Virological outcome and management of persistent low-level viraemia in HIV-1-infected patients: 11 years of the Swiss HIV Cohort Study

BACKGROUND Management of persistent low-level viraemia (pLLV) in patients on combined antiretroviral therapy (cART) with previously undetectable HIV viral loads (VLs) is challenging. We examined virological outcome and management among patients enrolled in the Swiss HIV Cohort Study (SHCS). METHODS In this retrospective study (2000-2011), pLLV was defined as a VL of 21-400 copies/mL on ≥3 consecutive plasma samples with ≥8 weeks between first and last analyses, in patients undetectable for ≥24 weeks on cART. Control patients had ≥3 consecutive undetectable VLs over ≥32 weeks. Virological failure (VF), analysed in the pLLV patient group, was defined as a VL>400 copies/mL. RESULTS Among 9972 patients, 179 had pLLV and 5389 were controls. Compared to controls, pLLV patients were more often on unboosted PI-based (adjusted odds ratio, aOR, [95%CI] 3.2 [1.8-5.9]) and NRTI-only combinations (aOR 2.1 [1.1-4.2]) than on NNRTI and boosted PI-based regimens. At 48 weeks, 102/155 pLLV patients (66%) still had pLLV, 19/155 (12%) developed VF, and 34/155 (22%) had undetectable VLs. Predictors of VF were previous VF (aOR 35 [3.8-315]), unboosted PI-based (aOR 12.8 [1.7-96]) or NRTI-only combinations (aOR 115 [6.8-1952]), and VLs>200 during pLLV (aOR 3.7 [1.1-12]). No VF occurred in patients with persistent very LLV (pVLLV, 21-49 copies/mL; N=26). At 48 weeks, 29/39 patients (74%) who changed cART had undetectable VLs, compared to 19/74 (26%) without change (P<0.001). CONCLUSIONS Among patients with pLLV, VF was predicted by previous VF, cART regimen and VL ≥200. Most patients who changed cART had undetectable VLs 48 weeks later. These findings support cART modification for pLLV >200 copies/ml.

HIV-1 Transmission During Recent Infection and During Treatment Interruptions as Major Drivers of New Infections in the Swiss HIV Cohort Study.

BACKGROUND  Reducing the fraction of transmissions during recent human immunodeficiency virus (HIV) infection is essential for the population-level success of "treatment as prevention". METHODS  A phylogenetic tree was constructed with 19 604 Swiss sequences and 90 994 non-Swiss background sequences. Swiss transmission pairs were identified using 104 combinations of genetic distance (1%-2.5%) and bootstrap (50%-100%) thresholds, to examine the effect of those criteria. Monophyletic pairs were classified as recent or chronic transmission based on the time interval between estimated seroconversion dates. Logistic regression with adjustment for clinical and demographic characteristics was used to identify risk factors associated with transmission during recent or chronic infection. FINDINGS  Seroconversion dates were estimated for 4079 patients on the phylogeny, and comprised between 71 (distance, 1%; bootstrap, 100%) to 378 transmission pairs (distance, 2.5%; bootstrap, 50%). We found that 43.7% (range, 41%-56%) of the transmissions occurred during the first year of infection. Stricter phylogenetic definition of transmission pairs was associated with higher recent-phase transmission fraction. Chronic-phase viral load area under the curve (adjusted odds ratio, 3; 95% confidence interval, 1.64-5.48) and time to antiretroviral therapy (ART) start (adjusted odds ratio 1.4/y; 1.11-1.77) were associated with chronic-phase transmission as opposed to recent transmission. Importantly, at least 14% of the chronic-phase transmission events occurred after the transmitter had interrupted ART. CONCLUSIONS  We demonstrate a high fraction of transmission during recent HIV infection but also chronic transmissions after interruption of ART in Switzerland. Both represent key issues for treatment as prevention and underline the importance of early diagnosis and of early and continuous treatment.

Eine warhafftige newe Zeitung : Welche sich begeben unnd zu getragen hat, in diesen 1614. Jahr, den 4. Augusti, ein halbe Meil von Basel in Schweitzerland, in einem Dorffe Freybach genandt, wie ...

