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BACKGROUND: There is a lack of evidence on acute kidney injury (AKI) and new-onset chronic kidney disease (CKD) after surgery for localised renal masses (LRMs) in patients with two kidneys and preserved baseline renal function. OBJECTIVE: To evaluate the prevalence and risk of AKI and new-onset clinically significant CKD (csCKD) in patients with a single renal mass and preserved renal function after being treated with partial (PN) or radical (RN) nephrectomy. DESIGN SETTING AND PARTICIPANTS: We queried our prospectively maintained databases to identify patients with a preoperative estimated glomerular filtration rate (eGFR) of ≥60 ml/min/1.73 m2 and a normal contralateral kidney who underwent PN or RN for a single LRM (cT1-T2N0M0) between January 2015 and December 2021 at four high-volume academic institutions. INTERVENTION: PN or RN. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The outcomes of this study were AKI at hospital discharge and the risk of new-onset csCKD, defined as eGFR

OBJECTIVES: In biomedical research, spin is the overinterpretation of findings, and it is a growing concern. To date, the presence of spin has not been evaluated in prognostic model research in oncology, including studies developing and validating models for individualized risk prediction. STUDY DESIGN AND SETTING: We conducted a systematic review, searching MEDLINE and EMBASE for oncology-related studies that developed and validated a prognostic model using machine learning published between 1st January, 2019, and 5th September, 2019. We used existing spin frameworks and described areas of highly suggestive spin practices. RESULTS: We included 62 publications (including 152 developed models; 37 validated models). Reporting was inconsistent between methods and the results in 27% of studies due to additional analysis and selective reporting. Thirty-two studies (out of 36 applicable studies) reported comparisons between developed models in their discussion and predominantly used discrimination measures to support their claims (78%). Thirty-five studies (56%) used an overly strong or leading word in their title, abstract, results, discussion, or conclusion. CONCLUSION: The potential for spin needs to be considered when reading, interpreting, and using studies that developed and validated prognostic models in oncology. Researchers should carefully report their prognostic model research using words that reflect their actual results and strength of evidence. ispartof: JOURNAL OF CLINICAL EPIDEMIOLOGY vol:157 pages:120-133 ispartof: location:United States status: published

Background Drug eluting stents (DES) are associated with a 2% to 4% annual rate of target lesion failure through 5-to-10-year follow-up. The presence of a metallic protheses is a trigger for neo-atherosclerosis and very late stent thrombosis. A "leave nothing behind" strategy using Drug Coated Balloons has been suggested; however, paclitaxel coated balloons are only recommended in selected indications. Recently a novel sirolimus eluting balloon, the SELUTION SLR TM 014 PTCA balloon (SEB) (M.A. MedAlliance SA, Nyon, Switzerland) has been developed.Hypothesis A strategy of percutaneous coronary intervention (PCI) with SEB and provisional DES is non-inferior to a strategy of systematic DES on target vessel failure (TVF) at one and five years. If non-inferiority is met at 5 years, superiority will be tested.Design SELUTION DeNovo is a multi-center international open-label randomized trial. Subjects meeting eligibility criteria are randomized 1:1 to treatment of all lesions with either SEB and provisional DES or systematic DES. Major inclusion criteria are PCI indicated for >= 1 lesion considered suitable for treatment by either SEB or DES and clinical presentation with chronic coronary syndrome, unstable angina or non-ST segment elevation myocardial infarction (NSTEMI). There is no limitation in the number of lesions to be treated. Target lesions diameters are between 2 and 5 mm. Major exclusion criteria are lesions in the left main artery, chronic total occlusions, ST segment elevation myocardial infarction and unstable non-ST segment elevation myocardial infarction. Three thousand three hundred twenty six patients will be included in 50 sites in Europe and Asia. TVF rates and their components will be determined at 30 days, 6 months and annually up to 5 years post-intervention. Among secondary endpoints, bleeding events, cost-effectiveness data and net clinical benefits will be assessed.Summary SELUTION DeNovo trial is an open-label, multi-center international randomized trial comparing a strategy of PCI with SEB and provisional DES to a strategy of PCI with systematic DES on TVF at one and five years. Non-inferiority will be tested at one and five years. If non-inferiority is met at five years, superiority will be tested. (Am Heart J 2023;258:77-84.) The SELUTION DeNovo trial is funded by MedAlliance CardioVascular SA, Rue de Rive 5, 1260 Nyon, Switzerland.

