Qualitative Interviews with Stakeholders in Herbal Pharmacovigilance and Recommendations for Best Practices to be Applied Worldwide.

BACKGROUND AND OBJECTIVE: The use of herbal products globally is substantial, but varying definitions and regulatory frameworks have led to differences in their status as medicinal products and in approaches to monitoring their safety. This article explores the current landscape of herbal pharmacovigilance, drawing insights from interviews with global experts in the field, and offers recommendations for best practices to enhance the safety and benefit-to-harm balance of herbal products. METHODS: This study comprised semi-structured interviews with members of the International Society of Pharmacovigilance-Herbal and Traditional Medicines Special Interest Group and the Nutrivigilance Information Exchange Network, recruited using purposive sampling. Data were stored and coded using NVIVO® and analysed thematically using a qualitative inductive approach. RESULTS: Sixteen participants from 11 countries were interviewed, revealing diverse regulatory approaches and challenges in herbal pharmacovigilance. Key themes included legal status, awareness, identification and coding of herbal products, pre-/post-marketing product control, reporting of adverse drug reactions, causality assessment and signals of herbal products. This study yielded five general recommendations to further improve herbal pharmacovigilance worldwide. CONCLUSIONS: This study offers an overview of the global landscape of herbal pharmacovigilance, highlighting challenges in monitoring herbal products and presenting universal recommendations. These recommendations encompass increasing awareness, enhancing education and improving legislative frameworks. Given the growing use of herbal products, the implementation of strong pharmacovigilance practices is crucial to ensure consumer safety.

Efficient point-based simulation of four-way coupled particles in turbulence at high number density.

In many natural and industrial applications, turbulent flows encompass some form of dispersed particles. Although this type of multiphase turbulent flow is omnipresent, its numerical modeling has proven to be a remarkably challenging problem. Models that fully resolve the particle phase are computationally very expensive, strongly limiting the number of particles that can be considered in practice. This warrants the need for efficient reduced order modeling of the complex system of particles in turbulence that can handle high number densities of particles. Here we present an efficient method for point-based simulation of particles in turbulence that are four-way coupled. In contrast with traditional one-way coupled simulations, where only the effect of the fluid phase on the particle phase is modeled, this method additionally captures the back-reaction of the particle phase on the fluid phase, as well as the interactions between particles themselves. We focus on the most challenging case of very light particles or bubbles, which show strong clustering in the high-vorticity regions of the fluid. This strong clustering poses numerical difficulties which are systematically treated in our work. Our method is valid in the limit of small particles with respect to the Kolmogorov scales of the flow and is able to handle very large number densities of particles. This methods paves the way for comprehensive studies of the collective effect of small particles in fluid turbulence for a multitude of applications.

Developing Medication Reviews to Improve the Aruban Healthcare System: A Mixed-Methods Pilot Study.

This study investigated whether and how medication reviews (MRs) conducted by pharmacists and general practitioners (GPs) with patient involvement can be performed on the island of Aruba (Dutch Caribbean). In this mixed-methods pilot study (both qualitative and quantitative), constructive and observational methodologies were combined. Healthcare providers' and patients' views on MRs and aspects of Aruban healthcare and culture relevant to MRs were examined. These insights were used to develop a protocol for conducting and implementing MRs in Aruba. Surveys were distributed and semi-structured interviews were held among Aruban community pharmacists and GPs, and a pilot program was created in which MRs were carried out with four Aruban patients and their GPs. According to the included healthcare providers, the main purpose of MRs is to optimize the patient experience and achieve concordance. Even though pharmacists and GPs consider their partnership equal, they have different views as to who should bear which responsibility in the MR process in matters regarding patient selection and follow-up. Common Aruban themes that were mentioned by the healthcare providers and deemed relevant for conducting MRs included behaviour/culture, healthcare, lifestyle, and therapy compliance. Anamnesis should be concise during the MR, and questions about medication storage, concerns, beliefs, and practical problems, as well as checks for limited health literacy, were considered important. In the pilot, at least three to, maximally, eight pharmacotherapy-related problems (PRPs) were detected per MR consultation, such as an incorrect dosage of acetylsalicylic acid, an inappropriate combination tablet for blood pressure regulation, and the absence of important laboratory values. All patients considered their consultation to be positive and of added value. In addition, it was observed that an MR can potentially generate cost savings. The information obtained from the healthcare providers and patients, together with the basic principles for MRs, as applied in the Netherlands, led to a definitive and promising MR format with practical recommendations for community pharmacists in Aruba: in comparison with the Dutch MR approach, GPs and pharmacists in Aruba could collaborate more on patient selection for MRs and their follow-up, because of their specific knowledge regarding the medications patients are taking chronically (pharmacists), and possible low levels of health literacy (GPs). Taking into account the Aruban culture, pharmacists could ask extra questions during MRs, referring to lifestyle (high prevalence of obesity), readability of medication labels (limited literacy), and herbal product use (Latin American culture). GPs and medical specialists sometimes experience miscommunication regarding the prescription of medication, which means that pharmacists must carefully take into account possible duplicate medications or interactions.

