Four-Month Rifapentine Regimens with or without Moxifloxacin for Tuberculosis.

BACKGROUND: Rifapentine-based regimens have potent antimycobacterial activity that may allow for a shorter course in patients with drug-susceptible pulmonary tuberculosis. METHODS: In an open-label, phase 3, randomized, controlled trial involving persons with newly diagnosed pulmonary tuberculosis from 13 countries, we compared two 4-month rifapentine-based regimens with a standard 6-month regimen consisting of rifampin, isoniazid, pyrazinamide, and ethambutol (control) using a noninferiority margin of 6.6 percentage points. In one 4-month regimen, rifampin was replaced with rifapentine; in the other, rifampin was replaced with rifapentine and ethambutol with moxifloxacin. The primary efficacy outcome was survival free of tuberculosis at 12 months. RESULTS: Among 2516 participants who had undergone randomization, 2343 had a culture positive for Mycobacterium tuberculosis that was not resistant to isoniazid, rifampin, or fluoroquinolones (microbiologically eligible population; 768 in the control group, 791 in the rifapentine-moxifloxacin group, and 784 in the rifapentine group), of whom 194 were coinfected with human immunodeficiency virus and 1703 had cavitation on chest radiography. A total of 2234 participants could be assessed for the primary outcome (assessable population; 726 in the control group, 756 in the rifapentine-moxifloxacin group, and 752 in the rifapentine group). Rifapentine with moxifloxacin was noninferior to the control in the microbiologically eligible population (15.5% vs. 14.6% had an unfavorable outcome; difference, 1.0 percentage point; 95% confidence interval [CI], -2.6 to 4.5) and in the assessable population (11.6% vs. 9.6%; difference, 2.0 percentage points; 95% CI, -1.1 to 5.1). Noninferiority was shown in the secondary and sensitivity analyses. Rifapentine without moxifloxacin was not shown to be noninferior to the control in either population (17.7% vs. 14.6% with an unfavorable outcome in the microbiologically eligible population; difference, 3.0 percentage points [95% CI, -0.6 to 6.6]; and 14.2% vs. 9.6% in the assessable population; difference, 4.4 percentage points [95% CI, 1.2 to 7.7]). Adverse events of grade 3 or higher occurred during the on-treatment period in 19.3% of participants in the control group, 18.8% in the rifapentine-moxifloxacin group, and 14.3% in the rifapentine group. CONCLUSIONS: The efficacy of a 4-month rifapentine-based regimen containing moxifloxacin was noninferior to the standard 6-month regimen in the treatment of tuberculosis. (Funded by the Centers for Disease Control and Prevention and others; Study 31/A5349 ClinicalTrials.gov number, NCT02410772.).

A Standardized Approach for Collection of Objective Data to Support Outcome Determination for Late-Phase Tuberculosis Clinical Trials.

Rationale: We developed a standardized method, possible poor treatment response (PPTR), to help ascertain efficacy endpoints in Study S31/A5349 (NCT02410772), an open-label trial comparing two 4-month rifapentine-based regimens with a standard 6-month regimen for the treatment of pulmonary tuberculosis (TB). Objectives: We describe the use of the PPTR process and evaluate whether the goals of minimizing bias in efficacy endpoint assessment and attainment of relevant data to determine outcomes for all participants were achieved. Methods: A PPTR event was defined as the occurrence of one or more prespecified triggers. Each PPTR required initiation of a standardized evaluation process that included obtaining multiple sputum samples for microbiology. Measurements and Main Results: Among 2,343 participants with culture-confirmed drug-susceptible TB, 454 individuals (19.4%) had a total of 534 individual PPTR events, of which 76.6% were microbiological (positive smear or culture at or after 17 wk). At least one PPTR event was experienced by 92.4% (133 of 144) of participants with TB-related unfavorable outcome and between 13.8% and 14.7% of participants with favorable and not-assessable outcomes. A total of 75% of participants with TB-related unfavorable outcomes had microbiological confirmation of failure to achieve a disease-free cure. Conclusions: Standardized methodologies, such as our PPTR approach, could facilitate unbiased efficacy outcome determinations, improve discrimination between outcomes that are related and unrelated to regimen efficacy, and enhance the ability to conduct pooled analyses of contemporary trials.

