Background Suboptimal antiretroviral (ART) adherence can lead to virologic failure with consequent HIV-1 resistance. Tenofovir diphosphate (TFV-DP) in dried blood spots (DBS) is a powerful biomarker ...of cumulative adherence, predictive of future viremia. It has been associated with resistance in Persons With HIV (PWH) in South Africa and the US. We explored the relationship of TFV-DP concentrations with antiretroviral drug resistance at the time of treatment failure in SA. Methods Adult PWH from health clinics in Cape Town, South Africa on efavirenz-based first-line ART containing tenofovir disoproxil fumarate (TDF) with an undetectable (< 50 copies/mL) HIV-1 viral load (VL) were prospectively enrolled in an observational cohort for 12 months. Monthly study visits included blood collection for HIV-1 VL and DBS for TFV-DP. The first confirmed viral breakthrough (VB) > 400 copies/mL triggered HIV-1 genotyping at the subsequent visit. An electronic adherence (EA) device monitored ART adherence in real-time, estimated as a percent for the 30-days prior to VB. Wilcoxon rank sum test was used to compare median IQR TFV-DP by genotype outcome. Results Of 250 individuals, (n = 195, 78% women), 21 experienced VB, with a median of 5 4;7 months on study, and a median EA of 33.3 13.3;53.3%. Demographic characteristics between those with and without VB were similar. Median VL at VB was 4.0 3.2;4.5 log copies/mL. TFV-DP concentrations trended down towards the VB visit. Median TFV-DP concentrations were significantly higher in those HIV-1 genotype did not amplify due to being virally suppressed at the subsequent visit (n = 10; 380 227-661 fmol/punch, p = 0.035; EA 45 24.9; 59.2%); than in those who were successfully genotyped with evidence of drug resistance (n = 5, 241 150-247 fmol/punch, EA 20 6.7;36.7%) and in individuals who did not have resistance (n = 3, 39.9 16.6; 93.9 fmol/punch; EA 33.3 16-38%). Three genotype collections were not done. Only non-nucleoside reverse transcriptase inhibitor-associated mutations were identified on resistance testing. (K103N, E138K, Y118H). Conclusion TFV-DP in DBS showed a step-wise inverse relationship with VB and drug resistance, with evidence of low cumulative ART adherence in PWH who developed antiretroviral resistance. Monitoring TFV-DP concentrations could be a valuable tool for predicting future VB and future resistance. Keywords: South Africa, HIV resistance, Adherence, Dried blood spots, Tenofovir diphosphate
The Impact of Age and Gender on Papillary Thyroid Cancer Survival from the National Thyroid Cancer Treatment Cooperative Study Group; Jonklaas, J; Nogueras-Gonzalez, G ...
The journal of clinical endocrinology and metabolism,
2012-June, Letnik:
97, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Context:
Thyroid cancer predominately affects women, carries a worse prognosis in older age, and may have higher mortality in men. Superimposed on these observations is the fact that most women have ...attained menopause by age 55 yr.
Objective:
The objective of the study was to determine whether men contribute disproportionately to papillary thyroid cancer (PTC) mortality or whether menopause affects PTC prognosis.
Design:
Gender-specific mortality was normalized using age-matched subjects from the U.S. population. Multivariate Cox proportional hazard regression models incorporating gender, age, and National Thyroid Cancer Treatment Cooperative Study Group stage were used to model disease-specific survival (DSS).
Participants and Setting:
Patients were followed in a prospective registry.
Main Outcome Measure:
The relationships between gender, age, and PTC outcomes were analyzed.
Results:
The unadjusted hazard ratio (HR) for DSS for women was 0.40 confidence interval (CI) 0.24–0.65. This female advantage diminished when DSS was adjusted for age at diagnosis and stage with a HR encompassing unity (HR 0.72, CI 0.44–1.19). Additional multivariate models of DSS considering gender, disease stage, and various age groupings showed that the DSS for women diagnosed at under 55 yr was improved over men (HR 0.33, CI 0.13–0.81). However, the HR for DSS increased to become similar to men for women diagnosed at 55–69 yr (HR 1.01, CI 0.42–2.37) and at 70 yr or greater (HR 1.17, CI 0.48–2.85).