QTL discovery for agronomic and quality traits in diploid potato clones using PotatoMASH amplicon sequencing.

We genotyped a population of 618 diploid potato clones derived from six independent potato-breeding programmes from NW-Europe. The diploids were phenotyped for 23 traits, using standardised protocols and common check varieties, enabling us to derive whole population estimators for most traits. We subsequently performed a Genome-Wide Association Study (GWAS) to identify quantitative trait loci (QTL) for all traits with SNPs and short-read haplotypes derived from read-backed phasing. In this study, we used a marker platform called PotatoMASH (Potato Multi-Allele Scanning Haplotags); a pooled multiplex amplicon sequencing based approach. Through this method, neighbouring SNPs within an amplicon can be combined to generate multi-allelic short-read haplotypes (haplotags) that capture recombination history between the constituent SNPs, and reflect the allelic diversity of a given locus in a different way than single bi-allelic SNPs. We found a total of 37 unique QTL across both marker types. A core of 10 QTL were detected with SNPs as well as with haplotags. Haplotags allowed to detect an additional 14 QTL not found based on the SNP set. Conversely, the bi-allelic SNP set also found 13 QTL not detectable using the haplotag set. We conclude that both marker types should routinely be used in parallel to maximize the QTL detection power. We report 19 novel QTL for nine traits: Skin Smoothness, Sprout Dormancy, Total Tuber Number, Tuber Length, Yield, Chipping Colour, After-cooking Blackening, Cooking Type and Eye depth.

Evaluation of a super powerful bone-anchored hearing system and its users: A retrospective study.

INTRODUCTION: Although the Baha 5SP has been commercially available for six years, very few studies have been performed on the device's efficacy. The current study aims to evaluate the characteristics and audiological results in patients with severe-to-profound mixed hearing loss fitted with this superpower sound processor. METHODS: This retrospective evaluation was conducted at a tertiary referral centre where a series of 82 adult patients with severe-to-profound mixed hearing loss were implanted with a percutaneous bone-anchored hearing system and fitted with a superpower sound processor between 2016 and 2019. Patients with incomplete or unreliable audiological data (n = 24) were excluded, resulting in 58 data sets for analysis. The main outcome measures were unaided and aided pure-tone thresholds and aided free-field speech perception in quiet. RESULTS: The median unaided air conduction (AC) threshold averaged across 0.5, 1 and 2 kHz (PTA0.5-2kHz) of all patients was 75 dB hearing loss (HL); the median unaided AC averaged across 1, 2 and 4 kHz (PTA1-4kHz) was 84 dB HL. For bone conduction and direct bone conduction, the median PTA0.5-2kHz was 52 and 47 dB HL, respectively. With the superpower device, the median free-field speech reception threshold was 54 dB sound pressure level (SPL), and the median speech perception score at 65 dB SPL was 80%. CONCLUSIONS: At least 75% of the patients reached a maximum phoneme score of 70%. For patients with lower scores, the superpower device still provides a substantial hearing benefit. This makes the superpower device particularly suitable for patients with severe-to-profound mixed hearing loss with a contraindication for conventional hearing aids and/or cochlear implants.

