A phase I dose escalation and expansion trial of the next-generation oral SERD camizestrant in women with ER-positive, HER2-negative advanced breast cancer: SERENA-1 monotherapy results.

BACKGROUND: SERENA-1 (NCT03616587) is a phase I, multi-part, open-label study of camizestrant in pre- and post-menopausal women with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. Parts A and B aim to determine the safety and tolerability of camizestrant monotherapy and define doses for clinical evaluation. PATIENTS AND METHODS: Women aged ≥18 years with metastatic or recurrent ER+, HER2- breast cancer, refractory (or intolerant) to therapy, were assigned 25 mg up to 450 mg once daily (QD; escalation) or 75, 150, or 300 mg QD (expansion). Safety and tolerability, antitumor efficacy, pharmacokinetics, and impact on mutations in the estrogen receptor gene (ESR1m) circulating tumor (ct)DNA levels were assessed. RESULTS: By 9 March 2021, 108 patients received camizestrant monotherapy at 25-450 mg doses. Of these, 93 (86.1%) experienced treatment-related adverse events (TRAEs), 82.4% of which were grade 1 or 2. The most common TRAEs were visual effects (56%), (sinus) bradycardia (44%), fatigue (26%), and nausea (15%). There were no TRAEs grade 3 or higher, or treatment-related serious adverse events at doses ≤150 mg. Median tmax was achieved ∼2-4 h post-dose at all doses investigated, with an estimated half-life of 20-23 h. Efficacy was observed at all doses investigated, including in patients with prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) and/or fulvestrant treatment, with and without baseline ESR1 mutations, and with visceral disease, including liver metastases. CONCLUSIONS: Camizestrant is a next-generation oral selective ER antagonist and degrader (SERD) and pure ER antagonist with a tolerable safety profile. The pharmacokinetics profile supports once-daily dosing, with evidence of pharmacodynamic and clinical efficacy in heavily pre-treated patients, regardless of ESR1m. This study established 75-, 150-, and 300-mg QD doses for phase II testing (SERENA-2, NCT04214288 and SERENA-3, NCT04588298).

Estimating the real-world performance of the PROMISE minimal-risk tool.

BACKGROUND: Stable chest pain is a common indication for cardiac catheterization. We assessed the prognostic value of the Prospective Multicenter Imaging Study for Evaluation (PROMISE) Minimal-Risk Tool in identifying patients who are at very low risk of obstructive coronary artery disease (CAD) or downstream cardiovascular adverse outcomes. METHODS: We applied the PROMISE Minimal-Risk Tool to consecutive patients without known CAD who underwent elective cardiac catheterization for stable angina from January 1, 2000 to December 31, 2014 in the Duke Databank for Cardiovascular Disease (DDCD). Patients with scores >0.46 (top decile of lowest-risk from the PROMISE cohort) were classified as low-risk. Logistic regression modeling compared likelihood of freedom from obstructive coronary artery disease on index angiography, 2-year survival, and 2-year survival free of myocardial infarction (MI) and MI/revascularization between low- and non low-risk patients. Alternative cut points to define low- risk patients were also explored. RESULTS: Among 6251 patients undergoing cardiac catheterization for stable chest pain, 1082 (17.3%) were low-risk per the PROMISE minimal-risk tool. Among low risk patients, obstructive coronary artery disease was observed in 14.9% and left main disease (≥ 50% Stenosis) was rare (0.9%). Compared with other patients, low risk patients had a higher likelihood of freedom from obstructive coronary disease on index catheterization (85.1% vs. 44.2%, OR 4.84, 95% CI 4.06-5.77). Low risk patients had significantly higher survival (98.2% vs. 94.4%, OR 3.18, 95% CI 1.99-5.08), MI-free survival (97.2% vs. 91.9%, OR 3.03, 95% CI 2.07-4.45), and MI/revascularization-free survival (86.2 vs. 59.9%, OR 4.19, 95% CI 3.48-5.05) at 2 years than non-low risk patients. Operating characteristics for predicting the outcomes of interest varied modestly depending on the low-risk cut-point used but the positive predictive value for 2 year freedom from death was >98% regardless. CONCLUSION: The PROMISE minimal-risk tool identifies 17% of stable chest pain patients referred to cardiac catheterization as low risk. These patients have a low prevalence of obstructive CAD and better survival than non-low risk patients. While this suggests that these patients are unlikely to benefit from catheterization, further research is needed to confirm a favorable downstream prognosis with medical management alone.