In Fraktur

Na 1 Nachlass Max Horkheimer, 705 - Studien über Nationalismus und Autorität; Darmstädter Gemeindestudie; "Project on Attitudes of German Youth" u.a. (p. IX 176 - IX 181a)

"Gruppenuntersuchung über Nationalismus", Juni 1950. Typoskript mit handschriftlichen Ergänzungen von Friedrich Pollock, 18 Blatt; "Beitrag des Instituts für Sozialforschung zu dem Forschungsobjekt (Forschungsprojekt?) über Autorität", 1950/51, a) Typoskript, 5 Blatt, b) Typoskript mit dem Titel "New Project on Authority" mit handschriftlichen Korrekturen, 7 Blatt; "Memorandum über eine Studie zum Problem der Autorität im deutschen Erziehungswesen", ca. 1950. Typoskript, 4 Blatt; "Darmstädter Gemeindestudie", 1950-52: 1. Theodor W. Adorno: "Memorandum re: Stand der Darmstädter Gemeindestudie bei der Abreise von Theodor W. Adorno", 15.10.1952. Typoskript mit eigenhändigen Korrekturen, 2 Blatt; 2. Ansprache bei der Überreichung der ersten Publikationen der Studie an den Minister und den Bürgermeister von Darmstadt, 2.7.1952, Typoskript, 9 Blatt; 3. Max Horkheimer: "Gutachten über die Darmstädter Gemeindestudie", 1.4.1952. Typoskript, 2 Blatt; 4. "Memorandum on the Participation of the Institute of Social Research in the Darmstadt Community Study", 31.3.1952. Typoskript, 3 Blatt; 5. Theodor W. Adorno: 'Memorandum re: Darmstadt', 4.9.1951. Typoskript, 1 Blatt; 6. "Eine Untersuchung über die Einstellung der Arbeitnehmer zu ihren wirtschaftlichen Interessenvertretungen (Darmstädter Gemeindestudie). Entwurf", 20.7.1951. Typoskript mit handschriftlichen Korrekturen, 6 Blatt; 7. Theodor W. Adorno: "Memorandum über zwei an das Institut für Sozialforschung zu vergebende Aufträge im Rahmen der Darmstädter Gemeindestudie". Typoskripte, 6 Blatt; 8. Theodor W. Adorno: "Aktennotiz über die Besprechung am 20. November 1950 zwischen den Leitern der Darmstädter Gemeindestudie, insbesondere Dr. Grigsy und Magnifizenz Rolfes, und Theodor W. Adorno". Typoskript, 2 Blatt; 9. Bemerkungen zum Abbruch und zur Neuorganisation der Studie, für eine Rede in Chicago, Typoskript, englisch, ohne Datum, 1 Blatt; "Outline of a Study of In-Between-Culture" ("Edelkitsch"), Anfang der 1950er Jahre. Typoskript, englisch, 1 Blatt; "Project on Attitudes of German Youth", 1951: 1. "Some Remarks of the Present German Social Situation", a) Typoskript, 24 Blatt, b) Typoskript mit handschriftlichen Korrekturen, 23 Blatt, c) Typoskript, 23 Blatt, d) Typoskript, 21 Blatt, e) Entwurf, Typoskript, 23 Blatt; 2. "Estimate for six month project on Attitudes of German Youth", 2 Blatt; Institut für Sozialforschung: "Umfrage unter Frankfurter Studenten" (Max Horkheimer: "Vorbemerkung"): Über die soziale Situation und die Einstellun der Studenten, 1952, Ergebnisse eines Praktikums zur empirischen Sozialforschung, Wintersemester 1951/52, als Typoskript vervielfältigt, gebunden, 126 Blatt;

ATP- and carbachol -stimulated 1,2-diacylglycerol production during sensitization of adenylyl cyclase