Comparative electrophysiological characterization of ammodytoxin A, a ß-neurotoxin from the nose-horned viper venom, and its enzymatically inactive mutant.

Presynaptic- or ß-neurotoxicity of secreted phospholipases A2 (sPLA2) is a complex process. For full expression of ß-neurotoxicity, the enzymatic activity of the toxin is essential. However, it has been shown that not all toxic effects of a ß-neurotoxin depend on its enzymatic activity, for example, the inhibition of mitochondrial cytochrome c oxidase. The main objective of this study was to verify whether it is possible to observe and study the phospholipase-independent actions of ß-neurotoxins by a standard ex vivo twitch-tension experimental approach. To this end, we compared the effects of a potent snake venom ß-neurotoxin, ammodytoxin A (AtxA), and its enzymatically inactive mutant AtxA(D49S) on muscle contraction of the mouse phrenic nerve-hemidiaphragm preparation. While AtxA significantly affected the amplitude of the indirectly evoked isometric muscle contraction, the resting tension of the neuromuscular (NM) preparation, the amplitude of the end-plate potential (EPP), the EPP half decay time and the resting membrane potential, AtxA(D49S) without enzymatic activity did not. From this, we can conclude that the effects of AtxA independent of enzymatic activity cannot be studied with classical electrophysiological measurements on the isolated NM preparation. Our results also suggest that the inhibition of cytochrome c oxidase activity by AtxA is not involved in the rapid NM blockade by this ß-neurotoxin, but that its pathological consequences are rather long-term. Interestingly, in our experimental setup, AtxA upon direct stimulation reduced the amplitude of muscle contraction and induced contracture of the hemidiaphragm, effects that could be interpreted as myotoxic.

Development and Implementation of an Ultraviolet-Dye-Based Qualification Procedure for Hand Washing and Disinfection to Improve Quality Assurance of Pharmacy Preparations and Compounding, Especially in Cleanrooms: A Pilot Study.

Even though, nowadays, most medicines are manufactured industrially, patients may have medical needs that can only be met by a tailor-made approach. This requires the availability of pharmacy preparations made under Good Manufacturing Practice (GMP) conditions. An efficient hand hygiene practice is essential herewith, especially if sterile products that are prepared in a cleanroom are concerned. The effectiveness of hand washing and hand disinfection procedures greatly relies on adequate training. We carried out an observational cross-sectional pilot study aimed at optimizing hand hygiene training with objective and measurable quality assessments using an ultraviolet (UV) dye. Practical acceptance criteria for qualifying personnel through this method were set and evaluated. In total, 25 GMP-qualified cleanroom operators washed and disinfected their hands with UV dye hand wash lotion and UV dye hand alcohol, respectively. To obtain a proof-of-concept, the results were judged based on adherence to the WHO six-step protocol and associated acceptance criteria. Commonly missed areas were brought to light, and the influence of procedure duration was investigated. UV-dye-based assessments appeared to be more valuable in hand disinfection than in hand washing. In both procedures, the back of the hands and the thumbs were frequently missed. This underpins the need for enhanced and repeated education on hand washing and disinfection. Additionally, a dry skin gave rise to extra cleaning challenges. From this pharmacy practice pilot study with a focus on pharmaceutical product care, it may be concluded that the application of UV-dye-based assessments offers valuable insights for pharmacists to optimize hand hygiene, thereby increasing the safety of tailor-made medicines and on-site preparations.

Single organ metastatic sites in non-small cell lung cancer: Patient characteristics, treatment patterns and outcomes from a large retrospective Canadian cohort.

