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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. [ABSTRACT FROM AUTHOR]

We describe nine Rhizobium microvirus genomes identified in wastewater in Tempe, AZ, USA, between October 2019 and March 2020. The major capsid protein (MCP) encoded in these genomes phylogenetically cluster together and are distinct from the MCPs of Rhizobium microviruses identified in Mexico and Argentina., Competing Interests: The authors declare no conflict of interest.

Objectives: Post-diagnostic support is a significant factor in facilitating personal recovery following a diagnosis of dementia, but access is often inconsistent and insufficient. Recovery Colleges offer peer-led, co-produced courses that can support people to have meaningful lives and have been adapted for use in the context of dementia. A realist review was conducted to understand the application and sustainability of Recovery College dementia courses., Method: An iterative, five-step process combined literature published to 2023 with knowledge from stakeholders with lived and professional experience of dementia involved with Recovery College dementia courses (PROSPERO registration CRD42021293687)., Results: Thirty-five documents and discussions with 19 stakeholders were used to build the initial programme theory comprising of 24 context-mechanism-outcome configurations. Reoccurring factors included: attending to aspects of co-production and course delivery to ensure they promoted inclusion and were not compromised by organisational pressures; how stigma impacted access to course opportunities; and embedding personal recovery principles throughout course development to be relevant for people living with dementia and those who support them., Conclusion: People struggling to reconcile their future alongside dementia need practical and emotional support to access and benefit from Recovery College dementia courses, ways to achieve this will be explored through a realist evaluation.

Objective: Cytotoxic chemotherapy for ovarian cancer can be augmented by co-administration of vascular endothelial growth factor inhibitors but these are contraindicated in patients with bowel obstruction due to the risk of gastrointestinal perforation. We evaluated the safety and feasibility of paclitaxel plus cediranib to treat patients with platinum-resistant ovarian cancer at risk of malignant bowel obstruction., Methods: A phase II trial included eligible patients between March 2018 and February 2021, identified by clinical symptoms and radiographic risk factors for malignant bowel obstruction. Cediranib (20 mg/day) was added to paclitaxel (70 mg/m 2 /week) within 9 weeks of starting paclitaxel if pretreatment bowel symptoms had improved. The primary endpoint was the number of patients treated for ≥5 days with cediranib that were free of grade 3-5 gastrointestinal perforation or fistula. Secondary endpoints were hospitalization for bowel obstruction, grade ≥3 adverse events, treatment compliance assessed by relative dose intensity, objective response, progression-free survival, and overall survival., Results: Thirty patients were recruited. Of these, 12 received paclitaxel alone and 17 received paclitaxel and cediranib in combination. One patient died before starting treatment. No patient developed a grade 3-5 gastrointestinal perforation or fistula (one sided 95% confidence interval (CI) upper limit 0.16). One patient required hospitalization for bowel obstruction but recovered with conservative management. The most common cediranib-related grade ≥3 adverse events were fatigue (3/17), diarrhorea (2/17), and hypomagnesemia (2/17). Relative dose intensity for paclitaxel was 90% (interquartile range (IQR) 85-100%; n=29) and for cediranib 88% (IQR 76-93%; n=17). The objective response in patients who received paclitaxel and cediranib was 65.0% (one complete and 10 partial responses). Median progression-free survival was 6.9 months (95% CI 4.4-11.5 months; n=17) and overall survival was 19.4 months (95% CI 10.1-20.4 months; n=17). Median follow-up was 12.4 months (8.9-not reached; n=17)., Conclusions: The unexpectedly high withdrawal rate during paclitaxel alone, before introducing cediranib, meant we were unable to definitely conclude that paclitaxel plus cediranib did not cause gastrointestinal perforation or fistula. The regimen was however tolerated., Trial Registration Number: EudraCT 2016-004618-93., Competing Interests: Competing interests: ARC and GCJ have received research funding for this and other investigator initiated studies from AstraZeneca. RDM is supported by a National Institute for Health Research Clinical Lectureship (CL-2022-06-002)., (© IGCS and ESGO 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Neutrophils are increasingly implicated in chronic inflammation and metabolic disorders. Here, we show that visceral adipose tissue (VAT) from individuals with obesity contains more neutrophils than in those without obesity and is associated with a distinct bacterial community. Exploring the mechanism, we gavaged microbiome-depleted mice with stool from patients with and without obesity during high-fat or normal diet administration. Only mice receiving high-fat diet and stool from subjects with obesity show enrichment of VAT neutrophils, suggesting donor microbiome and recipient diet determine VAT neutrophilia. A rise in pro-inflammatory CD4+ Th1 cells and a drop in immunoregulatory T cells in VAT only follows if there is a transient spike in neutrophils. Human VAT neutrophils exhibit a distinct gene expression pattern that is found in different human tissues, including tumors. VAT neutrophils and bacteria may be a novel therapeutic target for treating inflammatory-driven complications of obesity, including insulin resistance and colon cancer., (© 2024. The Author(s).)

