Adherence to prescribing restrictions for HER2-positive metastatic breast cancer in Australia: A national population-based observational study (2001-2016)

Background: Targeted cancer therapy is often complex, involving multiple agents and chemotherapeutic partners. In Australia, prescribing restrictions are put in place to reflect existing evidence of cost-effectiveness of these medicines. As therapeutic options continue to expand, these restrictions may not be perceived to align with best practice and it is not known if their use in the real-world clinic adheres to these restrictions. We examined the treatment of women receiving trastuzumab for HER2-positive metastatic breast cancer (HER2+MBC) to determine the extent to which treatment adhered to national prescribing restrictions. Patients and methods: Our population-based, retrospective cohort study used dispensing records for every Australian woman initiating publicly-subsidised trastuzumab for HER2+MBC between 2001±2013, followed through 2016. We used group-based trajectory models (GBTMs) to cluster patients, first on their patterns of trastuzumab exposure, and then on their patterns of lapatinib and chemotherapy exposure. We described the characteristics of patients within each cluster, and examined their treatments and combinations of treatments to determine restriction adherence. Results: Of 5,052 patients initiating trastuzumab, 1,795 (36%) received at least one non-adherent HER2-targeted treatment. The most common non-adherent treatments were trastuzumab combinations involving vinorelbine (24% of non-adherent treatments); capecitabine (24%); and anthracyclines (10%). Non-adherent lapatinib use was observed in 4% of patients. GBTM identified three trastuzumab exposure clusters, each containing three further subclusters. The largest proportions of non-adherent treatments were in sub-clusters with longer trastuzumab exposure and more non-taxane chemotherapy. Patients in these sub-clusters were younger than those in sub-clusters with less non-adherent treatment. Conclusions: Our study highlights that, even during the relatively simpler treatment era of our study period, a substantial amount of treatment did not adhere to prescribing restrictions. As more trials are conducted exploring pertuzumab and T-DM1 in combination with different chemotherapies and other HER2-targeted therapies, the regulation and funding of HER2-targeted treatment will become more challenging

Parental age influences offspring telomere loss

1. The age of the parents at the time of offspring production can influence offspring longevity, but the underlying mechanisms remain poorly understood. The effect of parental age on offspring telomere dynamics (length and loss rate) is one mechanism that could be important in this context. 2. Parental age might influence the telomere length that offspring inherit or age-related differences in the quality of parental care could influence the rate of offspring telomere loss. However, these routes have generally not been disentangled. 3. Here, we investigated whether parental age was related to offspring telomere dynamics using parents ranging in age from 2 to 22 years old in a free-living population of a long-lived seabird, the European shag (Phalacrocorax aristotelis). By measuring the telomere length of offspring at hatching and towards the end of the post-natal growth period, we could assess whether any potential parental age effect was confined to the post-natal rearing period. 4. There was no effect of maternal or paternal age on the initial telomere length of their chicks. However, chicks produced by older mothers and fathers experienced significantly greater telomere loss during the post-natal nestling growth period. We had relatively few nests in which the ages of both parents were known, and individuals in this population mate assortatively with respect to age. Thus, we could not conclusively determine whether the parental age effect was due to maternal age, paternal age, or both; however, it appears that the effect is stronger in mothers. 5. These results demonstrate that in this species, there was no evidence that parental age was related to offspring hatching telomere length. However, telomere loss during nestling growth was reduced in the offspring of older parents. This could be due to an age-related deterioration in the quality of the environment that parents provide, or because parents that invest less in offspring rearing live to an older age

Azole Drugs Are Imported By Facilitated Diffusion in Candida albicans and Other Pathogenic Fungi

