Dose-Weighted Adjusted Mantel-Haenszel Tests for Numeric Scaled Strata in a Randomized Trial

A recent three-arm parallel groups randomized clinical prevention trial had a protocol deviation causing participants to have fewer active doses of an in-office treatment than planned. The original statistical analysis plan stipulated a minimal assumption randomization-based extended Mantel-Haenszel (EMH) trend test of the high frequency, low frequency, and zero frequency treatment groups and a binary outcome. Thus a dose-weighted adjusted EMH (DWAEMH) test was developed with an extra set of weights corresponding to the number of active doses actually available, in the spirit of a pattern mixture model. The method can easily be implemented using standard statistical software. A set of Monte Carlo simulations using a logistic model was undertaken with (and without) actual dose-response effects through 1000 replicates for empirical power estimates (and 2100 for empirical size). Results showed size was maintained and power was improved for DWAEMH versus EMH and logistic regression Wald tests in the presence of a dose effect and treatment by dose interaction

Ovarian reserve diminished by oral cyclophosphamide therapy for granulomatosis with polyangiitis (Wegener's)

Objective Standard treatment for severe granulomatosis with polyangiitis (Wegener's) (GPA) is daily oral cyclophosphamide (CYC), a cytotoxic agent associated with ovarian failure. In this study, we assessed the rate of diminished ovarian reserve in women with GPA who received CYC versus methotrexate (MTX). Methods Patients in the Wegener's Granulomatosis Etanercept Trial received either daily CYC or weekly MTX and were randomized to etanercept or placebo. For all women ages <50 years, plasma samples taken at baseline or early in the study were evaluated against samples taken later in the study to compare levels of anti‐Müllerian hormone (AMH) and follicle‐stimulating hormone (FSH), endocrine markers of remaining egg supply. Diminished ovarian reserve was defined as an AMH level of <1.0 ng/ml. Results Of 42 women in this analysis (mean age 35 years), 24 had CYC exposure prior to enrollment and 28 received the drug during the study. At study entry, women with prior CYC exposure had significantly lower AMH, higher FSH, and a higher rate of early menstruation cessation. For women with normal baseline ovarian function, 6 of 8 who received CYC during the trial developed diminished ovarian reserve, compared to 0 of 4 who did not receive CYC ( P < 0.05). Changes in AMH correlated inversely with cumulative CYC dose ( P < 0.01), with a 0.74 ng/ml decline in AMH level for each 10 gm of CYC. Conclusion Daily oral CYC, even when administered for less than 6 months, causes diminished ovarian reserve, as indicated by low AMH levels. These data highlight the need for alternative treatments for GPA in women of childbearing age.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/88079/1/20605_ftp.pd

Water Arsenic Exposure and Children’s Intellectual Function in Araihazar, Bangladesh

Exposure to arsenic has long been known to have neurologic consequences in adults, but to date there are no well-controlled studies in children. We report results of a cross-sectional investigation of intellectual function in 201 children 10 years of age whose parents participate in our ongoing prospective cohort study examining health effects of As exposure in 12,000 residents of Araihazar, Bangladesh. Water As and manganese concentrations of tube wells at each child’s home were obtained by surveying all wells in the study region. Children and mothers came to our field clinic, where children received a medical examination in which weight, height, and head circumference were measured. Children’s intellectual function on tests drawn from the Wechsler Intelligence Scale for Children, version III, was assessed by summing weighted items across domains to create Verbal, Performance, and Full-Scale raw scores. Children provided urine specimens for measuring urinary As and creatinine and were asked to provide blood samples for measuring blood lead and hemoglobin concentrations. Exposure to As from drinking water was associated with reduced intellectual function after adjustment for sociodemographic covariates and water Mn. Water As was associated with reduced intellectual function, in a dose–response manner, such that children with water As levels > 50 μg/L achieved significantly lower Performance and Full-Scale scores than did children with water As levels < 5.5 μg/L. The association was generally stronger for well-water As than for urinary As

Water Arsenic Exposure and Intellectual Function in 6-Year-Old Children in Araihazar, Bangladesh