Conclusions:
Although the overall outcome of women with PTC is similar to men, subgroup analysis showed that this composite outcome is composed of two periods with different outcomes. The first period is a period with better outcomes for women than men when the diagnosis occurs at younger than 55 yr; the second is a period with similar outcomes for both women and men diagnosed at ages greater than 55 yr. These data raise the question of whether an older age cutoff would improve current staging systems. We hypothesize that older age modifies the effect of gender on outcomes due to menopause-associated hormonal alterations.
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•Nano-B4C reinforced Bi0.5Sb1.5Te3 p-type thermoelectric produced by SPS.•Addition of B4C up to 0.2vol% to SPS’d material has little effect on zT.•Vickers hardness improved by 27% by ...adding 0.2vol% B4C.•Fracture toughness of SPS material: KIC=0.80MPam1/2 by SEVNB.•Mechanical properties much better than commercial directionally solidified material.
The mechanical properties of bismuth telluride based thermoelectric materials have received much less attention in the literature than their thermoelectric properties. Polycrystalline p-type Bi0.5Sb1.5Te3 materials were produced from powder using spark plasma sintering (SPS). The effects of nano-B4C addition on the thermoelectric performance, Vickers hardness and fracture toughness were measured. Addition of 0.2vol% B4C was found to have little effect on zT but increased hardness by approximately 27% when compared to polycrystalline material without B4C. The KIC fracture toughness of these compositions was measured as 0.80MPam1/2 by Single-Edge V-Notched Beam (SEVNB). The machinability of polycrystalline materials produced by SPS was significantly better than commercially available directionally solidified materials because the latter is limited by cleavage along the crystallographic plane parallel to the direction of solidification.
Rationale
Reversal learning requires associative learning and executive functioning to suppress non-adaptive responding. Reversal-learning deficits are observed in e.g. schizophrenia and ...obsessive-compulsive disorder and implicate neural circuitry including the orbitofrontal cortex (OFC). Serotonergic function has been strongly linked to visual reversal learning in humans and experimental animals but less is known about which receptor subtypes are involved.
Objectives
The objectives of the study were to test the effects of systemic and intra-OFC 5-HT
2C
-receptor antagonism on visual reversal learning in rats and assess the psychological mechanisms underlying these effects within novel touchscreen paradigms.
Methods
In experiments 1–2, we used a novel 3-stimulus task to investigate the effects of 5-HT
2C
-receptor antagonism through SB 242084 (0.1, 0.5 and 1.0 mg/kg i.p.) cross-site. Experiment 3 assessed the effects of SB 242084 in 2-choice reversal learning. In experiment 4, we validated a novel touchscreen serial visual reversal task suitable for neuropharmacological microinfusions by baclofen-/muscimol-induced OFC inactivation. In experiment 5, we tested the effect of intra-OFC SB 242084 (1.0 or 3.0 μg/side) on performance in this task.
Results
In experiments 1–3, SB 242084 reduced early errors but increased late errors to criterion. In experiment 5, intra-OFC SB 242084 reduced early errors without increasing late errors in a reversal paradigm validated as OFC dependent (experiment 4).
Conclusion
Intra-OFC 5-HT
2C
-receptor antagonism decreases perseveration in novel touchscreen reversal-learning paradigms for the rat. Systemic 5-HT
2C
-receptor antagonism additionally impairs late learning—a robust effect observed cross-site and potentially linked to impulsivity. These conclusions are discussed in terms of neural mechanisms underlying reversal learning and their relevance to psychiatric disorders.
Parkinson's disease (PD) is associated with a loss of central dopaminergic pathways in the brain leading to an abnormality of movement, including saccades. In PD, analysis of saccadic latency ...distributions, rather than mean latencies, can provide much more information about how the neural decision process that precedes movement is affected by disease or medication. Subject to the constraints of intersubject variation and reproducibility, latency distribution may represent an attractive potential biomarker of PD. Here we report two studies that provide information about these parameters, and demonstrate a novel effect of dopamine on saccadic latency, implying that it influences the neural decision process itself. We performed a detailed cross-sectional study of saccadic latency distributions during a simple step task in 22 medicated patients and 27 age-matched controls. This revealed high intersubject variability and an overlap of PD and control distributions. A second study was undertaken on a different population specifically to investigate the effects of dopamine on saccadic latency distributions in 15 PD patients. L-dopa was found to prolong latency, although the magnitude of the effect varied between subjects. The implications of these observations for the use of saccadic latency distributions as a potential biomarker of PD are discussed, as are the effects of L-dopa on neural decision making, where it is postulated to increase the criterion level of evidence required before the decision to move is made.