The Impact of Hazard Statement Design Elements in Procedures: Counterintuitive Findings and Implications for Standards.

OBJECTIVE: The objective of these studies was to identify hazard statement (HS) design elements in procedures that affected whether both workers and lab participants performed the associated hazard mitigation. BACKGROUND: Many of the incidents in high-risk industries are the result of issues with procedures (e.g., standard operating procedures; SOPs) workers use to support their performance. HSs in these procedures are meant to communicate potential work hazards and methods of mitigating those hazards. However, there is little empirical research regarding whether current hazard design guidelines for consumer products translate to procedures. METHOD: Two experimental studies-(1) a laboratory study and (2) a high-fidelity simulation-manipulated the HS design elements present in procedures participants used while performing tasks. Participants' adherence to the mitigation of the hazard was compared for the HS designs. RESULTS: The guidelines for HSs from consumer products did not translate to procedures. Specifically, the presence of an alert icon, a box around the statement, and highlighting the statement did not improve adherence to HSs. Indeed, the only consistent finding was for the Icon, with its presence reliably predicting nonadherence in both studies. Additionally, the total number of design elements did not have a positive effect on adherence. CONCLUSION: These findings indicate that more fundamental procedure HSs research is needed to identify effective designs as well as to understand the potential attentional mechanisms associated with these findings. APPLICATION: The findings from these studies indicate that current regulations and guidelines should be revisited regarding hazard presentation in procedures.

Decreased frequency of transplantation and lower post-transplant survival free of re-transplantation in LVAD patients with the new heart transplant allocation system.

PURPOSE: To evaluate the effect of the new heart transplant (HT) allocation system in left ventricular assist device (LVAD) supported patients listed as bridge to transplantation (BTT). METHODS: Adult patients who were listed for HT between October 18, 2016 and October 17, 2019, and were supported with an LVAD, enrolled in the UNOS database were included in this study. Patients were classified in the old or new system if they were listed or transplanted before or after October 18, 2018, respectively. RESULTS: A total of 3261 LVAD patients were listed for transplant. Of these, 2257 were classified in the old and 1004 in the new system. The cumulative incidence of death or removal from the transplant list due to worsening clinical status at 360-days after listing was lower in the new system (4% vs. 7%, P = .011). LVAD Patients listed in the new system had a lower frequency of transplantation within 360-days of listing (52% vs. 61%, P < .001). A total of 1843 LVAD patients were transplanted, 1004 patients in the old system and 839 patients in the new system. The post-transplant survival at 360 days was similar between old and new systems (92.3% vs. 90%, P = .08). However, LVAD patients transplanted in the new system had lower frequency of the combined endpoint, freedom of death or re-transplantation at 360 days (92.2% vs. 89.6%, P = .046). CONCLUSION: The new HT allocation system has affected the LVAD-BTT population significantly. On the waitlist, LVAD patients have a decreased cumulative frequency of transplantation and a concomitant decrease in death or delisting due to worsening status. In the new system, LVAD patients have a decreased survival free of re-transplantation at 360 days post-transplant.

Increased frequency of heart transplantation, shortened waitlist time and preserved post-transplant survival in adults with congenital heart disease, on the new heart transplant allocation system.

Historically, adult congenital patients have longer waitlist time and worse outcomes on the heart transplant waitlist as well as poorer early post-transplant survival. A new heart transplantation allocation system was implemented in the United States on October 18, 2018. The effect of the new allocation system on adult congenital patients is unknown. Adult congenital patients listed for transplantation between November 1, 2015 and September 30, 2019 registered in the United Network for Organ Sharing were included in the study. October 18, 2018 was used as the limit to distribute listed and transplanted patients into old and new groups. A total of 399 patients were listed for heart transplant only, 284 in the old system and 115 in the new system. Clinical characteristics were similar between both groups. The cumulative incidence of poor outcome on the transplant list was similar in both groups (P = .23), but the cumulative incidence of transplant was higher in the new system group (P < .009) and was associated with a shorter waitlist time. The one-year post-transplant outcome was similar between old and new groups (P = .37). The new allocation system has benefited adult congenital patients with increased cumulative frequency of transplantation without worsening short-term survival after transplantation.

Impact of weekend admission and changes in treating team on patient flow and outcomes in adults admitted to hospital with community-acquired pneumonia.

