Appraisal of health care: from patient value to societal benefit

Aim: This paper summarizes the deficiencies and weaknesses of the most frequently used methods for the allocation of health-care resources. New, more transparent and practical methods for optimizing the allocation of these resources are proposed. Method: The examples of quality-adjusted life years (QALYs) and efficiency frontier (EF) are analyzed to describe weaknesses and problems in decisions regulating health-care provision. After conducting a literature search and discussions with an international group of professionals, three groups of professionals were formed to discuss the assessment and appraisal of health-care services and allocation of available resources. Results: At least seven essential variables were identified that should be heeded when applying the concept of QALYs for decisions concerning health-care provision. The efficiency frontier (EF) concept can be used to set a ceiling price and perform a cost-benefit analysis of provision, but different stakeholders—a biostatistician (efficacy), an economist (costs), a clinician (effectiveness), and the patient (value)—could provide a fairer appraisal of health-care services. Efficacy and costs are often based on falsifiable data. Effectiveness and value depend on the success with which a particular clinical problem has been solved. These data cannot be falsified. The societal perspective is generated by an informal cost-benefit analysis including appraisals by the above-mentioned stakeholders and carried out by an authorized institution. Conclusion: Our analysis suggests that study results expressed in QALYs or as EF cannot be compared unless the variables included in the calculation are specified. It would be far more objective and comprehensive if an authorized institution made an informal decision based on formal assessments of the effectiveness of health-care services evaluated by health-care providers, of the value assessed by consumers, of efficacy described by biostatisticians, and of costs calculated by economists

Across-arc geochemical variations in the Southern Volcanic Zone, Chile (34.5- 38.0°S): Constraints on Mantle Wedge and Input Compositions

Crustal assimilation (e.g. Hildreth and Moorbath, 1988) and/or subduction erosion (e.g. Stern, 1991; Kay et al., 2005) are believed to control the geochemical variations along the northern portion of the Chilean Southern Volcanic Zone. In order to evaluate these hypotheses, we present a comprehensive geochemical data set (major and trace elements and O-Sr-Nd-Hf-Pb isotopes) from Holocene primarily olivine-bearing volcanic rocks across the arc between 34.5-38.0°S, including volcanic front centers from Tinguiririca to Callaqui, the rear arc centers of Infernillo Volcanic Field, Laguna del Maule and Copahue, and extending 300 km into the backarc. We also present an equivalent data set for Chile Trench sediments outboard of this profile. The volcanic arc (including volcanic front and rear arc) samples primarily range from basalt to andesite/trachyandesite, whereas the backarc rocks are low-silica alkali basalts and trachybasalts. All samples show some characteristic subduction zone trace element enrichments and depletions, but the backarc samples show the least. Backarc basalts have higher Ce/Pb, Nb/U, Nb/Zr, and Ta/Hf, and lower Ba/Nb and Ba/La, consistent with less of a slab-derived component in the backarc and, consequently, lower degrees of mantle melting. The mantle-like δ18O in olivine and plagioclase phenocrysts (volcanic arc = 4.9-5.6 and backarc = 5.0-5.4 per mil) and lack of correlation between δ18O and indices of differentiation and other isotope ratios, argue against significant crustal assimilation. Volcanic arc and backarc samples almost completely overlap in Sr and Nd isotopic composition. High precision (double-spike) Pb isotope ratios are tightly correlated, precluding significant assimilation of older sialic crust but indicating mixing between a South Atlantic Mid Ocean-Ridge Basalt (MORB) source and a slab component derived from subducted sediments and altered oceanic crust. Hf-Nd isotope ratios define separate linear arrays for the volcanic arc and backarc, neither of which trend toward subducting sediment, possibly reflecting a primarily asthenospheric mantle array for the volcanic arc and involvement of enriched Proterozoic lithospheric mantle in the backarc. We propose a quantitative mixing model between a mixed-source, slab-derived melt and a heterogeneous mantle beneath the volcanic arc. The model is consistent with local geodynamic parameters, assuming water-saturated conditions within the slab

Tuberculous disseminated lymphadenopathy in an immunocompetent non-HIV patient: a case report

