Scientific Rationale Research Articles

Комплексные средства для коррекции уровня рН мочи при метафилактике мочекаменной болезни.

Introduction. Urolithiasis is a serious medical, social and economic problem. Over the past decades the world has seen a progressive, approximately 3% per year, increase in its incidence. Urolithiasis occupies a leading position in the structure of urological diseases and has a high recurrence rate in the absence of metaphylaxis. In turn, the effectiveness of properly selected anti-relapse therapy has been proven by many studies and is about 50- 80%. The development of “tools” for rational metaphylaxis represents a potential “growth area” for improving the effectiveness of treatment for patients with urolithiasis. One of these tools is the correction of urine pH levels, since its violations are the most common. However, drugs used to correct pH levels have a number of limitations, which greatly complicates their use. One of the possible solutions to these shortcomings may be the creation of combined drugs that can comprehensively influence the factors that provoke the recurrence of stone formation such as the line of Litcontrol® Litura® products from Devicare (Spain). The purpose of this publication is the scientific rationale of the clinical effects of Litura® Up and Litura® Down in the metaphylaxis of urolithiasis. Materials and methods. A literature search and analysis of foreign and domestic literature was carried out from 1990 to 2024 with the selection of relevant publications in the еLibrary, PubMed databases and Google including keywords – the active components of Lit-Control® pH Up – potassium-magnesium citrate, theobromine, zinc, vitamin A, and Lit-Control® pH Down – phytates, L-methionine, zinc, vitamin A. References in included sources were reviewed to identify additional potentially relevant studies. 189 sources were found, based on the relevance of which 60 articles were selected. Results. The use of Litura® Up and Litura® Down has a scientific basis, and the included substances and their combination potentiate the clinical effect in the metaphylaxis of urolithiasis. However, controlled clinical studies are necessary to assess the prospects for using these complex agents. Conclusions. Based on foreign data from experimental and clinical studies, we can conclude that the Lit-Control® Litura® line of products used to correct urine pH levels and inhibit crystallization in various types of stone formation can be considered as a new promising approach to the metaphylaxis of urolithiasis.

Autism spectrum disorder and a possible role of anti-inflammatory treatments: experience in the pediatric allergy/immunology clinic.

Autism spectrum disorder (ASD1) is a behaviorally defined syndrome encompassing a markedly heterogeneous patient population. Many ASD subjects fail to respond to the 1st line behavioral and pharmacological interventions, leaving parents to seek out other treatment options. Evidence supports that neuroinflammation plays a role in ASD pathogenesis. However, the underlying mechanisms likely vary for each ASD patient, influenced by genetic, epigenetic, and environmental factors. Although anti-inflammatory treatment measures, mainly based on metabolic changes and oxidative stress, have provided promising results in some ASD subjects, the use of such measures requires the careful selection of ASD subjects based on clinical and laboratory findings. Recent progress in neuroscience and molecular immunology has made it possible to allow re-purposing of currently available anti-inflammatory medications, used for autoimmune and other chronic inflammatory conditions, as treatment options for ASD subjects. On the other hand, emerging anti-inflammatory medications, including biologic and gate-keeper blockers, exert powerful anti-inflammatory effects on specific mediators or signaling pathways. It will require both a keen understanding of the mechanisms of action of such agents and the careful selection of ASD patients suitable for each treatment. This review will attempt to summarize the use of anti-inflammatory agents already used in targeting ASD patients, and then emerging anti-inflammatory measures applicable for ASD subjects based on scientific rationale and clinical trial data, if available. In our experience, some ASD patients were treated under diagnoses of autoimmune/autoinflammatory conditions and/or post-infectious neuroinflammation. However, there are little clinical trial data specifically for ASD subjects. Therefore, these emerging immunomodulating agents for potential use for ASD subjects will be discussed based on preclinical data, case reports, or data generated in patients with other medical conditions. This review will hopefully highlight the expanding scope of immunomodulating agents for treating neuroinflammation in ASD subjects.