Antitumor activity of ipatasertib combined with chemotherapy: results from a phase Ib study in solid tumors.

BACKGROUND: This phase Ib study evaluated the safety, tolerability, pharmacokinetics, and preliminary efficacy of the oral AKT inhibitor ipatasertib and chemotherapy or hormonal therapy in patients with advanced or metastatic solid tumors to determine combined dose-limiting toxicities (DLTs), maximum tolerated dose, and recommended phase II doses and schedules. PATIENTS AND METHODS: The clinical study comprised four combination treatment arms: arm A (with docetaxel), arm B [with mFOLFOX6 (modified leucovorin, 5-fluorouracil, and oxaliplatin)], arm C (with paclitaxel), and arm D (with enzalutamide). Primary endpoints were safety and tolerability; secondary endpoints were pharmacokinetics, clinical activity per Response Evaluation Criteria in Solid Tumors v1.1, and prostate-specific antigen levels. RESULTS: In total, 122 patients were enrolled. Common adverse events were diarrhea, nausea, vomiting, decreased appetite, and fatigue. The safety profiles of the combination regimens were consistent with those of the background regimens, except for diarrhea, hyperglycemia, and rash, which were previously observed with ipatasertib treatment. The only combination DLT across all treatment arms was one event of grade 3 dehydration (ipatasertib 600 mg and paclitaxel). Recommended phase II doses for ipatasertib were 600 mg (and mFOLFOX6) and 400 mg (and paclitaxel), respectively. The maximum assessed dose of ipatasertib 600 mg combined with docetaxel or enzalutamide was well tolerated. Coadministration with enzalutamide (a cytochrome P450 3A inducer) resulted in approximately 50% lower ipatasertib exposure. CONCLUSIONS: Ipatasertib in combination with chemotherapy or hormonal therapy was well tolerated with a safety profile consistent with that of ATP-competitive AKT inhibitors. CLINICAL TRIAL NUMBER: NCT01362374.

Optical and radiometric models of the NOMAD instrument part II: the infrared channels - SO and LNO.

NOMAD is a suite of three spectrometers that will be launched in 2016 as part of the joint ESA-Roscosmos ExoMars Trace Gas Orbiter mission. The instrument contains three channels that cover the IR and UV spectral ranges and can perform solar occultation, nadir and limb observations, to detect and map a wide variety of Martian atmospheric gases and trace species. Part I of this work described the models of the UVIS channel; in this second part, we present the optical models representing the two IR channels, SO (Solar Occultation) and LNO (Limb, Nadir and Occultation), and use them to determine signal to noise ratios (SNRs) for many expected observational cases. In solar occultation mode, both the SO and LNO channel exhibit very high SNRs >5000. SNRs of around 100 were found for the LNO channel in nadir mode, depending on the atmospheric conditions, Martian surface properties, and observation geometry.

Defining Multiple Characteristic Raman Bands of α-Amino Acids as Biomarkers for Planetary Missions Using a Statistical Method.

Biomarker molecules, such as amino acids, are key to discovering whether life exists elsewhere in the Solar System. Raman spectroscopy, a technique capable of detecting biomarkers, will be on board future planetary missions including the ExoMars rover. Generally, the position of the strongest band in the spectra of amino acids is reported as the identifying band. However, for an unknown sample, it is desirable to define multiple characteristic bands for molecules to avoid any ambiguous identification. To date, there has been no definition of multiple characteristic bands for amino acids of interest to astrobiology. This study examined L-alanine, L-aspartic acid, L-cysteine, L-glutamine and glycine and defined several Raman bands per molecule for reference as characteristic identifiers. Per amino acid, 240 spectra were recorded and compared using established statistical tests including ANOVA. The number of characteristic bands defined were 10, 12, 12, 14 and 19 for L-alanine (strongest intensity band: 832 cm(-1)), L-aspartic acid (938 cm(-1)), L-cysteine (679 cm(-1)), L-glutamine (1090 cm(-1)) and glycine (875 cm(-1)), respectively. The intensity of bands differed by up to six times when several points on the crystal sample were rotated through 360 °; to reduce this effect when defining characteristic bands for other molecules, we find that spectra should be recorded at a statistically significant number of points per sample to remove the effect of sample rotation. It is crucial that sets of characteristic Raman bands are defined for biomarkers that are targets for future planetary missions to ensure a positive identification can be made.