BACKGROUND: The effect of workflow factors, such as timing of admission and changes in treating team, on patient outcomes remains inconclusive. AIMS: To investigate the impact of weekend admission and changes in treating team on four pre-defined outcomes in patients admitted to hospital with community-acquired pneumonia (CAP). METHODS: We performed an observational cohort study by utilising prospective longitudinal data collected during the IMPROVE-GAP trial, a stepped-wedge randomised study investigating an evidence-based bundle of care in the management of CAP. We assessed the effect of two exposure variables, day of admission and change of treating team, on four pre-specified outcomes: (i) length of stay; (ii) time to clinical stability; (iii) readmission within 30 days; and (iv) mortality at 30 days. Our analysis was restricted to patients with a primary diagnosis of CAP and employed multivariable Cox regression and logistic regression to adjust for potential measured confounders. RESULTS: Of 753 participants, 224 (29.7%) were admitted on the weekend and 71 (9.4%) changed treating team during admission. Weekend admissions had significantly longer hospital stays than weekday admissions (hazard ratio (95% confidence interval; P-value) 0.82 (0.70-0.98; 0.03)) and took longer to reach clinical stability (0.80 (0.68-0.95; 0.01)). Change of treating team doubled the odds of readmission at 30 days (odds ratio 1.95 (1.08-3.58; 0.03)). CONCLUSIONS: These results suggest workflow factors can negatively impact both health service and patient outcomes. Systems interventions aimed at improving out of hours service and reducing changes in treating team should be considered.

CONDITION OF FETURES AND NEWBORNS FROM WOMEN WITH INFERTILITY TREATED WITH ASSISTED REPRODUCTIVE TECHNOLOGIES AND WITH CONCOMITANT INTRAHEPATIC CHOLESTASIS.

OBJECTIVE: The aim: Improving the effects of pregnancy on the fetus and newborn through early diagnosis and timely comprehensive therapy of pregnant women with intrahepatic cholestasis. PATIENTS AND METHODS: Materials and methods: We have conducted a complex examination of 60 women who got pregnant owing to assisted reproductive technologies, with concomitant intrahepatic cholestasis, and 20 practically healthy women with a physiological course of pregnancy and labor (reference group), aged between 18 and 42. The research did not involve pregnant women with chronic liver diseases, viral hepatitis, skin diseases. Womens who underwent the suggested complex drug therapy with Ursofalc, L-arginine and Omega 3, with peroral administration for 14 days according to the following scheme: Ursofalc - 250 mg once a day, L-arginine - 5 ml 3 times a day, Omega 3 - 1 capsule a day. The complex examination of pregnant women with IHC was conducted before and after treatment. We analyzed the data of anamnesis, carried out anthropometric measurements, clinical biochemical examinations of the women with IHC, including the measurement of the levels of alanine aminotransferase, aspartate aminotransferase, total and direct bilirubin, total and placental alkaline phosphatase, leucine aminopeptidase, 5'-nucleotidase, cholic, deoxycholic and chenodeoxycholic acids as wells as their total level. RESULTS: Results: Almost 40 % of women with intrahepatic cholestasis gave birth to babies with asphyxia, including severe one in 11.1 % of cases, 1/3 of the newborns were premature, 40% had signs of hypotrophy, and 66.7 % experienced a disturbed course of early neonatal adaptation. There was also a higher level of perinatal mortality. The newborns from women who had undergone the suggested complex therapy presented no cases of hypotrophy, prenatal infection or cerebral circulation disorder. CONCLUSION: Conclusions: Thus, functional hepatic disorders in women with infertility play a certain role in the carrying of pregnancy after ART, in the development of pregnancy complications and adverse consequences for women and their newborns. The conducted research shows that early diagnosis and timely complex therapy of pregnant women with intrahepatic cholestasis makes it possible to influence the pathogenesis of perinatal complications and improve the consequences of pregnancy for the fetus and the newborn.

Nonparticipation reasons in a randomized international trial of a new latent tuberculosis infection regimen.