BACKGROUND: There is a paucity of information about the characteristics, treatment patterns, and outcomes of non-small cell lung cancer (NSCLC) patients with single organ metastasis (SOM). METHODS: This retrospective cohort study includes all patients with a diagnosis of stage IV NSCLC diagnosed from 2014 to 2016 and treated at Princess Margaret Cancer Centre. We compared baseline characteristics and patterns of metastatic sites between patients with SOM versus multiple (M)OM. Additionally, we identified treatment modalities and outcomes for patients with SOM. Cox multivariable models (MVA) were utilized to evaluate differences in overall survival (OS) between the SOM and MOM cohorts. RESULTS: Of 893 pts analyzed, 457 (51 %) had SOM, while 436 (49 %) had MOM at initial diagnosis. Demographics were comparable between the two groups. Brain was the most common site of metastasis for SOM patients. When compared to the MOM group, the SOM group had lower percentages of liver and adrenal metastases. Amongst SOM patients, 54 % received single modality treatment, and 20 % did not receive any treatment for their SOM. In MVA, patients with liver (HR 2.4), bone (HR 1.8), and pleural (HR 1.7) metastasis as their SOM site had the worst outcomes, with median OS of 6.8 months, 12.1 months, and 13.0 months respectively. Patients with SOM had a significantly improved median OS compared to those with MOM (15.9 months vs. 10.6 months; HR 0.56, 95 % CI 0.47-0.66, p < 0.001). CONCLUSION: In NSCLC patients who presented with SOM, survival correlated with the initial organ involved and was better overall compared to patients with MOM. SOM NSCLC may benefit from specific management strategies and SOM patients could be considered as a specific subgroup for survival analyses in observational and non-randomized interventional studies. In clinical trials, SOM can be considered as a stratification factor in the future.

The Therapeutic Potential of Essential Oils in Managing Inflammatory Skin Conditions: A Scoping Review.

Conventional therapy is commonly used for the treatment of inflammatory skin conditions, but undesirable effects, such as erythema, dryness, skin thinning, and resistance to treatment, may cause poor patient compliance. Therefore, patients may seek complementary treatment with herbal plant products including essential oils (EOs). This scoping review aims to generate a broad overview of the EOs used to treat inflammatory skin conditions, namely, acne vulgaris, dermatitis and eczema, psoriasis, and rosacea, in a clinical setting. The quality, efficacy, and safety of various EOs, as well as the way in which they are prepared, are reviewed, and the potential, as well as the limitations, of EOs for the treatment of inflammatory skin conditions are discussed. Twenty-nine eligible studies (case studies, uncontrolled clinical studies, and randomized clinical studies) on the applications of EOs for inflammatory skin conditions were retrieved from scientific electronic databases (PubMed, Embase, Scopus, and the Cochrane Library). As an initial result, tea tree (Melaleuca alternifolia) oil emerged as the most studied EO. The clinical studies with tea tree oil gel for acne treatment showed an efficacy with fewer adverse reactions compared to conventional treatments. The uncontrolled studies indicated the potential efficacy of ajwain (Trachyspermum ammi) oil, eucalyptus (Eucalyptus globulus) oil, and cedarwood (Cedrus libani) oil in the treatment of acne, but further research is required to reach conclusive evidence. The placebo-controlled studies revealed the positive effects of kanuka (Kunzea ericoides) oil and frankincense (Boswellia spp.) oil in the treatment of psoriasis and eczema. The quality verification of the EO products was inconsistent, with some studies lacking analyses and transparency. The quality limitations of some studies included a small sample size, a short duration, and the absence of a control group. This present review underscores the need for extended, well-designed clinical studies to further assess the efficacy and safety of EOs for treating inflammatory skin conditions with products of assured quality and to further elucidate the mechanisms of action involved.

Identification of two mutant JASON-RELATED genes associated with unreduced pollen production in potato.