BACKGROUND: We recently reported results of a cross-sectional investigation of intellectual function in 10-year-olds in Bangladesh, who had been exposed to arsenic from drinking water in their home wells. OBJECTIVES: We present results of a similar investigation of 301 randomly selected 6-year-olds whose parents participated in our ongoing prospective study of the health effects of As exposure in 12,000 residents of Araihazar, Bangladesh. METHODS: Water As and manganese concentrations of tube wells at each home were obtained by surveying all study region wells. Children and mothers were first visited at home, where the quality of home stimulation was measured, and then seen in our field clinic, where children received a medical examination wherein weight, height, and head circumference were assessed. We assessed children’s intellectual function using subtests drawn from the Wechsler Preschool and Primary Scale of Intelligence, version III, by summing weighted items across domains to create Verbal, Performance, Processing Speed, and Full-Scale raw scores. Children provided urine specimens for measuring urinary As and were asked to provide blood samples for blood lead measurements. RESULTS: Exposure to As from drinking water was associated with reduced intellectual function before and after adjusting for water Mn, for blood lead levels, and for sociodemographic features known to contribute to intellectual function. With covariate adjustment, water As remained significantly negatively associated with both Performance and Processing Speed raw scores; associations were less strong than in our previously studied 10-year-olds. CONCLUSION: This second cross-sectional study of As exposure expands our concerns about As neurotoxicity to a younger age group

Filtration Improves the Performance of a High-Throughput Screen for Anti-Mycobacterial Compounds

The tendency for mycobacteria to aggregate poses a challenge for their use in microplate based assays. Good dispersions have been difficult to achieve in high-throughput screening (HTS) assays used in the search for novel antibacterial drugs to treat tuberculosis and other related diseases. Here we describe a method using filtration to overcome the problem of variability resulting from aggregation of mycobacteria. This method consistently yielded higher reproducibility and lower variability than conventional methods, such as settling under gravity and vortexing

The Diaphragm and Lubricant Gel for Prevention of Cervical Sexually Transmitted Infections: Results of a Randomized Controlled Trial

BACKGROUND: We evaluated the effectiveness of the Ortho All-Flex Diaphragm, lubricant gel (Replens) and condoms compared to condoms alone on the incidence of chlamydial and gonococcal infections in an open-label randomized controlled trial among women at risk of HIV/STI infections. METHODS: We randomized 5045 sexually-active women at three sites in Southern Africa. Participants who tested positive for curable STIs were treated prior to enrollment as per local guidelines. Women were followed quarterly and tested for Chlamydia trachomatis (CT) or Neisseria gonorrhoeae (GC) infection by nucleic-acid amplification testing (Roche Amplicor) using first-catch urine specimens. STIs detected at follow-up visits were treated. We compared the incidence of first infection after randomization between study arms in both intent-to-treat (ITT) and per-protocol populations. FINDINGS: Baseline demographic, behavioral and clinical characteristics were balanced across study arms. Nearly 80% of participants were under 35 years of age. Median follow-up time was 21 months and the retention rate was over 93%. There were 471 first chlamydia infections, 247 in the intervention arm and 224 in the control arm with an overall incidence of 6.2/100 woman-years (wy) (relative hazard (RH) 1.11, 95% Confidence Interval (CI): 0.93-1.33; p = 0.25) and 192 first gonococcal infections, 95 in the intervention arm and 97 in the control arm with an overall incidence of 2.4/100wy (RH 0.98, 95%CI: 0.74-1.30; p = 0.90). Per protocol results indicated that when diaphragm adherence was defined as "always use" since the last visit, there was a significant reduction in the incidence of GC infection among women randomized to the intervention arm (RH 0.61, 95%CI: 0.41-0.91, P = 0.02). INTERPRETATION: There was no difference by study arm in the rate of acquisition of CT or GC. However, our per-protocol results suggest that consistent use of the diaphragm may reduce acquisition of GC. TRIAL REGISTRATION: ClinicalTrials.gov NCT00121459

