The Impact of the COVID-19 Pandemic on Patient Disparities in Long-Term Opioid Therapy.

BACKGROUND: The COVID-19 pandemic disrupted how primary care patients with chronic pain received care. Our study sought to understand how long-term opioid therapy (LtOT) for chronic pain changed over the course of the pandemic overall and for different demographic subgroups. METHODS: We used data from electronic health records of 64 primary care clinics across Washington state and Idaho to identify patients who had a chronic pain diagnosis and were receiving long-term opioid therapy. We defined 10-month periods in 2019 to 2021 as prepandemic, early pandemic and late pandemic and used generalized estimating equations analysis to compare across these time periods and demographic characteristics. RESULTS: We found a proportional decrease in LtOT for chronic pain in the early months of the pandemic (OR = 0.94, P = .007) followed by an increase late pandemic (OR = 1.08, P = .002). Comparing late pandemic to prepandemic, identifying as Asian or Black, having fewer comorbidities, or living in an urban area were associated with higher likelihood of being prescribed LtOT. DISCUSSION: The use of LtOT for chronic pain in primary care has increased from before to after the COVID-19 pandemic with racial/ethnic and geographic disparities. Future research is needed to understand these disparities in LtOT and their effect on patient outcomes.

Effects of root-derived organic acids on sorption of pharmaceutically active compounds in sandy topsoil.

The presence and fate of pharmaceutically active compounds (PhACs) in agricultural fields are rarely investigated. The present study highlights that root-derived low-molecular-weight organic acids (LMWOAs) affect the mobility of PhACs in cultivated humic Arenosol. Sorption experiments are conducted using three PhACs characterised by different physicochemical properties: carbamazepine (CBZ), 17α-ethinylestradiol (EE2), and diclofenac-sodium (DFC). The results suggest that the adsorption of EE2 is more intense than the other two PhACs, whereas DFC and CBZ are primarily dominated by desorption. LMWOAs mainly provide additional low-energy adsorption sites for the PhACs, and slight pH changes do not significantly affect the sorption mechanism. During competitive adsorption, the high-energy sites of the adsorbents are initially occupied by EE2 owing to its high adsorption energy (∼15 kJ/mol). The new low-energy binding sites enhance the adsorption of DFC (from 8.5 % to 72.0 %) and CBZ (from 31.0 % to 70.0 %) during multicomponent adsorption. LMWOAs not only affect adsorption by modifying the pH but also provide additional binding sites that allow the PhACs to remain in the root environment for a longer period. As the concentration of LMWOAs temporarily changes, so does the availability of PhACs in the root zone. Environmental changes in the humic horizon enhance the mobility of the adsorbed PhACs, which renders them continuously available for uptake by plants, thus increasing the possibility of PhACs entering the human food chain.

A 4-year study of bovine reproductive hormones that are induced by pharmaceuticals and appear as steroid estrogenic pollutants in the resulting slurry, using in vitro and instrumental analytical methods.

The main objective of the research was to study the environmental "price" of the large-scale, milk production from a rarely known perspective, from the mapping of the estrogenic footprint (the amount of oestrus-inducer hormonal products, and the generated endoestrogens) in the resulting slurry in a dairy cow farm. These micropollutants are endocrine-disrupting chemicals (EDCs) and can be dangerous to the normal reproductive functions even at ng/kg concentration. One of them, 17ß-estradiol, has a 20,000 times stronger estrogenic effect than bisphenol-A, a widely known EDC of industrial origin. While most studies on EDCs are short-term and/or laboratory based, this study is longitudinal and field-based. We sampled the slurry pool on a quarterly basis between 2017 and 2020. Our purpose was testing the estrogenic effects using a dual approach. As an effect-based, holistic method, we developed and used the YES (yeast estrogen screen) test employing the genetically modified Saccharomyces cerevisiae BJ3505 strain which contains human estrogenic receptor. For testing exact molecules, UHPLC-FLD was used. Our study points out that slurry contains a growing amount of EDCs with the risk of penetrating into the soil, crops and the food chain. Considering the Green Chemistry concept, the most benign ways to prevent of the pollution of the slurry is choosing appropriate oestrus-inducing veterinary pharmaceuticals (OIVPs) and the separation of the solid and liquid parts with adequate treatment methods. To our knowledge, this is the first paper on the adaptation of the YES test for medicine and slurry samples, extending its applicability. The adapted YES test turned out to be a sensitive, robust and reliable method for testing samples with potential estrogenic effect. Our dual approach was successful in evaluating the estrogenic effect of the slurry samples.

