Idelalisib for Treatment of Relapsed Follicular Lymphoma and Chronic Lymphocytic Leukemia: A Comparison of Treatment Outcomes in Clinical Trial Participants vs Medicare Beneficiaries.

Importance: Idelalisib (IDEL) is approved as monotherapy in relapsed follicular lymphoma (FL) and with rituximab (IDEL+R) for relapsed chronic lymphocytic leukemia (CLL). Toxic effects can be severe and treatment-limiting. Outcomes in a real-world population are not yet characterized. Objective: We compared IDEL treatment outcomes in the clinical setting with outcomes in clinical trial data. Design, Setting, and Participants: This cohort study compared clinical trial participants treated with IDEL, aged 65 years or older, in studies 101-09 and 312-0116 with Medicare beneficiaries treated with IDEL of the same disease state and treatment regimen. Study 101-09 was a phase 2, single-group, open-label trial supporting accelerated approval of IDEL for relapsed or refractory FL. Study 312-0116 was a phase 3, multicenter, randomized, double-blind trial supporting approval of IDEL+R for relapsed CLL. Analyses were conducted between February and December 2018. Main Outcomes and Measures: Treatment duration, on-treatment and overall mortality, and serious and fatal infections were compared between trial participants and Medicare beneficiaries. Cox proportional hazards models quantified differences by cohort. Results: We identified 26 trial participants (mean [SD] age, 73 [4.9] years; 12 [46.2%] women) and 305 Medicare beneficiaries (mean [SD] age, 76 [6.9] years; 103 [54.8%] women) receiving IDEL for FL and 89 trial participants (mean [SD] age, 74 [6.0] years; 30 [33.7%] women) and 294 Medicare beneficiaries (mean age, 76 [6.3] years; 111 [37.8%] women) receiving IDEL+R for CLL. Medicare beneficiaries were older with higher comorbidity; had a shorter median treatment duration for CLL (173 days vs 473 days, P < .001) but not FL (114, days vs 160 days, P = .38); a numerically higher mortality rate (CLL: HR, 1.40; 95% CI, 0.93-2.11; FL: HR, 1.39; 95% CI, 0.69-2.78); and a significantly higher fatal infection rate per 100 person-years for CLL (18.4 vs 9.8, P = .04) and a numerically higher rate for FL (27.6 vs 18.6, P = .54), compared with trial participants. Trial participants had approximately twice as many dose reductions (CLL: 32.6% vs 18.0%; P = .003; FL: 38.5% vs 16.1%; P = .02). Among Medicare beneficiaries, a hospitalized infection within 6 months prior to IDEL initiation was associated with a 2.11-fold increased risk for on-treatment fatal infections (95% CI, 1.44-3.10). Despite a March 2016 recommendation for Pneumocystis jirovecii pneumonia prophylaxis in patients treated with IDEL, prophylaxis rates were low after March 2016 (FL: 25%, CLL: 37%). Conclusions and Relevance: We observed substantial imbalances in baseline comorbidities and treatment outcomes between Medicare beneficiaries and trial participants aged 65 years or older. Immunosuppression-related toxic effects, including infections, may have been somewhat reduced in trials by more frequent dose reductions and exclusion of patients with ongoing infections. Selective eligibility criteria and closer monitoring of trial patients may be responsible for limited generalizability of trial data to clinical practice.

Qualitative and quantitative differences between common occupational health risk assessment models in typical industries.

OBJECTIVE: The differences in the methodologies of various occupational health risk assessment (OHRA) models have not been extensively reported. We aimed to understand the qualitative and quantitative differences between common OHRA models in typical industries. METHODS: The Environmental Protection Agency (EPA), Australian, Romanian, Singaporean, International Council on Mining and Metals (ICMM), and the Control of Substances Hazardous to Health (COSHH) models were evaluated, and a theoretical framework was established for a comparative study. RESULTS: Qualitative comparisons showed that each OHRA model had its own strengths and limitations, and exhibited a diverse distribution at different levels for each evaluation indicator. The Singaporean, COSHH, and EPA models had a much higher comprehensive advantage than the other models for all indicators. Quantitative comparisons demonstrated that these three models also had a stronger ability to distinguish the difference in risk ratios between different industries. The Singaporean model had the strongest correlation with the other models. CONCLUSION: Each model possessed its own strengths and limitations depending on its unique methodological principles. Combining the EPA, Singaporean, and COSHH models might be advantageous for developing an OHRA strategy. More studies comparing multiple models in key industries are required.