<p>Abstract</p> <p>Introduction</p> <p>In cases of patients with disseminated lymphadenopathy, the differential diagnosis has to include both benign and malignant causes, including sarcoidosis, metastatic disease, lymphoma and, although rarely present, tuberculosis. Tuberculosis is still one of the most frequently occurring infectious diseases worldwide. However, disseminated mycobacterial lymphadenitis is rare in immunocompetent patients.</p> <p>Case presentation</p> <p>We present the case of a 56-year-old Caucasian Greek male, who was immunocompetent and HIV negative, with a two-month history of recurring fever, loss of appetite and disseminated lymphadenopathy. The patient was diagnosed with mycobacterial lymphadenopathy.</p> <p>Conclusion</p> <p>This case highlights the need for suspicion in order to identify mycobacterial infection in patients with generalized lymphadenopathy, since misdiagnosis is possible and may lead to fatal complications for the patient.</p

Helminth-Associated Systemic Immune Activation and HIV Co-receptor Expression: Response to Albendazole/Praziquantel Treatment

Background: It has been hypothesized that helminth infections increase HIV susceptibility by enhancing systemic immune activation and hence contribute to elevated HIV-1 transmission in sub-Saharan Africa. Objective: To study systemic immune activation and HIV-1 co-receptor expression in relation to different helminth infections and in response to helminth treatment. Methods: HIV-negative adults with (n = 189) or without (n = 57) different helminth infections, as diagnosed by Kato-Katz, were enrolled in Mbeya, Tanzania. Blinded to helminth infection status, T cell differentiation (CD45RO, CD27),activation (HLA-DR, CD38) and CCR5 expression was determined at baseline and 3 months after Albendazole/Praziquantel treatment. Plasma cytokine levels were compared using a cytometric bead array. Results: Trichuris and Ascaris infections were linked to increased frequencies of "activated'' CD4 and/or CD8 T cells (p< 0.05),whereas Hookworm infection was associated with a trend towards decreased HLA-DR+ CD8 T cell frequencies (p = 0.222). In Trichuris infected subjects, there was a linear correlation between HLA-DR+ CD4 T cell frequencies and the cytokines IL-1 beta and IL-10 (p<0.05). Helminth treatment with Albendazole and Praziquantel significantly decreased eosinophilia for S. mansoni and Hookworm infections (p<0.005) but not for Trichuris infection and only moderately modulated T cell activation. CCR5 surface density on memory CD4 T cells was increased by 1.2-fold during Trichuris infection (p-value: 0.053) and reduced after treatment (p = 0.003). Conclusions: Increased expression of T cell activation markers was associated with Trichuris and Ascaris infections with relatively little effect of helminth treatment

Louisville Seamount Trail: implications for geodynamic mantle flow models and the geochemical evolution of primary hotspots