KEY MESSAGE: Multiple QTLs control unreduced pollen production in potato. Two major-effect QTLs co-locate with mutant alleles of genes with homology to AtJAS, a known regulator of meiotic spindle orientation. In diploid potato the production of unreduced gametes with a diploid (2n) rather than a haploid (n) number of chromosomes has been widely reported. Besides their evolutionary important role in sexual polyploidisation, unreduced gametes also have a practical value for potato breeding as a bridge between diploid and tetraploid germplasm. Although early articles argued for a monogenic recessive inheritance, the genetic basis of unreduced pollen production in potato has remained elusive. Here, three diploid full-sib populations were genotyped with an amplicon sequencing approach and phenotyped for unreduced pollen production across two growing seasons. We identified two minor-effect and three major-effect QTLs regulating this trait. The two QTLs with the largest effect displayed a recessive inheritance and an additive interaction. Both QTLs co-localised with genes encoding for putative AtJAS homologs, a key regulator of meiosis II spindle orientation in Arabidopsis thaliana. The function of these candidate genes is consistent with the cytological phenotype of mis-oriented metaphase II plates observed in the parental clones. The alleles associated with elevated levels of unreduced pollen showed deleterious mutation events: an exonic transposon insert causing a premature stop, and an amino acid change within a highly conserved domain. Taken together, our findings shed light on the natural variation underlying unreduced pollen production in potato and will facilitate interploidy breeding by enabling marker-assisted selection for this trait.

Effect of Fungicide and Timing of Application on Management of Phoma Black Stem of Cultivated Sunflowers in the United States.

Phoma black stem (PBS), caused by Phoma macdonaldii Boerema (teleomorph Leptosphaeria lindquistii Frezzi), is the most common stem disease of sunflower (Helianthus annuus L.) in the northern Great Plains region of the United States. However, the impact of PBS on sunflower yield in the United States is unclear, and a near complete absence of information on the impact of fungicides on disease management exists. The objectives of this study were to determine the impact of PBS on sunflower yield, the efficacy of available fungicides, the optimal fungicide application timing, and the economic viability of fungicides as a management tool. Fungicide timing efficacy was evaluated by applying single and/or sequential applications of pyraclostrobin fungicide at three sunflower growth stages in 10 field trials between 2017 and 2019. Efficacy of 10 fungicides from the Fungicide Resistance Action Committee (FRAC) groups 3, 7, and 11 were evaluated in four field trials between 2018 and 2019. The impact of treatments on PBS were evaluated by determination of incidence, severity, maximum lesion height, disease severity index (DSI), and harvested yield. Nine of the 10 fungicides evaluated and all fungicide timings that included an early bud application resulted in disease reductions when compared with the nontreated controls. The DSI was negatively correlated to sunflower yield in high-yield environments (P = 0.0004; R2 = 0.3425) but not in low- or moderate-yield environments. Although FRAC 7 fungicides were generally most efficacious, the sufficient efficacy and lower cost of FRAC 11 fungicides make them more economically viable in high-yielding environments at current market conditions.

Key considerations in navigating ticagrelor's reported effect on heparin-induced thrombocytopenia functional assays in a landscape of limited data.

PURPOSE: This article discusses key considerations regarding ticagrelor's reported effect on heparin-induced thrombocytopenia functional assays, such as literature gaps and possible management strategies. SUMMARY: Limited data indicate that ticagrelor may induce false-negative results in functional assays used in the diagnosis of heparin-induced thrombocytopenia. False-negative functional assays for heparin-induced thrombocytopenia could have catastrophic consequences. The manufacturer labeling of ticagrelor now includes a warning for this potential drug-laboratory interaction. This article suggests areas that would benefit from further research and strategies in navigating this possible interaction. CONCLUSION: Clinicians should exercise caution when evaluating functional assays for heparin-induced thrombocytopenia in patients receiving ticagrelor. This article offers suggestions for future areas of research and potential management strategies.

Crossover shortage in potato is caused by StMSH4 mutant alleles and leads to either highly uniform unreduced pollen or sterility.