Background: In the paediatric liver transplant programme in Johannesburg, South Africa (SA), tacrolimus is the calcineurin inhibitor of choice, comprising an essential component of the immunosuppression regimen. It is characterised by a narrow therapeutic index and wide interpatient variability, necessitating therapeutic drug monitoring of whole-blood concentrations. Pharmacogenetic research, although not representative of SA population groups, suggests that single-nucleotide polymorphisms within the cytochrome P450 3A5 (CYP3A5) gene contribute to the variability in tacrolimus dosing requirements. The rs776746 polymorphism, CYP3A5*3, results in a splice defect and a non-functional enzyme. Clinically, to reach the same tacrolimus concentration-to-dose ratio (CDR), expressors (CYP3A5*1/*1 and *1/*3) require a higher tacrolimus dose than non-expressors (*3/*3)., Objectives: To compare the pharmacokinetics of tacrolimus in paediatric liver transplant recipients with their donors' CYP3A5 genotypes, considering both donor and recipient characteristics., Methods: Blood samples from 46 living liver donors were collected, their genomic DNA was extracted, and their CYP3A5 genotype was established (polymerase chain reaction and restriction fragment length polymorphism analysis, validated by Sanger sequencing). The relationship of donor and recipient characteristics with the mean tacrolimus CDR was analysed using a general linear model. Non- confounding significant variables were included in a multiple regression model., Results: The study showed that all expressor donors genotyped as CYP3A5*1/*1 were of black African self-reported race and ethnicity. During the first 15 days post-transplant, we found that children who received grafts from donor CYP3A5 expressors (CYP3A5*1/*1 and *1/*3) had significantly lower mean tacrolimus CDRs compared with those who received grafts from donor CYP3A5 non-expressors (*3/*3); the recipients of CYP3A5 expressor grafts therefore require higher doses of oral tacrolimus to achieve the same therapeutic target range. In addition, graft-to-recipient weight ratio and the CYP3A5 donor genotypes were independent factors that significantly (p<0.05) affected mean tacrolimus CDRs in recipients., Conclusion: In this study, we showed that all CYP3A5*1 homozygote donors were of black African self-reported race and ethnicity, and tacrolimus CDRs in paediatric living-donor liver transplant recipients were significantly affected by donor graft size and donor CYP3A5 genotypes. Information from this study may inform the development of an Afrocentric tacrolimus precision-medicine algorithm to optimise recipient safety and graft outcomes.

Unilateral visual neglect is a condition that negatively impacts the lives of many stroke survivors. Studies have investigated different forms of vestibular stimulation as a potential therapy, but evidence is yet to be systematically reviewed. We therefore reviewed the effects of vestibular stimulation on outcomes of neglect and activities of daily living (ADL) for people with visual neglect. We searched relevant databases up until September 2022. Eligible articles included any form of vestibular stimulation, study design, or control condition. Included participants were 18 years or older, presenting with neglect following a haemorrhagic or ischaemic stroke. Relevant outcomes were clinically validated measures of neglect and ADL. Cochrane risk of bias tools were used to assess study quality. Meta-analyses and narrative methods were used to synthesize the data. Our search returned 17 relevant studies comprising 180 participants. Meta-analyses showed no difference between galvanic vestibular stimulation and sham conditions on outcomes, whereas caloric vestibular stimulation led to improvement compared to pre-stimulation scores. Narrative syntheses showed mixed results. Clinical and methodological heterogeneity was found both within and between studies. Overall, results were inconsistent regarding the effects of vestibular stimulation as a treatment for neglect. Further trials are warranted but require more careful methodological planning.

Here, four MOFs, namely Sc-TBAPy, Al-TBAPy, Y-TBAPy, and Fe-TBAPy (TBAPy: 1,3,6,8-tetrakis(p-benzoic acid)pyrene), were characterized and evaluated for their ability to remediate glyphosate (GP) from water. Among these materials, Sc-TBAPy demonstrates superior performance in both the adsorption and degradation of GP. Upon light irradiation for 5 min, Sc-TBAPy completely degrades 100% of GP in a 1.5 mM aqueous solution. Femtosecond transient absorption spectroscopy reveals that Sc-TBAPy exhibits enhanced charge transfer character compared to the other MOFs, as well as suppressed formation of emissive excimers that could impede photocatalysis. This finding was further supported by hydrogen evolution half-reaction (HER) experiments, which demonstrated Sc-TBAPy's superior catalytic activity for water splitting. In addition to its faster adsorption and more efficient photodegradation of GP, Sc-TBAPy also followed a selective pathway towards the oxidation of GP, avoiding the formation of toxic aminomethylphosphonic acid observed with the other M 3+ -TBAPy MOFs. To investigate the selectivity observed with Sc-TBAPy, electron spin resonance, depleted oxygen conditions, and solvent exchange with D 2 O were employed to elucidate the role of different reactive oxygen species on GP photodegradation. The findings indicate that singlet oxygen ( 1 O 2 ) plays a critical role in the selective photodegradation pathway achieved by Sc-TBAPy., (© 2024. The Author(s).)