BACKGROUND/AIMS: Efficient recruitment of eligible participants, optimizing time and sample size, is a crucial component in conducting a successful clinical trial. Inefficient participant recruitment can impede study progress, consume staff time and resources, and limit quality and generalizability or the power to assess outcomes. Recruitment for disease prevention trials poses additional challenges because patients are asymptomatic. We evaluated candidates for a disease prevention trial to determine reasons for nonparticipation and to identify factors that can be addressed to improve recruitment efficiency. METHODS: During 2001-2009, the Tuberculosis Trials Consortium conducted Study 26 (PREVENT TB), a randomized clinical trial at 26 sites in four countries, among persons with latent tuberculosis infection at high risk for tuberculosis disease progression, comparing 3 months of directly observed once-weekly rifapentine plus isoniazid with 9 months of self-administered daily isoniazid. During March 2005-February 2008, non-identifying demographic information, risk factors for experiencing active tuberculosis disease, and reasons for not enrolling were collected from screened patients to facilitate interpretation of trial data, to meet Consolidated Standards of Reporting Trials standards, and to evaluate reasons for nonparticipation. RESULTS: Of the 7452 candidates screened in Brazil, Canada, Spain, and the United States, 3584 (48%) were not enrolled, because of ineligibility (41%), site decision (10%), or patient choice (49%). Among those who did not enroll by own choice, and for whom responses were recorded on whether they would accept treatment outside of the study (n = 1430), 68% reported that they planned to accept non-study latent tuberculosis infection treatment. Among 1305 patients with one or more reported reasons for nonparticipation, study staff recorded a total of 1886 individual reasons (reason count: median = 1/patient; range = 1-9) for why patients chose not to enroll, including grouped concerns about research (24% of 1886), work or school conflicts (20%), medication or health beliefs (16%), latent tuberculosis infection beliefs (11%), and patient lifestyle and family concerns (10%). CONCLUSION: Educational efforts addressing clinical research concerns and beliefs about medication and health, as well as study protocols that accommodate patient-related concerns (e.g. work, school, and lifestyle) might increase willingness to enter clinical trials. Findings from this evaluation can support development of communication and education materials for clinical trial sites at the beginning of a trial to allow study staff to address potential participant concerns during study screening.

Is Banning Texturized Implants to Prevent Breast Implant-Associated Anaplastic Large Cell Lymphoma a Rational Decision? A Meta-Analysis and Cost-Effectiveness Study.

BACKGROUND: Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is an emergent disease that threatens patients with texturized breast implants. Major concerns about the safety of these implants are leading to global changes to restrict the utilization of this product. The principal alternative is to perform breast augmentation utilizing smooth implants, given the lack of association with BIA-ALCL. The implications and costs of this intervention are unknown. OBJECTIVES: The authors of this study determined the cost-effectiveness of smooth implants compared with texturized implants for breast augmentation surgery. METHODS: A tree decision model was utilized to analyze the cost-effectiveness. Model input parameters were derived from published sources. The capsular contracture (CC) rate was calculated from a meta-analysis. Effectiveness measures were life years, avoided BIA-ALCL, avoided deaths, and avoided reoperations. A sensitivity analysis was performed to test the robustness of the model. RESULTS: For avoided BIA-ALCL, the incremental cost was $18,562,003 for smooth implants over texturized implants. The incremental cost-effectiveness ratio was negative for life years, and avoided death and avoided reoperations were negative. The sensitivity analysis revealed that to avoid 1 case of BIA-ALCL, the utilization of smooth implants would be cost-effective for a risk of developing BIA-ALCL equal to or greater than 1:196, and there is a probability of CC with smooth implants equal to or less than 0.096. CONCLUSIONS: The utilization of smooth implants to prevent BIA-ALCL is not cost-effective. Banning texturized implants to prevent BIA-ALCL may involve additional consequences, which should be considered in light of higher CC rates and more reoperations associated with smooth implants than with texturized implants.

Human Parasitism by Amblyomma parkeri Ticks Infected with Candidatus Rickettsia paranaensis, Brazil.

Spotted fever is the main rickettsial disease in Brazil. We report 12 cases of human parasitism by Amblyomma parkeri in the Atlantic rainforest, an area of Brazil to which spotted fever is endemic. Nine of the ticks were infected with Candidatus Rickettsia paranaensis.

Cu isotopes in marine black shales record the Great Oxidation Event.