Topical Testosterone Therapy Adherence and Outcomes Among Men With Primary or Secondary Hypogonadism.

BACKGROUND: Men with primary or secondary hypogonadism (HG) prescribed testosterone therapy (TTh) who terminate treatment early might not obtain the benefit of symptom relief. AIM: To estimate adherence to topical TTh and to compare baseline characteristics and follow-up outcomes between adherent and non-adherent patients in a population of commercially insured US men with primary or secondary HG. METHODS: A retrospective cohort of adult men with primary or secondary HG and initiating topical TTh from 2007 through 2014, with continuous coverage during 12-month baseline and follow-up periods, was identified from a large US health plan. Clinical conditions were assessed using International Classification of Diseases, 9th Revision, Clinical Modification codes. Adherence to initial topical TTh was defined as proportion of days covered of at least 80%. Characteristics and outcomes were compared across adherent and non-adherent patients. OUTCOMES: Adherence to topical TTh, occurrence of HG-related clinical outcomes, and total health care costs. RESULTS: We identified 3,184 topical TTh initiators (mean age = 49 years), of whom 17% (n = 538) were adherent at 12 months. Factors positively associated with adherence included prescribing by specialists, a lower prevalence of certain comorbidities at baseline, residence in the Northeast, and an earlier start year of the topical TTh prescription. Adherence to topical TTh was associated with lower odds of having HG-associated clinical conditions (composite measure) over 12-month follow-up. In the subset of patients with available laboratory results, adherent patients had greater increases in testosterone levels compared with non-adherent patients. Increased pharmacy costs for adherent patients were partly offset by decreases in medical costs. CLINICAL IMPLICATIONS: Adherence to topical testosterone is low but associated with positive outcomes, demonstrating the need for future efforts to focus on improving adherence in this population. STRENGTHS AND LIMITATIONS: Strengths of this study include the large number of analyzed patients and the routine care (rather than interventional trial) setting, which maximizes generalizability within the source population. Limitations are primarily a result of reliance on medical claims data, which lack clinical context and are subject to potential coding errors. Certain factors of potential importance for adherence, such as patient and provider preferences, were not available in the dataset. The study analyzed commercially insured US patients and our ability to generalize these results to the entire US population or other countries might be limited. CONCLUSION: Study findings provide further evidence for suboptimal topical TTh adherence among men treated for primary or secondary HG. Adherence is associated with greater improvement in total testosterone laboratory values and might be associated with a lower likelihood of having certain HG-related conditions. Grabner M, Hepp Z, Raval A, et al. Topical Testosterone Therapy Adherence and Outcomes Among Men With Primary or Secondary Hypogonadism. J Sex Med 2018;15:148-158.

Organizational characteristics associated with the provision of cultural competency training in home and hospice care agencies.

BACKGROUND: Despite the increasing interest in community-based health care, little information exists on cultural competency training (CCT) and its predictors in this setting. PURPOSE: We examined the associations between six organizational characteristics and the provision of CCT in home health care and hospice agencies. METHODOLOGY: We used cross-sectional data from the agency component of the 2007 National Home and Hospice Care Survey. The CCT provision composite was composed of three items: whether the agency provides mandatory cultural training to understand cultural differences/beliefs that may affect delivery of services to (a) all administrators, clerical, and management staff; (b) all direct service providers; and (c) all volunteers. Organizational characteristics were volume, ownership status, chain membership, teaching status, Joint Commission accreditation status, and formal contracts. PRINCIPAL FINDINGS: The weighted sample (n = 14,469) had a mean CCT provision score of 1.75 (range = 0-3). Our ordinal logistic regression model showed that Joint Commission accreditation increased CCT provision odds in the home health (odds ratio [OR] = 2.07, 95% confidence interval [CI] [1.01, 4.24]) and hospice (OR = 4.40, 95% CI [2.07, 9.38]) settings. Teaching status increased CCT provision odds (OR = 2.71, 95% CI [1.19, 6.17]) in the home health setting. Formal contracts increased CCT provision odds (OR = 4.03, 95% CI [1.80, 9.00]), whereas not-for-profit ownership decreased CCT provision odds (OR = 0.19; 95% CI [0.07, 0.50]) in the hospice setting. PRACTICE IMPLICATIONS: Home health care and hospice agencies need to increase their CCT practices to overcome health disparities in an increasingly diverse and aging population.

Use of Quantile Regression to Determine the Impact on Total Health Care Costs of Surgical Site Infections Following Common Ambulatory Procedures.

