A pharmacometric multistate model for predicting long-term treatment outcomes of patients with pulmonary TB.

BACKGROUND: Studying long-term treatment outcomes of TB is time-consuming and impractical. Early and reliable biomarkers reflecting treatment response and capable of predicting long-term outcomes are urgently needed. OBJECTIVES: To develop a pharmacometric multistate model to evaluate the link between potential predictors and long-term outcomes. METHODS: Data were obtained from two Phase II clinical trials (TMC207-C208 and TMC207-C209) with bedaquiline on top of a multidrug background regimen. Patients were typically followed throughout a 24 week investigational treatment period plus a 96 week follow-up period. A five-state multistate model (active TB, converted, recurrent TB, dropout, and death) was developed to describe observed transitions. Evaluated predictors included patient characteristics, baseline TB disease severity and on-treatment biomarkers. RESULTS: A fast bacterial clearance in the first 2 weeks and low TB bacterial burden at baseline increased probability to achieve conversion, whereas patients with XDR-TB were less likely to reach conversion. Higher estimated mycobacterial load at the end of 24 week treatment increased the probability of recurrence. At 120 weeks, the model predicted 55% (95% prediction interval, 50%-60%), 6.5% (4.2%-9.0%) and 7.5% (5.2%-10%) of patients in converted, recurrent TB and death states, respectively. Simulations predicted a substantial increase of recurrence after 24 weeks in patients with slow bacterial clearance regardless of baseline bacterial burden. CONCLUSIONS: The developed multistate model successfully described TB treatment outcomes. The multistate modelling framework enables prediction of several outcomes simultaneously, and allows mechanistically sound investigation of novel promising predictors. This may help support future biomarker evaluation, clinical trial design and analysis.

Nanomaterial-based biosensors for avian influenza virus: A new way forward.

Avian influenza virus (AIV) is a zoonotic virus that can be transmitted from animals to humans. Although human infections are rare, the virus has a high mortality rate when contracted. Appropriate detection methods are thus crucial for combatting this pathogen. There is a growing demand for rapid, selective, and accurate methods of identifying the virus. Numerous biosensors have been designed and commercialized to detect AIV. However, they all have considerable shortcomings. Nanotechnology offers a new way forward. Nanomaterials produce more eco-friendly, rapid, and portable diagnostic systems. They also exhibit high sensitivity and selectivity while achieving a low detection limit (LOD). This paper reviews state-of-the-art nanomaterial-based biosensors for AIV detection, such as those composed of quantum dots, gold, silver, carbon, silica, nanodiamond, and other nanoparticles. It also offers insight into potential trial protocols for creating more effective methods of identifying AIV and discusses key issues associated with developing nanomaterial-based biosensors.

Changing surface ocean circulation caused the local demise of echinoid Scaphechinus mirabilis in Taiwan during the Pleistocene-Holocene transition.

Abundant fossil specimens of Scaphechinus mirabilis, now occurring mostly in temperate waters, have been found in the Toukoshan Formation (Pleistocene) in Miaoli County, Taiwan. Environmental changes leading to its extirpation (local extinction) have thus far been elusive. Here, we reconstruct past environmental and oceanic conditions off northwest Taiwan by analyzing clumped isotopes, as well as stable oxygen isotopes, of well-preserved fossil echinoid tests collected from the Toukoshan Formation. Radiocarbon dates suggest that these samples are from Marine Isotope Stage 3 (MIS 3). Paleotemperature estimates based on clumped isotopes indicate that fossil echinoids were living in oceanic conditions that range from 9 to 14 °C on average, comparable with the estimate derived for a modern sample from Mutsu Bay, Japan. Notably, this temperature range is ~ 10 °C colder than today's conditions off northwest Taiwan. The substantially lower temperatures during ~ 30 ka (MIS 3) compared to the modern conditions might be due to the rerouting of surface currents off northwest Taiwan when the sea level was ~ 60 m lower than today, in addition to the cooling caused by a lower atmospheric CO2 level during the Last Glacial Period. Colder waters brought here by the China Coastal Current (CCC) and the existence of shallow subtidal zones termed "Miaoli Bay" (mainly located in the present-day Miaoli county) during MIS 3 plausibly sustained generations of S. mirabilis, yielding tens of thousands of fossil specimens in the well-preserved fossil beds. The likely extirpation driver is the drastic change from a temperate climate to much warmer conditions in the shallow sea during the Pleistocene-Holocene transition.

Short-course daily isoniazid and rifapentine for latent tuberculosis infection in people living with HIV who received coformulated bictegravir/emtricitabine/tenofovir alafenamide.