The Louisville Seamount Trail is a 4300 km long volcanic chain that has been built in the past 80 m.y. as the Pacific plate moved over a persistent mantle melting anomaly or hotspot. Because of its linear morphology and its long-lived age-progressive volcanism, Louisville is the South Pacific counterpart of the much better studied Hawaiian-Emperor Seamount Trail. Together, Louisville and Hawaii are textbook examples of two primary hotspots that have been keystones in deciphering the motion of the Pacific plate relative to a set of "fixed" deep-mantle plumes. However, drilling during Ocean Drilling Program (ODP) Leg 197 in the Emperor Seamounts documented a large ~15° southward motion of the Hawaiian hotspot prior to 50 Ma. Is it possible that the Hawaiian and Louisville hotspots moved in concert and thus constitute a moving reference frame for modeling plate motion in the Pacific? Alternatively, could they have moved independently, as predicted by mantle flow models that reproduce the observed latitudinal motion for Hawaii but that predict a largely longitudinal shift for the Louisville hotspot? These two end-member geodynamic models were tested during Integrated Ocean Drilling Program (IODP) Expedition 330 to the Louisville Seamount Trail. In addition, existing data from dredged lavas suggest that the mantle plume source of the Louisville hotspot has been remarkably homogeneous for as long as 80 m.y. These lavas are predominantly alkali basalts and likely represent a mostly alkalic shield-building stage, which is in sharp contrast to the massive tholeiitic shield-building stage of Hawaiian volcanoes. Geochemical and isotopic data for the recovered lavas during Expedition 330 will provide insights into the magmatic evolution and melting processes of individual Louisville volcanoes, their progression from shield-building to postshield and (maybe) posterosional stages, the temperature and depth of partial melting of their mantle plume source, and the enigmatic long-lived and apparent geochemical homogeneity of the Louisville mantle source. Collectively, this will enable us to characterize the Louisville Seamount Trail as a product of one of the few global primary hotspots, to better constrain its plume-lithosphere interactions, and to further test the hypothesis that the Ontong Java Plateau formed from the plume head of the Louisville mantle plume around 120 Ma. During Expedition 330 we replicated the drilling strategy of Leg 197, the first expedition to provide compelling evidence for the motion of the Hawaiian mantle plume between 80 and 50 Ma. For that reason we targeted Louisville seamounts that have ages similar to Detroit, Suiko, Nintoku, and Koko Seamounts in the Emperor Seamount Trail. In total, five seamounts were drilled in the Louisville Seamount Trail: Canopus, Rigil, Burton, Achernar, and Hadar Guyots (old to young). By analyzing a large number of time-independent in situ lava flows (and other volcanic eruptive products) from these seamounts using modern paleomagnetic, 40Ar/39Ar geochronological, and geochemical techniques, we will be able to directly compare the paleolatitude estimates and geochemical signatures between the two longest-lived hotspot systems in the Pacific Ocean. We drilled into the summits of the five Louisville guyots and reached volcanic basement at four of these drilling targets. In two cases we targeted larger seamount structures and drilled near the flanks of these ancient volcanoes, and in the other three cases we selected smaller edifices that we drilled closer to their centers. Drilling and logging plans for each of these sites were similar, with coring reaching 522.0 meters below seafloor (mbsf) for Site U1374 and 232.9, 65.7, 11.5, 182.8, and 53.3 mbsf for Sites U1372, U1373, U1375, U1376, and U1377, respectively. Some Expedition 330 drill sites were capped with only a thin layer of pelagic ooze between 6.6 and 13.5 m thick, and, if present, these were cored by using a low-rotation gravity-push technique with the rotary core barrel to maximize recovery. However, at Sites U1373 and U1376 no pelagic ooze was present, and the holes needed to be started directly into cobble-rich hardgrounds. In all cases, the bulk of the seamount sediment cover comprised sequences of volcanic sandstones and various kinds of basalt breccia or basalt conglomerate, which often were interspersed with basaltic lava flows, the spatter/tephra products of submarine eruptions, or other volcanic products, including auto-brecciated flows or peperites. Also several intervals of carbonate were cored, with the special occurrence of a ~15 m thick algal limestone reef at Site U1376 on Burton Guyot. In addition, some condensed pelagic limestone units were recovered on three of the other seamounts, but these did not exceed 30 cm in thickness. Despite their limited presence in the drilled sediment, these limestones provide valuable insights for the paleoclimate record at high ~50° southern latitudes since Mesozoic times. Several Louisville sites progressed from subaerial conditions in the top of volcanic basement into submarine eruptive environments, or drilling of the igneous basement immediately started in submarine volcanic sequences, as was the case for Sites U1376 and U1377 on Burton and Hadar Guyots. At three sites we cored >100 m into the igneous basement: 187.3 m at Site U1372, 505.3 m at Site U1374, and 140.9 m at Site U1376. At the other sites we did not core into basement (Site U1375) or we cored only 38.2 m (Site U1377) because of unstable hole conditions. Even so, drilling during Expedition 330 resulted in a large number of in situ lava flows, pillow basalts, or other types of volcanic products such as auto-brecciated lava flows, intrusive sheets or dikes, and peperites. In particular, the three holes on Canopus and Rigil Guyots (the two oldest seamounts drilled in the Louisville Seamount Trail), resulted in adequate numbers of in situ lava flows to average out paleosecular variation, with probable eruption ages estimated at ~78 and 73 Ma, respectively. Remarkably, at all drill sites large quantities of hyaloclastites, volcanic sandstones, and basaltic breccias were also recovered, which in many cases show consistent paleomagnetic inclinations compared to the lava flows bracketing these units. For Site U1374 on Rigil Guyot we also observed a magnetic polarity reversal in the cored sequence. Overall, this is very promising for determining a reliable paleolatitude record for the Louisville Seamounts following detailed postcruise examinations. The deeper penetrations of several hundred meters required bit changes and reentries using free-fall funnels. Basement penetration rates were 1.8–2.5 m/h depending on drill depth. In total, 1114 m of sediment and igneous basement at five seamounts was drilled, and 806 m was recovered (average recovery = 72.4%). At Site U1374 on Rigil Guyot, a total of 522 m was drilled, with a record-breaking 87.8% recovery. Most outstandingly, nearly all Expedition 330 core material is characterized by low degrees of alteration, providing us with a large quantity of samples of mostly well-preserved basalt, containing, for example, pristine olivine crystals with melt inclusions, fresh volcanic glass, unaltered plagioclase, carbonate, zeolite and celadonite alteration minerals, various micro- and macrofossils, and, in one case, mantle xenoliths and xenocrysts. The large quantity and excellent quality of the recovered sample material allow us to address all the scientific objectives of this expedition and beyond