OBJECTIVE: To determine the impact of surgical site infections (SSIs) on health care costs following common ambulatory surgical procedures throughout the cost distribution. BACKGROUND: Data on costs of SSIs following ambulatory surgery are sparse, particularly variation beyond just mean costs. METHODS: We performed a retrospective cohort study of persons undergoing cholecystectomy, breast-conserving surgery, anterior cruciate ligament reconstruction, and hernia repair from December 31, 2004 to December 31, 2010 using commercial insurer claims data. SSIs within 90 days post-procedure were identified; infections during a hospitalization or requiring surgery were considered serious. We used quantile regression, controlling for patient, operative, and postoperative factors to examine the impact of SSIs on 180-day health care costs throughout the cost distribution. RESULTS: The incidence of serious and nonserious SSIs was 0.8% and 0.2%, respectively, after 21,062 anterior cruciate ligament reconstruction, 0.5% and 0.3% after 57,750 cholecystectomy, 0.6% and 0.5% after 60,681 hernia, and 0.8% and 0.8% after 42,489 breast-conserving surgery procedures. Serious SSIs were associated with significantly higher costs than nonserious SSIs for all 4 procedures throughout the cost distribution. The attributable cost of serious SSIs increased for both cholecystectomy and hernia repair as the quantile of total costs increased ($38,410 for cholecystectomy with serious SSI vs no SSI at the 70th percentile of costs, up to $89,371 at the 90th percentile). CONCLUSIONS: SSIs, particularly serious infections resulting in hospitalization or surgical treatment, were associated with significantly increased health care costs after 4 common surgical procedures. Quantile regression illustrated the differential effect of serious SSIs on health care costs at the upper end of the cost distribution.

Rapid removal of bacterial endotoxin and natural organic matter in water by dielectric barrier discharge plasma: Efficiency and toxicity assessment.

Low-temperature plasma was used to control bacteria, endotoxins and natural organic matter (NOM) in water by a dielectric barrier discharge (DBD) device. Results indicate that DBD plasma has an obvious inactivation effect on various bacteria in water. The degree of inactivation from difficult to easy is as follows: Bacillus subtilis>Escherichia coli>Staphylococcus aureus. Activated ultrapure water treated using DBD plasma exhibited a sustained sterilization effect, but this sterilization effect decreased gradually after 1h. The total-endotoxin (free-endotoxin and bound-endotoxin) released by Escherichia coli during inactivation, as well as artificially simulated endotoxin in a control solution, was significantly controlled by DBD plasma. Both the metabolites that appeared after inactivation of microorganisms by plasma treatment, and the NOM in filtration effluent of a water treatment plant were well removed by DBD plasma if the treatment duration was sufficiently long. However, the acute toxicity increased significantly, and persisted for at least 2h, indicating that some long-life active substances were generated during the DBD process. Therefore, the removal of bacteria, endotoxins or NOM does not mean a safe water is produced. It is also important to eliminate the toxicity and byproducts produced during water treatment for the continuous promotion and industrial application of DBD plasma.

Care Utilization with China's New Rural Cooperative Medical Scheme: Updated Evidence from the China Health and Retirement Longitudinal Study 2011-2012.

BACKGROUND: China's New Rural Cooperative Medical Scheme (NRCMS), a healthcare financing system for rural residents in China, underwent significant enhancement since 2008. Studies based on pre-2008 NRCMS data showed an increase in inpatient care utilization after NRCMS coverage. However evidence was mixed for the relationship between outpatient care use and NRCMS coverage. PURPOSE: We assessed whether enrollment in the enhanced NRCMS was associated with less delaying or foregoing medical care, as a reduction in foregoing needed care signals about removing liquidity constraint among the enrollees. METHOD: Using a national sample of rural residents (N = 12,740) from the 2011-2012 wave of China Health and Retirement Longitudinal Study, we examined the association between NRCMS coverage and the likelihood of delaying or foregoing medical care (outpatient and inpatient) by survey-weighted regression models controlling for demographics, education, geographic regions, household expenditures, pre-existing chronic diseases, and access to local healthcare facilities. Zero-inflated negative binomial model was used to estimate the association between NRCMS coverage and number of medical visits. RESULTS: NRCMS coverage was significantly associated with lower odds of delaying or foregoing inpatient care (OR: 0.42, 95 % CI: 0.22-0.81). A negative but insignificant association was found between NRCMS coverage and delaying/foregoing outpatient care when ill. Among those who needed health care, the expected number of outpatient visits for NRCMS enrollees was 1.35 (95 % CI: 1.03-1.77) times of those uninsured, and the expected number of inpatient visits for NRCMS enrollees was 1.83 (95 % CI: 1.16-2.88) times of those uninsured. CONCLUSION: This study shows that the enhanced NRCMS coverage was associated with less delaying or foregoing inpatient care deemed as necessary by health professionals, which is likely to result from improved financial reimbursement of the NRCMS.

