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Background and Aims The reported progression rate from low-grade dysplasia (LGD) in Barrett’s esophagus (BE) to high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC) ranges from .4% to 13.4% per year. We hypothesize that some reported progression rates may be overestimated because of prevalent HGD or EAC that was not identified during endoscopic assessments performed in the community. Our aim is to determine the proportion of prevalent HGD or EAC detected by BE referral units (BERUs) in patients referred from the community with a recent diagnosis of LGD. Methods All patients referred from the community to 6 BERUs with a diagnosis of BE with LGD were identified. Patients with an assessment endoscopy performed at BERUs more than 6 months from their referral endoscopy in the community were excluded. Visible lesions and histology outcomes were compared between the community referral endoscopy and the assessment endoscopy performed at BERUs. Results The median time between BERU assessment and referral endoscopy was 79 days (interquartile range, 54-114). Of the 75 patients referred from the community with LGD, BERU assessment identified HGD or EAC in 20 patients (27%). BERU assessment identified more visible lesions than referral endoscopy performed in the community (39 [52%] vs 9 [12%], respectively; P = .029). Conclusions BERU assessment endoscopy identified more visible lesions than community referral endoscopy and identified HGD or EAC in 27% of patients referred from the community with a recent diagnosis of LGD. Reported progression rates from LGD to HGD or EAC may be overestimated.

Background and Aims Buried Barrett’s mucosa is defined as intestinal metaplasia that is “buried” under the normal-appearing squamous epithelium. This can occur in Barrett’s esophagus with or without previous endoscopic therapy. Dysplasia and neoplasia within buried Barrett’s mucosa have also been reported. However, endoscopic features of buried Barrett’s mucosa have not been described. At our tertiary referral center for Barrett’s esophagus, several endoscopic features have been observed in patients who were found to have buried Barrett’s mucosa on histology. These features are squamous epithelium which is (1) darker pink on white-light and darker brown on narrow-band imaging and/or (2) has a slightly raised or nodular appearance. It was also observed that either of these 2 features is frequently seen adjacent to a Barrett’s mucosa island. This study aimed to (1) evaluate the diagnostic accuracy of these endoscopic features, and (2) evaluate the frequency of endoscopically identifiable buried Barrett’s mucosa in patients with dysplastic Barrett’s esophagus, before and after endoscopic eradication therapy. Methods This was a retrospective analysis of a prospectively observed cohort of all cases of dysplastic Barrett’s esophagus referred to St Vincent’s Hospital, Melbourne. Endoscopy documentation software and histopathology reports of esophageal biopsy and EMR specimens between March 2013 and March 2019 were searched for terms “buried” or “subsquamous” Barrett’s mucosa. Endoscopic reports, images, and histopathology reports of suspected buried Barrett’s mucosa were then reviewed to apply the endoscopic features and correlate with the histologic diagnosis. Results In a cohort of 506 patients with dysplastic Barrett’s esophagus, 33 (7%) patients (73% male, median age at referral 70.5 years) had buried Barrett’s mucosa on histology. Twenty-seven (82%) patients had previous treatment for dysplastic Barrett’s esophagus; radiofrequency in 2 (6%), EMR in 4 (12%), and both modalities in 21 (64%). Six (18%) had no previous treatment. Histologically confirmed buried Barrett’s mucosa was suspected at endoscopy in 26 patients (79%). Endoscopic features were (1) darker pink or darker brown mucosa underneath squamous epithelium (24%), (2) raised areas underneath squamous mucosa (27%), and both features present concurrently (27%). These features were associated with adjacent islands of Barrett’s esophagus in 48%. Forty-four cases of buried Barrett’s mucosa were suspected endoscopically, and these were sampled by biopsy (50%) and EMR (50%). Buried Barrett’s mucosa was confirmed in 26 cases, with a positive predictive value of endoscopic suspicion of 59%. Eighteen cases of endoscopically suspected buried Barrett’s mucosa had no buried Barrett’s mucosa on histology; inflammation or reflux was identified in 12 (67%) patients. Dysplasia was identified within buried Barrett’s mucosa in 12 (36%) patients; 5 intramucosal adenocarcinoma, 1 high-grade dysplasia, and 6 low-grade dysplasia. Endoscopic features of buried Barrett’s mucosa were observed in 11 of 12 cases harboring dysplasia or neoplasia, compared with 15 of 21 cases of buried Barrett’s mucosa without dysplasia. Conclusions In this retrospective analysis of prospectively observed patients with dysplastic Barrett’s esophagus, buried Barrett’s mucosa was identified in 7%, including treatment-naive patients. The proposed endoscopic features of buried Barrett’s mucosa were seen in 79% of patients with histology confirmed disease. These endoscopic features may predict the presence of buried Barrett’s mucosa, which may contain dysplasia or neoplasia. An overlap between the endoscopic features of inflammation, reflux, and buried Barrett’s mucosa was observed. Future prospective studies are required to develop and validate endoscopic criteria for identifying buried Barrett’s mucosa.