THEMIS is a double-blind, randomized trial of 19,220 patients with diabetes mellitus and stable coronary artery disease (CAD) comparing ticagrelor to placebo, in addition to aspirin. The present study aimed to describe the proportion of patients eligible and reasons for ineligibility for THEMIS within a population of patients with diabetes and CAD included in the Reduction of Atherothrombosis for Continued Health (REACH) registry. The THEMIS eligibility criteria were applied to REACH patients. THEMIS included patients ≥50 years with type 2 diabetes and stable CAD as determined by either a history of previous percutaneous coronary intervention, coronary artery bypass grafting, or documentation of angiographic stenosis of ≥50% of at least one coronary artery. Patients with prior myocardial infarction or stroke were excluded. In REACH, 10,156 patients had stable CAD and diabetes. Of these, 6515 (64.1%) patients had at least one exclusion criteria. From the remaining population, 784 patients did not meet inclusion criteria (7.7%) mainly due to absence of aspirin treatment (7.2%), yielding a 'THEMIS-eligible population' of 2857 patients (28.1% of patients with diabetes and stable CAD). The main reasons for exclusion were a history of myocardial infarction (53.1%), use of oral anticoagulation (14.5%), or history of stroke (12.9%). Among the 4208 patients with diabetes and a previous PCI, 1196 patients (28.4%) were eligible for inclusion in the THEMIS-PCI substudy. In a population of patients with diabetes and stable coronary artery disease, a sizeable proportion appear to be 'THEMIS eligible.' http://www. gov identifier: NCT01991795. The THEMIS trial was funded by AstraZeneca. The REACH registry was sponsored by Sanofi, Bristol-Myers Squibb, and the Waksman Foundation (Tokyo, Japan) and is endorsed by the World Heart Federation. Sí

Poly (ADP-ribose) polymerase inhibitors (PARPis) have demonstrated clinical activity in patients with BRCA1 and/or BRCA2 mutated breast, ovarian, prostate, and pancreatic cancers. Notably, BRCA mutations are associated with defects in the homologous recombination repair (HRR) pathway. This homologous recombination deficiency (HRD) phenotype can also be observed as genomic instability in tumour cells. Accordingly, PARPi sensitivity has been observed in various tumours with HRD, independent of BRCA mutations. Currently, four PARPis are approved by regulatory agencies for the treatment of cancer across multiple tumour types. Most indications are specific to tumours with a confirmed BRCA mutation, mutations in other HRR-related genes, HRD evidenced by genomic instability, or evidence of platinum sensitivity. Regulatory agencies have also approved companion and complementary diagnostics to facilitate patient selection for each PARPi indication. This review aims to summarise the biological basis, clinical validation, and clinical relevance of the available diagnostic methods and assays to assess HRD. ispartof: EUROPEAN JOURNAL OF CANCER vol:179 pages:136-146 ispartof: location:England status: published

The effects of synthetic fertilizer and nutrient leaching are causing serious problems impacting soil function and its fertility. Mitigation of nutrient leaching and use of chemical fertilizer is crucial as fertile land adds up sustainability to climate changes. Biochar produced from agricultural bio-waste and municipal solid waste has been used for crop production and when applied in combination with organic nutrients may support mitigation of nutrient loss and adverse effects of chemical fertilizers. Different types of biochar and their application for soil enhancement have been observed, pine needle and sewage sludge derived low-temperature biochar along with compost, organic fertilizer in the form of manure and microalgal biomass may interact with soil chemistry and plant growth to impact nutrient loss and compensate the hazardous effect of chemical fertilizer, but it has not been investigated yet. This present study elaborates application of sewage sludge and pine needle biochar produced at 400 °C in an application rate of 5 % w/w and 10 t h-1 in combination with compost, manure and microalgal biomasses of Closteriopsis acicularis (BM1) and Tetradesmus nygaardi (BM2) on the growth of Chickpea (Cicer arietinum) and Fenugreek (Trigonella foenum-graecum) crop assessed in a pot experiment over a two crop (Chickpea - Fenugreek) cycle in Pakistan. Results depict that the pine needle biochar with additives has increased plant height by 104.1 ± 2.76 cm and fresh biomass by 49.9 ± 1.02 g, buffered the soil pH to 6.5 for optimum growth of crops and enhance carbon retention by 36 %. This study highlights the valorization of sewage sludge and pine needle into biochar and the effect of biochar augmentation, its impact on soil nutrients and plant biomass enhancement. The greener approach also mitigates and helps in the sustainable management of solid wastes.