Impact of horticulture on the sustainable livelihood development of smallholders: a SPAR-4-SLR & future research agenda

Purpose. The perishable nature of the horticulture (fruits, vegetables, and flowers) industry makes it more complex to study. The higher return and nutritional benefits compared to traditional agricultural products expand the research scope for the stakeholders’ sustainable benefit. Nevertheless, despite limited research, this study explicitly examines additional facets of smallholder development beyond the traditional economic, social, and environmental dimensions. Methodology / approach. To fill this knowledge gap, we comprehensively reviewed 73 articles published between 2013 and 2022 in international scientific journals with an SJR (Scimago Journal & Country Rank) Q1 ranking. We followed the “Scientific Procedures and Rationales for Systematic Literature Reviews” (SPAR-4-SLR) protocol to identify different aspects of smallholders’ development. Literature from Web of Science and Scopus databases was analysed and organised using the TCCM (Theory, Context, Characteristics, and Methodology) framework. Results. The study identified important factors like infrastructure, commercialisation, market access, marketing, credit, policies, information, intervention, training, technology, and collaboration that could uncover crucial economic, political, social, psychological, ecological, cultural, physical and nutritional aspects of development in general. The study also suggests that implementation Agriculture 4.0 through advanced technologies like IoT, AI, and vertical and bio-fortification practices can help in sustainable livelihood development in horticulture. Originality / scientific novelty. The limited or lack of comprehensive studies on smallholders’ sustainable livelihood development with different dimensions makes this research a bridge to identify other dimensions instead of only focusing on the horticultural sector’s economic, social, and ecological aspects. It uses the Agricultural Innovation System and Farmer First theories, stating that the farmer is the first priority and must collaborate and interact to implement technology and innovations for smallholder livelihood development. Practical value / implications. This research will help in decision-making regarding smallholders’ livelihoods in all eight dimensions at all levels of government, private and other stakeholders, suggesting a triple-helix model.

Kidney tea [Orthosiphon aristatus (Blume) Miq.] improves diabetic nephropathy via regulating gut microbiota and ferroptosis.

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. Due to its complex pathogenesis, new therapeutic agents are urgently needed. Orthosiphon aristatus (Blume) Miq., commonly known as kidney tea, is widely used in DN treatment in China. However, the mechanisms have not been fully elucidated. We used db/db mice as the DN model and evaluated the efficacy of kidney tea in DN treatment by measuring fasting blood glucose (FBG), serum inflammatory cytokines, renal injury indicators and histopathological changes. Furthermore, 16S rDNA gene sequencing, untargeted serum metabolomics, electron microscope, ELISA, qRT-PCR, and Western blotting were performed to explore the mechanisms by which kidney tea exerted therapeutic effects. Twelve polyphenols were identified from kidney tea, and its extract ameliorated FBG, inflammation and renal injury in DN mice. Moreover, kidney tea reshaped the gut microbiota, reduced the abundance of Muribaculaceae, Lachnoclostridium, Prevotellaceae_UCG-001, Corynebacterium and Akkermansia, and enriched the abundance of Alloprevotella, Blautia and Lachnospiraceae_NK4A136_group. Kidney tea altered the levels of serum metabolites in pathways such as ferroptosis, arginine biosynthesis and mTOR signaling pathway. Importantly, kidney tea improved mitochondrial damage, increased SOD activity, and decreased the levels of MDA and 4-HNE in the renal tissues of DN mice. Meanwhile, this functional tea upregulated GPX4 and FTH1 expression and downregulated ACSL4 and NCOA4 expression, indicating that it could inhibit ferroptosis in the kidneys. Our findings imply that kidney tea can attenuate DN development by modulating gut microbiota and ferroptosis, which presents a novel scientific rationale for the clinical application of kidney tea.