Structural basis for the geometry-driven localization of a small protein.

In bacteria, certain shape-sensing proteins localize to differently curved membranes. During sporulation in Bacillus subtilis, the only convex (positively curved) surface in the cell is the forespore, an approximately spherical internal organelle. Previously, we demonstrated that SpoVM localizes to the forespore by preferentially adsorbing onto slightly convex membranes. Here, we used NMR and molecular dynamics simulations of SpoVM and a localization mutant (SpoVM(P9A)) to reveal that SpoVM's atypical amphipathic α-helix inserts deeply into the membrane and interacts extensively with acyl chains to sense packing differences in differently curved membranes. Based on binding to spherical supported lipid bilayers and Monte Carlo simulations, we hypothesize that SpoVM's membrane insertion, along with potential cooperative interactions with other SpoVM molecules in the lipid bilayer, drives its preferential localization onto slightly convex membranes. Such a mechanism, which is distinct from that used by high curvature-sensing proteins, may be widely conserved for the localization of proteins onto the surface of cellular organelles.

Response assessment to neoadjuvant therapy in soft tissue sarcomas: using CT texture analysis in comparison to tumor size, density, and perfusion.

PURPOSE: To evaluate the role of computed tomography (CT) texture analysis in assessing response of soft tissue sarcoma (STS) treated with neoadjuvant bevacizumab (BVZ) plus radiotherapy in comparison to tumor size, density, and perfusion. METHODS: In the phase II clinical trial, 20 patients with STSs received BVZ alone for 2 weeks followed by BVZ plus radiotherapy for 6 weeks prior to surgery. All patients received CT perfusion at baseline, 2 and 8 weeks after the therapy, and tumor blood flow (BF) was measured. In contrast enhanced CT image at the arterial peak enhancement time, mean of positive pixels (MPP) was measured as a texture parameter using texture analysis software, and tumor size and density were also measured. The percent changes of these parameters were compared with pathological response on surgical specimen. RESULTS: After 2 weeks of the therapy, MPP and BF decreased by 10.42% and 20.08%, while changes of tumor size and density were not obvious. After 8 weeks, MPP, BF, and density decreased by 29.2% (p = 0.03), 53.2% (p = 0.001), and 30.41% (p = 0.005), respectively, without a significant change in size. The percent change of MPP after 8 weeks had a significant correlation with tumor necrosis in surgical specimen (r = -0.801, p < 0.001), whereas those of size, density, and BF did not. The receiver-operating characteristic analysis demonstrated that the percent change of MPP < -35.36% was an optimal cut-off value to differentiate pathological responders. CONCLUSION: The change of MPP is the best biomarker for the treatment response in STS.

Assessment of crystalline disorder in cryo-milled samples of indomethacin using atomic pair-wise distribution functions.

The aim of this study was to investigate the usefulness of the atomic pair-wise distribution function (PDF) to detect the extension of disorder/amorphousness induced into a crystalline drug using a cryo-milling technique, and to determine the optimal milling times to achieve amorphisation. The PDF analysis was performed on samples of indomethacin obtained by cryogenic ball milling (cryo-milling) for different periods of time. X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), polarised light microscopy (PLM) and solid state nuclear magnetic resonances (ss-NMR) were also used to analyse the cryo-milled samples. The high similarity between the γ-indomethacin cryogenic ball milled samples and the crude γ-indomethacin indicated that milled samples retained residual order of the γ-form. The PDF analysis encompassed the capability of achieving a correlation with the physical properties determined from DSC, ss-NMR and stability experiments. Multivariate data analysis (MVDA) was used to visualize the differences in the PDF and XRPD data. The MVDA approach revealed that PDF is more efficient in assessing the introduced degree of disorder in γ-indomethacin after cryo-milling than MVDA of the corresponding XRPD diffractograms. The PDF analysis was able to determine the optimal cryo-milling time that facilitated the highest degree of disorder in the samples. Therefore, it is concluded that the PDF technique may be used as a complementary tool to other solid state methods and that further investigations are warranted to elucidate the capabilities of this technique.

