Quantifying Isoniazid Levels in Small Hair Samples: A Novel Method for Assessing Adherence during the Treatment of Latent and Active Tuberculosis.

BackgroundTuberculosis (TB) is the leading cause of death from an infectious pathogen worldwide and the most prevalent opportunistic infection in people living with HIV. Isoniazid preventive therapy (IPT) reduces the incidence of active TB and reduces morbidity and mortality in HIV-infected patients independently of antiretroviral therapy. However, treatment of latent or active TB is lengthy and inter-patient variability in pharmacokinetics and adherence common. Current methods of assessing adherence to TB treatment using drug levels in plasma or urine assess short-term exposure and pose logistical challenges. Drug concentrations in hair assess long-term exposure and have demonstrated pharmacodynamic relevance in HIV.MethodsA large hair sample from a patient with active TB was obtained for assay development. Methods to pulverize hair and extract isoniazid were optimized and then the drug detected by liquid chromatography/ tandem mass spectrometry (LC/MS-MS). The method was validated for specificity, accuracy, precision, recovery, linearity and stability to establish the assay's suitability for therapeutic drug monitoring (TDM). Hair samples from patients on directly-observe isoniazid-based latent or active TB therapy from the San Francisco Department of Public Health TB clinic were then tested.ResultsOur LC/MS-MS-based assay detected isoniazid in quantities as low as 0.02ng/mg using 10-25 strands hair. Concentrations in spiked samples demonstrated linearity from 0.05-50ng/mg. Assay precision and accuracy for spiked quality-control samples were high, with an overall recovery rate of 79.5%. In 18 patients with latent or active TB on treatment, isoniazid was detected across a wide linear dynamic range.ConclusionsAn LC-MS/MS-based assay to quantify isoniazid levels in hair with performance characteristics suitable for TDM was developed and validated. Hair concentrations of isoniazid assess long-term exposure and may be useful for monitoring adherence to latent or active TB treatment in the setting of HIV

Climatic variability over the last 30,000 years recorded in La Piscina de Yuriria, a Central Mexican Crater lake

The Trans-Mexican Volcanic Belt provides an excellent setting for reconstruction of late Quaternary climate from different natural archives. Moreover human impact on the landscape since the mid Holocene provides a good opportunity to investigate the complex interplay of natural and anthropogenic forcing of landscape change. However despite the wealth of records, understanding of the environmental history of the region and its wider significance for climate change across the northern neotropics remains incomplete. We present a radiocarbon-dated, multiple-proxy (sedimentology, sedimentary geochemistry, ostracods, diatoms, stable isotopes) record of climatic and environmental change based on the lacustrine sediments from La Piscina de Yuriria, a hydrologically-closed volcanic crater in the northern TMVB. Much of the last glacial interval was characterised by low effective moisture associated with a weakened North American Monsoon (NAM) although the interval from 30,000 to 27,500 aBP experienced abrupt changes in rainfall. The period corresponding to the late glacial stadial was also dry and the lake may have dried out at this time. There was a change to wetter but variable conditions during the early Holocene as the NAM strengthened. Progressive drying during the later Holocene was accompanied by phases of catchment disturbance, which were partly the result of human impact

Association of anti-tuberculosis drug concentrations in hair and treatment outcomes in MDR- and XDR-TB.

Therapeutic drug monitoring for drug-resistant tuberculosis (TB) is likely to improve treatment outcomes. While assessments of plasma drug levels can explain pharmacokinetic variability among trial participants, these measures require phlebotomy and a cold chain, and are generally not repeated frequently enough to characterise drug exposure over time. Using a novel multi-analyte assay, we found evidence that higher anti-TB drug concentrations in hair, a non-biohazardous and noninvasively collected biomatrix, predict extensively-drug resistant-TB clinical outcomes in a high-burden setting

Exhumation history of the Higher Himalayan Crystalline along Dhauliganga-Goriganga river valleys, NW India: new constraints from fission track analysis