Different cellular p16(INK4a) localisation may signal different survival outcomes in head and neck cancer.

BACKGROUND: Recently, the management of head and neck squamous cell carcinoma (HNSCC) has focused considerable attention on biomarkers, which may influence outcomes. Tests for human papilloma infection, including direct assessment of the virus as well as an associated tumour suppressor gene p16, are considered reproducible. Tumours from familial melanoma syndromes have suggested that nuclear localisation of p16 might have a further role in risk stratification. We hypothesised p16 staining that considered nuclear localisation might be informative for predicting outcomes in a broader set of HNSCC tumours not limited to the oropharynx, human papilloma virus (HPV) status or by smoking status. METHODS: Patients treated for HNSCC from 2002 to 2006 at UNC (University of North Carolina at Chapel Hill) hospitals that had banked tissue available were eligible for this study. Tissue microarrays (TMA) were generated in triplicate. Immunohistochemical (IHC) staining for p16 was performed and scored separately for nuclear and cytoplasmic staining. Human papilloma virus staining was also carried out using monoclonal antibody E6H4. p16 expression, HPV status and other clinical features were correlated with progression-free (PFS) and overall survival (OS). RESULTS: A total of 135 patients had sufficient sample for this analysis. Median age at diagnosis was 57 years (range 20-82), with 68.9% males, 8.9% never smokers and 32.6% never drinkers. Three-year OS rate and PFS rate was 63.0% and 54.1%, respectively. Based on the p16 staining score, patients were divided into three groups: high nuclear, high cytoplasmic staining group (HN), low nuclear, low cytoplasmic staining group (LS) and high cytoplasmic, low nuclear staining group (HC). The HN and the LS groups had significantly better OS than the HC group with hazard ratios of 0.10 and 0.37, respectively, after controlling for other factors, including HPV status. These two groups also had significantly better PFS than the HC staining group. This finding was consistent for sites outside the oropharynx and did not require adjustment for smoking status. CONCLUSION: Different p16 protein localisation suggested different survival outcomes in a manner that does not require limiting the biomarker to the oropharynx and does not require assessment of smoking status.

Outcome of mild SARS-CoV-2-infected renal transplant recipients managed by supervised home-based self-monitoring.

OBJECTIVES: We aimed to compare the outcomes of COVID-19 Renal Transplant Recipients (RTRs) managed on an ambulatory basis to that of inpatient management. DESIGN, SETTING, MATERIALS, AND METHODS: We performed a retrospective study in Lucknow, India, comparing the ambulatory management with the historical cohort managed in the hospital.R RTRs with mild COVID-19 were managed by supervised home-based self-monitoring (HBSM), a strategy to manage this high-risk group on an outpatient basis during the second wave of the pandemic. The primary outcome was the clinical deterioration to a higher severity category among RTRs with mild COVID-19 managed by HBSM compared to hospitalized patients within two weeks of disease onset. RESULTS: Of the 149 RTRs with mild COVID-19, 94 (63%) and 55 (37%) were managed by HBSM and in the hospital, respectively. The proportion of RTRs who clinically deteriorated to a higher severity category (moderate or severe category) was similar among both groups (28.7% versus 27.2%, P=0.849). Among RTRs with clinical deterioration, COVID-19-related death was reported in two patients of the HBSM group and in none of the patients of the hospitalized group. Graft dysfunction was higher in the hospitalized group (7.4% versus 27.2%, P=0.002). Median time to complete clinical recovery (7 days in both groups), secondary bacterial infections (25% versus 33.3%, P=0.41), and the mean decline in EQ-5D score from baseline at six weeks (-6.6 versus-4.3, P=0.105) were found to be similar in both groups.