Prior to ~1 million years ago (Ma), variations in global ice volume were dominated by changes in obliquity; however, the role of precession remains unresolved. Using a record of North Atlantic ice rafting spanning the past 1.7 million years, we find that the onset of ice rafting within a given glacial cycle (reflecting ice sheet expansion) consistently occurred during times of decreasing obliquity whereas mass ice wasting (ablation) events were consistently tied to minima in precession. Furthermore, our results suggest that the ubiquitous association between precession-driven mass wasting events and glacial termination is a distinct feature of the mid to late Pleistocene. Before then (increasing), obliquity alone was sufficient to end a glacial cycle, before losing its dominant grip on deglaciation with the southward extension of Northern Hemisphere ice sheets since ~1 Ma.

ObjectiveTo develop and evaluate a modified version of the Victorian Institute of Sport Assessment-Achilles (VISA-A) questionnaire, for use in sedentary patients with Achilles tendinopathy, using the Consensus-based Standards for the selection of health Measurement Instruments recommendations.MethodsTwenty-two sedentary patients with Achilles tendinopathy completed the VISA-A and provided feedback regarding the relevance, comprehensiveness and comprehensibility of each item, response options and instructions. Patient and professional feedback was used to develop the VISA-A (sedentary) questionnaire. Reliability, validity and responsiveness of the VISA-A (sedentary) was evaluated in 51 sedentary patients with Achilles tendinopathy: 47.1% women, mean age 64.8 (SD 11.24).ResultsFactor analysis identified two dimensions (symptoms and activity) for the VISA-A (sedentary). Test–retest reliability was excellent for symptoms (intraclass correlation coefficient, ICC=0.991) and activity (ICC=0.999). Repeatability was 1.647 for symptoms and 0.549 for activity. There was a significant difference between the VISA-A and VISA-A (sedentary) scores both pretreatment and post-treatment. There was stronger correlation between the pretreatment to post-treatment change in the VISA-A (sedentary) scores (r=0.420 for symptoms, r=0.407 for activity) and the global rating of change than the VISA-A scores (r=0.253 for symptoms, r=0.186 for activity).ConclusionThe VISA-A (sedentary) demonstrates adequate reliability, validity and responsiveness in sedentary patients with Achilles tendinopathy. The VISA-A (sedentary) is a more appropriate measure than the VISA-A for this cohort and is recommended for clinical and research purposes.

Purpose The diagnostic accuracy of clinical tests for anterior cruciate ligament injury has been reported in previous systematic reviews. Numerous studies in these reviews include subjects with additional knee ligament injury, which could affect the sensitivity of the tests. Meta-analyses have also been performed using methods that do not account for the non-independence of sensitivity and specificity, potentially overestimating diagnostic accuracy. The aim of this study was to report the diagnostic accuracy of clinical tests for anterior cruciate ligament tears (partial and complete) without concomitant knee ligament injury. Methods A systematic review with meta-analysis was performed according to the PRISMA guidelines. Meta-analyses included studies reporting the specificity and/or sensitivity of tests with or without concomitant meniscal injury. Where possible, pooled diagnostic estimates were calculated with bivariate random-effects modelling to determine the most accurate effect sizes. Diagnostic accuracy values are presented for the anterior drawer, Lachman, Lever sign and pivot shift tests overall and in acute or post-acute presentations. Results Pooled estimates using a bivariate model for overall sensitivity and specificity respectively were as follows: anterior drawer test 83% [95% CI, 77–88] and 85% [95% CI, 64–95]; Lachman test 81% [95% CI, 73–87] and 85% [95% CI, 73–92]; pivot shift test 55% [95% CI, 47–62] and 94% [95% CI, 88–97]; Lever sign test 83% [95% CI, 68–92] and 91% [95% CI, 83–95]. For specific presentations, the sensitivity and specificity of the Lachman test, respectively, were: complete tears 68% [95% CI, 54–79] and 79% [95% CI, 51–93]; post-acute injuries 70% [95% CI, 57–80] and 77% [95% CI, 53–91]. Conclusions The pivot shift and Lever sign were the best tests overall for ruling in or ruling out an anterior cruciate ligament tear, respectively. The diagnostic accuracy of the Lachman test, particularly in post-acute presentations and for complete tears, is lower than previously reported. Further research is required to establish more accurate estimates for the Lachman test in acute presentations and partial ligament tears using bivariate analysis. Level of evidence III.