Amyloid aggregation is a key feature of Alzheimer's disease (AD) and a primary target for past and present therapeutic efforts. Recent research is making it increasingly clear that the heterogeneity of amyloid deposits, extending past the commonly targeted amyloid-β (Aβ), must be considered for successful therapy. We recently demonstrated that amyloid-α (Aα or p3), a C-terminal peptidic fragment of Aβ, aggregates rapidly to form amyloids and can expedite the aggregation of Aβ through seeding. Here, we advance the understanding of Aα biophysics and biology in several important ways. We report the first cryogenic electron microscopy (cryo-EM) structure of an Aα amyloid fibril, proving unambiguously that the peptide is fibrillogenic. We demonstrate that Aα induces Aβ to form amyloid aggregates that are less toxic than pure Aβ aggregates and use nuclear magnetic resonance spectroscopy (NMR) to provide insights into specific interactions between Aα and Aβ in solution. This is the first evidence that Aα can coassemble with Aβ and alter its biological effects at relatively low concentrations. Based on the above, we urge researchers in the field to re-examine the significance of Aα in AD.

Objective: Use of non-invasive ventilation (NIV) in very low birthweight infants to decrease the incidence of bronchopulmonary dysplasia can also lead to pressure injuries (PI) caused by the respiratory device interface. We aimed to decrease our incidence of PIs related to the mask/prongs interface used for NIV (PI-NIV)., Study Design: We identified correct use of barriers and appropriate interface fit as key targets for intervention. Over several PDSA cycles, we developed custom 3D printed barrier templates to allow for barriers to be cut at the bedside and created concise educational documents to assist with interface fitting and troubleshooting., Results: The incidence of all PI-NIV decreased from 5.64 to 2.27 per 1000 NIV patient-days and the incidence of reportable (stage 3-4 and unstageable) PI-NIV decreased from 1.13 to 0 per 1000 NIV patient-days during the study period., Conclusions: With appropriate barrier usage and targeted education, the risk of PI-NIV can be minimized., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Epithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein that plays several roles in cancer biology. EpCAM is an attractive therapeutic target because of its expression in most solid tumors. However, targeting EpCAM has been challenging because it is also highly expressed in normal epithelial tissues. Initial attempts to develop EpCAM-specific T-cell engagers were unsuccessful due to severe cytokine release effects, as well as serious on-target, off-tumor drug-related toxicities. We developed novel, conditionally active biological (CAB) bispecific antibodies that bind to both EpCAM and CD3 in an acidic tumor microenvironment. In healthy tissues, binding to EpCAM and CD3 is greatly reduced by a novel, dual CAB selection, where each binding domain is independently blocked by the presence of physiological chemicals known as Protein-associated Chemical Switches (PaCS). The CAB anti-EpCAM T-cell engagers displayed the anticipated bispecific binding properties and mediated the potent lysis of EpCAM-positive cancer cell lines through the recruitment of T cells in the tumor microenvironment. Xenograft studies showed that the efficacy of CAB bispecific antibodies is similar to that of a non-CAB anti-EpCAM bispecific antibody, but they have markedly reduced toxicity in non-human primates, indicating an unprecedentedly widened therapeutic index of over 100-fold. These preclinical results indicate that the dual CAB bispecific antibody is potentially both a powerful and safe therapeutic platform and a promising T cell-engaging treatment for patients with EpCAM-expressing tumors.

Cyanobacterial blooms are one of the most significant threats to global water security and freshwater biodiversity. Interactions among multiple stressors, including habitat degradation, species invasions, increased nutrient runoff, and climate change, are key drivers. However, assessing the role of anthropogenic activity on the onset of cyanobacterial blooms and exploring response variation amongst lakes of varying size and depth is usually limited by lack of historical records. In the present study we applied molecular, paleolimnological (trace metal, Itrax-µ-XRF and hyperspectral scanning, chronology), paleobotanical (pollen) and historical data to reconstruct cyanobacterial abundance and community composition and anthropogenic impacts in two dune lakes over a period of up to 1200 years. Metabarcoding and droplet digital PCR results showed very low levels of picocyanobacteria present in the lakes prior to about CE 1854 (1839-1870 CE) in the smaller shallow Lake Alice and CE 1970 (1963-1875 CE) in the larger deeper Lake Wiritoa. Hereafter bloom-forming cyanobacteria were detected and increased notably in abundance post CE 1984 (1982-1985 CE) in Lake Alice and CE 1997 (1990-2007 CE) in Lake Wiritoa. Currently, the magnitude of blooms is more pronounced in Lake Wiritoa, potentially attributable to hypoxia-induced release of phosphorus from sediment, introducing an additional source of nutrients. Generalized linear modelling was used to investigate the contribution of nutrients (proxy = bacterial functions), temperature, redox conditions (Mn:Fe), and erosion (Ti:Inc) in driving the abundance of cyanobacteria (ddPCR). In Lake Alice nutrients and erosion had a statistically significant effect, while in Lake Wiritoa nutrients and redox conditions were significant., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)