Impacts of Heterogeneous Chemistry on Vertical Profiles of Martian Ozone.

We show a positive vertical correlation between ozone and water ice using a vertical cross-correlation analysis with observations from the ExoMars Trace Gas Orbiter's Nadir and Occultation for Mars Discovery instrument. This is particularly apparent during L S = 0°-180°, Mars Year 35 at high southern latitudes, when the water vapor abundance is low. Ozone and water vapor are anti-correlated on Mars; Clancy et al. (2016, https://doi.org/10.1016/j.icarus.2015.11.016) also discuss the anti-correlation between ozone and water ice. However, our simulations with gas-phase-only chemistry using a 1-D model show that ozone concentration is not influenced by water ice. Heterogeneous chemistry has been proposed as a mechanism to explain the underprediction of ozone in global climate models (GCMs) through the removal of HO x . We find improving the heterogeneous chemical scheme by creating a separate tracer for the HO x adsorbed state, causes ozone abundance to increase when water ice is present (30-50 km), better matching observed trends. When water vapor abundance is high, there is no consistent vertical correlation between observed ozone and water ice and, in simulated scenarios, the heterogeneous chemistry has a minor influence on ozone. HO x , which are by-products of water vapor, dominate ozone abundance, masking the effects of heterogeneous chemistry on ozone, and making adsorption of HO x have a negligible impact on ozone. This is consistent with gas-phase-only modeled ozone, showing good agreement with observations when water vapor is abundant. Overall, the inclusion of heterogeneous chemistry improves the ozone vertical structure in regions of low water vapor abundance, which may partially explain GCM ozone deficits.

Global Variations in Water Vapor and Saturation State Throughout the Mars Year 34 Dusty Season.

To understand the evolving martian water cycle, a global perspective of the combined vertical and horizontal distribution of water is needed in relation to supersaturation and water loss and how it varies spatially and temporally. The global vertical water vapor distribution is investigated through an analysis that unifies water, temperature and dust retrievals from several instruments on multiple spacecraft throughout Mars Year (MY) 34 with a global circulation model. During the dusty season of MY 34, northern polar latitudes are largely absent of water vapor below 20 km with variations above this altitude due to transport from mid-latitudes during a global dust storm, the downwelling branch of circulation during perihelion season and the intense MY 34 southern summer regional dust storm. Evidence is found of supersaturated water vapor breaking into the northern winter polar vortex. Supersaturation above around 60 km is found for most of the time period, with lower altitudes showing more diurnal variation in the saturation state of the atmosphere. Discrete layers of supersaturated water are found across all latitudes. The global dust storm and southern summer regional dust storm forced water vapor at all latitudes in a supersaturated state to 60-90 km where it is more likely to escape from the atmosphere. The reanalysis data set provides a constrained global perspective of the water cycle in which to investigate the horizontal and vertical transport of water throughout the atmosphere, of critical importance to understand how water is exchanged between different reservoirs and escapes the atmosphere.

Martian CO2 Ice Observation at High Spectral Resolution With ExoMars/TGO NOMAD.