Colorectal Cancer Organoid-Stroma Biobank Allows Subtype-Specific Assessment of Individualized Therapy Responses.

In colorectal cancers, the tumor microenvironment plays a key role in prognosis and therapy efficacy. Patient-derived tumor organoids (PDTO) show enormous potential for preclinical testing; however, cultured tumor cells lose important characteristics, including the consensus molecular subtypes (CMS). To better reflect the cellular heterogeneity, we established the colorectal cancer organoid-stroma biobank of matched PDTOs and cancer-associated fibroblasts (CAF) from 30 patients. Context-specific phenotyping showed that xenotransplantation or coculture with CAFs improves the transcriptomic fidelity and instructs subtype-specific stromal gene expression. Furthermore, functional profiling in coculture exposed CMS4-specific therapeutic resistance to gefitinib and SN-38 and prognostic expression signatures. Chemogenomic library screening identified patient- and therapy-dependent mechanisms of stromal resistance including MET as a common target. Our results demonstrate that colorectal cancer phenotypes are encrypted in the cancer epithelium in a plastic fashion that strongly depends on the context. Consequently, CAFs are essential for a faithful representation of molecular subtypes and therapy responses ex vivo. SIGNIFICANCE: Systematic characterization of the organoid-stroma biobank provides a resource for context dependency in colorectal cancer. We demonstrate a colorectal cancer subtype memory of PDTOs that is independent of specific driver mutations. Our data underscore the importance of functional profiling in cocultures for improved preclinical testing and identification of stromal resistance mechanisms. This article is featured in Selected Articles from This Issue, p. 2109.

Modelling adult stem cells and their niche in health and disease with epithelial organoids.

Adult stem cells are responsible for homoeostasis and regeneration of epithelial tissues. Stem cell function is regulated by both cell autonomous mechanisms as well as the niche. Deregulated stem cell function contributes to diseases such as cancer. Epithelial organoid cultures generated from tissue-resident adult stem cells have allowed unprecedented insights into the biology of epithelial tissues. The subsequent adaptation of organoid technology enabled the modelling of the communication of stem cells with their cellular and non-cellular niche as well as diseases. Starting from its first model described in 2009, the murine small intestinal organoid, we discuss here how epithelial organoid cultures have been become a prime in vitro research tool for cell and developmental biology, bioengineering, and biomedicine in the last decade.

Pharmaceuticals in water and sediment of small streams under the pressure of urbanization: Concentrations, interactions, and risks.

Small streams are crucial but vulnerable elements of ecological networks. To better understand the occurrence of pharmaceutically active compounds (PhACs) in streams, this study focused on the occurrence, distribution, and environmental risk of 111 PhACs and 7 trace elements based on a total of 141 water and sediment samples from small streams located in the urbanizing region of Budapest, Hungary. Eighty-one PhACs were detected in the aqueous phase, whereas sixty-two compounds were detected in the sediment. Carbamazepine (CBZ) was the most frequently identified PhAC in water, and was found in 91.5% of all samples. However, the highest concentrations were measured for lamotrigine (344.8 µg·L-1) and caffeine (221.4 µg·L-1). Lidocaine was the most frequently occurring PhAC in sediment (73.8%), but the maximum concentrations were detected for CBZ (395.9 ng·g-1) and tiapride (187.7 ng·g-1). In both water and sediment, more PhACs were found downstream of the wastewater treatment plants (WWTPs) than in the samples not affected by treated wastewater, even though no relationship was observed between the total amount of treated wastewater and the number of detected PhACs. The PhAC concentrations were also independent of the distance from the WWTP effluents. PhAC-polluted samples were detected upstream of the WWTPs, thereby suggesting the relevance of diffuse emissions in addition to WWTP outlets. The most frequently detected PhACs in the sediment were usually also present in the water samples collected at the same place and time. The varying concentrations of PhACs and the fluctuating water-sediment properties resulted in a lack of correlation between the general chemical properties and the concentrations of PhACs, which makes it difficult to predict PhAC contamination and risks in urbanized small streams. The environmental risk assessment indicated that diclofenac had the highest risk in the sampling area.