INTRODUCTION: Short-course preventive therapy with 1-month course of daily administration of isoniazid (300-mg) plus rifapentine (600-mg) (1HP) and 3-month course of weekly administration of isoniazid (900-mg) plus rifapentine (900-mg) (3HP) has higher completion rates than 9-month course of daily isoniazid (9H) for individuals with latent tuberculosis infection (LTBI). We aimed to evaluate the effect, safety and tolerability of 1HP in people living with HIV (PLWH) and LTBI who received coformulated bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF). METHODS: PLWH testing positive by interferon-gamma release assay and having received BIC/FTC/TAF for >2 weeks with plasma HIV RNA load (PVL) <200 copies/ml were enrolled. BIC trough plasma concentrations and cytokine profiles were determined before the first dose (day 1/baseline), 24 h after the 14th (day 15) and 28th (day 29) doses of 1HP. PVL were determined on days 15 and 29 of 1HP and every 3 months subsequently after discontinuation of 1HP. RESULTS: From November 2019 to December 2020, 48 PLWH with LTBI were enrolled. One participant (2.1%) discontinued 1HP on day 15 due to fever and generalized rashes with PVL of 72 copies/ml, which was <50 copies/ml in three subsequent determinations while on BIC/FTC/TAF over the 12 months of follow-up. The percentages of BIC trough plasma concentrations above the protein-adjusted 95% effective concentration (paEC95 = 162 ng/ml) were 56.3% and 37.0% on days 15 and 29, respectively. The percentage of PVL <200 copies/ml was 91.7% on day 15, 97.8% on day 29 and 100% at both months 3 and 6. After a median observation of 52 weeks (interquartile range, 51-55), all participants continued BIC/FTC/TAF with a median PVL of 20 copies/ml (range 20-331). Except for the participant who discontinued 1HP because of allergic reactions, none of the participants had relevant symptoms or increases of the cytokine levels assessed between baseline and days 15 and 29 of 1HP. CONCLUSIONS: BIC/FTC/TAF in combination with 1HP was well tolerated with a high completion rate. BIC trough plasma concentrations were significantly decreased with concurrent use of 1HP among PLWH with LTBI. While transient viral blips were observed during 1HP without causing subsequent treatment failure, such combination should be applied with caution.

The Role of Intermittent Hypoxia on the Proliferative Inhibition of Rat Cerebellar Astrocytes.

Sleep apnea syndrome, characterized by intermittent hypoxia (IH), is linked with increased oxidative stress. This study investigates the mechanisms underlying IH and the effects of IH-induced oxidative stress on cerebellar astrocytes. Rat primary cerebellar astrocytes were kept in an incubator with an oscillating O2 concentration between 20% and 5% every 30 min for 1-4 days. Although the cell loss increased with the duration, the IH incubation didn't induce apoptosis or necrosis, but rather a G0/G1 cell cycle arrest of cerebellar astrocytes was noted. ROS accumulation was associated with cell loss during IH. PARP activation, resulting in p21 activation and cyclin D1 degradation was associated with cell cycle G0/G1 arrest of IH-treated cerebellar astrocytes. Our results suggest that IH induces cell loss by enhancing oxidative stress, PARP activation and cell cycle G0/G1 arrest in rat primary cerebellar astrocytes.

Poly (ADP-ribose) polymerase plays an important role in intermittent hypoxia-induced cell death in rat cerebellar granule cells.

BACKGROUND: Episodic cessation of airflow during sleep in patients with sleep apnea syndrome results in intermittent hypoxia (IH). Our aim was to investigate the effects of IH on cerebellar granule cells and to identify the mechanism of IH-induced cell death. METHODS: Cerebellar granule cells were freshly prepared from neonatal Sprague-Dawley rats. IH was created by culturing the cerebellar granule cells in the incubators with oscillating O2 concentration at 20% and 5% every 30 min for 1-4 days. The results of this study are based on image analysis using a confocal microscope and associated software. Cellular oxidative stress increased with increase in IH. In addition, the occurrence of cell death (apoptosis and necrosis) increased as the duration of IH increased, but decreased in the presence of an iron chelator (phenanthroline) or poly (ADP-ribose) polymerase (PARP) inhibitors [3-aminobenzamide (3-AB) and DPQ]. The fluorescence of caspase-3 remained the same regardless of the duration of IH, and Western blots did not detect activation of caspase-3. However, IH increased the ratio of apoptosis-inducing factor (AIF) translocation to the nucleus, while PARP inhibitors (3-AB) reduced this ratio. RESULTS: According to our findings, IH increased oxidative stress and subsequently leading to cell death. This effect was at least partially mediated by PARP activation, resulting in ATP depletion, calpain activation leading to AIF translocation to the nucleus. CONCLUSIONS: We suggest that IH induces cell death in rat primary cerebellar granule cells by stimulating oxidative stress PARP-mediated calpain and AIF activation.

In situ STM imaging of fused thienothiopene molecules adsorbed on Au(111) electrode.

In situ scanning tunneling microscopy (STM) was used to reveal the structures of dithieno[2,3-b:3,2-d]thiophene diphenyl (DTT) molecules deposited onto Au(111) electrode from a dosing solution made of dichlorobenzene and 50 muM DTT. Potential control was proven to be of prime importance in guiding the arrangement of DTT admolecules on Au(111) in 0.1 M HClO(4), as disorder DTT adlayer seen at E > 0.3 V (vs reversible hydrogen electrode) was transformed into a highly ordered (2 x 7 square root(3))rect -2DTT structure when the potential was made to 0.05 to 0.2 V. The ordered structure was stable for hours between 0.05 and 0.2 V. However, switching the potential further negative to 0 V resulted in slow melting of the ordered structure. The (2 x 7 square root(3))rect-DTT ordered adlattices recuperated when the potential was made positive to 0.2 V. Internal molecular functionalities of the thienothiophene and benzene in DTT admolecules were clearly discerned, from which the lateral structure for the (2 x 7 square root(3))rect-2DTT structure and registries of admolecules were deduced. The dynamics of the DTT adlattices on the Au(111) electrode surface was examined by real-time STM imaging, showing reorientation of as many as 150 DTT admolecules to join a neighboring ordered array within minutes.