The Nadir and Occultation for MArs Discovery (NOMAD) instrument suite aboard ExoMars/Trace Gas Orbiter spacecraft is mainly conceived for the study of minor atmospheric species, but it also offers the opportunity to investigate surface composition and aerosols properties. We investigate the information content of the Limb, Nadir, and Occultation (LNO) infrared channel of NOMAD and demonstrate how spectral orders 169, 189, and 190 can be exploited to detect surface CO2 ice. We study the strong CO2 ice absorption band at 2.7 µm and the shallower band at 2.35 µm taking advantage of observations across Martian Years 34 and 35 (March 2018 to February 2020), straddling a global dust storm. We obtain latitudinal-seasonal maps for CO2 ice in both polar regions, in overall agreement with predictions by a general climate model and with the Mars Express/OMEGA spectrometer Martian Years 27 and 28 observations. We find that the narrow 2.35 µm absorption band, spectrally well covered by LNO order 189, offers the most promising potential for the retrieval of CO2 ice microphysical properties. Occurrences of CO2 ice spectra are also detected at low latitudes and we discuss about their interpretation as daytime high altitude CO2 ice clouds as opposed to surface frost. We find that the clouds hypothesis is preferable on the basis of surface temperature, local time and grain size considerations, resulting in the first detection of CO2 ice clouds through the study of this spectral range. Through radiative transfer considerations on these detections we find that the 2.35 µm absorption feature of CO2 ice clouds is possibly sensitive to nm-sized ice grains.

Global Vertical Distribution of Water Vapor on Mars: Results From 3.5 Years of ExoMars-TGO/NOMAD Science Operations.

We present water vapor vertical distributions on Mars retrieved from 3.5 years of solar occultation measurements by Nadir and Occultation for Mars Discovery onboard the ExoMars Trace Gas Orbiter, which reveal a strong contrast between aphelion and perihelion water climates. In equinox periods, most of water vapor is confined into the low-middle latitudes. In aphelion periods, water vapor sublimated from the northern polar cap is confined into very low altitudes-water vapor mixing ratios observed at the 0-5 km lower boundary of measurement decrease by an order of magnitude at the approximate altitudes of 15 and 30 km for the latitudes higher than 50°N and 30-50°N, respectively. The vertical confinement of water vapor at northern middle latitudes around aphelion is more pronounced in the morning terminators than evening, perhaps controlled by the diurnal cycle of cloud formation. Water vapor is also observed over the low latitude regions in the aphelion southern hemisphere (0-30°S) mostly below 10-20 km, which suggests north-south transport of water still occurs. In perihelion periods, water vapor sublimated from the southern polar cap directly reaches high altitudes (>80 km) over high southern latitudes, suggesting more effective transport by the meridional circulation without condensation. We show that heating during perihelion, sporadic global dust storms, and regional dust storms occurring annually around 330° of solar longitude (L S) are the main events to supply water vapor to the upper atmosphere above 70 km.

The formation of araneiforms by carbon dioxide venting and vigorous sublimation dynamics under martian atmospheric pressure.

The local redistribution of granular material by sublimation of the southern seasonal [Formula: see text] ice deposit is one of the most active surface shaping processes on Mars today. This unique geomorphic mechanism is hypothesised to be the cause of the dendritic, branching, spider-like araneiform terrain and associated fans and spots-features which are native to Mars and have no Earth analogues. However, there is a paucity of empirical data to test the validity of this hypothesis. Additionally, it is unclear whether some araneiform patterns began as radial and then grew outward, or whether troughs connected at mutual centres over time. Here we present the results of a suite of laboratory experiments undertaken to investigate if the interaction between a sublimating [Formula: see text] ice overburden containing central vents and a porous, mobile regolith will mobilise grains from beneath the ice in the form of a plume to generate araneiform patterns. We quantify the branching and area of the dendritic features that form. We provide the first observations of plume activity via [Formula: see text] sublimation and consequent erosion to form araneiform features. We show that [Formula: see text] sublimation can be a highly efficient agent of sediment transport under present day Martian atmospheric pressure and that morphometry is governed by the Shields parameter.

Posttreatment Imaging in Patients with Head and Neck Cancer without Clinical Evidence of Recurrence: Should Surveillance Imaging Extend Beyond 6 Months?