Assessment of FAE1 polymorphisms in three Brassica species using EcoTILLING and their association with differences in seed erucic acid contents.

BACKGROUND: FAE1 (fatty acid elongase1) is the key gene in the control of erucic acid synthesis in seeds of Brassica species. Due to oil with low erucic acid (LEA) content is essential for human health and not enough LEA resource could be available, thus new LEA genetic resources are being sought for Brassica breeding. EcoTILLING, a powerful genotyping method, can readily be used to identify polymorphisms in Brassica. RESULTS: Seven B. rapa, nine B. oleracea and 101 B. napus accessions were collected for identification of FAE1 polymorphisms. Three polymorphisms were detected in the two FAE1 paralogues of B. napus using EcoTILLING and were found to be strongly associated with differences in the erucic acid contents of seeds. In genomic FAE1 sequences obtained from seven B. rapa accessions, one SNP in the coding region was deduced to cause loss of gene function. Molecular evolution analysis of FAE1 homologues showed that the relationship between the Brassica A and C genomes is closer than that between the A/C genomes and Arabidopsis genome. Alignment of the coding sequences of these FAE1 homologues indicated that 18 SNPs differed between the A and C genomes and could be used as genome-specific markers in Brassica. CONCLUSION: This study showed the applicability of EcoTILLING for detecting gene polymorphisms in Brassica. The association between B. napus FAE1 polymorphisms and the erucic acid contents of seeds may provide useful guidance for LEA breeding. The discovery of the LEA resource in B. rapa can be exploited in Brasscia cultivation.

[Estimation on the reliability and validity of the fatigue self-assessment scale].

OBJECTIVE: To analyze the reliability and validity of the Fatigue Self-assessment Scale (FSAS). METHODS: The scale was applied among the participants assigned to 4 groups, the differences in types, degrees and characteristics of fatigue of them were compared, and the reliability and constitutional validity of ESAS were assessed by internal consistency analysis, exploratory factor analysis and confirmatory factor analysis using the statistical software of SPSS and LISREL. RESULTS: Statistical differences of types, degrees and characteristics of fatigue presented in the participants of the 4 groups. The Cronbach's alpha of various factors in the scale were 0.772-0.908; the indexes for the section of assessing type, and degree of fatigue were RMSEA=0.065, NNFI=0.95, CFI=0.96; and those for the section of assessing characteristics of fatigue were: RMSEA=0.10, NNFI=0.93, CFI=0.96. CONCLUSION: The FSAS has good differentiability, reliability and constitutional validity for assessing the type, degree and characteristics of fatigue in various populations. In order to explore the relationship of TCM syndrome patterns with the type, degree and characteristics of fatigue, its future application for evaluation of fatigue and intervention effect of anti-fatigue should be combined with TCM syndrome differentiation.

Bioinformatics-enabled identification of the HrpL regulon and type III secretion system effector proteins of Pseudomonas syringae pv. phaseolicola 1448A.

The ability of Pseudomonas syringae pv. phaseolicola to cause halo blight of bean is dependent on its ability to translocate effector proteins into host cells via the hypersensitive response and pathogenicity (Hrp) type III secretion system (T3SS). To identify genes encoding type III effectors and other potential virulence factors that are regulated by the HrpL alternative sigma factor, we used a hidden Markov model, weight matrix model, and type III targeting-associated patterns to search the genome of P. syringae pv. phaseolicola 1448A, which recently was sequenced to completion. We identified 44 high-probability putative Hrp promoters upstream of genes encoding the core T3SS machinery, 27 candidate effectors and related T3SS substrates, and 10 factors unrelated to the Hrp system. The expression of 13 of these candidate HrpL regulon genes was analyzed by real-time polymerase chain reaction, and all were found to be upregulated by HrpL. Six of the candidate type III effectors were assayed for T3SS-dependent translocation into plant cells using the Bordetella pertussis calmodulin-dependent adenylate cyclase (Cya) translocation reporter, and all were translocated. PSPPH1855 (ApbE-family protein) and PSPPH3759 (alcohol dehydrogenase) have no apparent T3SS-related function; however, they do have homologs in the model strain P. syringae pv. tomato DC3000 (PSPTO2105 and PSPTO0834, respectively) that are similarly upregulated by HrpL. Mutations were constructed in the DC3000 homologs and found to reduce bacterial growth in host Arabidopsis leaves. These results establish the utility of the bioinformatic or candidate gene approach to identifying effectors and other genes relevant to pathogenesis in P. syringae genomes.