Search

The global carbon cycle has not been in steady state during the past 11,000 years, shown by a high-resolution ice-core record of atmospheric CO2 concentrations during the Holocene epoch. Changes in terrestrial biomass and sea surface temperatures are a possible cause for the observed millennial-scale changes of atmospheric CO2, following analysis of the CO2 concentration and carbon stable-isotope records.

Air bubbles which were trapped in polar ice have been analysed and the concentrations of CO2 over various periods have been calculated. Changes in the climate over many thousands of years tend to change the concentrations of CO2 in the atmosphere. However, CO2 concentrations during rapid climate changes are less certain. Research into CO2 from Greenland and Antarctic ice has been inconclusive. An accurate time scale is required to compare the data from Greenland with the Antarctic and a method has been developed which uses concentrations of atmospheric methane from both the ice samples.

In people with HIV-1 (PWH), Mycobacterium tuberculosis (MTB) infection poses a significant threat. While active tuberculosis (TB) accelerates immunodeficiency, the interaction between MTB and HIV-1 during asymptomatic phases remains unclear. Analysis of peripheral blood mononuclear cells (PBMC) transcriptomic profiles in PWH, with and without controlled viral loads, revealed distinct clustering in MTB-infected individuals. Functional annotation identified alterations in IL-6, TNF, and KRAS pathways. Notably, MTB-related genes displayed an inverse correlation with HIV-1 viremia, at both individual and signature score levels. These findings suggest that MTB infection in PWH induces a shift in immune system activation, inversely related to HIV-1 viral load. These results may explain the observed enhanced antiretroviral control in MTB-infected PWH. This study highlights the complex interplay between MTB and HIV-1, emphasizing the importance of understanding their interaction for managing co-infections in this population., Competing Interests: A.C. received grants from Merck Sharp & Dohme (MSD), ViiV Healthcare, and Gilead Sciences for unrelated research. R.D.K. received grants from Gilead Sciences and National Institutes of Health (NIH) for unrelated research. D.L.B. received honoraria for working on the advisory board of Gilead Sciences, Merck, ViiV, Pfizer, and AstraZeneca. D.L.B. received honoraria for presentations from Gilead Sciences and Merck. E.B. received grants from MSD for unrelated research. E.B. received payments for travel reimbursement from ViiV, MSD, Gilead Sciences, Pfizer, and Abbvie. E.B. received honoraria for working on the advisory board of ViiV, MSD, Pfizer, Gilead Sciences, AstraZeneca, and Ely Lilly. H.H.H. received honoraria for working on the advisory board of AiCuris, Merck, Vera Dx, and Molecular Partners. H.H.H. received honoraria for presentations from Merck, Gilead Sciences, Biotest, and Vera Dx. J.N. received honoraria for presentations from Oxford Immunotec, Gilead and ViiV. H.FG. received honoraria for working on the advisory board of Gilead Sciences, Merck, ViiV, Janssen, Johnson and Johnson, Novartis, and GlaxoSmithKline (GSK). H.F.G. received payments for travel reimbursements from Gilead Sciences. H.F.G. received grants from NIH, Yvonne Jacob Foundation, and Gilead Sciences., (© 2024 The Author(s).)

