype (NaHCO3 responsiveness) to two ß-lactams among 58 clinical MRSA bloodstream isolates. Of note, ∼75% and ∼36% of isolates displayed the NaHCO3 responsiveness phenotype to cefazolin (CFZ) and oxacillin (OXA), respectively. Neither intrinsic ß-lactam MICs in standard Mueller-Hinton broth (MHB) nor population analysis profiles were predictive of this phenotype. Several genotypic markers (clonal complex 8 [CC8]; agr I and spa t008) were associated with NaHCO3 responsiveness for OXA.

A New Bronchodilator Response Grading Strategy Identifies Distinct Patient Populations.

Rationale: A positive bronchodilator response (BDR) according to American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines require both 200 ml and 12% increase in forced expiratory volume in 1 second (FEV1) or forced vital capacity (FVC) after bronchodilator inhalation. This dual criterion is insensitive in those with high or low FEV1.Objectives: To establish BDR criteria with volume or percentage FEV1 change.Methods: The largest FEV1 and FVC were identified from three pre- and three post-bronchodilator maneuvers in COPDGene (Genetic Epidemiology of COPD) participants. A total of 7,741 individuals with coefficient of variation less than 15% for both FEV1 and FVC formed bronchodilator categories of FEV1 response: negative (≤0.00% or ≤0.00 L), minimal (>0.00% to ≤9.00% or >0.00 L to ≤0.09 L), mild (>9.00% to ≤16.00% or >0.09 L to ≤0.16 L), moderate (>16.00% to ≤26.00% or >0.16 L to ≤0.26 L), and marked (>26.00% or >0.26 L). These response size categories are based on empirical limits considering average FEV1 increase of approximately 160 ml and the clinically important difference for FEV1. To compare flow and volume response characteristics, BDR-FEV1 category assignments were applied for the BDR-FVC response.Results: Twenty percent met mild and 31% met moderate or marked BDR-FEV1 criteria, whereas 12% met mild and 33% met moderate or marked BDR-FVC criteria. In contrast, only 20.6% met ATS/ERS positive criteria. Compared with the negative BDR-FEV1 category, the minimal, mild, moderate, and marked BDR-FEV1 categories were associated with greater 6-minute-walk distance and lower St. George's Respiratory Questionnaire and modified Medical Research Council dyspnea scale scores. Compared with negative BDR, moderate and marked BDR-FEV1 categories were associated with fewer exacerbations, and minimal BDR was associated with lower computed tomography airway wall thickness. Compared with the negative category, all BDR-FVC categories were associated with increasing emphysema percentage and gas trapping percentage. Moderate and marked BDR-FVC categories were associated with higher St. George's Respiratory Questionnaire scores but fewer exacerbations and lower dyspnea scores.Conclusions: BDR grading by FEV1 volume or percentage response identified subjects otherwise missed by ATS/ERS criteria. BDR grades were associated with functional exercise performance, quality of life, exacerbation frequency, dyspnea, and radiological airway measures. BDR grades in FEV1 and FVC indicate different clinical and radiological characteristics.

Phototherapy for Neonatal Unconjugated Hyperbilirubinemia: Examining Outcomes by Level of Care.

OBJECTIVES: Newborns hospitalized with unconjugated hyperbilirubinemia without critical comorbidities may receive intensive phototherapy (IP) in non-ICU levels of care, such as a mother-newborn unit, or ICU levels of care. Our aim was to compare outcomes between each level. METHODS: Using hospital discharge data from 2005 to 2011 in New York's State Inpatient Database, we performed multivariate analyses to compare outcomes that included total cost of hospitalization, length of stay, 30-day readmission rate after IP, and the number of cases of death, exchange transfusion, and γ globulin infusion. We included term newborns treated with IP in their first 30 days of life and without diagnosis codes for other critical illnesses. Explanatory variables included level of care, sex, race, insurance type, presence or absence of hemolysis, hospital, volume of IP performed at each hospital, and year of hospitalization. RESULTS: Ninety-nine percent of IP was delivered in non-ICU levels of care. Incidence of major complications was rare (≤0.1%). After adjusting for confounders, ICU level of care was not associated with difference in length of stay (relative risk: 1.2; 95% confidence interval [CI]: 0.91 to 1.15) or 30-day readmission rate (odds ratio: 0.74; 95% CI: 0.50 to 1.09) but was associated with 1.51 (95% CI: 1.47 to 1.56) times higher costs. CONCLUSIONS: For otherwise healthy term newborns with jaundice requiring IP, most received treatment in a non-ICU level of care, and those in intensive care had no difference in outcomes but incurred higher costs. IP guideline authors may want to be more prescriptive about IP level of care to improve value.

Use of Dipstick Assay and Rapid PCR-DNA Analysis of Nasal Secretions for Diagnosis of Bacterial Sinusitis in Children With Chronic Cough.