The balanced segregation of homologous chromosomes during meiosis is essential for fertility and is mediated by crossovers (COs). A strong reduction of CO number leads to the unpairing of homologous chromosomes after the withdrawal of the synaptonemal complex. This results in the random segregation of univalents during meiosis I and ultimately to the production of unbalanced and sterile gametes. However, if CO shortage is combined with another meiotic alteration that restitutes the first meiotic division, then uniform and balanced unreduced male gametes, essentially composed of nonrecombinant homologs, are produced. This mitosis-like division is of interest to breeders because it transmits most of the parental heterozygosity to the gametes. In potato, CO shortage, a recessive trait previously referred to as desynapsis, was tentatively mapped to chromosome 8. In this article, we have fine-mapped the position of the CO shortage locus and identified StMSH4, an essential component of the class I CO pathway, as the most likely candidate gene. A 7 base-pair insertion in the second exon of StMSH4 was found to be associated with CO shortage in our mapping population. We also identified a second allele with a 3,820 base-pair insertion and confirmed that both alleles cannot complement each other. Such nonfunctional alleles appear to be common in potato cultivars. More than half of the varieties we tested are carriers of mutational load at the StMSH4 locus. With this new information, breeders can choose to remove alleles associated with CO shortage from their germplasm to improve fertility or to use them to produce highly uniform unreduced male gametes in alternative breeding schemes.

Effect of Laser-Exposed Volume and Irradiation Position on Nonphotochemical Laser-Induced Nucleation of Potassium Chloride Solutions.

Herein, we study the influences of the laser-exposed volume and the irradiation position on the nonphotochemical laser-induced nucleation (NPLIN) of supersaturated potassium chloride solutions in water. The effect of the exposed volume on the NPLIN probability was studied by exposing distinct milliliter-scale volumes of aqueous potassium chloride solutions stored in vials at two different supersaturations (1.034 and 1.050) and laser intensities (10 and 23 MW/cm2). Higher NPLIN probabilities were observed with increasing laser-exposed volume as well as with increasing supersaturation and laser intensity. The measured NPLIN probabilities at different exposed volumes are questioned in the context of the dielectric polarization mechanism and classical nucleation theory. No significant change in the NPLIN probability was observed when samples were irradiated at the bottom, top, or middle of the vial. However, a significant increase in the nucleation probability was observed upon irradiation through the solution meniscus. We discuss these results in terms of mechanisms proposed for NPLIN.

ZnO-based heterojunction catalysts for the photocatalytic degradation of methyl orange dye.

In this study, a variety of ZnO-based heterojunctions with disparate wt.% doping of WO3 and BiOI have been prepared for the photodestruction of methyl orange (MO) dye in aqueous solution. The composites were analysed by scanning electron microscopy, energy-dispersive X-ray spectroscopy, X-ray diffraction, optical studies, and nitrogen adsorption-desorption isotherms. The SEM images revealed non-uniform surfaces of the ZnO-BiOI based composites while mostly nodular morphology was observed for all three samples of ZnO-WO3. As the WO3 loading increased, more clustering was detected. The analysed samples exhibited characteristic peaks representative of the triclinic phase of WO3 and the hexagonal wurtzite structure of ZnO, while the diffractogram observed from the materials displayed distinct peaks corresponding to the crystalline phases of both BiOI and ZnO in their pure forms. Further evidence of the samples' characteristics includes the presence of distinct crystalline patterns without any impurity peaks, a red shift in the absorption spectra of the heterostructure, the detection of only the reference elements, and mostly Type IV isotherm adsorption. This study identified the ZnO-[10%]BiOI and ZnO-[10%]WO3 heterojunctions as the best performing photocatalysts, as MO was completely destroyed in 120 and 90 min, respectively. Thus, confirming 10% wt. as the optimal doping concentration for the best photo-activity in this study. The impact of varying process parameters demonstrates that at an elevated photocatalyst mass of 40 mg, both heterojunctions effectively degraded MO. The photodegradation efficiency of MO was more pronounced in strong acidic conditions (pH 2) when compared to high alkaline conditions (pH 11) for the ZnO-[10%]BiOI heterostructure. However, a decrease in performance was observed for both strong acidic and high alkaline pH values when the ZnO-[10%]WO3 heterostructure was applied. The kinetic analysis of the photodegradation study reveals that all the photodegradation experiments can be represented by the pseudo-first-order kinetic model. The findings from this investigation propose that the ZnO-[10%]BiOI heterojunction photocatalyst holds significant potential for the effective treatment of dye-contaminated wastewater.

