Ibrutinib for First-Line Treatment of Chronic Graft-Versus-Host Disease: Results From the Randomized Phase III iNTEGRATE Study.

PURPOSE: To present primary and final analyses from the randomized, double-blind, placebo-controlled, phase III iNTEGRATE study, which evaluated the safety and efficacy of ibrutinib with prednisone in previously untreated patients with chronic graft-versus-host disease (cGVHD). METHODS: Patients (age ≥ 12 years) with newly diagnosed moderate or severe cGVHD, requiring systemic corticosteroid therapy, and with no prior systemic treatment for cGVHD were randomly assigned 1:1 to receive ibrutinib 420 mg once daily plus prednisone, starting at 1 mg/kg once daily or placebo plus prednisone. The primary end point was response rate at 48 weeks according to 2014 National Institutes of Health Consensus Development Project Criteria. Other end points included event-free survival, duration of response, time to withdrawal of immunosuppressants, improvement in Lee cGVHD Symptom Scale score, overall survival (OS), and safety. RESULTS: Ninety-five and 98 patients enrolled in the ibrutinib-prednisone and placebo-prednisone arms, respectively. At 48 weeks, response rates were 41% (ibrutinib-prednisone) and 37% (placebo-prednisone; P = .54). At 33 months of follow-up, median duration of response was 19 months (ibrutinib-prednisone) and 10 months (placebo-prednisone; P = .10). Median event-free survival was 15 months (ibrutinib-prednisone) and 8 months (placebo-prednisone; hazard ratio, 0.76; 95% CI, 0.54 to 1.1; P = .11). Improvement in overall Lee cGVHD Symptom Scale was 43% (ibrutinib-prednisone) and 31% (placebo-ibrutinib; P = .07). Median OS was not reached in either arm. The 24-month Kaplan-Meier OS estimates were 80% for both arms (hazard ratio, 1.06; 95% CI, 0.59 to 1.90). Grade ≥ 3 serious adverse events occurred in 49% (ibrutinib-prednisone) and 47% (placebo-prednisone) of patients. CONCLUSION: There was no statistical difference observed in the primary and secondary end points with ibrutinib-prednisone treatment. No new safety signals were observed with ibrutinib treatment in previously untreated patients with cGVHD. The primary end point of iNTEGRATE was not met.

Real-World Evidence of Axicabtagene Ciloleucel for the Treatment of Large B Cell Lymphoma in the United States.

Axicabtagene ciloleucel (axi-cel) is a standard-of-care for patients with relapsed or refractory (r/r) large B cell lymphoma who have received 2 or more lines of prior therapy. Patients receiving axi-cel in the real world could have broader a demographic, disease, and treatment profile compared with that of the cohort in the pivotal ZUMA-1 trial. The present study was conducted to evaluate the outcomes of axi-cel therapy in the real-world setting. A total of 1297 patients receiving commercial axi-cel between 2017 and 2020 were selected from the Center for International Blood and Marrow Transplant Research's data registry, of whom 739 (57%) would have been ineligible for inclusion in the ZUMA-1 cohort. Efficacy and safety outcomes were described for the entire cohort and by ZUMA-1 eligibility. Their associations with age, Eastern Cooperative Oncology Group Performance Score, and comorbidities were evaluated using multivariable logistic and Cox regressions. At a median follow-up of 12.9 months, the overall response rate (ORR) was 73%, with a 56% complete response (CR) rate. Median overall survival (OS) and progression-free survival (PFS) were 21.8 months (95% confidence interval [CI], 17.4 to 28.8 months) and 8.6 months (95% CI, 6.5 to 12.1 months), respectively. Duration of response (DOR) was comparable in the ZUMA-1 ineligible patients and ZUMA-1 eligible patients (62% by 1 year [95% CI, 57% to 66%] versus 67% [95% CI, 62% to 72%]). Patients age ≥65 years had favorable ORR (odds ratio [OR], 1.39; 95% CI, 1.05 to 1.83) despite having a higher risk of cytokine release syndrome (CRS) (OR, 1.41; 95% CI, 1.02 to 1.94) and immune effector cell-associated neurotoxicity syndrome (ICANS) (OR, 1.77; 95% CI, 1.39-2.26). Eastern Cooperative Oncology Group Performance Score ≥2 was associated with inferior efficacy outcomes (OR for ORR, 0.32; 95% CI, 0.18-0.56; hazard ratio [HR] for OS, 3.27; 95% CI, 2.37 to 4.52) and higher incidence of ICANS (OR, 2.63; 95% CI, 1.40 to 4.93). The patients ineligible for ZUMA-1 still had a durable response with axi-cel. Elderly patients had favorable efficacy outcomes despite higher rates of CRS and ICANS. Patient selection for standard-of-care axi-cel should consider comorbidities and risk-to-benefit ratio rather than be based strictly on ZUMA-1 eligibility.