Background: Nine core domains for tendinopathy have been identified. For Achilles tendinopathy there is large variation in outcome measures used, and how these fit into the core domains has not been investigated. Objective: To identify all available outcome measures outcome measures used to assess the clinical phenotype of Achilles tendinopathy in prospective studies and to map the outcomes measures into predefined health-related core domains. Design: Systematic review. Data Sources: Embase, MEDLINE (Ovid), Web of Science, CINAHL, The Cochrane Library, SPORTDiscus and Google Scholar. Eligibility Criteria for Selecting Studies: Clinical diagnosis of Achilles tendinopathy, sample size ��� ten participants, age ��� 16 years, and the study design was a randomized or non-randomized clinical trial, observational cohort, single-arm intervention, or case series. Results: 9376 studies were initially screened and 307 studies were finally included, totaling 13,248 participants. There were 233 (177 core domain) different outcome measures identified across all domains. For each core domain outcome measures were identified, with a range between 8 and 35 unique outcome measures utilized for each domain. The proportion of studies that included outcomes for predefined core domains ranged from 4% for the psychological factors domain to 72% for the disability domain. Conclusion: 233 unique outcome measures for Achilles tendinopathy were identified. Most frequently, outcome measures were used within the disability domain. Outcome measures assessing psychological factors were scarcely used. The next step in developing a core outcome set for Achilles tendinopathy is to engage patients, clinicians and researchers to reach consensus on key outcomes measures. Prospero Registration: CRD42020156763.

The meridional variability of the Subtropical Front (STF) in the Southern Hemisphere, linked to expansions or contractions of the Southern Ocean, may have played an important role in global ocean circulation by moderating the magnitude of water exchange at the Indian-Atlantic Ocean Gateway, so called Agulhas Leakage. Here we present new biomarker records of upper water column temperature (and) and primary productivity (chlorins and alkenones) from marine sediments at IODP Site U1475 on the Agulhas Plateau, near the STF and within the Agulhas retroflection pathway. We use these multiproxy time-series records from 1.4 to 0.3Ma to examine implied changes in the upper oceanographic conditions at the mid-Pleistocene transition (MPT, ca. 1.2–0.8Ma). Our reconstructions, combined with prior evidence of migrations of the STF over the last 350 ka, suggest that in the Southwestern Indian Ocean the STF may have been further south from the Agulhas Plateau during the mid-Pleistocene Interim State (MPIS, MIS 23–12) and reached its northernmost position during MIS 34–24 and MIS 10. Comparison to aGloborotalia menardii-derived Agulhas Leakage reconstruction from the Cape Basin suggests that only the most extreme northward migrations of the STF are associated with reduced Agulhas Leakage. During the MPIS, STF migrations do not appear to control Agulhas Leakage variability, we suggest previously modeled shifting westerly winds may be responsible for the patterns observed. A detachment between STF migrations and Agulhas Leakage, in addition to invoking shifting westerly winds may also help explain changes in CO2ventilation seen during the MPIS.

HKB-Verletzungen werden in der Regel durch ein direktes Trauma des flektierten Knies verursacht und sind deutlich seltener als VKB-Rupturen. Das Wissen um die optimale physiotherapeutische Behandlung ist daher oft nicht präsent. Die britischen Kniespezialisten Richard Norris und Daniel Massey schaffen mit diesem physiopraxis-Refresher Abhilfe.

ObjectivesWith the goal of facilitating the use of HIV-TRePS to optimize therapy in settings with limited healthcare resources, we aimed to develop computational models to predict treatment responses accurately in the absence of commonly used baseline data.MethodsTwelve sets of random forest models were trained using very large, global datasets to predict either the probability of virological response (classifier models) or the absolute change in viral load in response to a new regimen (absolute models) following virological failure. Two ‘standard’ models were developed with all baseline variables present and 10 others developed without HIV genotype, time on therapy, CD4 count or any combination of the above.ResultsThe standard classifier models achieved an AUC of 0.89 in cross-validation and independent testing. Models with missing variables achieved AUC values of 0.78–0.90. The standard absolute models made predictions that correlated significantly with observed changes in viral load with a mean absolute error of 0.65 log10 copies HIV RNA/mL in cross-validation and 0.69 log10 copies HIV RNA/mL in independent testing. Models with missing variables achieved values of 0.65–0.75 log10 copies HIV RNA/mL. All models identified alternative regimens that were predicted to be effective for the vast majority of cases where the new regimen prescribed in the clinic failed. All models were significantly better predictors of treatment response than genotyping with rules-based interpretation.ConclusionsThese latest models that predict treatment responses accurately, even when a number of baseline variables are not available, are a major advance with greatly enhanced potential benefit, particularly in resource-limited settings. The only obstacle to realizing this potential is the willingness of healthcare professions to use the system.

Objectives To determine the accuracy of the dial test, used alone and in combination with additional clinical tests, in the diagnosis of an isolated posterolateral corner (PLC) injury, combined PLC-posterior cruciate ligament (PCL) injury or medial knee injury. Methods A retrospective analysis of consecutive patients who underwent arthroscopic and/or open knee ligament reconstruction surgery was conducted. The dial test was performed in an outpatient's clinic as part of a routine knee examination. Examination under anaesthetic and intraoperative findings were used as the reference standard test to determine the diagnostic accuracy of the dial test used alone and in combination with other PCL and medial knee tests. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (LR+) and negative likelihood ratio (LR−) were calculated with corresponding 95% CI. Results Data from 87 patients were available and included in the data analysis. For an isolated PLC injury, the dial test sensitivity and specificity were 0.20 (95% CI 0.08 to 0.39) and 1.00 (95% CI 0.92 to 1.00). The PPV and NPV were 1.00 (95% CI 0.52 to 1.00) and 0.70 (95% CI 0.59 to 0.80). LR+ and LR− of the dial test detecting isolated PLC injury were infinity (95% CI calculation not possible, infinity) and 0.80 (95% CI 0.41 to 1.57). The diagnostic accuracy of the dial test, when used alone and in combination with other PCL and medial knee tests, was also calculated for combined PLC-PCL and medial knee injuries. Conclusion A negative dial test at 30° of knee flexion can rule out a PLC injury, while a test that is positive at 30° and negative at 90° indicates a PLC injury, without concomitant injury to the PCL or medial knee ligaments. A positive test at both 30° and 90° can indicate isolated PLC, combined PLC-PCL or medial ligament injuries, and other knee examination findings are required to differentially diagnose these injury patterns. Level of evidence II.