BACKGROUND: Somatostatin receptor-2 (SSTR2) is expressed on cell surface of neuroendocrine neoplasias; its presence is exploited for the delivery of peptide receptor radionuclide therapy (PRRT). Patients with no or low expression of SSTR2 are not candidates for PRRT. SSTR2 promotor undergoes epigenetic modification, known to regulate gene expression. We investigated whether the demethylation agent, guadecitabine, could enhance the expression of SSTR2 in NET models, using radioligand uptake/PET imaging as a biomarker of epigenetic modification. METHODS: The effects of guadecitabine on the transcriptional, translational, and functional regulation of SSTR2 both in vitro and in vivo using low (QGP-1) and high (BON-1) methylated neuroendocrine neoplasia models was characterised. Promotor region methylation profiling of clinical samples (n = 61) was undertaken. Safety of combination guadecitabine and PRRT was assessed in vivo. RESULTS: Pyrosequencing of cell lines illustrated differential methylation indices - BON: 1 94%, QGP: 1 21%. Following guadecitabine treatment, a dose-dependent increase in SSTR2 in BON-1 at a transcriptional, translational, and functional levels using the SSTR2-directed radioligand, 18F-FET-βAG-TOCA ([18F]-FETO) (150% increase [18F]-FETO uptake, p

BACKGROUND: PAOLA-1/ENGOT-ov25 (NCT02477644) demonstrated a significant progression-free survival (PFS) benefit with maintenance olaparib plus bevacizumab versus placebo plus bevacizumab in newly diagnosed, advanced ovarian cancer. We report the prespecified main second progression-free survival (PFS2) analysis for PAOLA-1. METHODS: This randomised, double-blind, phase III trial was conducted in 11 countries. Eligible patients had newly diagnosed, advanced, high-grade ovarian cancer and were in response after first-line platinum-based chemotherapy plus bevacizumab. Patients were randomised 2:1 to olaparib (300 mg twice daily) or placebo for up to 24 months; all patients received bevacizumab (15 mg/kg every 3 weeks) for up to 15 months. Primary PFS end-point was reported previously. Time from randomisation to second disease progression or death was a key secondary end-point included in the hierarchical-testing procedure. RESULTS: After a median follow-up of 35.5 months and 36.5 months, respectively, median PFS2 was 36.5 months (olaparib plus bevacizumab) and 32.6 months (placebo plus bevacizumab), hazard ratio 0.78; 95% confidence interval (CI) 0.64-0.95; P = 0.0125. Median time to second subsequent therapy or death was 38.2 months (olaparib plus bevacizumab) and 31.5 months (placebo plus bevacizumab), hazard ratio 0.78; 95% CI 0.64-0.95; P = 0.0115. Seventy-two (27%) patients in the placebo plus bevacizumab group received a poly(ADP-ribose) polymerase inhibitor as first subsequent therapy. No new safety signals were observed for olaparib plus bevacizumab. CONCLUSION: In newly diagnosed, advanced ovarian cancer, maintenance olaparib plus bevacizumab provided continued benefit beyond first progression, with a significant PFS2 improvement and a time to second subsequent therapy or death delay versus placebo plus bevacizumab. ispartof: EUROPEAN JOURNAL OF CANCER vol:174 pages:221-231 ispartof: location:England status: published