Evaluation of the effect of the intrinsic chemical properties of pharmaceutically active compounds (PhACs) on sorption behaviour in soils and goethite.

The role of the chemical properties of Pharmaceutically Active Compounds (PhACs) in their sorption behaviour and consequently in their fate and mobility is of major environmental interest, but a comprehensive evaluation is still lacking. The sorption of nine PhAC molecules with distinct physico-chemical properties on soils and goethite was described using linear, Freundlich and Langmuir models and the relationship between the chemical structures of the compounds and the parameters of the adsorption was evaluated using redundancy analysis (RDA). The latter showed that the sorption of the pharmaceuticals was determined by the intrinsic chemical characteristics of the molecules, as shown by the 35% value of constrained variability. For the hydrophobic estrogens, E1, E2 and EE2, the logD value and the number of hydrogen bond sites were found to be the main controlling factors for adsorption, indicating that hydrophobic interaction and hydrogen bonding are the dominant sorption mechanisms. The π energy of the molecules also proved a very important parameter, governing the retention of PhACs in soils, especially in the case of carbamazepine, oxazepam and lamotrigine. The main controlling factor for ionic compounds, such as diclofenac sodium, tramadol or lidocaine, is the fraction of PhACs present as charged species, revealing the importance of Coulomb forces. The results of this study will allow semi-quantitative predictions to be made on how the molecular structure governs the sorption of PhACs and which sorption mechanism could be involved.

Dataset of pharmaceuticals in the Danube and related drinking water wells in the Budapest region.

The present dataset provides data on the pharmaceutically active compounds (PhACs) concentrations measured in the Danube and the drinking water abstraction wells (DWAW) in the Budapest region. Grab samples were collected during five periods. One hundred and seven water samples from the Danube and ninety water samples from the relevant DWAWs were analyzed to quantify physical-chemical parameters, trace element concentrations, and one hundred and eleven PhACs, including pharmaceutical derivatives, illicit drugs, and alkaloids. The ion concentrations were measured using dual channel ion chromatography, spectrophotometric and titrimetric methods, and inductively coupled plasma mass spectrometry. PhACs concentrations were measured after solid-phase extraction applying supercritical fluid chromatography coupled with tandem mass spectrometry. Fifty-two PhACs were quantified in the Danube, and ten PhACs were present in >80% of the samples. Whereas thirty-two PhACs were quantified in the DWAWs. The present dataset is useful for further comparisons and meta-analyses.

Occurrence of pharmaceuticals in the Danube and drinking water wells: Efficiency of riverbank filtration.

Surface waters are becoming increasingly contaminated by pharmaceutically active compounds (PhACs), which is a potential risk factor for drinking water quality owing to incomplete riverbank filtration. This study examined the efficiency of riverbank filtration with regard to 111 PhACs in a highly urbanized section of the river Danube. One hundred seven samples from the Danube were compared to 90 water samples from relevant drinking water abstraction wells (DWAW) during five sampling periods. The presence of 52 PhACs was detected in the Danube, the quantification of 19 agents in this section of the river was without any precedent, and 10 PhACs were present in >80% of the samples. The most frequent PhACs showed higher concentrations in winter than in summer. In the DWAWs, 32 PhACs were quantified. For the majority of PhACs, the bank filtration efficiency was >95%, and not influenced by concentrations measured in the river. For carbamazepine lidocaine, tramadol, and lamotrigine, low (<50%) filtration efficiency was observed; however, no correlations were observed between the concentrations detected in the Danube and in the wells. These frequently occurring PhACs in surface waters have a relatively even distribution, and their sporadic appearance in wells is a function of both space and time, which may be caused by the constantly changing environment and micro-biological parameters, the dynamic operating schedule of abstraction wells, and the resulting sudden changes in flow rates. Due to the changes in the efficiency of riverbank filtration in space and time, predicting the occurrence and concentrations of these four PhACs poses a further challenge to ensuring a safe drinking water supply.

Investigation of the sorption of 17α-ethynylestradiol (EE2) on soils formed under aerobic and anaerobic conditions.