BACKGROUND AND PURPOSE: Early detection of residual or recurrent disease is important for effective salvage treatment in patients with head and neck cancer. Current National Comprehensive Cancer Network guidelines do not recommend standard surveillance imaging beyond 6 months unless there are worrisome signs or symptoms on clinical examination and offer vague guidelines for imaging of high-risk patients beyond that timeframe. Our goal was to evaluate the frequency of clinically occult recurrence in patients with head and neck squamous cell carcinoma with positive imaging findings (Neck Imaging Reporting and Data Systems scores of 2-4), especially after 6 months. MATERIALS AND METHODS: This institutional review board-approved, retrospective data base search queried neck CT reports with Neck Imaging Reporting and Data Systems scores of 2-4 from June 2014 to March 2018. The electronic medical records were reviewed to determine outcomes of clinical and radiologic follow-up, including symptoms, physical examination findings, pathologic correlation, and clinical notes within 3 months of imaging. RESULTS: A total of 255 cases, all with Neck Imaging Reporting and Data Systems scores of 2 or 3, met the inclusion criteria. Fifty-nine patients (23%) demonstrated recurrence (45 biopsy-proven, 14 based on clinical and imaging progression), and 21 patients (36%) had clinically occult recurrence (ie, no clinical evidence of disease at the time of the imaging examination). The median overall time to radiologically detected, clinically occult recurrence was 11.4 months from treatment completion. CONCLUSIONS: Imaging surveillance beyond the first posttreatment baseline study was critical for detecting clinically occult recurrent disease in patients with head and neck squamous cell carcinoma. More than one-third of all recurrences were seen in patients without clinical evidence of disease; and 81% of clinically occult recurrences occurred beyond 6 months.

Activated 4E-BP1 represses tumourigenesis and IGF-I-mediated activation of the eIF4F complex in mesothelioma.

BACKGROUND: Insulin-like growth factor (IGF)-I signalling stimulates proliferation, survival, and invasion in malignant mesothelioma and other tumour types. Studies have found that tumourigenesis is linked to dysregulation of cap-dependent protein translation. METHODS: The effect of IGF stimulation on cap-mediated translation activation in mesothelioma cell lines was studied using binding assays to a synthetic 7-methyl GTP-cap analogue. In addition, cap-mediated translation was genetically repressed in these cells with a dominant active motive of 4E-BP1. RESULTS: In most mesothelioma cell lines, IGF-I stimulation resulted in a hyperphosphorylation-mediated inactivation of 4E-BP1 compared with that in normal mesothelial cells. An inhibitor of Akt diminished IGF-I-mediated phosphorylation of 4E-BP1, whereas inhibiting MAPK signalling had no such effect. IGF-I stimulation resulted in the activation of the cap-mediated translation complex as indicated by an increased eIF4G/eIF4E ratio in cap-affinity assays. Akt inhibition reversed the eIF4G/eIF4E ratio. Mesothelioma cells transfected with an activated 4E-BP1 protein (4E-BP1(A37/A46)) were resistant to IGF-I-mediated growth, motility, and colony formation. In a murine xenograft model, mesothelioma cells expressing the dominant active 4E-BP1(A37/A46) repressor protein showed abrogated tumourigenicity compared with control tumours. CONCLUSION: IGF-I signalling in mesothelioma cells drives cell proliferation, motility, and tumourigenesis through its ability to activate cap-mediated protein translation complex through PI3K/Akt/mTOR signalling.

Factors affecting human supragingival biofilm composition. II. Tooth position.

BACKGROUND AND OBJECTIVE: Little is known regarding the factors that affect the microbial composition of supragingival biofilms. This study was designed to test the hypothesis that tooth location affects the microbial composition of supragingival plaque beyond the effect due to plaque mass as reflected by total DNA probe count. MATERIAL AND METHODS: Supragingival plaque samples were taken from the mesiobuccal aspect of each tooth in 187 subjects (n = 4745 samples). All samples were individually analyzed for their content of 40 bacterial species using checkerboard DNA-DNA hybridization. Significance of differences in mean species counts and proportions were determined among tooth surfaces and six tooth type categories: molars, bicuspids, incisors/canines in the mandible and maxilla separately using the Kruskal-Wallis test. Stepwise multiple linear regression was employed to examine the relationship between species proportions and total DNA probe count, tooth location, periodontal and smoking status, age and sex. RESULTS: All species differed significantly among tooth types and among the six tooth categories. Higher plaque levels were seen on molars and lower incisors. Some differences observed between tooth types could be partly explained by the level of plaque. Teeth with high plaque mass exhibited high levels of Capnocytophaga gingivalis, Actinomyces naeslundii genospecies 2, Campylobacter rectus and Campylobacter showae. However, certain species, such as Veillonella parvula and Streptococcus sanguinis, differed significantly at different tooth locations despite similarities in plaque mass. Twenty of the test species exhibited a significant association with tooth location after adjusting for total DNA probe count and subject level factors. CONCLUSION: While plaque mass was associated with differences in proportions of many species in supragingival biofilms, tooth location also was strongly associated with species proportions in both univariate and multivariate analyses.