Chemotherapy; Quality of life; Symptoms Quimioterapia; Calidad de vida; Síntomas Quimioteràpia; Qualitat de vida; Símptomes Background In a phase III, randomised, active-controlled study (EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9; R2810-ONC-1676; NCT03257267) and cemiplimab significantly improved survival versus investigator's choice of chemotherapy among patients with recurrent cervical cancer who had progressed on platinum-based therapy. Here we report patient-reported outcomes in this pivotal study. Methods Patients were randomised 1:1 to open-label cemiplimab (350 mg intravenously every 3 weeks) or investigator's choice of chemotherapy in 6-week cycles. Patients completed the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 during cycles 1–16. Least-squares mean changes from baseline in global health status (GHS)/quality of life (QoL) and physical functioning (PF) were secondary end-points in the statistical hierarchy. Results Of 608 patients (304/arm), 77.8% patients had squamous cell carcinoma and 22.2% patients had adenocarcinoma. Questionnaire completion rates were ∼90% throughout. In the squamous cell carcinoma population, overall between-group differences statistically significantly favoured cemiplimab in GHS/QoL (8.49; 95% confidence interval [CI]: 3.77–13.21; P = 0.0003) and PF (8.35; 95% CI: 4.08–12.62; P < 0.0001). Treatment differences favoured cemiplimab in both histologic populations by cycle 2. Overall changes from baseline in most functioning and symptom scales favoured cemiplimab, with clinically meaningful treatment differences in role functioning, appetite loss and pain in both populations. The sensitivity analyses, responder analyses and time to definitive deterioration favoured cemiplimab in both populations. Conclusions Cemiplimab conferred favourable differences in GHS/QoL and PF compared with chemotherapy among patients with recurrent cervical cancer, with benefits in PF by cycle 2, and clinically meaningful differences favouring cemiplimab in role functioning, appetite loss, and pain. This work was supported by Regeneron Pharmaceuticals, Inc., and Sanofi.

Microplastic pollution is increasingly recognised as a global environmental challenge which stems from the rapid growth of the use of petrochemical-derived plastic. As researchers and practitioners face a myriad of environmental challenges, oceanic microplastic pollution has so far dominated interest. However, airborne microplastics present an increasing environmental and public health concern. There is currently a need for research addressing this emerging challenge, and at the same time, the lack of knowledge and consensus regarding airborne microplastics presents an obstacle to action. The purpose of this study is to utilise a participatory Structured Decision-Making (SDM) approach to understand the perspectives of a range of stakeholders involved in the microplastics landscape, and subsequently refine common research priorities and knowledge gaps to advance the field. Through two participatory workshops, we first defined shared objectives of stakeholders and then negotiated best courses of action to achieve these objectives based on discussion between stakeholders and facilitators. The qualitative approach taken has enabled the full, complex and multidisciplinary aspects of the research into airborne microplastic pollution to be considered. Our findings highlight some important potential consequences of airborne microplastic pollution, including impacts on human health, and the need for more interdisciplinary research, and collaborative, integrated approaches in this area. As a result of the first workshop, five fundamental objectives on the theme of airborne microplastics were identified. As a direct consequence of this, participants identified 84 actions split across eight themes, which are outlined later in this paper.

OBJECTIVE: Progression-free survival (PFS) is an important early efficacy endpoint in ovarian cancer (OC) and its relevance to patients should be assessed. PRIMA, a phase III trial, assessed niraparib in patients with OC; this post hoc analysis examined the relationship between disease progression in OC and health-related quality of life (HRQoL). METHODS: The PRIMA trial randomized patients with advanced OC responsive to first-line platinum-based chemotherapy to once daily maintenance oral niraparib or placebo. This post hoc analysis evaluated the impact of disease progression on HRQoL by comparing HRQoL at the last visit pre-progression to end of treatment (EoT), and after 4, 8, 12, and 24 weeks. Assessments included the Functional Assessment of Cancer Therapy-Ovarian Symptom Index (FOSI), the European Quality of Life Five Dimension Five Level questionnaire (EQ-5D-5L) and EQ Visual Analogue Scale (EQ-VAS), the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (EORTC-QLQ-C30), and the EORTC Quality of Life Questionnaire Ovarian Cancer module (EORTC-QLQ-OV28). RESULTS: This post hoc analysis included 733 patients. Mean FOSI, EQ-5D-5L, and EQ-VAS scores deteriorated from last visit pre-progression to EoT and remained low up to 24-week follow-up. Least squares mean changes from last visit pre-progression to EoT were -2.1 (95% confidence interval -2.4, -1.7) for FOSI, -4.6 (-5.6, -3.5) for the EQ-5D-5L index, and -7.9 (-9.6, -6.3) for EQ-VAS. CONCLUSIONS: Disease progression negatively impacted HRQoL in patients with OC. PFS is clinically relevant, and prolonging PFS may preserve HRQoL. ispartof: GYNECOLOGIC ONCOLOGY vol:166 issue:3 pages:494-502 ispartof: location:United States status: published