Human papillomavirus type 16 (HPV16)-E6 antibodies are detectable in peripheral blood before diagnosis in the majority of HPV16-driven oropharyngeal squamous cell carcinoma (OPSCC), but the timing of ...seroconversion is unknown.
We formed the HPV Cancer Cohort Consortium which comprises nine population cohorts from Europe, North America and Australia. In total, 743 incident OPSCC cases and 5814 controls provided at least one pre-diagnostic blood sample, including 111 cases with multiple samples. Median time between first blood collection and OPSCC diagnosis was 11.4years (IQR=6–11years, range=0–40years). Antibodies against HPV16-E6 were measured by multiplex serology (GST fusion protein based Luminex assay).
HPV16-E6 seropositivity was present in 0.4% of controls (22/5814; 95% CI 0.2% to 0.6%) and 26.2% (195/743; 95% CI 23.1% to 29.6%) of OPSCC cases. HPV16-E6 seropositivity increased the odds of OPSCC 98.2-fold (95% CI 62.1–155.4) in whites and 17.2-fold (95% CI 1.7–170.5) in blacks. Seropositivity in cases was more frequent in recent calendar periods, ranging from 21.9% pre-1996 to 68.4% in 2005 onwards, in those with blood collection near diagnosis (lead time <5years). HPV16-E6 seropositivity increased with lead time: 0.0%, 13.5%, 23.7%, and 38.9% with lead times of >30years (N=24), 20–30years (N=148), 10–20years (N=228), and <10years (N=301 cases) (p-trend<0.001). Of the 47 HPV16-E6 seropositive cases with serially-collected blood samples, 17 cases seroconverted during follow-up, with timing ranging from 6 to 28years before diagnosis. For the remaining 30 cases, robust seropositivity was observed up to 25years before diagnosis.
The immune response to HPV16-driven tumorigenesis is most often detectable several decades before OPSCC diagnosis. HPV16-E6 seropositive individuals face increased risk of OPSCC over several decades.
Lay-counsellors in resource-limited settings convey critical HIV- and ART-information, and face challenges including limited training and variable application of counselling. This study explored ...lay-counsellors and Department of Health (DoH) perspectives on the utility of a multimedia adherence counselling program. Masivukeni, an mHealth application that provides scaffolding for delivering standardized ART counselling was used in a 3-year randomized control trail at two primary health care clinics in Cape Town, South Africa. In this programmatic and descriptive narrative report, we describe the application; lay-counsellors’ response to open-ended questions regarding their experience with using Masivukeni; and perspectives of the City of Cape Town and Western Cape Government DoH, obtained through ongoing engagements and feedback sessions. Counsellors reported Masivukeni empowered them to provide high quality counselling. DoH indicated strong support for a future implementation study assessing feasibility for larger scale roll-out. Masivukeni has potential as a counselling tool in resource-limited settings.
Human heart transplantation started 40 years ago. Medical records of all cardiac transplants performed at Stanford were reviewed. A total of 1446 heart transplantations have been performed between ...January 1968 and December 2007 with an increase of 1‐year survival from 43.1% to 90.2%. Sixty patients who were transplanted between 1968 and 1987 were identified who survived at least 20 years. Twenty‐year survivors had a mean age at transplant of 29.4 ± 13.6 years. Rejection‐free and infection‐free 1‐year survivals were 14.3% and 18.8%, respectively. At their last follow‐up, 86.7% of long‐term survivors were treated for hypertension, 28.3% showed chronic renal dysfunction, 6.7% required hemodialysis, 10% were status postkidney transplantation, 13.3% were treated for diabetes mellitus, 36.7% had a history of malignancy and 43.3% had evidence of allograft vasculopathy. The half‐life conditional on survival to 20 years was 28.1 years. Eleven patients received a second heart transplant after 11.9 ± 8.0 years. The most common causes of death were allograft vasculopathy (56.3%) and nonlymphoid malignancy (25.0%). Twenty‐year survival was achieved in 12.5% of patients transplanted before 1988. Although still associated with considerable morbidity, long‐term survival is expected to occur at much higher rates in the future due to major advances in the field over the past decade.