Despite the wealth of knowledge regarding the mechanisms of action and the mechanisms of resistance to azole antifungals, very little is known about how the azoles are imported into pathogenic fungal cells. Here the in-vitro accumulation and import of Fluconazole (FLC) was examined in the pathogenic fungus, Candida albicans. In energized cells, FLC accumulation correlates inversely with expression of ATP-dependent efflux pumps. In de-energized cells, all strains accumulate FLC, suggesting that FLC import is not ATP-dependent. The kinetics of import in de-energized cells displays saturation kinetics with a Km of 0.64 uM and Vmax of 0.0056 pmol/min/108 cells, demonstrating that FLC import proceeds via facilitated diffusion through a transporter rather than passive diffusion. Other azoles inhibit FLC import on a mole/mole basis, suggesting that all azoles utilize the same facilitated diffusion mechanism. An analysis of related compounds indicates that competition for azole import depends on an aromatic ring and an imidazole or triazole ring together in one molecule. Import of FLC by facilitated diffusion is observed in other fungi, including Cryptococcus neoformans, Saccharomyces cerevisiae, and Candida krusei, indicating that the mechanism of transport is conserved among fungal species. FLC import was shown to vary among Candida albicans resistant clinical isolates, suggesting that altered facilitated diffusion may be a previously uncharacterized mechanism of resistance to azole drugs

Antidepressant and antipsychotic drug prescribing and diabetes outcomes: A systematic review of observational studies

AIMS: Psychotropic medication may be associated with adverse effects, including among people with diabetes. We conducted a systematic review of observational studies investigating the association between antidepressant or antipsychotic drug prescribing and type 2 diabetes outcomes. METHODS: We systematically searched PubMed, EMBASE, and PsycINFO to 15th August 2022 to identify eligible studies. We used the Newcastle-Ottawa scale to assess study quality and performed a narrative synthesis. RESULTS: We included 18 studies, 14 reporting on antidepressants and four on antipsychotics. There were 11 cohort studies, one self-controlled before and after study, two case-control studies, and four cross-sectional studies, of variable quality with highly heterogeneous study populations, exposure definitions, and outcomes analysed. Antidepressant prescribing may be associated with increased risk of macrovascular disease, whilst evidence on antidepressant and antipsychotic prescribing and glycaemic control was mixed. Few studies reported microvascular outcomes and risk factors other than glycaemic control. CONCLUSIONS: Studies of antidepressant and antipsychotic drug prescribing in relation to diabetes outcomes are scarce, with shortcomings and mixed findings. Until further evidence is available, people with diabetes prescribed antidepressants and antipsychotics should receive monitoring and appropriate treatment of risk factors and screening for complications as recommended in general diabetes guidelines

Ultra-Short-Chain PFASs in the Sources of German Drinking Water: Prevalent, Overlooked, Difficult to Remove, and Unregulated

acceptedVersio

Seasonal variation of zooplankton community structure and trophic position in the Celtic Sea: a stable isotope and biovolume spectrum approach

Zooplankton on continental shelves represent an important intermediary in the transfer of energy and matter from phytoplankton to the wider ecosystem. Their taxonomic composition and trophic interactions with phytoplankton vary in space and time, and interpreting the implications of this constantly evolving landscape remains a major challenge. Here we combine plankton taxonomic data with the analysis of biovolume spectra and stable isotopes to provide insights into the trophic interactions that occur in a shelf sea ecosystem (Celtic Sea) across the spring-summer-autumn transition. Biovolume spectra captured the seasonal development of the zooplankton community well, both in terms of total biomass and trophic positioning, and matched trophic positions estimated by stable isotope analysis. In early April, large microplankton (63-200 µm) occupied higher trophic positions than mesozooplankton (>200 µm), likely reflecting the predominance of nanoplankton (2-20 µm) that were not readily available to mesozooplankton grazers. Biomass and number of trophic levels increased during the spring bloom as elevated primary production allowed for a higher abundance of predatory species. During July, the plankton assemblage occupied relatively high trophic positions, indicating important links to the microbial loop and the recycling of organic matter. The strong correlation between biomass and community trophic level across the study suggests that the Celtic Sea is a relatively enclosed and predominantly energy-limited ecosystem. The progression of the zooplankton biomass and community structure within the central shelf region was different to that at the shelf-break, potentially reflecting increased predatory control of copepods by macrozooplankton and pelagic fishes at the shelf break. We suggest that the combination of size spectra and stable isotope techniques are highly complementary and useful for interpreting the seasonal progression of trophic interactions in the plankton