The oxygenation of the atmosphere ∼2.45-2.32 billion years ago (Ga) is one of the most significant geological events to have affected Earth's redox history. Our understanding of the timing and processes surrounding this key transition is largely dependent on the development of redox-sensitive proxies, many of which remain unexplored. Here we report a shift from negative to positive copper isotopic compositions (δ(65)CuERM-AE633) in organic carbon-rich shales spanning the period 2.66-2.08 Ga. We suggest that, before 2.3 Ga, a muted oxidative supply of weathering-derived copper enriched in (65)Cu, along with the preferential removal of (65)Cu by iron oxides, left seawater and marine biomass depleted in (65)Cu but enriched in (63)Cu. As banded iron formation deposition waned and continentally sourced Cu became more important, biomass sampled a dissolved Cu reservoir that was progressively less fractionated relative to the continental pool. This evolution toward heavy δ(65)Cu values coincides with a shift to negative sedimentary δ(56)Fe values and increased marine sulfate after the Great Oxidation Event (GOE), and is traceable through Phanerozoic shales to modern marine settings, where marine dissolved and sedimentary δ(65)Cu values are universally positive. Our finding of an important shift in sedimentary Cu isotope compositions across the GOE provides new insights into the Precambrian marine cycling of this critical micronutrient, and demonstrates the proxy potential for sedimentary Cu isotope compositions in the study of biogeochemical cycles and oceanic redox balance in the past.

Stress echocardiography for left ventricular diastolic dysfunction detection in patients with non-severe chronic obstructive pulmonary disease: a cross-sectional study.

AIM: To assess whether the simultaneous performance of exercise stress echocardiography and cardio-pulmonary testing (ESE-CPET) may facilitate the timely diagnosis of subclinical left ventricular diastolic dysfunction (LVDD) in patients with non-severe chronic obstructive pulmonary disease (COPD), preserved left ventricular systolic function, and exertional dyspnea or exercise intolerance. METHODS: This cross-sectional study, conducted between May 2017 and April 2018, involved 104 non-severe COPD patients with exertional dyspnea and preserved ejection fraction who underwent echocardiography before CPET and 1-2 minutes after peak exercise. Based on the peak E/e' ratio, patients were divided into the group with stress-induced LVDD - E/e'>15 and the group without stress-induced LVDD. We assessed the association between LVDD and the following CPET variables: minute ventilation, peak oxygen uptake (VO2), ventilatory efficiency, heart rate reserve, and blood pressure. RESULTS: During ESE-CPET, stress-induced LVDD occurred in 67/104 patients (64%). These patients had lower work load, peak VO2, O2 pulse, and minute ventilation (VE), and higher VE/VCO2 slope than patients without stress-induced LVDD (35.18±10.4 vs 37.01±11.11, P<0.05). None of the CPET variables correlated with E/e'. CONCLUSION: Combined ESE-CPET may distinguish masked LVDD in patients with non-severe COPD with exertional dyspnea and preserved left ventricular systolic function. None of the CPET variables was a predictor for subclinical LVDD.

Benthic perspective on Earth's oldest evidence for oxygenic photosynthesis.

The Great Oxidation Event (GOE) is currently viewed as a protracted process during which atmospheric oxygen increased above ∼10(-5) times the present atmospheric level (PAL). This threshold represents an estimated upper limit for sulfur isotope mass-independent fractionation (S-MIF), an Archean signature of atmospheric anoxia that begins to disappear from the rock record at 2.45 Ga. However, an increasing number of papers have suggested that the timing for oxidative continental weathering, and by conventional thinking the onset of atmospheric oxygenation, was hundreds of million years earlier than previously thought despite the presence of S-MIF. We suggest that this apparent discrepancy can be resolved by the earliest oxidative-weathering reactions occurring in benthic and soil environments at profound redox disequilibrium with the atmosphere, such as biological soil crusts and freshwater microbial mats covering riverbed, lacustrine, and estuarine sediments. We calculate that oxygenic photosynthesis in these millimeter-thick ecosystems provides sufficient oxidizing equivalents to mobilize sulfate and redox-sensitive trace metals from land to the oceans while the atmosphere itself remained anoxic with its attendant S-MIF signature. As continental freeboard increased significantly between 3.0 and 2.5 Ga, the chemical and isotopic signatures of benthic oxidative weathering would have become more globally significant from a mass-balance perspective. These observations help reconcile evidence for pre-GOE oxidative weathering with the history of atmospheric chemistry, and support the plausible antiquity of a terrestrial biosphere populated by cyanobacteria well before the GOE.