Key Clinical Message Despite growing evidence for GLP‐1R molecular‐based imaging, successful localization of insulinomas may require the use of multiple imaging modalities. Not all benign insulinomas express the GLP‐1R as expected. Our case demonstrates that there is a still an important role for traditional methods for the anatomical localization of an insulinoma.

Resection margins in colorectal cancer carry clinical significance with regard to disease recurrence risk and selection for multimodal adjuvant therapy, especially with circumferential resection margins in rectal cancer. Colorectal cancer specimens are routinely fixed in formalin, which results in specimen and tumor-free margin shrinkage. However, the effects of shrinkage have not traditionally been taken into account when analyzing tumor-free margins. In this prospective study, 46 colorectal cancer specimens were measured in the fresh state and subsequently after formalin fixation for total specimen length, distal resection margin, and radial margin (circumferential resection margin for rectal cancer). The mean reduction after formalin fixation was 17.48 mm (14.7%) for distal resection margin and 1.20 mm (10.5%) for radial margin. For rectal cancer, circumferential resection margin reduction was 0.88 mm (11.8%); this was not affected by neoadjuvant chemoradiotherapy. Duration of formalin fixation did not significantly affect the extent of margin shrinkage. This is the first study to evaluate the effect of formalin fixation on radial resection margins, specifically as it relates to rectal cancer, and it demonstrates that shrinkage from formalin fixation should be a consideration in decision-making where the magnitude of tumor-free margins is small.

Early stages of type 1 diabetes (T1D) are characterized by local autoimmune inflammation and progressive loss of insulin-producing pancreatic β cells. We show here that exposure to pro-inflammatory cytokines unmasks a marked plasticity of the β-cell regulatory landscape. We expand the repertoire of human islet regulatory elements by mapping stimulus-responsive enhancers linked to changes in the β-cell transcriptome, proteome and 3D chromatin structure. Our data indicates that the β cell response to cytokines is mediated by the induction of novel regulatory regions as well as the activation of primed regulatory elements pre-bound by islet-specific transcription factors. We found that T1D-associated loci are enriched of the newly mapped cis-regulatory regions and identify T1D-associated variants disrupting cytokine-responsive enhancer activity in human β cells. Our study illustrates how β cells respond to a pro-inflammatory environment and implicate a role for stimulus-response islet enhancers in T1D.

A detailed paleoenvironment reconstruction from the Mozambique Channel, western Indian Ocean, based on the calcareous nannoplankton assemblages was conducted for the interval between 2.85 and 1.85 Myr. This study covers the period during which the successive extinction of the last five species of discoasters occurred. New productivity data obtained from the abundances of the Discoaster species (Discoaster brouweri, D. triradiatus, D. pentaradiatus, D. surculus, and D. tamalis) and other indicative calcareous nannoplankton taxa showed abundance variations, which were at paced with the 100, 41, and 23 kyr astronomical periodicities. A shift in the productivity and water-column stratification proxies occurred at ~2.4 Ma, after the onset of the Northern Hemisphere glaciation. Here we propose that the variability recorded at International Ocean Discovery Program Site U1476 reflects the interplay between forcing associated with warm tropical Pacific and cold southern ocean influences. The former is shown by consistent occurrence of warm water taxa (Calcidiscus leptoporus, Oolithotus spp., Rhabdosphaera clavigera, Syracosphaera spp., Umbellosphaera spp.), typical of Indonesian Throughflow surface waters. On the other hand, the occurrence of Coccolithus pelagicus indicates the influence of cold, nutrient-rich sub-Antarctic surface waters. A more mixed water column initiated at ~2.4 Ma, and a consequent productivity increase led to the gradual reduction of the Discoaster species, until their extinction at 1.91 Ma. This period was characterized by the low values of the Florisphaera profunda index and high abundances of upper photic zone flora, indicative of nutrient-rich surface water conditions. High productivity at the location during this period could have also been amplified by localized upwelling events driven by the Mozambique Channel eddies.