Factors affecting human supragingival biofilm composition. I. Plaque mass.

BACKGROUND AND OBJECTIVE: Little is known about the factors that affect the microbial composition of supragingival biofilms. This study was designed to examine the relationship between total DNA probe counts of supragingival biofilm samples, clinical parameters and supragingival biofilm composition. MATERIAL AND METHODS: Supragingival plaque samples were taken from 187 systemically healthy adult subjects (n = 4745 samples). All samples were individually analyzed for their content of 40 bacterial species using checkerboard DNA-DNA hybridization. The relationship between total DNA probe counts and microbial composition was examined by subsetting the data into 10 groups based on 10 percentile increments of the total DNA probe counts. Differences among groups in terms of species counts and proportions were sought, as well as relationships of total plaque DNA probe count and clinical parameters. RESULTS: There was a wide distribution in mean total DNA probe counts among the 187 subjects. With increasing total plaque levels there was a change in the proportions of individual species and microbial complexes. 'Small plaques' were characterized by high proportions of species in the yellow, orange, purple and 'other' complexes; plaques of moderate mass were characterized by high proportions of Actinomyces and purple complex species, while 'large plaques' exhibited increased proportions of green and orange complex species. Measures of gingival inflammation, pocket depth and recession were significantly positively associated with total DNA probe counts. Increased plaque numbers were related to increased pocket depth irrespective of presence or absence of gingival inflammation. CONCLUSION: The proportions of individual species and microbial complexes in supragingival biofilms are influenced by the total numbers of organisms in the biofilm.

Drug-eluting versus bare metal stenting in acute myocardial infarction. A clinical review.

Coronary heart disease is a leading cause of death around the world. The treatment of acute myocardial infarction has evolved with the advent of novel thrombolytic agents, anticoagulants, antiplatelets, and innovative percutaneous techniques. The development of drug-eluting stents has dramatically lowered the risk of in-stent restenosis compared to bare metal stents. Clinicians in the United States and Europe have begun utilizing DES in the setting of AMI despite the fact that no practice guidelines exist to support their use. Lingering concerns exist about the reported increased risk of early and late stent thrombosis after DES implantation. In this review, we will highlight the >7,500 patients studied in randomized controlled trials and >30,000 registry patients comparing drug-eluting and bare metal stent implantation during acute myocardial infarction. In the selected patient populations of the 13 randomized controlled trials comparing drug-eluting and bare metal stent implantation, death/re-infarction/stent thrombosis were not different between groups while target vessel revascularization was significantly lower in the drug-eluting stent patients. In the "real world" registry studies, mortality/target vessel revascularization/stent thrombosis were less frequent in the first year after drug-eluting stent implantation while re-infarction was not different between the groups. While multiple questions remain regarding long-term follow up and especially late stent thrombosis, it appears that drug-eluting stents are effective at decreasing target vessel revascularization while not being associated with an elevated risk of death/re-infarction/stent thrombosis in the first year post myocardial infarction.

Policies, practices and barriers to implementing tuberculosis preventive treatment-35 countries, 2017.