(053) THE CONSORTIUM FOR THE STUDY OF WOMEN’S SEXUAL WELLNESS: RATIONAL, MISSION AND CALL TO ACTION

Abstract Introduction Female sexual wellness products have been growing and this growth was accelerated during the pandemic and the increased interest in self-care. While trying to find a place in beauty, sexual wellness really is only slightly beauty-adjacent. The beauty industry is built on delivering many products based solely on a promise. Little science is applied in this field to show any MOA or clinical efficacy. However, even in this sector the status quo is being disrupted by the FDAs Modernization of Cosmetic Regulations Act of 2022 (MoCRA). However, sexual wellness products are really more pharma-adjacent, even while using non-pharmaceuticals (nutraceuticals) ingredients. We reviewed all non-device based sexual wellness products that claimed functional benefit and based on these results, we make some recommendations. Objective To challenge the female sexual wellness industry to adopt basic and clinical science in the development and marketing of female sexual wellness products. Methods Over a three-year span, we reviewed the ingredients and claims as well as any clinical trial data on products claiming a functional benefit in sexual desire, arousal and/or orgasm. Following the unsurprising findings, we propose a number of solutions. Results Without naming the companies or products, we found an abundance of unusual products that did not seem to have a scientific rationale for ingredients and virtually all claims were unsubstantiated. Two entities have performed clinical studies. The first is a cannabis company which performed a study without a validated instruments and soft-endpoints, and as expected, there was a 100% response rate. The second entity has performed pre-clinical studies (organ bath and MOA studies) and an open-label pilot study employing a modified FSFI and diary data and efficacy and safety output. However, this was not a randomized, double-blind, placebo-controlled study. Conclusions Seismic changes are happening in the beauty and wellness industry. Female sexual wellness is closely pharma-adjacent and, as such, should adopt the preclinical and clinical trial approach that has already been developed for the evaluation of drugs in female sexual dysfunction. While these agents may only enhance normal function and don’t treat diseases or disorders, the learnings from the last half century in sexual pharmacotherapy are readily adapted to the development and evaluation of sexual wellness products. Vella Bioscience is rapidly moving to follow these principles, as follows: 1. We are performing a three-month RCT with liposomal cannabidiol vs placebo that has been powered to demonstrate statistical and clinical significance. The outcome instruments include both the PROMIS database and diary data. 2. The establishment of the Consortium for the Study of Women’s Sexual Wellness, with the following mission: Bring scientific rigor to the basic science and clinical science research of sexual wellness products, including the utilization of double-blind, placebo-controlled, randomized clinical trials. Support research, education, and public awareness of female sexual health and wellness. Enable healthcare providers and customers to directly access research protocols and validated products for the management of sexual wellness. Critical to this mission are the members of the Scientific Advisory Board of the Consortium, including Alan Altman, MD, FACOG, Anita Clayton, MD, Peter Fodor, MD, FACS, Sheryl Kingsberg, PhD, Cindy Meston, PhD, James Pfaus, PhD, Nicole Prause, PhD, Raymond Rosen, PhD, and James Simon, MD, FACOG. We invite other corporate entities to utilize the consortium and we hope that ISSWSH will adopt these principles as well. Women deserve data and not a promise. Disclosure Yes, this is sponsored by industry/sponsor: Vella Bioscience, Inc. Clarification: Industry initiated, executed and funded study. Any of the authors act as a consultant, employee or shareholder of an industry for: Vella Bioscience, Inc.

The Application of Scientific Evidence-Based Changes to an Animal Shelter’s Rehoming Practices

Abstract Shelters devote much of their often very limited resources to screening potential adopters, including spending copious amounts of time collecting information from them about their family structure, lifestyle, etc. However, in a study that surveyed rehoming organisations’ practices, it was found that they gather substantially more information about potential adopters than there is scientific evidence to justify. Some information gathered for which there is no scientific rationale which could cause adopters to be denied adopting any dog from the organisation. Consequently, the study concluded that organisations may be turning away perfectly suitable homes due to their often strict rehoming criteria, resulting in dogs staying with the organisation for longer than necessary. Therefore, the study recommended organisations relax their strict rehoming criteria and instead focus on ensuring adopters have appropriate expectations and education for adopting a dog. With knowledge of the study’s findings, a shelter in Northern Ireland overhauled their rehoming practices to be in line with the study’s recommendations for change. Their goal was to increase the number of animals adopted per month with a focus on ensuring successful placements, to decrease staff/volunteer workload, and for potential adopters to have an overall better experience with the shelter. Despite challenges in uptake of the changes by staff working with dogs, noteworthy improvements were observed, with the greatest improvements with cats and small animals. Three months after the shelter overhauled their rehoming practices, adoptions increased year-over-year, staff motivation and morale improved and potential adopters reported a more positive experience with the organisation. Information © The Author 2024

EVICTION study: ICT01, an anti-Butyrophilin 3A monoclonal antibody activating γ9δ2 T cells in combination with pembrolizumab in checkpoint inhibitor refractory melanoma.