WNT signaling enhances breast cancer cell motility and blockade of the WNT pathway by sFRP1 suppresses MDA-MB-231 xenograft growth

ABSTRACT: INTRODUCTION: In breast cancer deregulation of the WNT signaling pathway occurs by autocrine mechanisms. WNT ligands and Frizzled (FZD) receptors are coexpressed in primary breast tumors and cancer cell lines. Moreover, many breast tumors show hypermethylation of secreted Frizzled-related protein 1 (sFRP1)'s promoter region, causing low expression of this WNT antagonist. We have previously shown that the WNT pathway influences proliferation of breast cancer cell lines via activation of canonical signaling and epidermal growth factor receptor (EGFR) transactivation, and that interference with WNT signaling reduces proliferation. Here we examine the role of WNT signaling in breast tumor cell migration and on xenograft outgrowth. METHODS: The breast cancer cell line MDA-MB-231 was used to study WNT signaling. We examined the effects of activating or blocking the WNT pathway on cell motility by treatment with WNT ligands or by ectopic sFPR1 expression, respectively. The ability of sFRP1 expressing MDA-MB-231 cells to grow as xenografts was also tested. Microarray analyses were carried out to identify targets with roles in MDA-MB-231/sFRP1 tumor growth inhibition. RESULTS: We show that WNT stimulates the migratory ability of MDA-MB-231 cells. Furthermore, ectopic expression of sFRP1 in MDA-MB-231 cells blocks canonical WNT signaling and decreases their migratory potential. Moreover, the ability of MDA-MB-231/sFRP1 expressing cells to grow as xenografts in mammary glands and to form lung metastases is dramatically impaired. Microarray analyses led to the identification of two genes, CCND1 and CDKN1A, whose expression level is selectively altered in vivo in sFRP1 expressing tumors. The encoded proteins, Cyclin D1 and p21Cip1 were down- and up-regulated, respectively, in sFRP1 expressing tumors, suggesting that they are downstream mediators of WNT signaling. CONCLUSIONS: Our results show that the WNT pathway influences multiple biological properties of MDA-MB-231 breast cancer cells. WNT stimulates tumor cell motility; conversely sFRP1 mediated WNT pathway blockade reduces motility. Moreover, ectopic sFRP1 expression in MDA-MB-231 cells has a strong negative impact on tumor outgrowth and blocked lung metastases. These results suggest that interference with WNT signaling using sFRP1 to block the ligand-receptor interaction may be a valid therapeutic approach in breast cancer

Functional Remineralization of Dentin Lesions Using Polymer-Induced Liquid-Precursor Process

It was hypothesized that applying the polymer-induced liquid-precursor (PILP) system to artificial lesions would result in time-dependent functional remineralization of carious dentin lesions that restores the mechanical properties of demineralized dentin matrix. 140 µm deep artificial caries lesions were remineralized via the PILP process for 7–28 days at 37°C to determine temporal remineralization characteristics. Poly-L-aspartic acid (27 KDa) was used as the polymeric process-directing agent and was added to the remineralization solution at a calcium-to-phosphate ratio of 2.14 (mol/mol). Nanomechanical properties of hydrated artificial lesions had a low reduced elastic modulus (ER = 0.2 GPa) region extending about 70 μm into the lesion, with a sloped region to about 140 μm where values reached normal dentin (18–20 GPa). After 7 days specimens recovered mechanical properties in the sloped region by 51% compared to the artificial lesion. Between 7–14 days, recovery of the outer portion of the lesion continued to a level of about 10 GPa with 74% improvement. 28 days of PILP mineralization resulted in 91% improvement of ER compared to the artificial lesion. These differences were statistically significant as determined from change-point diagrams. Mineral profiles determined by micro x-ray computed tomography were shallower than those determined by nanoindentation, and showed similar changes over time, but full mineral recovery occurred after 14 days in both the outer and sloped portions of the lesion. Scanning electron microscopy and energy dispersive x-ray analysis showed similar morphologies that were distinct from normal dentin with a clear line of demarcation between the outer and sloped portions of the lesion. Transmission electron microscopy and selected area electron diffraction showed that the starting lesions contained some residual mineral in the outer portions, which exhibited poor crystallinity. During remineralization, intrafibrillar mineral increased and crystallinity improved with intrafibrillar mineral exhibiting the orientation found in normal dentin or bone