Aerobic bacterial pyrite oxidation and acid rock drainage during the Great Oxidation Event.

The enrichment of redox-sensitive trace metals in ancient marine sedimentary rocks has been used to determine the timing of the oxidation of the Earth's land surface. Chromium (Cr) is among the emerging proxies for tracking the effects of atmospheric oxygenation on continental weathering; this is because its supply to the oceans is dominated by terrestrial processes that can be recorded in the Cr isotope composition of Precambrian iron formations. However, the factors controlling past and present seawater Cr isotope composition are poorly understood. Here we provide an independent and complementary record of marine Cr supply, in the form of Cr concentrations and authigenic enrichment in iron-rich sedimentary rocks. Our data suggest that Cr was largely immobile on land until around 2.48 Gyr ago, but within the 160 Myr that followed--and synchronous with independent evidence for oxygenation associated with the Great Oxidation Event (see, for example, refs 4-6)--marked excursions in Cr content and Cr/Ti ratios indicate that Cr was solubilized at a scale unrivalled in history. As Cr isotope fractionations at that time were muted, Cr must have been mobilized predominantly in reduced, Cr(III), form. We demonstrate that only the oxidation of an abundant and previously stable crustal pyrite reservoir by aerobic-respiring, chemolithoautotrophic bacteria could have generated the degree of acidity required to solubilize Cr(III) from ultramafic source rocks and residual soils. This profound shift in weathering regimes beginning at 2.48 Gyr ago constitutes the earliest known geochemical evidence for acidophilic aerobes and the resulting acid rock drainage, and accounts for independent evidence of an increased supply of dissolved sulphate and sulphide-hosted trace elements to the oceans around that time. Our model adds to amassing evidence that the Archaean-Palaeoproterozoic boundary was marked by a substantial shift in terrestrial geochemistry and biology.

Current Pathologic Scoring Systems for Metal-on-metal THA Revisions are not Reproducible.

BACKGROUND: The aseptic lymphocyte vasculitis-associated lesion (ALVAL) score and the modified Oxford ALVAL score are frequently used scoring methods to evaluate the morphologic features of periprosthetic tissues around metal-on-metal (MoM) hip implants. Except for the initial studies of these two morphology scoring methods, to our knowledge, no other studies have reported on intraclass correlation coefficient (ICC) values for interobserver reliability of these scoring methods. QUESTIONS/PURPOSES: Are the ALVAL and Oxford ALVAL scores reproducible? METHODS: The periprosthetic tissue of 37 revisions of 36 patients with failed MoM THAs were independently scored by three experienced pathologists using ALVAL and Oxford ALVAL scoring methods. All patients were included who underwent revision surgery in our hospital until January 2013, with a large-head MoM prosthesis and also met the criteria: blood serum cobalt levels, available MRI scan, and intraarticular cobalt levels. The population included 26 patients with pseudotumors diagnosed by two radiologists using the method described by Matthies et al. The ALVAL describes morphologic features of the synovial lining, tissue organization, and inflammatory cell infiltrate in periprosthetic tissues. The Oxford-ALVAL score uses a semiquantitative measure of the immune response which should be easier to score. RESULTS: The ALVAL score showed an ICC of 0.38 (95% CI, 0.18-0.58) (fair) for the sum score and this improved up to 0.50 (95% CI, 0.31-0.68) (moderate) using the modified Oxford ALVAL score. The individual parameters of the ALVAL score showed an ICC for the scoring of inflammatory infiltrate of 0.37 (95% CI, 0.17-0.57), an ICC of 0.32 (95% CI, 0.12-0.53) for the scoring of tissue organization, and an ICC of 0.14 (95% CI, -0.04 to 0.34) for synovial lining. CONCLUSIONS: Scoring morphologic features of MoM tissue is not reproducible using the ALVAL score or the Oxford ALVAL score. This may reflect heterogeneous morphologic features in tumor tissue and between different tumor tissue samples that cannot be reliably quantified by pathologists using the parameters of these two scoring methods. An alternative, simplified scoring system should be developed to improve the interrater agreement. LEVEL OF EVIDENCE: Level III, diagnostic study.