BACKGROUND: Chronic cough in children is a diagnostic challenge. OBJECTIVE: To discover the utility of nasal dipsticks and polymerase chain reaction (PCR)-DNA analysis in differentiating bacterial sinusitis from other causes of chronic cough and identifying pathogens from the nasal cavity. METHOD: We recruited 22 patients under 15 years of age with cough lasting longer than 4 weeks (group 1), 7 controls with allergic rhinitis (group 2), and 10 controls without respiratory symptoms (group 3). Based on symptoms, the results of nasal secretion assays, and nasal endoscopy, a diagnosis of clinical bacterial sinusitis was made. We identified potential pathogens by quantitative PCR of nasal secretions. RESULTS: Group 1A (cough with clinical bacterial sinusitis n = 10): Eight (80%) patients had bacterial sinusitis associated with dominant potential pathogenic bacteria (PPB): Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. Group 1B (cough without clinical bacterial sinusitis n = 12): None had dominant PPB. Group 2 (allergic rhinitis n = 7): None had dominant PPB. Group 3 (asymptomatic n = 10): None had dominant PPB. Twenty to 57% of all groups were colonized with Staphylococcus aureus. Fifty to 70% were colonized with Staphylococcus epidermidis, Corynebacterium pseudodiphtheriticum, and Dolosigranulum pigrum. CONCLUSION: In children with chronic cough, clinicians can utilize a simple and inexpensive nasal secretion dipstick assay for rapid diagnosis of sinusitis and identify PPB by DNA-PCR test for specific antibiotic treatment.

Safety and Pharmacokinetics of Single-Dose Novel Oral Androgen 11ß-Methyl-19-Nortestosterone-17ß-Dodecylcarbonate in Men.

Context: 11ß-Methyl-19-nortestosterone-17ß-dodecylcarbonate (11ß-MNTDC) is an orally bioavailable prodrug of 11ß-methyl-19-nortestosterone (11ß-MNT) with androgenic and progestational activity. Objectives: (i) Quantify 11ß-MNT binding to androgen and progesterone receptors. (ii) Evaluate safety, tolerability, and serum gonadotropin and testosterone suppression by 11ß-MNTDC in men. Design and Setting: (i) In vitro receptor binding and transactivation studies and (ii) randomized, double-blind, placebo-controlled single-dose, dose-escalating phase I study at two academic medical centers. Participants and Intervention: Twelve healthy male volunteers were randomized (five active, one placebo) to escalating single oral doses (100, 200, 400, and 800 mg) of 11ß-MNTDC or placebo given with or without food. Main Outcome Measures: (i) In vitro 11ß-MNT/11ß-MNTDC human receptor binding and transactivation and (ii) safety and tolerability, pharmacokinetics, and quantification of serum gonadotropin and testosterone concentrations for 24 hours following dosing. Results: 11ß-MNT avidly binds and activates human androgen and progesterone receptors, but 11ß-MNTDC has minimal activity. Single oral doses of 11ß-MNTDC were well tolerated without serious adverse events. Administration of 11ß-MNTDC with food markedly increased average 11ß-MNTDC and 11ß-MNT serum concentrations (P < 0.001 for all doses) compared with fasting with a significant dose-related effect on average serum drug concentrations (P < 0.0001). The 200-, 400-, and 800-mg doses significantly suppressed average serum testosterone concentrations (P < 0.05). Conclusions: A single, oral dose of 11ß-MNTDC up to 800 mg administered with food is safe and well tolerated in healthy men. The active drug 11ß-MNT has androgenic and progestational activity, rapidly suppresses serum testosterone, and is a promising candidate for an effective once-daily oral male hormonal contraceptive.

Interaction of body mass index or waist-to-hip ratio and sun exposure associated with nonmelanoma skin cancer: A prospective study from the Women's Health Initiative.

BACKGROUND: The incidence of nonmelanoma skin cancer (NMSC) exceeds the incidence of all other types of cancers combined. Cumulative sun exposure and intermittent sun exposure are known risk factors for the development of NMSC. Because obesity has been shown to decrease the risk of NMSC incidence, this study investigated whether the risk of NMSC with sun exposure was consistent across different levels of body size. METHODS: Body size was assessed with the body mass index (BMI) and the waist-to-hip ratio (WHR). Sun exposure was assessed in watts and langleys and by the amount of time spent outdoors per day in the summer during a person's 30s. RESULTS: Among 71,645 postmenopausal women eligible for inclusion in this study, 13,351 participants (18.6%) developed NMSC. A BMI ≥ 25 kg/m2 or a WHR ≥ 0.80 was associated with lower NMSC hazard rates (hazard ratio for BMI, 0.78; hazard ratio for WHR, 0.89); however, the association between higher levels of sun exposure and a higher risk of NMSC was more apparent among women with a BMI ≥ 25 kg/m2 or a WHR ≥ 0.80 in comparison with those of a normal weight (P for interaction for BMI < .001; P for interaction for WHR = .022). CONCLUSIONS: Although most studies have considered sun exposure as a covariate, none have addressed the potential interaction of body size with sun exposure; therefore, the effect size of being overweight or obese may have been overestimated. In comparison to the normal-weight group, those in the overweight group had increasingly higher hazard rates with increasing sun exposure. Further studies are warranted to investigate how increased weight interacts with sun exposure to influence skin cancer pathogenesis.