New apatite and zircon fission track data collected from two transects along the Dhauliganga and Goriganga rivers in the NW Himalaya document exhumation of the Higher Himalayan Crystalline units. Despite sharing the same structural configuration and rock types and being separated by only 60 km, the two study areas show very different patterns of exhumation. Fission track (FT) data from the Dhauliganga section show systematic changes in age (individual apatite FT ages range from 0.9 ± 0.3 to 3.6 ± 0.5 Ma, r 2 = 0.82) that record faster exhumation across a zone that extends from the Main Central Thrust to north of the Vaikrita thrust. By contrast, FT results from the Goriganga Valley show a stepwise change in ages across the Vaikrita thrust that suggests Quaternary thrust sense displacement. Footwall samples yield a weighted mean apatite age of 1.6 ± 0.1 Ma compared to 0.7 ± 0.04 Ma in the hanging wall. A constant zircon fission track age of 1.8 ± 0.4 Ma across both the footwall and hanging wall shows the 0.9 Ma difference in apatite ages is due to movement on the Vaikrita thrust that initiated soon after ∼1.8 Ma. The Goriganga section provides clear evidence for >1 Ma of tectonic deformation in the brittle crust that contrasts with previous exhumation studies in other areas of the high Himalaya ranges; these studies have been unable to decouple the role of climate erosion from tectonics. One possibility why there is a clear tectonic signal in the Goriganga Valley is that climate erosion has not yet fully adjusted to the tectonic perturbation

Groundwater–rock interactions in crystalline rocks: evidence from SIMS oxygen isotope data

The diffusive exchange of dissolved material between fluid flowing in a fracture and the enclosing wallrocks (rock matrix diffusion) has been proposed as a mechanism by which radionuclides derived from a radioactive waste repository may be removed from groundwater and incorporated into the geosphere. To test the effectiveness of diffusive exchange in igneous and metamorphic rocks, we have carried out an investigation of veins formed at low temperatures (<100°C), comparing the oxygen isotopic composition of vein calcite with that of secondary calcite in the wallrocks. Two examples of veins from the Borrowdale Volcanic Group, Cumbria, and one from the Mountsorrel Granodiorite, Leicestershire, UK, have remarkably similar vein calcite compositions, ca. +20‰(SMOW) or greater, substantially heavier than the probable compositions of the host rocks, and these vein calcite compositions are inferred to reflect the infiltrating fluid and the temperature of vein formation. Calcites from the wallrocks are similar to those in veins, with little evidence for exchange with the wallrocks. The results support existing models for this type of vein which suggest low-temperature growth from formation brines originally linked to Permian or Triassic evaporites. The results are consistent with flow through fractures being attenuated through a damage zone adjacent to the fracture and provide no evidence of diffusional exchange with pore waters from wallrocks

Natural analogue evidence for controls on radionuclide uptake by fractured crystalline rock

Fractured Crystalline Rocks (FCR) are being considered in several countries as hosts for radioactive waste repositories. In FCR, radionuclides may be transported relatively rapidly by bulk groundwater flow through open fractures, but much more slowly by diffusion through porewater in the rock matrices. Rock matrix diffusion (RMD) is the diffusion of radionuclides in the aqueous phase, between open fractures and rock matrices. Sorption or co-precipitation on the fracture surfaces and walls of the matrix pores causes further radionuclide retardation. RMD may be important in a repository's safety case and has been investigated by many published short-term (to a few years) laboratory and in-situ experiments. To improve understanding over longer timescales, we investigated evidence for RMD of several natural radioelements, and radioelement analogues, in five exemplar fractured crystalline rock (FCR) samples aged between c. 70 Ma and c. 455 Ma. The sample suite consisted of two samples of Borrowdale Volcanic Group (BVG) meta-tuff from northwest England, a sample of Carnmenellis Granite from southwest England and two samples of Toki Granite from central Japan. Uptake or loss of the studied elements is limited to an altered damage zone in each sample, coupled to mineral alteration processes. These zones are most extensive (a few tens of millimetres) in the Toki Granite samples. We also found unstable primary igneous minerals to persist in the immediate wallrocks of fractures in studied granite samples, suggesting that pores were not permanently water saturated in these samples. Although only a small sample suite was studied, the results show that while RMD may be important in some kinds of FCR, in others it may be negligible. Site-specific information is therefore needed to determine how much reliance can be placed on RMD when developing a safety case