9534 Background: γ9δ2 T-cell tumor infiltration is associated with a favorable prognosis making these cells a new potential target for immunotherapy. The anti-BTN3A mAb ICT01 selectively activates γ9δ2 T cells and is being studied in the phase1/2a EVICTION Trial (NCT04243499). In preclinical studies, ICT01 induces upregulation of PD-1 on γ9δ2 T-cells and combination with pembrolizumab leads to enhanced cancer cell killing, providing scientific rationale to evaluate this combination. Here we present interim results from EVICTION of ICT01 in combination with pembrolizumab in patients with checkpoint inhibitor (CPI) refractory melanoma. Methods: EVICTION evaluated ICT01 (20 µg to 200 mg, Q3W) plus pembrolizumab (200mg IV Q3W) in a dose escalation solid tumor basket design that resulted in an ongoing expansion cohort of patients with CPI refractory melanoma (2 dose levels, 7 and 200 mg ICT01). Patients are selected based on higher baseline γ9δ2 T cells. Efficacy evaluations by i/RECIST 1.1 are conducted every 8 weeks. Disease Control Rate (DCR) as primary efficacy endpoint is defined as the sum of complete response (CR), partial response (PR) and stable disease (SD, minimum week 16). Baseline and on-treatment blood and biopsy specimens are collected for correlative translational work. Results: ICT01 plus pembrolizumab has a favorable safety profile with first-dose Grade 1/2 infusion related reactions (IRR) and cytokine release syndrome (CRS) as most common adverse events (in 38% and 19% of patients respectively, 5%and 2% Grade 3) among all doses and indications. To date, 35 CPI refractory melanoma patients have been enrolled, of which 65% have received 2+ prior lines of CPI. Currently 21 patients are evaluable at week 16 with a DCR of 42% (including 3 PR) and a 6-month progression free survival of 38%. In the circulation, full BTN3A receptor occupancy on immune cells was achieved at 7 mg dose, with down-modulation of BTN3A observed at doses greater than 20 mg. Clinical response was related to baseline tumoral BTN3A expression, sustained elevation of IFNg levels, and tumor microenvironment remodeling, including increased PD-L1 expression and CD8 T cells proliferation and activation. Conclusions: ICT01 in combination with pembrolizumab has a favorable safety profile and promising efficacy data. Patient selection based on BTN3A tumor expression will be further evaluated as an enrichment strategy. Clinical trial information: NCT04243499 .

A phase 2 study to evaluate efficacy and safety of PRGN-2009, a novel gorilla adenovirus-based immunotherapy, in combination with pembrolizumab versus pembrolizumab monotherapy in patients with recurrent or metastatic cervical cancer.

TPS5623 Background: The association between cervical cancer and human papillomavirus (HPV) is well understood, with nearly all cervical cancer known to be caused by high risk HPV infection. HPV16 and HPV18 are the most common high-risk HPV types and are responsible for about 70% of cervical cancer cases. Recurrent or metastatic cervical cancer is currently treated with pembrolizumab alone or in combination with chemotherapy, however t there remains a significant need for treatments for patients that recur or do not respond at all to pembrolizumab treatment. PRGN-2009 is a gorilla adenovirus-based immunotherapy targeting cancers caused by HPV16 or HPV18. PRGN-2009 includes a novel HPV antigen design to induce HPV16/18-specific T cell immune responses against cancer cells. The rationale for combining the PRGN-2009 with immune checkpoint inhibitor is based on preclinical and clinical data demonstrating that combination of cancer vaccines and immune checkpoint inhibitors can trigger intensified immunogenicity leading to increased antitumor efficacy compared to either treatment alone. PRGN-2009 has been characterized in both in vitroand in vivostudies to support the scientific rationale and the safety of PRGN-2009 has been demonstrated in evaluated in initial Phase 1/2 studies in patients with HPV+ malignancies. Methods: This is a randomized, Phase 2 study to evaluate efficacy and safety of PRGN-2009 in combination with pembrolizumab compared to pembrolizumab alone in patients with recurrent or metastatic cervical cancer. Key inclusion criteria include recurrent or metastatic cervical cancer (histologically or cytologically confirmed) resistant to pembrolizumab. Subjects will be randomized 1:1 to Cohort 1: Combination of PRGN-2009, 5 x 1011 PU (Day 0, Day 21 and Day 42, then q6w), plus pembrolizumab, 400mg q6w, or to Cohort 2: pembrolizumab alone (400 mg q6w). Subjects randomized to Cohort 2 (pembrolizumab monotherapy) and who have confirmed disease progression (per RECIST 1.1) after at least one cycle of pembrolizumab and have had no Grade ≥ 3 adverse events related to treatment will be offered the option to crossover to Cohort 1 (PRGN-2009 plus pembrolizumab). All subjects will be evaluated for safety and efficacy of PRGN-2009 in combination with pembrolizumab, and for biological correlative assays. The primary endpoint is objective response rate (ORR) following treatment with PRGN-2009 in combination with pembrolizumab or pembrolizumab monotherapy, and will be tested using Fleming’s two-stage design and the stopping boundaries for futility and efficacy applied. The study is currently recruiting patients with recurrent or metastatic cervical cancer (NCT06157151). Clinical trial information: NCT06157151 .