Analysis of Safety Concerns on Herbal Products with Assumed Phytoestrogenic Activity.

Phytoestrogens (PEs) are plant-based compounds that can interact with estrogen receptors and are mainly used to treat menopausal complaints. However, the safety of products with assumed phytoestrogenic activity is not fully understood. This study aimed to identify plant species with assumed phytoestrogenic activity, review existing literature on their use and safety, and critically evaluate adverse reaction (AR) reports of single-herb, multi-herb, and mixed-multiple products, as submitted to the Netherlands Pharmacovigilance Centre Lareb and to VigiBase of the World Health Organization (WHO). In the Lareb database, the most commonly reported plant species to cause ARs (total of 67 reports) were Actaea racemosa L. (black cohosh) (47.8%), Humulus lupulus L. (hops) (32.8%), and Glycine max (L.) Merr. (soybean) (22.4%). In the VigiBase database (total of 21,944 reports), the top three consisted of Glycine max (L.) Merr. (71.4%), Actaea racemosa L. (11.6%), and Vitex agnus-castus L. (chaste tree) (6.4%). In the scoping review (total of 73 articles), Actaea racemosa L. (30.1%), Glycine max (L.) Merr. (28.8%), and Trifolium pratense L. (13.7%) were the most frequently mentioned plant species. ARs were most frequently reported in the system organ classes "gastrointestinal disorders", "skin and subcutaneous tissue disorders", "reproductive system and breast disorders", and "general disorders and administration site conditions". Furthermore, from the scoping review, it appeared that the use of products with assumed phytoestrogenic activity was associated with postmenopausal bleeding. It was concluded that, while the potential benefits of products with assumed phytoestrogenic activity have been extensively pursued, the potential occurrence of ARs after using these products is less well understood. This study highlights the need for further investigation and careful monitoring of these products to better understand their effects and ensure the safety and well-being of individuals using them.

Design and Validation of a Droplet-based Microfluidic System To Study Non-Photochemical Laser-Induced Nucleation of Potassium Chloride Solutions.

Non-photochemical laser-induced nucleation (NPLIN) has emerged as a promising primary nucleation control technique offering spatiotemporal control over crystallization with potential for polymorph control. So far, NPLIN was mostly investigated in milliliter vials, through laborious manual counting of the crystallized vials by visual inspection. Microfluidics represents an alternative to acquiring automated and statistically reliable data. Thus we designed a droplet-based microfluidic platform capable of identifying the droplets with crystals emerging upon Nd:YAG laser irradiation using the deep learning method. In our experiments, we used supersaturated solutions of KCl in water, and the effect of laser intensity, wavelength (1064, 532, and 355 nm), solution supersaturation (S), solution filtration, and intentional doping with nanoparticles on the nucleation probability is quantified and compared to control cooling crystallization experiments. Ability of dielectric polarization and the nanoparticle heating mechanisms proposed for NPLIN to explain the acquired results is tested. Solutions with lower supersaturation (S = 1.05) exhibit significantly higher NPLIN probabilities than those in the control experiments for all laser wavelengths above a threshold intensity (50 MW/cm2). At higher supersaturation studied (S = 1.10), irradiation was already effective at lower laser intensities (10 MW/cm2). No significant wavelength effect was observed besides irradiation with 355 nm light at higher laser intensities (≥50 MW/cm2). Solution filtration and intentional doping experiments showed that nanoimpurities might play a significant role in explaining NPLIN phenomena.

Reynolds number scaling and energy spectra in geostrophic convection.