Objectives Optimizing antiretroviral drug combination on an individual basis can be challenging, particularly in settings with limited access to drugs and genotypic resistance testing. Here we describe our latest computational models to predict treatment responses, with or without a genotype, and compare their predictive accuracy with that of genotyping. Methods Random forest models were trained to predict the probability of virological response to a new therapy introduced following virological failure using up to 50 000 treatment change episodes (TCEs) without a genotype and 18 000 TCEs including genotypes. Independent data sets were used to evaluate the models. This study tested the effects on model accuracy of relaxing the baseline data timing windows, the use of a new filter to exclude probable non-adherent cases and the addition of maraviroc, tipranavir and elvitegravir to the system. Results The no-genotype models achieved area under the receiver operator characteristic curve (AUC) values of 0.82 and 0.81 using the standard and relaxed baseline data windows, respectively. The genotype models achieved AUC values of 0.86 with the new non-adherence filter and 0.84 without. Both sets of models were significantly more accurate than genotyping with rules-based interpretation, which achieved AUC values of only 0.55–0.63, and were marginally more accurate than previous models. The models were able to identify alternative regimens that were predicted to be effective for the vast majority of cases in which the new regimen prescribed in the clinic failed. Conclusions These latest global models predict treatment responses accurately even without a genotype and have the potential to help optimize therapy, particularly in resource-limited settings.

IL28B polymorphisms strongly predict spontaneous and treatment-induced clearance of hepatitis C virus (HCV) infection. A recent study proposed a 32-base pair deletion in the CC-chemokine receptor 5 (CCR5) gene (CCR5-D32) interacting with the IL28B polymorphisms to influence spontaneous HCV clearance. The aim of this study was to clarify the role of CCR5-D32 in treatmentinduced clearance of chronic hepatitis C (CHC). A cross-sectional cohort of 813 Caucasian patients with CHC genotype 1 (365 responders and 448 non-responders) who had received standard of care dual therapy with interferon (IFN)-a and ribavirin (RBV) was genotyped for the CCR5-D32 and IL28B polymorphisms to examine their interaction with respect to treatment response. CCR5-D32 did not influence treatment-induced recovery to IFN-a/RBV in CHC, and did not improve prediction of sustained virological response in the context of the IL28B polymorphisms in a multivariate model. CCR5-D32 homozygotes were significantly more frequent in those with CHC than healthy controls in the European cohorts (2.9% vs 0.4%, Po0.0001), but not in Australians of European ancestry. In conclusion, CCR5-D32 does not influence treatment response in the context of IL28B polymorphisms. Although CCR5-D32 may affect viral clearance within closely controlled geographical and genetic environments, we found no effect in larger cohorts treated with dual therapy. Refereed/Peer-reviewed

Background SCH532706 is a novel small molecule chemokine receptor-5 (CCR5) antagonist with high in vitro potency (mean 90% inhibitory concentration [IC90] 0.15– 7.0 nM) against diverse HIV type-1 (HIV-1) isolates. Methods A single arm study was undertaken to examine the safety, antiviral activity and pharmacokinetics (PK) of 10 days of SCH532706 coadministered with ritonavir (RTV). The trial enrolled formerly treated (off therapy >3 months) or untreated HIV-1-infected patients. Results The study enrolled 12 males with CD4+ T-cell count >100 cells/μl. Median (range) CD4+ T-cell count was 327 cells/μl (117–1,008), HIV-1–RNA was 4.6 log10 copies/ml (3.8–5.5) and patients had phenotypically con-firmed R5-tropic HIV-1 only. Mean (95% confidence interval) changes from baseline plasma HIV-1–RNA at days 10 and 15 (4 days off SCH532706) were -1.31 log10 copies/ ml (-1.6– -1.0) and -1.62 log10 copies/ml (-2.0– -1.3), respectively. Day 10 median (range) time to maximum plasma concentration, mean (±sd) effective half-life and mean (±sd) trough concentration were 1.4 h (1.0-4.0), 39.4 h (±14.5) and 178 ng/ml (±34), respectively. All virus isolates remained R5-tropic pre-study, on study and at study end. There were no laboratory or QTc interval changes reportable as adverse events. In total, 11 patients reported ≥1 treatment emergent adverse event, most commonly gastrointestinal upset. One serious adverse event, pericarditis (grade 2), occurred 13 days after drug administration. It was considered to be possibly related to study drug. Conclusions Overall, SCH532706 with RTV was safe, generally well tolerated and active against HIV-1 over 10 days of dosing. In this setting, SCH532706 trough concentrations exceed the mean in vitro IC (1.1 ng/ml) by >30-fold (after correction for 80% plasma protein binding) and provide a PK rationale for the observed efficacy.

SUMMARY A 36-year-old woman presented with a 2-year history of multiple, raised, brown papules and indurated skin over her lower legs. She had received a renal transplant 11 years earlier, and had a history of recurrent deep vein thromboses despite a negative thrombophilic screen. The patient had no history of exposure to gadolinium. Histology at this time revealed a light perivascular lymphoid infiltrate, activated fibroblasts and prominent capillary vessels. The patient re-presented 1 year later with persistence of these lesions, in the setting of worsening renal function requiring haemodialysis. Repeat skin biopsies demonstrated increased dermal collagen and angiogenesis. The dermatopathological findings, in association with renal insufficiency and multiple deep vein thromboses, led to the diagnosis of nephrogenic systemic fibrosis.