Cardiac Uptake of the Adrenergic Imaging Agent meta-Iodobenzylguanidine (mIBG) Is Mediated by Organic Cation Transporter 3 (Oct3).

Heart failure (HF) is a chronic disease affecting 1%-2% of the global population.123I-labeled meta-iodobenzylguanidine (mIBG) is US Food and Drug Administration-approved for cardiac imaging and prognosis risk assessment in patients with HF. As a norepinephrine analog, mIBG is believed to be transported into adrenergic nerve terminals by the neuronal norepinephrine transporter (NET) and hence image sympathetic innervation of the myocardium. We previously showed that mIBG is an excellent substrate of organic cation transporter 3 (OCT3), an extraneuronal transporter expressed in cardiomyocytes. Here, we evaluated the in vivo impact of Oct3 on mIBG disposition and tissue distribution using Oct3 knockout mice. Oct3 +/+ and Oct3 -/- mice were administered with mIBG intravenously, and mIBG plasma pharmacokinetics and tissue exposures were determined. In Oct3 +/+ mice, mIBG exhibited extensive accumulation in multiple tissues (heart, salivary gland, liver, and adrenal gland). No difference was observed in overall plasma exposure between Oct3 +/+ and Oct3 -/- mice. Strikingly, cardiac mIBG was depleted in Oct3 -/- mice, resulting in 83% reduction in overall cardiac exposure (AUC0-24 h: 12.7 vs. 2.1 μg × h/g). mIBG tissue exposure (AUC0-24 h) was also reduced by 66%, 36%, and 31% in skeletal muscle, salivary gland, and lung, respectively, in Oct3 -/- mice. Our data demonstrated that Oct3 is the primary transporter responsible for cardiac mIBG uptake in vivo and suggested that cardiac mIBG imaging mainly measures OCT3 activity in cardiomyocytes but not NET-mediated uptake in adrenergic nerve endings. Our findings challenge the current paradigm in interpreting cardiac mIBG imaging results and suggest OCT3 as a potential genetic risk marker for HF prognosis. SIGNIFICANCE STATEMENT: 123I-labeled meta-iodobenzylguanidine is used for cardiac imaging and risk assessment in heart failure patients. Contrary to the current belief that meta-iodobenzylguanidine (mIBG) tracks cardiac sympathetic innervation due to its uptake by the neuronal norepinephrine transporter, the authors demonstrated that cardiac mIBG uptake is mediated by the extraneuronal transporter Oct3. Their findings warrant a re-evaluation of the scientific rationale behind cardiac mIBG scan and further suggest organic cation transporter 3 as a risk factor for disease progression in heart failure patients.

A reactogenic "placebo" and the ethics of informed consent in Gardasil HPV vaccine clinical trials: A case study from Denmark.

Medical ethics guidelines require of clinical trial investigators and sponsors to inform prospective trial participants of all known and potential risks associated with investigational medical products, and to obtain their free informed consent. These guidelines also require that clinical research be so designed as to minimize harms and maximize benefits. To examine Merck's scientific rationale for using a reactogenic aluminum-containing "placebo" in Gardasil HPV vaccine pre-licensure clinical trials. We examined the informed consent form and the recruitment brochure for the FUTURE II Gardasil vaccine trial conducted in Denmark; and we interviewed several FUTURE II trial participants and their treating physicians. We also reviewed regulatory documentation related to Gardasil vaccine approval process and the guidelines on evaluation of adjuvants used in human vaccines. It was found that the vaccine manufacturer Merck made several inaccurate statements to trial participants that compromised their right to informed consent. First, even though the study protocol listed safety testing as one of the study's primary objectives, the recruitment brochure emphasized that FUTURE II was not a safety study, and that the vaccine had already been proven safe. Second, the advertising material for the trial and the informed consent forms stated that the placebo was saline or an inactive substance, when, in fact, it contained Merck's proprietary highly reactogenic aluminum adjuvant which does not appear to have been properly evaluated for safety. Several trial participants experienced chronic disabling symptoms, including some randomized to the adjuvant "placebo" group. In our view, the administration of a reactive placebo in Gardasil clinical trials was without any possible benefit, needlessly exposed study subjects to risks, and was therefore a violation of medical ethics. The routine use of aluminum adjuvants as "placebos" in vaccine clinical trials is inappropriate as it hinders the discovery of vaccine-related safety signals.