We report flow measurements in rotating Rayleigh-Bénard convection in the rotationally-constrained geostrophic regime. We apply stereoscopic particle image velocimetry to measure the three components of velocity in a horizontal cross-section of a water-filled cylindrical convection vessel. At a constant, small Ekman number Ek = 5 × 10-8 we vary the Rayleigh number Ra between 1011 and 4 × 1012 to cover various subregimes observed in geostrophic convection. We also include one nonrotating experiment. The scaling of the velocity fluctuations (expressed as the Reynolds number Re) is compared to theoretical relations expressing balances of viscous-Archimedean-Coriolis (VAC) and Coriolis-inertial-Archimedean (CIA) forces. Based on our results we cannot decide which balance is most applicable here; both scaling relations match equally well. A comparison of the current data with several other literature datasets indicates a convergence towards diffusion-free scaling of velocity as Ek decreases. However, the use of confined domains leads at lower Ra to prominent convection in the wall mode near the sidewall. Kinetic energy spectra point at an overall flow organisation into a quadrupolar vortex filling the cross-section. This quadrupolar vortex is a quasi-two-dimensional feature; it only manifests in energy spectra based on the horizontal velocity components. At larger Ra the spectra reveal the development of a scaling range with exponent close to -5/3, the classical exponent for inertial-range scaling in three-dimensional turbulence. The steeper Re(Ra) scaling at low Ek and development of a scaling range in the energy spectra are distinct indicators that a fully developed, diffusion-free turbulent bulk flow state is approached, sketching clear perspectives for further investigation.

Potential, Limitations and Risks of Cannabis-Derived Products in Cancer Treatment.

The application of cannabis products in oncology receives interest, especially from patients. Despite the plethora of research data available, the added value in curative or palliative cancer care and the possible risks involved are insufficiently proven and therefore a matter of debate. We aim to give a recommendation on the position of cannabis products in clinical oncology by assessing recent literature. Various types of cannabis products, characteristics, quality and pharmacology are discussed. Standardisation is essential for reliable and reproducible quality. The oromucosal/sublingual route of administration is preferred over inhalation and drinking tea. Cannabinoids may inhibit efflux transporters and drug-metabolising enzymes, possibly inducing pharmacokinetic interactions with anticancer drugs being substrates for these proteins. This may enhance the cytostatic effect and/or drug-related adverse effects. Reversely, it may enable dose reduction. Similar interactions are likely with drugs used for symptom management treating pain, nausea, vomiting and anorexia. Cannabis products are usually well tolerated and may improve the quality of life of patients with cancer (although not unambiguously proven). The combination with immunotherapy seems undesirable because of the immunosuppressive action of cannabinoids. Further clinical research is warranted to scientifically support (refraining from) using cannabis products in patients with cancer.

Inter- and Intra-Observer Variability and the Effect of Experience in Cine-MRI for Adhesion Detection.

Cine-MRI for adhesion detection is a promising novel modality that can help the large group of patients developing pain after abdominal surgery. Few studies into its diagnostic accuracy are available, and none address observer variability. This retrospective study explores the inter- and intra-observer variability, diagnostic accuracy, and the effect of experience. A total of 15 observers with a variety of experience reviewed 61 sagittal cine-MRI slices, placing box annotations with a confidence score at locations suspect for adhesions. Five observers reviewed the slices again one year later. Inter- and intra-observer variability are quantified using Fleiss' (inter) and Cohen's (intra) κ and percentage agreement. Diagnostic accuracy is quantified with receiver operating characteristic (ROC) analysis based on a consensus standard. Inter-observer Fleiss' κ values range from 0.04 to 0.34, showing poor to fair agreement. High general and cine-MRI experience led to significantly (p < 0.001) better agreement among observers. The intra-observer results show Cohen's κ values between 0.37 and 0.53 for all observers, except one with a low κ of -0.11. Group AUC scores lie between 0.66 and 0.72, with individual observers reaching 0.78. This study confirms that cine-MRI can diagnose adhesions, with respect to a radiologist consensus panel and shows that experience improves reading cine-MRI. Observers without specific experience adapt to this modality quickly after a short online tutorial. Observer agreement is fair at best and area under the receiver operating characteristic curve (AUC) scores leave room for improvement. Consistently interpreting this novel modality needs further research, for instance, by developing reporting guidelines or artificial intelligence-based methods.