Factors Associated With Noncompletion of Latent Tuberculosis Infection Treatment: Experience From the PREVENT TB Trial in the United States and Canada.

BACKGROUND: Overall rates of noncompletion of treatment (NCT) for latent tuberculosis infection (LTBI) in the PREVENT TB trial were 18% for 3 months of directly observed once-weekly rifapentine (maximum dose, 900 mg) plus isoniazid (maximum dose, 900 mg) (3HP-DOT) and 31% for 9 months of daily self-administered isoniazid (maximum dose, 300 mg; 9H-SAT). NCT for LTBI reduces its effectiveness. The study objective was to assess factors associated with NCT for LTBI among adult participants enrolled at US and Canadian sites of the PREVENT TB trial. METHODS: This was a post hoc exploratory analysis of the randomized, open-label PREVENT TB trial. Factors were analyzed by univariate and multivariate logistic regression (with enrollment site as a random effect). RESULTS: From 6232 participants analyzed, 1406 (22.6%) did not complete LTBI treatment (317 NCT attributed to an adverse event [NCT-AE] and 1089 NCT attributed to reasons other than an adverse event [NCT-O]). The proportion of NCT-AE was similar with both regimens (3HP-DOT = 6.4% vs 9H-SAT = 5.9%; P = .23); NCT-O was higher among participants enrolled in 9H-SAT (9H-SAT = 24.5% vs 3HP-DOT = 12.7%; P = .02). Among those in the NCT-AE group, being non-Hispanic and receiving 3HP-DOT, having cirrhosis and receiving 9H-SAT, alcohol consumption among men, and use of concomitant medication were associated with NCT-AE. Among those in the NCT-O group, receiving 9H-SAT, missing ≥1 early visit, men receiving 9H-SAT, men with a history of incarceration, alcohol abuse, use ever of intravenous drugs, younger age receiving 9H-SAT, and smoking were associated with NCT-O. CONCLUSIONS: Factors associated with NCT, such as missing a clinic visit early during treatment, might help identify persons for whom tailored interventions could improve completion of LTBI treatment. CLINICAL TRIALS REGISTRATION: NCT00023452.

Malignancy rate of biopsied suspicious bone lesions identified on FDG PET/CT.

PURPOSE: To determine the malignancy rate of bone lesions identified on FDG PET/CT in patients who have undergone CT-guided biopsy because of the suspicion of malignancy. METHODS: This single-centre retrospective study spanned eight consecutive years and included all patients who underwent both FDG PET/CT and CT-guided bone biopsy because of the suspicion of malignancy. The positive predictive value (PPV) for malignancy was calculated, and different patient and imaging characteristics were compared between malignant and benign bone lesions. RESULTS: Of 102 included patients with bone lesions that all showed FDG uptake exceeding mediastinal uptake, bone biopsy showed a malignant lesion in 91 patients, yielding a PPV for malignancy of 89.2 % (95 % CI 81.7 - 93.9 %). In the 94 patients with bone lesions that showed FDG uptake exceeding liver uptake, bone biopsy showed a malignant lesion in 83 patients, yielding a PPV for malignancy of 88.3 % (95 % CI 80.1 - 93.5 %). Higher age, bone marrow replacement of the lesion seen on CT, expansion of the lesion seen on CT, and presence of multifocal lesions on FDG PET/CT were significantly more frequent in patients with malignant lesions than in those with benign bone lesions (P = 0.044, P = 0.009, P = 0.015, and P = 0.019, respectively). Furthermore, there was a trend towards a higher incidence of cortical destruction (P = 0.056) and surrounding soft tissue mass (P = 0.063) in patients with malignant bone lesions. CONCLUSION: The PPV for malignancy of suspicious bone lesions identified on FDG PET/CT is not sufficiently high to justify changes in patient management without histopathological confirmation. Nevertheless, ancillary patient and imaging characteristics may increase the likelihood of a malignant bone lesion.

The evolution of the marine phosphate reservoir.