Objectives: The optimal individualized selection of antiretroviral drugs in resource-limited settings is challenging because of the limited availability of drugs and genotyping. Here we describe the development of the latest computational models to predict the response to combination antiretroviral therapy without a genotype, for potential use in such settings. Methods: Random forest models were trained to predict the probability of a virological response to therapy (

Elevated temperature tests were performed on titanium alloy 6-2222 (Ti 6-2222) sheet material to determine the creep deformation behavior and to evaluate the suitability of crack tip parameters for characterizing creep crack growth behavior in the temperature range of 350–450°C. At temperatures of 400°C and above, the material behaves essentially as a creep-ductile material in which the creep crack growth rate is characterized by the Ct parameter. At 350°C, transition from creep-ductile to creep-brittle behavior was observed. A correlation which is independent of temperature for creep-ductile conditions in the range of 350–450°C between creep crack growth rate and Ct is derived from these tests. The creep-brittle behavior observed at 350°C was in the transient range where no well-accepted crack tip parameter is available for characterizing the crack growth behavior. A methodology for predicting creep crack growth in Ti 6-2222 sheet structures at elevated temperature when creep-ductile behavior is observed is briefly discussed.

Background Lipoatrophy can complicate thymidine analogue nucleoside reverse transcriptase inhibitor (tNRTI)-based antiretroviral therapy (ART). Lipoatrophy may be less likely with ART including ritonavir-boosted lopinavir (LPV/r). Small, placebo-controlled studies found that uridine (in tNRTI recipients) and pravastatin improved HIV lipoatrophy over 12 weeks. Today, most patients with lipoatrophy receive non-tNRTI-based ART; the effect of uridine in such patients is unknown. Methods We performed a prospective, randomized trial in lipoatrophic adults with plasma HIV RNA

THE LETTERS BY ARCHIBALD ET AL., KELLER ET al., and Courtillot and Fluteau question our conclusion that the Cretaceous-Paleogene mass extinction was caused by the asteroid impact at Chicxulub. All three Letters stress that Deccan flood basalt volcanism played a major role in the extinction. Keller et al. and Archibald et al. also mention that climate change was a factor, and Archibald et al. We disagree with the hypothesis that vol- canic activity can explain the extinction.

To determine whether participating in physical activity affects psychological well-being in an adolescent population, 147 adolescents completed self-reports of exercise and psychological stress and well-being. Analysis revealed that those who reported greater physical activity also reported less stress and lower levels of depression. Adolescents who experienced a higher incidence of life events also demonstrated a strong association between stress and anxiety/depression/hostility. To investigate the effects of exercise training on psychological well-being, adolescents were assigned to either high or moderate intensity aerobic training, flexibility training or a control group. The training groups met twice per week for 25-30 min. Aerobic fitness levels, heart rate, blood pressure and self-report of stress and well-being were measured prior to and following 10 weeks of training. Post-training fitness measures confirmed the effectiveness of the high intensity aerobic exercise and between groups differences for physiological and some psychological measures were found. Subjects undergoing high intensity exercise reported significantly less stress than subjects in the remaining three groups. The relationship between stress and anxiety/depression/hostility for the high intensity group was considerably weakened at the end of the training period. For the remaining subjects, however, this relationship was, if anything, strengthened. This experiment provides evidence to suggest that in an adolescent population, high intensity aerobic exercise has positive effects on well-being.

BACKGROUND: Reduced bone mineral density (BMD) is common in adults infected with human immunodeficiency virus (HIV). The role of proximal renal tubular dysfunction (PRTD) and alterations in bone metabolism in HIV-related low BMD are incompletely understood. METHODS: We quantified BMD (dual-energy x-ray absorptiometry), blood and urinary markers of bone metabolism and renal function, and risk factors for low BMD (hip or spine T score, -1 or less) in an ambulatory care setting. We determined factors associated with low BMD and calculated 10-year fracture risks using the World Health Organization FRAX equation. RESULTS: We studied 153 adults (98% men; median age, 48 years; median body mass index, 24.5; 67 [44%] were receiving tenofovir, 81 [53%] were receiving a boosted protease inhibitor [PI]). Sixty-five participants (42%) had low BMD, and 11 (7%) had PRTD. PI therapy was associated with low BMD in multivariable analysis (odds ratio, 2.69; 95% confidence interval, 1.09-6.63). Tenofovir use was associated with increased osteoblast and osteoclast activity (P< or = .002). The mean estimated 10-year risks were 1.2% for hip fracture and 5.4% for any major osteoporotic fracture. CONCLUSIONS: In this mostly male population, low BMD was significantly associated with PI therapy. Tenofovir recipients showed evidence of increased bone turnover. Measurement of BMD and estimation of fracture risk may be warranted in treated HIV-infected adults.