Intervention with fructooligosaccharides, Saccharomyces boulardii, and their combination in a colitis mouse model.

To examine the effects of an intervention with fructooligosaccharides (FOS), Saccharomyces boulardii, and their combination in a mouse model of colitis and to explore the mechanisms underlying these effects. The effects of FOS, S. boulardii, and their combination were evaluated in a DSS-induced mouse model of colitis. To this end, parameters such as body weight, the disease activity index (DAI), and colon length were examined in model mice. Subsequently, ELISA was employed to detect the serum levels of proinflammatory cytokines. Histopathological analysis was performed to estimate the progression of inflammation in the colon. Gas chromatography was used to determine the content of short-chain fatty acids (SCFAs) in the feces of model mice. Finally, 16S rRNA sequencing technology was used to analyze the gut microbiota composition. FOS was slight effective in treating colitis and colitis-induced intestinal dysbiosis in mice. Meanwhile, S. boulardii could significantly reduced the DAI, inhibited the production of IL-1β, and prevented colon shortening. Nevertheless, S. boulardii treatment alone failed to effectively regulate the gut microbiota. In contrast, the combined administration of FOS/S. boulardii resulted in better anti-inflammatory effects and enabled microbiota regulation. The FOS/S. boulardii combination (109 CFU/ml and 107 CFU/ml) significantly reduced the DAI, inhibited colitis, lowered IL-1β and TNF-α production, and significantly improved the levels of butyric acid and isobutyric acid. However, FOS/S. boulardii 109 CFU/ml exerted stronger anti-inflammatory effects, inhibited IL-6 production and attenuated colon shortening. Meanwhile, FOS/S. boulardii 107 CFU/ml improved microbial regulation and alleviated the colitis-induced decrease in microbial diversity. The combination of FOS and S. boulardii significantly increased the abundance of Parabacteroides and decreased the abundance of Escherichia-Shigella. Additionally, it promoted the production of acetic acid and propionic acid. Compared with single administration, the combination can significantly increase the abundance of beneficial bacteria such as lactobacilli and Bifidobacteria and effectively regulate the gut microbiota composition. These results provide a scientific rationale for the prevention and treatment of colitis using a FOS/S. boulardii combination. They also offer a theoretical basis for the development of nutraceutical preparations containing FOS and S. boulardii.

Understanding Antibiotic Detection with Fluorescence Quantum Dots: A Review.

The utilization of fluorescent quantum dots (FL QDs) has gained significant traction in the realm of antibiotic detection, owing to their exceptional FL properties and versatility. Various types of QDs have been tailored to exhibit superior FL characteristics, employing diverse capping agents such as metals, surfactants, polymers, and biomass to protect and stabilize their surfaces. In their evolution, FL QDs have demonstrated both "turn-off" and "turn-on" mechanisms in response to the presence of analytes, offering promising avenues for biosensing applications. This review article provides a comprehensive overview of the recent advancements in antibiotic detection utilizing FL QDs as biosensors. It encompasses an extensive examination of different types of FL QDs, including carbon, metal, and core-shell QDs, deployed for the detection of antibiotics. Furthermore, the synthesis methods employed for the fabrication of various FL QDs are elucidated, shedding light on the diverse approaches adopted in their preparation. Moreover, this review delves into the intricate sensing mechanisms underlying FL QDs-based antibiotic detection. Various mechanisms, such as photoinduced electron transfer, electron transfer, charge transfer, Forster resonance energy transfer, static quenching, dynamic quenching, inner filter effect, hydrogen bonding, and aggregation-induced emission, are discussed in detail. These mechanisms provide a robust scientific rationale for the detection of antibiotics using FL QDs, showcasing their potential for sensitive and selective sensing applications. Finally, the review addresses current challenges and offers perspectives on the future improvement of FL QDs in sensing applications. Insights into overcoming existing limitations and harnessing emerging technologies are provided, charting a course for the continued advancement of FL QDs-based biosensing platforms in the field of antibiotic detection.

"Notification! You May Have Cancer." Could Smartphones and Wearables Help Detect Cancer Early?