A New Ciboria sp. for Soil Mycoremediation and the Bacterial Contribution to the Depletion of Total Petroleum Hydrocarbons.

A Ciboria sp. strain (Phylum Ascomycota) was isolated from hydrocarbon-polluted soil of an abandoned oil refinery in Italy. The strain was able to utilize diesel oil as a sole carbon source for growth. Laboratory-scale experiments were designed to evaluate the use of this fungal strain for treatment of the polluted soil. The concentration of total petroleum hydrocarbons (TPH) in the soil was 8,538 mg/kg. Mesocosms containing the contaminated soil were inoculated with the fungal strain at 1 or 7%, on a fresh weight base ratio. After 90 days of incubation, the depletion of TPH contamination was of 78% with the 1% inoculant, and 99% with the 7% inoculant. 16S rDNA and ITS metabarcoding of the bacterial and fungal communities was performed in order to evaluate the potential synergism between fungi and bacteria in the bioremediation process. The functional metagenomic prediction indicated Arthrobacter, Dietzia, Brachybacerium, Brevibacterium, Gordonia, Leucobacter, Lysobacter, and Agrobacterium spp. as generalist saprophytes, essential for the onset of hydrocarbonoclastic specialist bacterial species, identified as Streptomyces, Nocardoides, Pseudonocardia, Solirubrobacter, Parvibaculum, Rhodanobacter, Luteiomonas, Planomicrobium, and Bacillus spp., involved in the TPH depletion. The fungal metabolism accelerated the onset of specialist over generalist bacteria. The capacity of the Ciboria sp. to deplete TPH in the soil in treatment was also ascertained.

Prophylactic Activity of Orally Administered FliD-Reactive Monoclonal SIgA Against Campylobacter Infection.

Campylobacter infection is one of the most common causes of bacterial gastroenteritis worldwide and a major global health threat due to the rapid development of antibiotic resistance. Currently, there are no vaccines approved to prevent campylobacteriosis, and rehydration is the main form of therapy. Secretory immunoglobulin A (SIgA) is the main antibody class found in mucous secretions, including human milk, and serves as the first line of defense for the gastrointestinal epithelium against enteric pathogens. In this study, we describe the prophylactic activity of orally delivered recombinant SIgA generated from two human monoclonal antibodies (CAA1 and CCG4) isolated for their reactivity against the flagellar-capping protein FliD, which is essential for bacteria motility and highly conserved across Campylobacter species associated with severe enteritis. In an immunocompetent weaned mouse model, a single oral administration of FliD-reactive SIgA CAA1 or CCG4 at 2 h before infection significantly enhances Campylobacter clearance at early stages post-infection, reducing the levels of inflammation markers associated with epithelial damage and polymorphonuclear (PMN) cells infiltration in the cecum lamina propria. Our data indicate that the prophylactic activity of CAA1 and CCG4 is not only dependent on the specificity to FliD but also on the use of the SIgA format, as the immunoglobulin G (IgG) versions of the same antibodies did not confer a comparable protective effect. Our work emphasizes the potential of FliD as a target for the development of vaccines and supports the concept that orally administered FliD-reactive SIgA can be developed to prevent or mitigate the severity of Campylobacter infections as well as the development of post-infection syndromes.