As deployment of fiber to the home (FTTH) within multiple dwelling units (MDUs) is growing, more technicians will be involved in the deployment of optical drop cables, and there is a desire to use craft and practice similar to what is used for copper cables. We introduce a solid bend insensitive fiber in this application that is backwards compatible to G.652D fiber, and has macrobending, splice loss and system performance to meet the very demanding conditions of these applications. A closer look at the demands of this environment has made it necessary to re-evaluate reliability in these critical applications. We apply the Power Law Model to predict reliability in these demanding applications, and provide experimental evaluation of the model through testing on optical fibers and cables. It will be shown that bends and tension need to be considered together when evaluating the reliability of the passive optical plant.

A 36-year-old woman presented with a 2-year history of multiple, raised, brown papules and indurated skin over her lower legs. She had received a renal transplant 11 years earlier, and had a history of recurrent deep vein thromboses despite a negative thrombophilic screen. The patient had no history of exposure to gadolinium. Histology at this time revealed a light perivascular lymphoid infiltrate, activated fibroblasts and prominent capillary vessels. The patient re-presented 1 year later with persistence of these lesions, in the setting of worsening renal function requiring haemodialysis. Repeat skin biopsies demonstrated increased dermal collagen and angiogenesis. The dermatopathological findings, in association with renal insufficiency and multiple deep vein thromboses, led to the diagnosis of nephrogenic systemic fibrosis.

OBJECTIVES To determine the effect of the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, pravastatin, on markers of cardiovascular risk and lipodystrophy in HIV-infected, protease inhibitor (PI)-treated men with hypercholesterolaemia. METHODS A randomized, placebo-controlled, 16-week study was carried out on 33 HIV-infected, hypercholesterolaemic men (fasting total cholesterol > 6.5 mmol/L) on PI-containing therapy. Patients commenced dietary assessment and advice at week 0 and were randomized to 12 weeks pravastatin (40 mg each night) or placebo from week 4. The primary endpoint was the time-weighted change (TWAUC) in total cholesterol from week 0. Secondary endpoints included TWAUC cholesterol from week 4 (start of pravastatin), total and regional body fat, fasting lipids, glucose, insulin, and markers of cardiovascular risk. RESULTS Of 33 men randomized (pravastatin n = 16, mean age 48 years), 31 completed the study. Groups were matched for baseline cholesterol and body composition. Although there was no significant between-group difference in TWAUC cholesterol from week 0 (pravastatin -0.6 +/- 1.0 versus placebo -0.4 +/- 1.0 mmol/L/week; P = 0.8), TWAUC cholesterol from week 4 decreased more in the pravastatin group (-0.8 +/- 1.0 versus -0.3 +/- 0.9 mmol/L/week; P = 0.04). Neither triglycerides nor dietary intake changed. Subcutaneous fat increased significantly with pravastatin (+0.72 +/- 1.55 versus +0.19 +/- 0.48 kg change in limb fat, P < 0.04; +5.2 +/- 8.7 versus -1.3 +/- 13.7 cm change in abdominal subcutaneous fat, P = 0.02). Apart from homocystine, which decreased in the pravastatin group, there were no significant differences in other cardiovascular, lipid or glucose parameters. CONCLUSIONS Despite limited effects on cholesterol, 12 weeks use of pravastatin 40 mg each night in HIV-infected men with hypercholesterolaemia resulted in significant increases in subcutaneous fat.

Apocrypha' and 'apocryphal' originally signified something hidden or secret, and they were applied in this sense to esoteric writings, that is, writings which circulated only within a narrow group of persons 'in the know'. Several apocryphal gospels are attributed to apostles, thus tacitly claiming apostolic authority for their content. Of more interest to historians are the Gospel of Thomas and the Gospel of Peter. The first of these is known only from the Nag Hammadi corpus, and therefore in a Coptic translation of the original Greek. Like the Gospel of Thomas, the Acts of Thomas, an early third-century composition, identifies its subject as 'Judas Thomas, also called Didymus. The early Christians wrote and consulted works of the sort that are styled 'apocalypse'. One type of apocalypse is represented by the Ascension of Isaiah, which combines an old Jewish legend of the martyrdom of Isaiah, originally in Hebrew, with a Christian interpolation and supplement originally in Greek.

The expression 'Apostolic Fathers' corresponds to an idea of seventeenth century origin. The primitive Christian literature takes a variety of forms, but by far the most frequent form is that of the letter. In the Roman-Hellenistic world letters were a common, if not frequent, means of communication among ordinary folk, for personal or business purposes. Of the letters in the New Testament, fourteen were traditionally attributed to Paul. Of these, the unquestionably genuine ones are 1 Thessalonians, 1 Corinthians, 2 Corinthians, Philippians, Philemon, Galatians and Romans. The term 'gospel' eventually came, in early Christianity, to identify works of widely differing sorts. The Valentinian Gospel of Truth appears to be a sermon or treatise. The Gospel of Thomas is an anthology of sayings of Jesus. Among the Apostolic Fathers, some of the characteristics of the apocalyptic literature are shared by The Shepherd of Hermas, which stems from the Roman Church of the early second century.