People with HIV may report neurocognitive complaints, with or without associated neurocognitive impairment, varying between individuals and populations. While the HIV genome could play a major role, large systematic viral genome-wide screens to date are lacking. The Swiss HIV Cohort Study biannually enquires neurocognitive complaints. We quantified broad-sense heritability estimates using partial 'pol' sequences from the Swiss HIV Cohort Study resistance database and performed a viral near full-length genome-wide association study for the longitudinal area under the curve of neurocognitive complaints. We performed all analysis (i) restricted to HIV Subtype B and (ii) including all HIV subtypes. From 8547 people with HIV with neurocognitive complaints, we obtained 6966 partial 'pol' sequences and 2334 near full-length HIV sequences. Broad-sense heritability estimates for presence of memory loss complaints ranged between 1% and 17% (Subtype B restricted 1-22%) and increased with the stringency of the phylogenetic distance thresholds. The genome-wide association study revealed one amino acid (Env L641E), after adjusting for multiple testing, positively associated with memory loss complaints ( P = 4.3 * 10 -6 ). Other identified mutations, while insignificant after adjusting for multiple testing, were reported in other smaller studies (Tat T64N, Env *291S). We present the first HIV genome-wide association study analysis of neurocognitive complaints and report a first estimate for the heritability of neurocognitive complaints through HIV. Moreover, we could identify one mutation significantly associated with the presence of memory loss complaints. Our findings indicate that neurocognitive complaints are polygenetic and highlight advantages of a whole genome approach for pathogenicity determination., Competing Interests: An.R. received research grants from Gilead, paid to his institution; travel expenses from Gilead and Pfizer, paid to his institution; and honoraria for data safety monitoring board or advisory board consultations from MSD and Moderna, paid to his institution. C.P. received personal research grants from the Swiss HIV Cohort Study, Collegium Helveticum and the University of Zurich. E.B. received research grants from MSD, paid to his institution; consulting fees from Moderna, paid to his institution; honoraria for presentations from Pfizer, paid to his institution; travel expenses from ViiV, MSD, Gilead and Pfizer, paid to his institution; and honoraria for data safety monitoring board or advisory board consultations from ViiV, MSD, Pfizer, Gilead, Moderna, AstraZeneca, AbbVie and Ely Lilly, paid to his institution. H.F.G. has received research grants from the Swiss National Science Foundation, Swiss HIV Cohort Study, Yvonne Jacob Foundation, NIH, Gilead, ViiV and Bill and Melinda Gates foundation, paid to his institution; personal honoraria for data safety monitoring board or advisory board consultations from Merck, ViiV healthcare, Gilead Sciences, Janssen, Johnson and Johnson, Novartis and GSK; and personal travel expenses from Gilead. J.N. received research grants from the Swiss HIV Cohort Study and the cantonal hospital St. Gallen, paid to her institution, and travel expenses from Gilead. K.J.M. received unrestricted research grants from Gilead and Novartis, paid to her institution, and personal honoraria for advisory board consultations from ViiV. M.C. received research grants from Gilead, ViiV and MSD, paid to his institution; payment for expert testimony from Gilead, ViiV and MSD, paid to his institution; and travel expenses from Gilead, paid to his institution. M.S. received honoraria for data safety monitoring board advisory board consultations from Gilead, ViiV, Moderna, Pfizer and MSD, paid to his institution, and travel expenses for conferences from Gilead, paid to his institution. P.F. received personal travel expenses from the University Zurich, payment for equipment from the University Zurich and personal honoraria for presentations from the University of Zurich. R.D.K. received research grants from Gilead and NIH, paid to his institution. All other authors report no potential conflicts., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Human immunodeficiency virus type 1 (HIV-1) infection is treated with antiretroviral therapy (ART), usually consisting of 2-3 different drugs, referred to as combination ART (cART). Our recent randomized clinical trial comparing a switch to dolutegravir monotherapy with continuation of cART in early-treated individuals demonstrated sustained virological suppression over 48 weeks. Here, we characterize the longitudinal landscape of the HIV-1 reservoir in these participants, with particular attention to potential differences between treatment groups regarding evidence of evolution as a proxy for low-level replication. Near full-length HIV-1 proviral polymerase chain reaction and next-generation sequencing was applied to longitudinal peripheral blood mononuclear cell samples to assess proviral evolution and the potential emergence of drug resistance mutations (DRMs). Neither an increase in genetic distance nor diversity over time was detected in participants of both treatment groups. Single proviral analysis showed high proportions of defective proviruses and low DRM numbers. No evidence for evolution during dolutegravir monotherapy was found in these early-treated individuals., Competing Interests: Potential conflicts of interest. D. L. B. reports honoraria for advisory boards from Gilead, Merck, and ViiV, outside the present work. K. J. M. has received travel grants and honoraria from Gilead Sciences, Roche Diagnostics, GlaxoSmithKline, Merck Sharp & Dohme, Bristol Myers Squibb, ViiV, and Abbott, and has received advisory board honoraria from Gilead Sciences and ViiV. The University of Zurich received research grants from Gilead Sciences, Novartis, Roche, and Merck Sharp & Dohme for studies for which K. J. M. serves as principal investigator. H. F. G. has received grants from the SNF, Swiss HIV Cohort Study, Yvonne Jacob Foundation, University of Zurich's Clinical Research Priority Program, Zurich Primary HIV Infection, Systems.X, NIH, Gilead Sciences, and Roche; personal fees from Merck, Gilead Sciences, ViiV, Janssen, GSK, Johnson & Johnson, and Novartis for consultancy or data and safety monitoring board membership; and a travel grant from Gilead. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

The European Pharmacopeia (EP) and the United States Pharmacopeia (USP) pyrogen test for parenterals involve the measurement of the temperature rise in rabbits following the intravenous injection of the test solution. Between the two methods, the conditions for the result "pyrogen free" or "pyrogen", as well as the number of rabbits tested, differ substantially. Therefore, both methods were compared with respect to the differences in temperature rise interpretations with special attention to the selectivity of the tests. To exclusively study the temperature rise interpretations, the temperature measurements were simulated with models. With an increasing mean temperature rise, an intermediate range exists where the probability of "pyrogen free" and of "pyrogen" cannot be ignored. A single pyrogen test still gives an unambiguous result, but in this range, the probability is rather high that additional tests will not reproduce the same result. This range is approximately 0.3 degrees C wide for the USP test and 0.2 degrees C wide for the EP test. Simulating the temperature rise with a normally distributed model, the intermediate range is narrower for the interpretation according to the EP than the USP. For a USP test, the probability of the test result "pyrogen free" decreases as lower mean temperature rises. However, the two methods are similar in the high probability range for the presence of pyrogens. At the edge of the intermediate range, a slight mean temperature rise of 0.05 degrees C significantly changes the probability of a pyrogen result. Within a rather wide mean temperature rise range (approximately 0.15 degrees C wide), a product will reliably fulfil the EP requirements but not the USP requirements. These main statements are rather robust and do not depend significantly on the model used. Different temperature rise distributions only result in negligible variations in the interpretation of the tests. Information more detailed than mean temperature rise and standard deviation of the temperature rises is not absolutely necessary. For product quality, it is much more useful to review and interpret all individual temperature rises measured than to interpret the results of the pyrogen test only [corrected].

We present a quantitative experimental comparison of fiber-based, single- and few-mode dynamic light scattering with the classical pinhole-detection optics. The recently presented theory of mode-selective dynamic light scattering [Appl. Opt. 32, 2860 (1993)] predicts a collection efficiency and a signal-tobaseline ratio superior to that of a classical pinhole setup. These predictions are confirmed by our experiments. Using single-mode optical fibers with different cutoff wavelengths and commercially available mechanical components, we have constructed a mode-selective detection optics in a simple and compact dynamic light-scattering spectrometer that permits an optimal compromise between signal intensity and dynamical resolution.