The ESA Hera Mission : Detailed Characterization of the DART Impact Outcome and of the Binary Asteroid (65803) Didymos

Funding Information: To achieve these objectives, Milani is carrying two scientific payloads, the ASPECT visual and near-infrared (Vis-NIR) imaging spectrometer and the VISTA thermogravimeter aimed at collecting and characterizing volatiles and dust particles below 10 μm. Additionally, navigation payloads include a visible navigation camera and lidar. The Milani consortium is composed of entities and institutions from Italy, the Czech Republic, and Finland. The consortium Prime is Tyvak International, responsible for the whole program management and platform design, development, integration, testing, and final delivery to the customer. Politecnico di Torino is tasked with defining requirements and performing thermal, radiation, and debris analysis. Politecnico di Milano is responsible for mission analysis and GNC. Altec will support the Ground Segment architecture and interface definition. Centro Italiano per la Ricerca Aerospaziale (CIRA) is responsible for the execution of the vehicle environmental campaign. HULD contributes to developing the mission-specific software. VTT is the main payload (ASPECT hyperspectral imager) provider and is supported by the following entities dealing with ASPECT-related development: University of Helsinki (ASPECT calibration); Reaktor Space Lab (ASPECT Data Processing Unit development), Institute of Geology of the Czech Academy of Sciences (ASPECT scientific algorithms requirements and testing); and Brno University of Technology (ASPECT scientific algorithms development). INAF-IAPS is the secondary Payload (VISTA, dust detector) provider. Funding Information: The Mission PI is appointed by ESA and is the primary interface to ESA. The Hera SMB consists of the ESA Hera Project Scientist (ESA PS), the Mission PI, and the Hera Advisory Board, consisting of four mission advisors. The Mission PI chairs the HIT and is supported by the Hera Advisory Board. The tasks of the Hera SMB are 1. advising the Hera mission project team on all aspects related to the Hera mission objectives; 2. ensuring that the WGs’ activities cover the needs of the Hera mission; 3. providing recommendations to ESA concerning the membership in the HIT; and 4. implementing the Publication Policy. Funding Information: Hera is the ESA contribution to the AIDA collaboration. Hera, Juventas, Milani, and their instruments are developed under ESA contract supported by national agencies. This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No. 870377 (project NEO-MAPP), the CNRS through the MITI interdisciplinary programs, ASI, CNES, JAXA, the Academy of Finland project no. 335595, and was conducted with institutional support RVO 67985831 of the Institute of Geology of the Czech Academy of Sciences. M.L., E.P., P.T .and E.D. are grateful to the Italian Space Agency (ASI) for financial support through Agreement No. 2022-8-HH.0 in the context of ESA’s Hera mission. We are grateful to the whole Hera team, including Working Group core members and other contributors for their continuous efforts and support. Their names can be found on the following website: https:// www.heramission.space/team. Publisher Copyright: © 2022. The Author(s). Published by the American Astronomical Society.Hera is a planetary defense mission under development in the Space Safety and Security Program of the European Space Agency for launch in 2024 October. It will rendezvous in late 2026 December with the binary asteroid (65803) Didymos and in particular its moon, Dimorphos, which will be impacted by NASA’s DART spacecraft on 2022 September 26 as the first asteroid deflection test. The main goals of Hera are the detailed characterization of the physical properties of Didymos and Dimorphos and of the crater made by the DART mission, as well as measurement of the momentum transfer efficiency resulting from DART’s impact. The data from the Hera spacecraft and its two CubeSats will also provide significant insights into asteroid science and the evolutionary history of our solar system. Hera will perform the first rendezvous with a binary asteroid and provide new measurements, such as radar sounding of an asteroid interior, which will allow models in planetary science to be tested. Hera will thus provide a crucial element in the global effort to avert future asteroid impacts at the same time as providing world-leading science.Peer reviewe