This viewpoint paper considers the authors' perspectives on the potential role of smartphones, wearables, and other technologies in the diagnosis of cancer. We believe that these technologies could be valuable additions in the pursuit of early cancer diagnosis, as they offer solutions to the timely detection of signals or symptoms and monitoring of subtle changes in behavior that may otherwise be missed. In addition to signal detection, technologies could assist symptom interpretation and guide and facilitate access to health care. This paper aims to provide an overview of the scientific rationale as to why these technologies could be valuable for early cancer detection, as well as outline the next steps for research and development to drive investigation into the potential for smartphones and wearables in this context and optimize implementation. We draw attention to potential barriers to successful implementation, including the difficulty of the development of signals and sensors with sufficient utility and accuracy through robust research with the target group. There are regulatory challenges; the potential for innovations to exacerbate inequalities; and questions surrounding acceptability, uptake, and correct use by the intended target group and health care practitioners. Finally, there is potential for unintended consequences on individuals and health care services including unnecessary anxiety, increased symptom burden, overinvestigation, and inappropriate use of health care resources.

Escalation of adjuvant endocrine therapy for early hormone-dependent HER2-negative breast cancer: to whom, when and why?

This review presents the evolution of adjuvant endocrine therapy for early hormone-dependent HER2-negative breast cancer, describes late relapse phenomenon, provides clinical rationale for escalation of treatment, analyzes the key stages of the metastatic cascade, and provides a scientific rationale for the introduction of CDK4/6 inhibitors into adjuvant treatment regimens. The main results of two large randomized studies of therapy including abemaciclib (MonarchE) and ribociclib (NATALEE) in patients with early stages of hormone-dependent HER2-negative breast cancer are presented; the oncological results of escalation of treatment and the safety of therapy are assessed.

In vitro and genomic mining studies of anti-Clostridium perfringens Compounds Derived from Bacillus amyloliquefaciens

Clostridium perfringens is an important opportunistic microorganism in commercial poultry production that is implicated in necrotic enteritis (NE) outbreaks. This disease poses a severe financial burden on the global poultry industry, causing estimated annual losses of $6 billion globally. The ban on in-feed antibiotic growth promoters has spurred investigations into approaches of alternatives to antibiotics, among which Bacillus probiotics have demonstrated varying degrees of effectiveness against NE. However, the precise mechanisms underlying Bacillus-mediated beneficial effects on host responses in NE remain to be further elucidated. In this manuscript, we conducted in vitro and genomic mining analysis to investigate anti-C. perfringens activity observed in the supernatants derived from 2 Bacillus amyloliquefaciens strains (FS1092 and BaD747). Both strains demonstrated potent anti-C. perfringens activities in in vitro studies. An analysis of genomes from 15 B. amyloliquefaciens, 11 B. velezensis, and 2 B. subtilis strains has revealed an intriguing clustering pattern among strains known to possess anti-C. perfringens activities. Furthermore, our investigation has identified 7 potential antimicrobial compounds, predicted as secondary metabolites through antiSMASH genomic mining within the published genomes of B. amyloliquefaciens species. Based on in vitro analysis, BaD747 may have the potential as a probiotic in the control of NE. These findings not only enhance our understanding of B. amyloliquefaciens's action against C. perfringens but also provide a scientific rationale for the development of novel antimicrobial therapeutic agents against NE.

Determining recommended acceptable intake limits for N-nitrosamine impurities in pharmaceuticals: Development and application of the Carcinogenic Potency Categorization Approach (CPCA)

N-Nitrosamine impurities, including nitrosamine drug substance-related impurities (NDSRIs), have challenged pharmaceutical industry and regulators alike and affected the global drug supply over the past 5 years. Nitrosamines are a class of known carcinogens, but NDSRIs have posed additional challenges as many lack empirical data to establish acceptable intake (AI) limits. Read-across analysis from surrogates has been used to identify AI limits in some cases; however, this approach is limited by the availability of robustly-tested surrogates matching the structural features of NDSRIs, which usually contain a diverse array of functional groups. Furthermore, the absence of a surrogate has resulted in conservative AI limits in some cases, posing practical challenges for impurity control. Therefore, a new framework for determining recommended AI limits was urgently needed. Here, the Carcinogenic Potency Categorization Approach (CPCA) and its supporting scientific rationale are presented. The CPCA is a rapidly-applied structure-activity relationship-based method that assigns a nitrosamine to 1 of 5 categories, each with a corresponding AI limit, reflecting predicted carcinogenic potency. The CPCA considers the number and distribution of α-hydrogens at the N-nitroso center and other activating and deactivating structural features of a nitrosamine that affect the α-hydroxylation metabolic activation pathway of carcinogenesis. The CPCA has been adopted internationally by several drug regulatory authorities as a simplified approach and a starting point to determine recommended AI limits for nitrosamines without the need for compound-specific empirical data.