Examining trends in the incidence of HIV infection among people with a history of drug use to inform an outbreak investigation and response: a retrospective cohort study

Background: In the context of an outbreak of HIV among people who inject drugs in Glasgow, Scotland, identified in 2015, our objectives were to: (1) develop epidemiological methods to estimate HIV incidence using data linkage, and (2) examine temporal changes in HIV incidence to inform public health responses. Methods: This was a retrospective cohort study involving data linkage of laboratory HIV testing data to identify individuals with a history of drug use. Person-years (PY) and Poisson regression were used to estimate incidence by time period (pre-outbreak: 2000–2010 and 2011–2013; early outbreak: 2014–2016; ongoing outbreak: 2017–2019). Results: Among 13 484 individuals tested for HIV, 144 incident HIV infections were observed from 2000 to 2019. Incidence rates increased from pre-outbreak periods (1.00/1000 PY (95% confidence interval, CI: 0.60–1.65) in 2000–2010 and 1.70/1000 PY (95% CI: 1.14–2.54) in 2011–2013) to 3.02/1000 PY (95% CI: 2.36–3.86) early outbreak (2014–2016) and 2.35 (95% CI 1.74–3.18) during the ongoing outbreak period (2017–2019). Compared with the pre-outbreak period (2000–2010), the incidence rates were significantly elevated during both the early outbreak (2014–16) (adjusted incidence rate ratio (aIRR) = 2.87, 95% CI: 1.62–5.09, p &lt; 0.001) and the ongoing outbreak periods (2017–19) (aIRR = 2.12, 95% CI: 1.16–3.90, p = 0.015). Conclusions: Public health responses helped to curb the rising incidence of HIV infection among people with a history of drug use in Glasgow, but further efforts are needed to reduce it to levels observed prior to the outbreak. Data linkage of routine diagnostic test data to assess and monitor incidence of HIV infection provided enhanced surveillance, which is important to inform outbreak investigations and guide national strategies on elimination of HIV transmission.</p

Intravenous sodium nitrite in acute ST-elevation myocardial infarction: a randomized controlled trial (NIAMI).

AIM: Despite prompt revascularization of acute myocardial infarction (AMI), substantial myocardial injury may occur, in part a consequence of ischaemia reperfusion injury (IRI). There has been considerable interest in therapies that may reduce IRI. In experimental models of AMI, sodium nitrite substantially reduces IRI. In this double-blind randomized placebo controlled parallel-group trial, we investigated the effects of sodium nitrite administered immediately prior to reperfusion in patients with acute ST-elevation myocardial infarction (STEMI). METHODS AND RESULTS: A total of 229 patients presenting with acute STEMI were randomized to receive either an i.v. infusion of 70 μmol sodium nitrite (n = 118) or matching placebo (n = 111) over 5 min immediately before primary percutaneous intervention (PPCI). Patients underwent cardiac magnetic resonance imaging (CMR) at 6-8 days and at 6 months and serial blood sampling was performed over 72 h for the measurement of plasma creatine kinase (CK) and Troponin I. Myocardial infarct size (extent of late gadolinium enhancement at 6-8 days by CMR-the primary endpoint) did not differ between nitrite and placebo groups after adjustment for area at risk, diabetes status, and centre (effect size -0.7% 95% CI: -2.2%, +0.7%; P = 0.34). There were no significant differences in any of the secondary endpoints, including plasma troponin I and CK area under the curve, left ventricular volumes (LV), and ejection fraction (EF) measured at 6-8 days and at 6 months and final infarct size (FIS) measured at 6 months. CONCLUSIONS: Sodium nitrite administered intravenously immediately prior to reperfusion in patients with acute STEMI does not reduce infarct size