Pharmacokinetics, safety and tolerability of olaparib and temozolomide for recurrent glioblastoma: results of the phase I OPARATIC trial

Background: The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib potentiated radiation and temozolomide chemotherapy in pre-clinical glioblastoma models but brain penetration was poor. Clinically, PARP inhibitors exacerbate the hematological side-effects of temozolomide. The OPARATIC trial was conducted to measure penetration of recurrent glioblastoma by olaparib, and assess the safety and tolerability of its combination with temozolomide. Methods: Pre-clinical pharmacokinetic studies evaluated olaparib tissue distribution in rats and tumor-bearing mice. Adult patients with recurrent glioblastoma received various doses and schedules of olaparib and low-dose temozolomide in a 3+3 design. Suitable patients received olaparib prior to neurosurgical resection; olaparib concentrations in plasma, tumour core and tumour margin specimens were measured by mass spectrometry. A dose expansion cohort tested tolerability and efficacy of the recommended phase II dose (RP2D). Radiosensitizing effects of olaparib were measured by clonogenic survival in glioblastoma cell lines. Results: Olaparib was a substrate for multi-drug resistance protein-1 and showed no brain penetration in rats but was detected in orthotopic glioblastoma xenografts. Clinically, olaparib was detected in 71/71 tumor core specimens (27 patients, median 496nM) and 21/21 tumor margin specimens (9 patients, median 512.3nM). Olaparib exacerbated TMZ-related hematological toxicity, necessitating intermittent dosing. RP2D was olaparib 150mg (3 days/week) with TMZ 75mg/m2 daily for 42 days. Fourteen (36%) of 39 evaluable patients were progression-free at 6 months. Olaparib radiosensitized six glioblastoma cell lines at clinically relevant concentrations of 100 and 500 nM. Conclusions: Olaparib reliably penetrates recurrent glioblastoma at radiosensitizing concentrations, supporting further clinical development and highlighting the need for better pre-clinical models

The GstLAL Search Analysis Methods for Compact Binary Mergers in Advanced LIGO's Second and Advanced Virgo's First Observing Runs

After their successful first observing run (September 12, 2015 - January 12, 2016), the Advanced LIGO detectors were upgraded to increase their sensitivity for the second observing run (November 30, 2016 - August 26, 2017). The Advanced Virgo detector joined the second observing run on August 1, 2017. We discuss the updates that happened during this period in the GstLAL-based inspiral pipeline, which is used to detect gravitational waves from the coalescence of compact binaries both in low latency and an offline configuration. These updates include deployment of a zero-latency whitening filter to reduce the over-all latency of the pipeline by up to 32 seconds, incorporation of the Virgo data stream in the analysis, introduction of a single-detector search to analyze data from the periods when only one of the detectors is running, addition of new parameters to the likelihood ratio ranking statistic, increase in the parameter space of the search, and introduction of a template mass-dependent glitch-excision thresholding method.Comment: 12 pages, 7 figures, to be submitted to Phys. Rev. D, comments welcom

The GstLAL template bank for spinning compact binary mergers in the second observation run of Advanced LIGO and Virgo

We describe the methods used to construct the aligned-spin template bank of gravitational waveforms used by the GstLAL-based inspiral pipeline to analyze data from the second observing run of Advanced LIGO and Virgo. The bank expands upon the parameter space covered during the first observing run, including coverage for merging compact binary systems with total mass between 2 $\mathrm{M}_{\odot}$ and 400 $\mathrm{M}_{\odot}$ and mass ratios between 1 and 97.989. Thus the systems targeted include merging neutron star-neutron star systems, neutron star-black hole binaries, and black hole-black hole binaries expanding into the intermediate-mass range. Component masses less than 2 $\mathrm{M}_{\odot}$ have allowed (anti-)aligned spins between $\pm0.05$ while component masses greater than 2 $\mathrm{M}_{\odot}$ have allowed (anti-)aligned between $\pm0.999$. The bank placement technique combines a stochastic method with a new grid-bank method to better isolate noisy templates, resulting in a total of 677,000 templates.Comment: 9 pages, 13 figure