Prevalence of SARS-CoV-2 infection among asymptomatic healthcare workers in greater Houston: a cross-sectional analysis of surveillance data from a large healthcare system

ObjectiveTo determine the prevalence of SARS-CoV-2 infection among asymptomatic COVID-19 facing and non-COVID-19 facing Healthcare Workers (HCWs), with varying job categories across different hospitals. DesignCross-sectional analysis of a healthcare system surveillance program that included asymptomatic clinical (COVID-19 facing and non-COVID-19 facing), and non-clinical HCWs. A convenience sample of asymptomatic community residents (CR) was also tested. Proportions and 95% confidence Intervals (CI) of SARS-CoV-2 positive HCWs are reported. Proportional trend across HCW categories was tested using Chi Square trend test. Logistic regression model-based likelihood estimates of SARS-CoV-2 prevalence among HCWs with varying job functions and across different hospitals are reported as adjusted odds ratios (aOR) and CI. SettingHealthcare system comprising one tertiary care academic medical center and six large community hospitals across Greater Houston and a community sample. Participants2,872 self-reported asymptomatic adult (> 18 years) HCWs and CRs. ExposureClinical HCWs in COVID-19 and non-COVID-19 units, non-Clinical HCWs, and CRs. Job categories of Nursing, Providers, Allied Health, Support, and Administration / Research. Seven hospitals in the healthcare system. Main OutcomesPositive reverse transcriptase polymerized chain reaction (RT-PCR) test for SARS-CoV-2 ResultsAmong 2,872 asymptomatic HCWs and CRs, 3.9% (CI: 3.2 - 4.7) tested positive for SARS-CoV-2. Mean (SD) age was 40.9 (11.7) years and 73% were females. Among COVID-19 facing HCWs 5.4% (CI: 4.5 - 6.5) were positive, whereas 0.6% (CI: 0.2 - 1.7%) of non COVID-19 facing HCWs and none of the non-clinical HCWs or CRs were positive (Ptrend < 0.001). Among COVID-19 facing HCWs, SARS-CoV-2 positivity was similar for all job categories (p = 0.74). However, significant differences in positivity were observed across hospitals. Conclusions and RelevanceAsymptomatic HCWs with COVID-19 patient exposure had a higher rate of SARS-CoV-2 positive testing than those not routinely exposed to COVID-19 patients and those not engaged in patient care. Among HCWs with routine COVID-19 exposure, all job types had relatively similar infection rates. These data can inform hospital surveillance and infection control practices for patient-facing job classifications and suggest that general environmental exposure within hospitals is not a significant source of asymptomatic SARS-CoV-2 infection. What is already known on this topicO_LIA sizeable proportion of individuals who contract the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) can remain largely asymptomatic. C_LIO_LIThough such individuals may not develop symptoms, they continue to shed enough viral particles to trigger positive reverse transcriptase polymerized chain reaction (RT PCR) test for SARS-CoV-2 C_LIO_LIPrior reports on proportion of asymptomatic SARS-CoV-2 individuals are highly variable with positivity ranging across < 1% to 36% C_LIO_LIAsymptomatic SARS-CoV-2 infection among healthcare workers is specifically critical to understand C_LI What this study addsO_LIThis study demonstrates that overall rate of SARS-CoV-2 infection among asymptomatic healthcare workers in a large healthcare system of a metropolitan city in the United States was 3.9% C_LIO_LIThe rate of SARS-CoV-2 infection among healthcare workers who provided direct care to COVID-19 patients was 5.4% whereas it was 0.6% among those healthcare workers who did not provide direct care to COVID-19 patients C_LIO_LIThere was no difference in SARS-CoV-2 positivity rate for different job categories of healthcare workers who provided direct care to COVID-19 patients C_LI

Logique de la soumission et du commandement: de l'expérience de S. milgram au slogan / Logic of submission and commandment: from S. milgram experiment to the slogan power / Lógica de submissão e mandamento: da experiência de S. milgram ao poder do slogan