A study was conducted on the sorption of 17α-ethynylestradiol (EE2) on five soils formed under different redox conditions: an Arenosol (A_20) with fully aerobic conditions, two Gleysol samples (G_20 and G_40) with suboxic and anoxic conditions and two Histosols (H_20 and H_80) with mostly anoxic conditions. The soils were characterized on the basis of total organic carbon (TOC), specific surface area (SSA) and the Fourier transform infrared spectra of the humic acid and humin fractions (the soil remaining after alkali extraction) of the soil. The maximum adsorption capacity of the soils (Qmax) ranged from 10.7 to 83.6 mg/g in the order G_20 > H_20 > G_40 > A_20 > H_80, which reflected the organic matter content of the soils. The sorption isotherms were found to be nonlinear for all the soil samples, with Freundlich n values of 0.45-0.68. The strong nonlinearity found in the adsorption of the H_80 samples could be attributed to their high hard carbon content, which was confirmed by the high aromaticity of the humin fraction. The maximum sorption capacity (Qmax) of the soils did not increase indefinitely as the organic carbon content of the soils rose. There could be two reasons for this: (i) the large amount of organic matter may reduce the number of binding sites on the surface, and (ii) the decrease in SSA with increasing soil OC content may limit the ability to adsorb EE2 molecules. In anaerobic soil samples, where organic matter accumulation is pronounced, the amount of aromatic and phenolic compounds was higher than in better aerated soil profiles. Strong correlations were found between the amount of aromatic and phenolic compounds in the organic matter and the adsorption of EE2 molecules, indicating that π-π interaction and H-bonding are the dominant sorption mechanisms.

Thermal baths as sources of pharmaceutical and illicit drug contamination.

Despite the fact that there are tens of thousands of thermal baths in existence, knowledge about the occurrence of pharmaceutically active compounds (PhACs) in untreated thermal wastewater is very limited. Because used thermal water is typically legally discharged into surface waters without any treatment, the effluent poses environmental risks for the receiving water bodies. The aim of this study was to show the occurrence patterns and spatiotemporal characteristics of 111 PhACs in thermal wastewater. Six thermal water outflows of different thermal baths were tested in different seasons in the Budapest metropolitan region (Hungary), and diurnal analysis was performed. After solid-phase extraction, the samples were analysed and quantified by coupling supercritical fluid chromatography and mass spectrometry to perform simultaneous multi-residue drug analysis. The results confirm that water discharge pipes directly transport pharmaceuticals into surface water bodies; 34 PhACs were measured to be over the limit of quantification at least once, and 21 of them were found in more than one water sample. The local anaesthetic drug lidocaine, antiepileptic carbamazepine, analgesic derivative tramadol and illicit drug cocaine were detected in more than half of the samples. Caffeine, metoprolol and bisoprolol (cardiovascular drugs), benzoylecgonine (cocaine metabolite), diclofenac (NSAID), citalopram (antidepressant) and certain types of hormones also have a significant frequency of 30-50%. However, the occurrence and concentrations of PhACs vary according to the season and number/types of visitors. As demonstrated by the diurnal fluctuation, drug contamination of thermal waters can significantly vary, even for similar types of baths; furthermore, the quantity and types of some pollutants rapidly change in the discharged thermal wastewater.

Extracellular vesicle release from intestinal organoids is modulated by Apc mutation and other colorectal cancer progression factors.

Extracellular vesicles (EVs) are membrane-surrounded structures that transmit biologically important molecules from the releasing to target cells, thus providing a novel intercellular communication mechanism. Since EVs carry their cargo in a protected form and their secretion is generally increased in tumorigenesis, EVs hold a great potential for early cancer diagnosis. By 3D culturing, we provide evidence that colorectal cancer (CRC) patient-derived organoids, representing a state-of-the-art established and essential approach for studying human CRC, is a suitable model for EV analysis. When testing the effects of major factors promoting CRC progression on EV release in the organoid model, we observed that Apc mutation, leading to uncontrolled Wnt activation and thus to tumorigenesis in the vast majority in CRC patients, critically induces EV release by activating the Wnt pathway. Furthermore, the extracellular matrix component collagen, known to accumulate in tumorigenesis, enhances EV secretion as well. Importantly, we show that fibroblast-derived EVs induce colony formation of CRC organoid cells under hypoxia. In contrast, there was no major effect of tumor cell-derived EVs on the activation of fibroblasts. Collectively, our results with CRC and Apc-mutant adenoma organoids identify Apc mutation and collagen deposition as critical factors for increasing EV release from tumors. Furthermore, we provide evidence that stromal fibroblast-derived EVs contribute to tumorigenesis under unfavorable conditions in CRC.