Magnitude and Complexity of Rectal Mucosa HIV-1-Specific CD8+ T-Cell Responses during Chronic Infection Reflect Clinical Status

The intestinal mucosa displays robust virus replication and pronounced CD4+ T-cell loss during acute human immunodeficiency virus type 1 (HIV-1) infection. The ability of HIV-specific CD8+ T-cells to modulate disease course has prompted intensive study, yet the significance of virus-specific CD8+ T-cells in mucosal sites remains unclear.We evaluated five distinct effector functions of HIVgag-specific CD8+ T-cells in rectal mucosa and blood, individually and in combination, in relationship to clinical status and antiretroviral therapy (ART). In subjects not on ART, the percentage of rectal Gag-specific CD8+ T-cells capable of 3, 4 or 5 simultaneous effector functions was significantly related to blood CD4 count and inversely related to plasma viral load (PVL) (p<0.05). Polyfunctional rectal CD8+ T-cells expressed higher levels of MIP-1beta and CD107a on a per cell basis than mono- or bifunctional cells. The production of TNFalpha, IFN-gamma, and CD107a by Gag-specific rectal CD8+ T-cells each correlated inversely (p<0.05) with PVL, and MIP-1beta expression revealed a similar trend. CD107a and IFN-gamma production were positively related to blood CD4 count (p<0.05), with MIP-1beta showing a similar trend. IL-2 production by rectal CD8+ T-cells was highly variable and generally low, and showed no relationship to viral load or blood CD4 count.The polyfunctionality of rectal Gag-specific CD8+ T-cells appears to be related to blood CD4 count and inversely related to PVL. The extent to which these associations reflect causality remains to be determined; nevertheless, our data suggest a potentially important role for mucosal T-cells in limiting virus replication during chronic infection

Intra- and Inter-clade Cross-reactivity by HIV-1 Gag Specific T-Cells Reveals Exclusive and Commonly Targeted Regions: Implications for Current Vaccine Trials

The genetic diversity of HIV-1 across the globe is a major challenge for developing an HIV vaccine. To facilitate immunogen design, it is important to characterize clusters of commonly targeted T-cell epitopes across different HIV clades. To address this, we examined 39 HIV-1 clade C infected individuals for IFN-γ Gag-specific T-cell responses using five sets of overlapping peptides, two sets matching clade C vaccine candidates derived from strains from South Africa and China, and three peptide sets corresponding to consensus clades A, B, and D sequences. The magnitude and breadth of T-cell responses against the two clade C peptide sets did not differ, however clade C peptides were preferentially recognized compared to the other peptide sets. A total of 84 peptides were recognized, of which 19 were exclusively from clade C, 8 exclusively from clade B, one peptide each from A and D and 17 were commonly recognized by clade A, B, C and D. The entropy of the exclusively recognized peptides was significantly higher than that of commonly recognized peptides (p = 0.0128) and the median peptide processing scores were significantly higher for the peptide variants recognized versus those not recognized (p = 0.0001). Consistent with these results, the predicted Major Histocompatibility Complex Class I IC50 values were significantly lower for the recognized peptide variants compared to those not recognized in the ELISPOT assay (p<0.0001), suggesting that peptide variation between clades, resulting in lack of cross-clade recognition, has been shaped by host immune selection pressure. Overall, our study shows that clade C infected individuals recognize clade C peptides with greater frequency and higher magnitude than other clades, and that a selection of highly conserved epitope regions within Gag are commonly recognized and give rise to cross-clade reactivities

Seamounts

Definition: Seamounts are literally mountains rising from the seafloor. More specifically, they are “any geographically isolated topographic feature on the seafloor taller than 100 m, including ones whose summit regions may temporarily emerge above sea level, but not including features that are located on continental shelves or that are part of other major landmasses” (Staudigel et al., 2010). The term “guyot” can be used for seamounts having a truncated cone shape with a flat summit produced by erosion at sea level (Hess, 1946), development of carbonate reefs (e.g., Flood, 1999), or partial collapse due to caldera formation (e.g., Batiza et al., 1984). Seamounts <1,000 m tall are sometimes referred to as “knolls” (e.g., Hirano et al., 2008). “Petit spots” are a newly discovered subset of sea knolls confined to the bulge of subducting oceanic plates of oceanic plates seaward of deep-sea trenches (Hirano et al., 2006)