Nous proposons une relecture psychanalytique de l'expérience de Stanley Milgram pour souligner les fonctions de la soumission et de l'obéissance, ainsi que des conditions corrélatives à l'établissement d'une logique du commandement. En référence aux concepts lacaniens, sont développés les rapports du signifiant et de la jouissance, convoqués conjointement à l'endroit d'une scène réactualisée, celle du fantasme qui oriente le sujet dans la réalité: c'est autour de ces notions que nous pouvons déplier les rapports d'un sujet et de sa division devant le diverses figures personnifiant un grand Autre, Autre alors supposé en charge de boucher le trou dans la garantie du monde. Aussi, afin de se débarrasser des affres de la division et de son malaise, le sujet peut en appeler aisément à la consistance de cet Autre. Les effets d'une subjectivité orientée par une telle cause peuvent sans doute se décliner de diverses manières dans notre modernité, celle-ci se spécifiant d'un lien social où prime le "fétichisme de la marchandise", soit un discours capitaliste où les promesses de jouissances foisonnent à mesure d'un idéal normatif de liberté du sujet. Mais de quelle liberté parlons-nous en tant que sujet?

We propose a psychoanalytic reading of the Stanley Milgram experiment to underline the functions of submission and obedience, and consequential conditions for establishing a logic of commandment. Refering to the Lacanian concepts, relations between the signifier and the jouissance are developed, jointly arranged in an updated scene of the fantasy, guiding subjectivity into reality: it is around these notions that we can unfold the links of a subject and its division to the various figures personifying the Other, a great Other who is supposed to assume responsibility to fill the hole in the guarantee of the world. So in order to get rid of the pangs of his division and malaise, the subject can easily request the consistency of this Other. The effects of subjectivity oriented by such a cause can probably be presented in various ways in our modernity, which is specified by a social link where reigns the "fetishism of merchandise": it's a capitalist discourse which promises jouissances related to a normative ideal of liberty. Nonetheless what "liberty" are we talking about as a subject?

Propomos uma leitura psicanalítica da experiência de Stanley Milgram para destacar as funções de submissão e obediência, e as condições consequentes para o estabelecimento de uma lógica de mandamento. Em referência aos conceitos lacanianos, são desenvolvidas as relações entre o significante e gozo, convocados juntos em uma cena atualizada, a da fantasia que orienta o assunto na realidade: é em torno dessas noções que podemos desdobrar as relações de um sujeito e sua divisão diante das várias figuras que personificam um grande Outro, Outro então supostamente encarregado de tapar o buraco para a garantia do mundo. Igualmente, a fim de se livrar dos tormentos da divisão e de seu mal-estar, o sujeito pode facilmente apelar à consistência desse Outro. Os efeitos de uma subjetividade orientada por uma tal causa provavelmente podem sem dúvida ser declinados de diversas maneiras em nossa modernidade, esta se especificando por um laço social no qual domina o "fetichismo da mercadoria", ou seja, um discurso capitalista em que as promessas de gozo abundam como um ideal normativo da liberdade do sujeito. Mas de qual liberdade falamos enquanto sujeito?

Sonochemical and sonocatalytic degradation of monolinuron in water.

The degradation of the phenylurea monolinuron (MLN) by ultrasound irradiation alone and in the presence of TiO(2) was investigated in aqueous solution. The experiments were carried out at low and high frequency (20 and 800 kHz) in complete darkness. The degradation of MLN by ultrasounds occurred mainly by a radical pathway, as shown the inhibitory effect of adding tert-butanol and bicarbonate ions to scavenge hydroxyl radicals. However, CO(3)(-) radicals were formed with bicarbonate and reacted in turn with MLN. In this study, the degradation rate of MLN and the rate constant of H(2)O(2) formation were used to evaluate the oxidative sonochemical efficiency. It was shown that ultrasound efficiency was improved in the presence of nanoparticles of TiO(2) and SiO(2) only at 20 kHz. These particles provide nucleation sites for cavitation bubbles at their surface, leading to an increase in the number of bubbles when the liquid is irradiated by ultrasound, thereby enhancing sonochemical reaction yield. In the case of TiO(2), sonochemical efficiency was found to be greater than with SiO(2) for the same mass introduced. In addition to the increase in the number of cavitation bubbles, activated species may be formed at the TiO(2) surface that promote the formation of H(2)O(2) and the decomposition of MLN.