Stimulation of LM5 cells with the phorbol ester 4$\beta$-phorbol 12-myristate 13-acetate (PMA), causes a 2-4 fold sensitization of hormonally-stimulated adenylyl cyclase (AC) activity. This effect is thought to be due to protein kinase C (PKC)-mediated phosphorylation of either G$\sb{\rm i}$ or the catalytic subunit of AC. PKC are components of the phosphatidylinositol-4,5-bisphosphate phospholipase C (PIP$\sb2$-PLC) pathway. The currently accepted model of this pathway is that its activation by an agonist results in the production of inositol 1,4,5-triphosphate (IP$\sb3$) which causes Ca$\sp{++}$ mobilization, and 1,2-diacylglycerols (DAG) which activate PKC. Based on this model, we predicted that stimulation of purinergic and muscarinic receptors with the agonists ATP and carbachol (CCh), respectively in the LM5 cells, should sensitize AC. Surprisingly we found that only stimulation of the purinergic receptors in these cells caused a sensitization of PGE$\sb1$-stimulated AC measured in cell-free assays.^ We hypothesized that ATP-and CCh-stimulated differential DAG production contributes to the effectiveness of these two agonists to sensitize PGE$\sb1$-stimulated AC activity. To test this hypothesis directly, we performed a combined high-performance liquid chromatography and gas-liquid chromatography analysis of the DAG produced in the LM5 cells in response to stimulation with ATP and CCh.^ We found that both ATP and CCh increased levels of 23 species of DAG. Relative to the control levels (0.261 nmol DAG/100 nmol phospholipid) the CCh-induced increase in DAG levels was 280% (0.738 $\pm$ 0.051 nmol DAG/100 nmol phospholipid) whereas the ATP-induced levels increased 180% (0.441 t 0.006 nmol DAG/100 nmol phospholipid). Neither agonist created new species or eliminated the existing ones. The major species which comprised $\approx$50% of the total cellular DAG in all of the groups were 16:0-18:1, 18:0-18:1, 18:1-18:1, and 18:0-20:4. CCh was more effective than ATP at stimulating these major DAG species.^ It is concluded that factor(s) other than DAG contribute(s) to the differences between ATP-and CCh-sensitization of PGE$\sb1$-stimulated AC activity in the LM5 cells. ^

(Table 1) Age determination of Cape Shpindler, Yugorski Peninsula, northwest Russia

Depositional environments, stratigraphic relations, and 35 new AMS 14C dates at Cape Shpindler, Yugorski Peninsula, help constrain the late Pleistocene glacial and environmental history of the southern Kara Sea region. Fifteen- to fifty-meter-high coastal exposures reveal a complex package of shallow marine, fluvial, glacial, and postglacial deposits, and are documented here in a 19-km-long cross-section and eight vertical sections. The shallow marine (Unit A), estuarine or prodeltaic (Unit B), and fluvio-deltaic (Unit C) deposits contain an interglacial molluscan fauna, yield radiocarbon dates greater than 40 ka, and may correspond with a regional sea-level highstand during the Eemian. These units are overlain by a diamicton (Unit D), and are pervasively deformed by folds and low- to high-angle faults into a stacked glaciotectonic accretionary complex. The diamicton (Unit D) is a subglacial till, and associated massive ground ice with deformed debris bands (Unit E) appears to be relict glacier ice. Glaciotectonic structures document both southward- and northward-directed glacier movement. Above the till and associated glaciotectonic horizons lies 0- to 11-m-thick postglacial deposits of peatland, eolian, fluvial, and primarily lacustrine origin (Unit F). The postglacial deposits yield radiocarbon ages of 12.8 to 0.8 ka. Thus, at least one regional glaciation is prominently represented in the stratigraphy, and occurred probably after the Eemian but before 12.8 ka. We infer that the bulk of the glacial record corresponds with southward advance by an early Weichselian Kara Sea Ice Sheet, in agreement with other recently documented, regional records from Yamal Peninsula and the Pechora Basin. The timing and source of northward-directed glacier ice are less well constrained. Across the broad expanse of the Eurasian Arctic, Quaternary stratigraphy is still sparsely documented. The new data from Cape Shpindler fill a spatial gap in paleoenvironmental research.

(Table 1) Oxygen and carbon isotope ratios of benthic foraminifera of DSDP Holes 12-119 and 48-401

We present here oxygen and carbon isotopic records of Eocene to Oligocene benthic foraminifera from two Bay of Biscay Deep Sea Drilling Project (DSDP) sites (119 and 401). d18O of benthic foraminifera increases 1.9 per mil from a middle Eocene minimum (Zones P10-P11) to an earliest Oligocene maximum (Zone NP21). Approximately 1.4 per mil of the increase in benthic foraminiferal d18O occurs during the late Eocene to earliest Oligocene (Zones P15/16-NP21). Previous results from other North Atlantic DSDP sites (400A and 398) have significantly lower d18O values of benthic foraminifera, some by as much as 2 per mil (Vergnaud-Grazzini et al., 1978; 1989, doi:10.2973/dsdp.proc.48.119.1979; Vergnaud-Grazzini, 1979, doi:10.2973/dsdp.proc.47-2.117.1979 ). We believe that these differences result from diagenetic alteration of the sediments in the deeper-buried Sites 400A and 398.