Regarding repeated implantation failures coupled to assisted reproductive technologies

Embryo implantation is the first key step in successful pregnancy, but implantation failures remain quite common in patients undergoing assisted reproductive technology (ART) programs. The main known factors of repeated implantation failures (RIF) in patients undergoing ART are unhealthy lifestyle, genetic factor and low gamete quality, uterus pathology, endometriosis and adenomyosis, thrombophilia as well as male factor and embryonic factors. RIF factors and ways to overcome them have received much attention. Despite multiple RIF causes being identified, the underlying etiology and management remain poorly investigated. In clinical practice, studies and interventions providing no clear scientific rationale or convincing evidence on their effectiveness due to the lack of standardized diagnostic and treatment methods that are often used. An effective strategy for treating RIF risk factors is necessary to increase chances for successful pregnancy in ART programs.

Fermatean fuzzy sets and its extensions: a systematic literature review

The Fermatean Fuzzy Set (FFS) theory emerges as a crucial and prevalent tool in addressing uncertainty across diverse domains. Despite its recognized utility in managing ambiguous information, recent research lacks a comprehensive analysis of key FFS areas, applications, research gaps, and outcomes. This study, conducted through the Scientific Procedures and Rationales for Systematic Literature Reviews (SPAR-4-SLR) protocol, delves into an exploration of the FFS literature, reviewing 135 relevant articles. The documents are meticulously analyzed based on their integrated methodologies, Aggregation Operators (AOs), linguistic sets, and extensions. Additionally, a thematic analysis, facilitated by the Bibliometrix tool, is presented to provide nuanced insights into future research directions and crucial areas within the literature. The study unveils valuable findings, including the integration of linguistic variables with interval-valued FFS, fostering robust environments for dynamic decision-making—a mere glimpse of the potential directions for future research. The gaps and future directions section further articulates recommendations, offering a structured foundation for researchers to enhance their understanding of FFS and chart future studies confidently.

Leishmania major MAPK4 intercepts and redirects CD40 signaling promoting infection

The parasite Leishmania resides as amastigotes within the macrophage parasitophorous vacuoles inflicting the disease Leishmaniasis. Leishmania selectively modulates mitogen-activated protein kinase (MAPK) phosphorylation subverting CD40-triggered anti-leishmanial functions of macrophages. The mechanism of any pathogen-derived molecule induced host MAPK modulation remains poorly understood. Herein, we show that of the fifteen MAPKs, LmjMAPK4 expression is higher in virulent L. major. LmjMAPK4- detected in parasitophorous vacuoles and cytoplasm- binds MEK-1/2, but not MKK-3/6. Lentivirally-overexpressed LmjMAPK4 augments CD40-activated MEK-1/2-ERK-1/2-MKP-1, but inhibits MKK3/6-p38MAPK-MKP-3, phosphorylation. A rationally-identified LmjMAPK4 inhibitor reinstates CD40-activated host-protective anti-leishmanial functions in L. major-infected susceptible BALB/c mice. These results identify LmjMAPK4 as a MAPK modulator at the host-pathogen interface and establish a pathogen-intercepted host receptor signaling as a scientific rationale for identifying drug targets.

Advancing the consumer behaviour theory in halal food: review literature and directions for future research

Purpose This paper aims to examine existing literature on halal food consumption from the perspective of consumer behaviour research. It identifies progress, current state and gaps and provides direction for future research to advance the field. Design/methodology/approach This paper reviewed papers from 2007 to 2023 using Scopus and WOS databases. The review used the Theories–Context–Characteristics–Methods (TCCM) framework and followed the scientific procedures and rationales for systematic literature reviews (SPAR-4-SLR) protocol. Findings The review summarises the methods, theory and approaches used in the topic and presents key findings and a proposed framework. It can guide future researchers in developing their models, making it a valuable starting point for future research. Despite the existence of SRL in halal food to the best of the authors’ knowledge, this work is the first review that proposes a model for halal food in consumer behaviour. Originality/value This review provides a twofold contribution. First, this review's theoretical contribution is advancing consumer behaviour literature on halal food. Second, this work's practical contribution is to enrich practitioners' understanding of the antecedents of consumer behaviour regarding halal food. This is the first review proposing a consumer behaviour model for Halal food. It makes a theoretical contribution to understanding consumer behaviour on Halal food and provides practical insights for practitioners.