Sensitivity of two hepatitis B virus, hepatitis C virus (HCV), and human immunodeficiency virus (HIV) nucleic acid test systems relative to hepatitis B surface antigen, anti-HCV, anti-HIV, and p24/anti-HIV combination assays in seroconversion panels.

BACKGROUND: Accurate determination of the infectious window period (IWP) that remains with individual-donation (ID) or minipool (MP) NAT compared to those with serology assays is essential for residual risk estimations. STUDY DESIGN AND METHODS: The relative sensitivity of the Procleix Tigris system (Gen-Probe/Chiron) used in ID-NAT format and cobas s 201 (Roche Molecular Systems) applied in 1:6 diluted samples to mimic six-minipool (MP6) nucleic acid test (NAT) was assessed by quadruplicate testing of five seroconversion panels per marker. A mathematical analysis based on the log-linear increase of viremia in the ramp-up phase, as established with bDNA 3.0 assays enabled estimation of the IWP for human immunodeficiency virus (HIV) and hepatitis B virus (HBV) assays. RESULTS: The mean IWPs were Tigris HIV RNA 5.5 days, s 201 (1:6) HIV RNA 7.4 days, GenScreen Plus p24/anti-HIV 17.8 days, PRISM anti-HIV 19.0 days, Tigris HBV DNA 20.6 days, s 201 (1:6) HBV DNA 22.6 days, Bio-Rad hepatitis B surface antigen (HBsAg) 37.8 days, and PRISM HBsAg 35.5 days. At estimated 50 percent NAT seroconversion rates, s 201 (1:6) and Tigris showed mean window-period reduction times (WPRTs) of 30.5 to 35.5 days to hepatitis C virus antibody (anti-HCV) assays, 10.4 to 13.5 days to anti-HIV, or combination p24/anti-HIV assays and 12.8 to 17.2 days to HBsAg assays. CONCLUSIONS: Tigris ID-NAT detected HIV RNA 2 days earlier than s 201 MP6-NAT, but the difference in sensitivity between the two NAT systems was not significant in HBV seroconversion panels. Insufficient seroconversion samples were available for reliable modeling of WPRT in early HCV infection, but 1.4 to 2.0 days could be predicted by translating analytical sensitivity data. Both multiplex NAT systems demonstrate significant WPRTs compared to (combined) antigen and antibody assays.

Sonochemical degradation of PAH in aqueous solution. Part I: monocomponent PAH solution.

The sonolysis of selected monocomponent PAH aqueous solution is studied at 20 and 506 kHz in the microg l(-1) range. The highest activity observed at 506 kHz, compared to 20 kHz, is tentatively explained by examination of the physical characteristics of bubbles (size and life-time) as well as by the calculation of the number of bubble at both frequency (5 x 10(3)bubbles l(-1) at 20 kHz and 4.5 x 10(9)bubbles l(-1) at 506 kHz). It is demonstrated that the main mechanism of sonodegradation is the pyrolysis of PAHs in the heart of the cavitation bubbles, and that a possible PAH oxidation by means of HO degrees appears as a minor way, since gaseous byproducts such as CO, CO2, C2H2 and CH4 have been detected. Correlations have been found by examination of kinetic variations in terms of the physical-chemical properties of PAHs. The rate constants of PAH degradation increase when the water solubility, the vapour pressure and the Henry's law constant increase.

Comparison of the analytical and operational performance of two viral nucleic acid test blood screening systems: Procleix Tigris and cobas s 201.