BACKGROUND: Tuberculosis preventive treatment (TPT) reduces the development of tuberculosis (TB) disease and mortality in people living with human immunodeficiency virus (HIV) infection. Despite this known effectiveness, global uptake of TPT has been slow. We aimed to assess current status of TPT implementation in countries supported by the US President's Emergency Plan for AIDS Relief (PEPFAR).METHODS: We surveyed TB-HIV program staff at US Centers for Disease Control and Prevention (CDC) country offices in 42 PEPFAR-supported countries about current TPT policies, practices, and barriers to implementation. Surveys completed from July to December 2017 were analyzed.RESULTS: Of 42 eligible PEPFAR-supported countries, staff from 35 (83%) CDC country offices completed the survey. TPT was included in national guidelines in 33 (94%) countries, but only 21 (60%) reported nationwide programmatic TPT implementation. HIV programs led TPT implementation in 20/32 (63%) countries, but TB programs led drug procurement in 18/32 (56%) countries. Stock outs were frequent, as 21/28 (75%) countries reported at least one isoniazid stock out in the previous year.CONCLUSION: Despite widespread inclusion of TPT in guidelines, programmatic TPT implementation lags. Successful scale-up of TPT requires uninterrupted drug supply chains facilitated by improved leadership and coordination between HIV and TB programs.

The transfer of unsterilized material from Mars to Phobos: Laboratory tests, modelling and statistical evaluation.

Sample return missions to Phobos are the subject of future exploration plans. Given the proximity of Phobos to Mars, Mars' potential to have supported life, and the possibility of material transfer from Mars to Phobos, careful consideration of planetary protection is required. If life exists, or ever existed, on Mars, there is a possibility that material carrying organisms could be present on Phobos and be collected by a sample return mission such as the Japanese Martian Moons eXplorer (MMX). Here we describe laboratory experiments, theoretical modelling and statistical analysis undertaken to quantify whether the likelihood of a sample from Phobos material containing unsterilized material transferred from Mars is less than 10-6, the threshold to transition between restricted and unrestricted sample return classification for planetary protection. We have created heat, impact and radiation sterilization models based on the Phobos environment, and through statistical analyses investigated the level of sterilization expected for martian material transferred to Phobos. These analyses indicate that radiation is the major sterilization factor, sterilizing the Phobos surface over timescales of millions of years. The specific events of most relevance in the Phobos sample return context are the 'young' cratering events on Mars that result in Zunil-sized craters, which can emplace a large mass of martian material on Phobos, in a short period of time, thus inhibiting the effects of radiation sterilization. Major unknowns that cannot yet be constrained accurately enough are found to drive the results - the most critical being the determination of exact crater ages to statistical certainty, and the initial biological loading on Mars prior to transfer. We find that, when taking a conservative perspective and assuming the best-case scenario for organism survival, for a 100 g sample of the Phobos regolith to be below the planetary protection requirement for unrestricted sample return, the initial biological loading on Mars must be <8.2 × 103cfu kg-1. For the planned MMX mission, a ∼10 g sample to be obtained from a 25-30 mm diameter core as planned would require an initial martian biological loading to be <1.6 × 104cfu kg-1, in order to remain compliant with the planetary protection threshold.

Aeolian abrasion of rocks as a mechanism to produce methane in the Martian atmosphere.

Seasonal changes in methane background levels and methane spikes have been detected in situ a metre above the Martian surface, and larger methane plumes detected via ground-based remote sensing, however their origin have not yet been adequately explained. Proposed methane sources include the UV irradiation of meteoritic-derived organic matter, hydrothermal reactions with olivine, organic breakdown via meteoroid impact, release from gas hydrates, biological production, or the release of methane from fluid inclusions in basalt during aeolian erosion. Here we quantify for the first time the potential importance of aeolian abrasion as a mechanism for releasing trapped methane from within rocks, by coupling estimates of present day surface wind abrasion with the methane contents of a variety of Martian meteorites, analogue terrestrial basalts and analogue terrestrial sedimentary rocks. We demonstrate that the abrasion of basalt under present day Martian rates of aeolian erosion is highly unlikely to produce detectable changes in methane concentrations in the atmosphere. We further show that, although there is a greater potential for methane production from the aeolian abrasion of certain sedimentary rocks, to produce the magnitude of methane concentrations analysed by the Curiosity rover they would have to contain methane in similar concentrations as economic reserved of biogenic/thermogenic deposits on Earth. Therefore we suggest that aeolian abrasion is an unlikely origin of the methane detected in the Martian atmosphere, and that other methane sources are required.