Irenaeus, head of the Christian community at Lyon in Gaul, was a central figure in the second-century debate stimulated in the Christian churches by gnosticism and by the teachings of Marcion. One may assume that Irenaeus' hostility to Christian gnosticism as well as to the teachings of Marcion was brought with him from Asia. In his Ecclesiastical History, Eusebius of Caesarea mentions a number of writings of Irenaeus. Irenaeus 'New Testament' is basically a collection of works conceived to be written by, or to report the teaching of, apostles; and while he differs radically from Valentinians about how such books should be read, he does not, save in the case of the Acts, seem to differ with them about the books that constitute the core list. It is Marcion, not the gnostics, whom he openly accuses of truncating the list of essential Christian Scriptures.

The Goodrich DB-110 system is discussed in terms of its basic design and concept. An operational platform utilizing the DB-110 system known as the Reconnaissance Airborne Pod for the TORnado (RAPTOR) aircraft is overviewed describing the complete automatic turnkey operation of the system. Dual-band imagery from RAPTOR displays DB-110's imaging capability for long, medium, and short standoff range as well as over-flight mission performance. Additionally, enhancing the resolution and other multi-spectral and Hyper-spectral formats of the DB-110 system are introduced as evidence of future products based on the present DB-110 system.© (2003) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

In order to increase the technology readiness level of the hypersonic scramjet technology, the Air Force Research Laboratory HyTech Program Office funded Aerojet to develop an innovative strut-based dual-mode scramjet engine design under the Storable Fuel Scramjet Flow Path Concepts (SFSFPC) program. Effective system thermal management over the entire flight envelope is critical to the success of the mission. This paper presents a thermal management system operational for a Mach 4 to 8 flight envelope. The design of the thermal system is based (at every Mach number) on delivering fuel to the combustor at the conditions required to support ignition at Mach 4 and high-efficiency combustion at all Mach numbers. The engine thermal management system includes the C/SiC engine shell and struts, a regeneratively fuel-cooled titanium plate between the engine and the vehicle, regeneratively fuel-cooled fins inside the C/SiC struts, a heat exchanger, and a solid propellant gas generator. Due to the radiation cooling, no endothermic reaction is required to cool the engine at full throttle operation at Mach 8. At the Mach 8 cruise condition at the 80 percent power level, the radiation and fuel cooling are augmented by an endothermic reaction requiring less than 40 percent of cracked n-decane fuel. This level of endothermic reaction has been demonstrated under realistic engine conditions. INTRODUCTION Aerojet has been actively pursuing the application of dual-mode ramjet to hypersonic missiles and global reach vehicles (refs. 1-4). To increase the technology readiness level of hypersonic scramjet technology, the Air Force Research Laboratory (AFRL) HyTech Program Office funded Aerojet to develop an innovative, strut-based, dual-mode ramjet engine design under the Storable Fuel Scramjet Flow Path Concepts (SFSFPC) program. A potential application for a Mach 4 to 8 liquid hydrocarbon fueled scramjet propulsion system is a fast-response long-range, hypersonic missile. Mission objectives include a range of at least 750 nautical miles in not more than 12 minutes with carriage from both fighter and bomber aircraft. Effective system thermal management over the entire flight envelope is critical to the success of the mission. This paper presents an efficient, flexible thermal management system for a Mach 4 to 8 flight envelope. The technical challenge is to identify a flexible thermal management system design that will be responsive to the combustor fuel conditioning requirements and to significant variations of structural heat load, fuel temperature, fuel density, and pressure over the entire flight envelope. During Mach 4 operation, the most challenging task is to ensure that the liquid fuel ignites and burns efficiently at ramjet '* Technical Principal, member AIAA, ** Engineering manager, *** Program manager # HyTech SFSFPC Program Manager on the Aerojet Contract This work has been supported by the Air Force Research Laboratory under Contract number F33615-96-C-2693. This paper is declared a work of the U.S. Government and is not subject to copyright protection in the United States.

This article describes the concepts for characterizing and predicting elevated-temperature crack growth in structural materials. It discusses both creep and creep-fatigue crack growth and focuses mainly on creep crack growth tests that are carried out in accordance with ASTM E 1457. The article provides information on typical test procedures and equipment used for these tests. It concludes with information on crack growth correlations.

To determine whether fitness alters psychological and physiological indices of well-being, male police officers were assigned to either an aerobic or anaerobic training condition or to a no treatment control group. The training groups met three times per week in 45 min sessions aimed at improving either cardiovascular endurance or muscle strength. Aerobic fitness level, heart rate, blood pressure and self-report of stress and well-being were measured prior to and following 10 weeks of training. Post-training fitness measures confirmed the effectiveness of training and between group differences for physiological and self-report measures were found. Subjects undergoing aerobic training evinced larger changes on the self-report measures of well-being and stress than the anaerobic trainers and both groups showed significant improvement when compared to controls. This experiment provides support for the hypothesis that exercise, and in particular aerobic exercise, has positive effects of well-being. It is suggested that future research might usefully explore the particular contribution of different aspects of the training situation to these effects.