BACKGROUND: The operational and analytical performance of two automated triplex hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV) nucleic acid test (NAT) systems were compared in four screening laboratories of the French Blood Service. STUDY DESIGN AND METHODS: Two laboratories evaluated the Procleix Tigris system (Chiron/Gen-Probe) in individual donation (ID) format and two sites used the cobas s 201 system (Roche Molecular Systems) on minipools (MPs) of six donations. The analytical sensitivity, the specificity, and operational performance were compared. RESULTS: The ID to MP-NAT relative sensitivity factors in standard dilution panels of different genotypes varied between 8.7 and 21.9 for HCV RNA, 6.7 and 14.8 for HIV RNA, and 0.71 and 11.6 for HBV DNA. Tigris was 800-fold more sensitive than cobas s 201 (1:6) for a HIV group O sample, but did not detect the HIV-2 sample picked up by cobas s 201 with equal sensitivity as the HIV-1 group M samples. The specificity of both NAT systems after initial screening of 10,520 donations with Tigris and 1444 test pools on s 201 was 99.9 percent for both systems, but reached 100 percent after the repeat and pool resolution test algorithms. A higher throughput of the pool test protocol on cobas s 201 became apparent when the daily workload was more than 400 donations. CONCLUSIONS: Tigris ID-NAT format was significantly more sensitive than cobas s 201 MP-NAT in detecting HCV RNA and HIV RNA dilution panels, but despite the 1:6 dilution factor in s 201 the difference in sensitivity was not significant for some of the HBV genotype panels. Both NAT systems demonstrated acceptable operational performance, but for routine use further improvement in system reliability is desirable.

A statistical thermodynamic approach to sonochemical reactions.

The calculation of the equilibrium constants K of the sonolysis reactions of CO2 into CO and O atom, the recombination of O atoms into O2 and the formation of H2O starting with H and O atoms, has been studied by means of statistical thermodynamic. The constants have been calculated at 300 kHz versus the pressure and the temperature according to the extreme conditions expected in a cavitation bubble, e.g. in the range from ambient temperature to 15200 K and from ambient pressure to 300 bar. The decomposition of CO2 appears to be thermodynamically favored at 15200 K and 1 bar with a constant K1=1.52 x 10(6), whereas the formation of O2 is not expected to occur (K2=1.8 x10(-8) maximum value at 15200 K and 300 bar) in comparison to the formation of water (K3=3.4 x 10(47) at 298 K and 300 bar). The most thermodynamic favorable location of each reactions is then proposed, the surrounding shell region for the thermic decomposition of CO2 and the wall of the cavitation bubble for the formation of water. Starting from a work of Henglein on the sonolysis of CO2 in water at 300 kHz, the experimental amount of CO formed (7.2 x 10(20)molecules L(-1)) is compared to the theoretical CO amount (1.4 x 10(27)molecules L(-1)) which can be produced by the sonolysis of the same starting amount CO2. With the help of the literature data, the number of cavitation bubble has been evaluated to 6.2 x 10(15) bubbles L(-1) at 300 kHz, in 15 min. This means that about 1 bubble on 1900000 is efficient for undergoing the sonolysis of CO2.

Bone collected during dental implant surgery: a clinical and histological study.

Bone traps vary in design, although the effect of pore size on the nature of the debris collected in vivo has not yet been established. The aims of this study were 1) to compare the clinical performance of two bone collectors during implant surgery, ii) to establish the mass of tissue collected by each device, and iii) to characterize the nature of the collected debris. Thirty-eight patients (paired for implant site) were categorised into three clinical groups according to the site and the number of implants they were to receive. Patients underwent bone collection with the Frios bone trap or the Osseous Coagulum Trap according to a randomisation sequence. The samples were fixed in formalin, frozen, freeze-dried and weighed. Material from each sample was embedded in paraffin wax and stained with haematoxylin and eosin. All sections were examined by optical microscopy and the proportion of bone to coagulum was established histomorphometrically. During surgery, the Frios bone trap blocked once and the Osseous Coagulum Trap blocked 11 times. In all cases where blockage occurred, excess coagulum was apparent. All the samples that were collected by the Frios bone trap contained bone and coagulum, with a mean proportion of 90.6% bone. With regard to the Osseous Coagulum Trap, one sample contained no bone and two samples contained only trace amounts of bone; the remaining samples contained a mean proportion of 67.3% bone. Pore size affects both clinical performance and the histological composition of the debris collected, and this might have important implications if used as an augmentation material.