This study of 60 patients who survived more than 20 years after heart transplantation reveals a high incidence of hypertension, chronic renal failure, diabetes, malignancy, and allograft vasculopathy. See also editorial by Yacoub in this issue on page 1767.
Understanding the morphological characteristics of craters that are indicative of their formation environment can provide insight into surface geology. Layered ejecta (LE) craters, found on Mars and ...some other planetary bodies, have been hypothesized to have formed as a result of either interaction with subsurface volatiles (volatile fluidization model) and/or with the atmosphere (atmospheric entrainment model). Formation of LE craters by either model should result in different grain size distributions throughout the ejecta deposit. Using thermal inertia to infer surface properties, we investigated LE craters and their ejecta deposits in an effort to distinguish between possible LE formation processes on Mars. We used thermophysical properties of crater ejecta to determine grain size distribution, to model horizontal mixtures and vertical layering, and to identify materials present within the ejecta. We assessed the thermal properties of 50 uniformly sampled LE craters using Mars Odyssey Thermal Emission Imaging System (THEMIS) and Mars Global Surveyor Thermal Emission Spectrometer (TES) data. Our THEMIS analysis identifies 12 craters with grain size distributions consistent with the volatile fluidization model, 3 craters that have characteristics potentially associated with either model, and 22 craters that do not exhibit characteristics matching either model. Our TES analysis identifies 11 craters with characteristics consistent with the volatile fluidization model and 8 craters that are consistent with the atmospheric entrainment model. While some observations of grain size distributions provide evidence for either or both models, there is not overwhelming support for either model, potentially due to uncertainties of derived thermal inertia data.
Plain Language Summary
Impact craters are found throughout the solar system and can tell us about the geology around them. A specific type of crater, layered ejecta (LE) craters, may help us identify underground ice on Mars and other planetary bodies. LE craters are hypothesized to form when the energy of an impactor causes sub‐surface ice to become fluid or gas and flow outward. This hypothesis requires the presence of sub‐surface ice, and if it was found to be true, then identifying LE craters could be used to identify the locations of subsurface ice and water in the solar system. LE craters are identified by their ejecta deposits, which is the material that resettles around a crater following an impact. Grain size distributions throughout the ejecta deposits can tell us about their formation. We examined the grain size distribution of ejecta deposits surrounding 50 LE craters on Mars and looked at their thermal inertia, which is how well material holds onto heat, where smaller sand particles release their heat more quickly than large particles like boulders. Overall, the observed grain size distributions and thermal properties do not provide overwhelming support for the hypothesis that requires sub‐surface ice and thus further research is warranted.
Key Points
The formation process of Martian layered ejecta (LE) craters could have important implications for the presence of subsurface volatiles
In a sampling of 50 LE craters, we find no distinct relationship between crater type and trends in apparent thermal inertia
Results provide no overwhelming support for either the atmospheric entrainment or the volatile fluidization model for LE crater formation
Cardiovascular abnormalities are newly recognized features of duplication 17p11.2 syndrome. In a single-center study, we evaluated subjects with duplication 17p11.2 syndrome for cardiovascular ...abnormalities.
Twenty-five subjects with 17p11.2 duplication identified by chromosome analysis and/or array-based comparative genomic hybridization were enrolled in a multidisciplinary protocol. In our clinical evaluation of these subjects, we performed physical examinations, echocardiography, and electrocardiography. Three of these subjects were followed up longitudinally at our institution.
Cardiovascular anomalies, including structural and conduction abnormalities, were identified in 10 of 25 (40%) of subjects with duplication 17p11.2 syndrome. The most frequent abnormality was dilated aortic root (20% of total cohort). Bicommissural aortic valve (2/25), atrial (3/25) and ventricular (2/25) septal defects, and patent foramen ovale (4/25) were also observed.
Duplication 17p11.2 syndrome is associated with structural heart disease, aortopathy, and electrocardiographic abnormalities. Individuals with duplication 17p11.2 syndrome should be evaluated by electrocardiography and echocardiography at the time of diagnosis and monitored for cardiovascular disease over time. Further clinical investigation including longitudinal analysis would likely determine the age of onset and characterize the progression (if any) of vasculopathy in subjects with duplication 17p11.2 syndrome, so that specific guidelines can be established for cardiovascular management.
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