Phosphorus is a biolimiting nutrient that has an important role in regulating the burial of organic matter and the redox state of the ocean-atmosphere system. The ratio of phosphorus to iron in iron-oxide-rich sedimentary rocks can be used to track dissolved phosphate concentrations if the dissolved silica concentration of sea water is estimated. Here we present iron and phosphorus concentration ratios from distal hydrothermal sediments and iron formations through time to study the evolution of the marine phosphate reservoir. The data suggest that phosphate concentrations have been relatively constant over the Phanerozoic eon, the past 542 million years (Myr) of Earth's history. In contrast, phosphate concentrations seem to have been elevated in Precambrian oceans. Specifically, there is a peak in phosphorus-to-iron ratios in Neoproterozoic iron formations dating from ∼750 to ∼635 Myr ago, indicating unusually high dissolved phosphate concentrations in the aftermath of widespread, low-latitude 'snowball Earth' glaciations. An enhanced postglacial phosphate flux would have caused high rates of primary productivity and organic carbon burial and a transition to more oxidizing conditions in the ocean and atmosphere. The snowball Earth glaciations and Neoproterozoic oxidation are both suggested as triggers for the evolution and radiation of metazoans. We propose that these two factors are intimately linked; a glacially induced nutrient surplus could have led to an increase in atmospheric oxygen, paving the way for the rise of metazoan life.

Where Does Diffuse Large B-Cell Lymphoma Relapse?

OBJECTIVE: This study aimed to investigate the anatomic pattern of disease spread at first disease relapse compared with baseline in diffuse large B-cell lymphoma (DLBCL). MATERIALS AND METHODS: All patients who were newly diagnosed as having DLBCL between January 2004 and June 2014 who initially achieved complete remission but who eventually developed relapsed disease during follow-up were retrospectively identified. Available histological and imaging data were used to determine which nodal regions and extranodal locations were involved at relapse. RESULTS: A total of 21 patients with relapsed DLBCL were included, of whom 8 (38.1%) presented with disease relapse at previously involved sites only, 7 (33.3%) presented with disease relapse at both previously involved and new sites, and 6 (28.6%) presented with disease relapse at new sites only. A total of 57 nodal stations and 34 extranodal locations were involved in all 21 relapsed DLBCL patients. Of these 57 involved nodal regions, 47 (82.5%) were also involved at baseline, whereas 10 (17.5%) were not involved at baseline. Of the 34 involved extranodal locations, 17 (50.0%) were also involved at baseline, whereas 17 (50.0%) were not involved at baseline. CONCLUSIONS: Relapsed DLBCL generally tends to affect previously involved sites, although close to one third of patients seem to have disease recurrence exclusively in previously uninvolved sites. The great majority of involved nodal stations at relapse are also involved at baseline, whereas only one half of involved extranodal locations at relapse are involved at baseline.

Brain glucose metabolism in diffuse large B-cell lymphoma patients as assessed with FDG-PET: impact on outcome and chemotherapy effects.

BACKGROUND: There is a lack of data on the effect of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy on brain glucose metabolism of diffuse large B-cell lymphoma (DLBCL) patients, as measured by 18F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET). Moreover, the prognostic value of brain glucose metabolism measurements is currently unknown. PURPOSE: To investigate the use of FDG-PET for measurement of brain glucose metabolism in R-CHOP-treated DLBCL patients, and to assess its prognostic value. MATERIAL AND METHODS: This retrospective study included DLBCL patients who underwent FDG-PET including the brain. FDG-PET metabolic volume products (MVPs) of the entire brain, cerebral cortex, basal ganglia, and cerebellum were measured, before and after R-CHOP therapy. Whole-body total lesion glycolysis (TLG) was also measured. RESULTS: Thirty-eight patients were included, of whom 18 had an appropriate end-of-treatment FDG-PET scan. There were no significant differences (P > 0.199) between pre- and post-treatment brain glucose metabolism metrics. Low basal ganglia MVP was associated with a significantly worse progression-free survival (PFS) and overall survival (OS) (P = 0.020 and P = 0.032), and low cerebellar MVP was associated with a significantly worse OS (P = 0.034). There were non-significant very weak correlations between pretreatment brain glucose metabolism metrics and TLG. In the multivariate Cox regression, only the National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) remained an independent predictor of PFS (hazard ratio 3.787, P = 0.007) and OS (hazard ratio 2.903, P = 0.0345). CONCLUSION: Brain glucose metabolism was not affected by R-CHOP therapy. Low pretreatment brain glucose metabolism was associated with a worse outcome, but did not surpass the predictive value of the NCCN-IPI.