Since the introduction of live-attenuated rotavirus vaccines in Belgium in 2006, surveillance has routinely detected rotavirus vaccine-derived strains. However, their genomic landscape and potential role in gastroenteritis have not been thoroughly investigated. We compared VP7 and VP4 nucleotide sequences obtained from rotavirus surveillance with the Rotarix vaccine sequence. As a result, we identified 80 vaccine-derived strains in 5125 rotavirus-positive infants with gastroenteritis from 2007 to 2018. Using both viral metagenomics and reverse transcription qPCR, we evaluated the vaccine strains and screened for co-infecting enteropathogens. Among the 45 patients with known vaccination status, 39 were vaccinated and 87% received the vaccine less than a month before the gastroenteritis episode. Reconstruction of 30 near complete vaccine-derived genomes revealed 0-11 mutations per genome, with 88% of them being non-synonymous. This, in combination with several shared amino acid changes among strains, pointed at selection of minor variant(s) present in the vaccine. We also found that some of these substitutions were true revertants (e.g., F167L on VP4, and I45T on NSP4). Finally, co-infections with known (e.g., Clostridioides difficile and norovirus) and divergent or emerging (e.g., human parechovirus A1, salivirus A2) pathogens were detected, and we estimated that 35% of the infants likely had gastroenteritis due to a 'non-rotavirus' cause. Conversely, we could not rule out the vaccine-derived gastroenteritis in over half of the cases. Continued studies inspecting reversion to pathogenicity should monitor the long-time safety of live-attenuated rotavirus vaccines. All in all, the complementary approach with NGS and qPCR provided a better understanding of rotavirus vaccine strain evolution in the Belgian population and epidemiology of co-infecting enteropathogens in suspected rotavirus vaccine-derived gastroenteritis cases. ispartof: VACCINE vol:40 issue:35 pages:5114-5125 ispartof: location:Netherlands status: published

INTRODUCTION: Older patients are at higher risk of chemotherapy-induced toxicity, raising interest in less toxic anti-HER2 regimens for older persons with HER2-positive (HER2+) metastatic breast cancer (MBC). PATIENTS AND METHODS: This phase II study randomized (1:1) patients with HER2+ MBC, aged 70+ or frail 60+, to first line chemotherapy with metronomic oral cyclophosphamide (M) + Trastuzumab (T) and Pertuzumab (P) or TP alone. T-DM1 was offered in case of progression. RESULTS: In total, 39 and 41 patients were randomized to TP and TPM arm respectively. Median follow-up is 54.0 months. 24-month PFS was 18.7% (95% CI 8.2-32.4) and 28.7% (95% CI 15.8-43.0), respectively. A total of 49 (61.3%) patients died of whom 37 (75.5%) from disease progression; number of deaths per arm was 27 (69.2%) for TP and 22 (53.7%) for TPM. There was no significant difference in OS between the two arms (median OS TP vs TPM: 32.1 vs 37.5 months, p 0.25). Among the 40 patients who have started T-DM1 after disease progression on TP/TPM, PFS rate at 6 months after start of T-DM1 was 43.6% (95% CI: 27.7-58.5) and grade 3 or higher AE occurred in 18 pts (45%). CONCLUSIONS: Metronomic chemotherapy-based dual blockade (TPM), followed by T-DM1 after progression, provides an active and relatively well tolerated treatment option in an older/frail HER2+ MBC population, with a median survival of over 3 years. Nevertheless, the majority of this older/frail population died from breast cancer, highlighting the need for well tolerated and efficacious treatments in these patients. ispartof: BREAST vol:64 pages:100-111 ispartof: location:Netherlands status: published

BACKGROUND AND AIM: Dose management systems (DMS's) have been widely used for radiation dose data collection and analysis, and have been proven useful for optimization. Although DMS's are used for patient dosimetry, a quality assurance (QA) program has not yet been developed. The aim of this work was to propose vendor neutral quality tests and discuss how QA can be established for DMS's to ensure robustness and quality of patient dose data. MATERIALS & METHODS: Different DMS's functions were organized in three groups according to their complexity. As basic functions, we defined those that depend on simple data collection and require data verification. Intermediate functions provide calculations such as effective dose or higher dose alerts, while the advanced group aims to address complicated analyses, such as peak skin dose calculations. RESULTS: An Excel file was developed that includes quality tests on basic and intermediate functions for different modalities (radiography, interventional radiology, CT and mammography) and is provided as Annex. For advanced functionalities, tests are discussed to guide medical physics experts to design their QA program as appropriate. CONCLUSIONS: The QA program is intended to ensure the trustworthy functioning for applications in normal circumstances and patient outliers. As DMS's are systems with regular upgrades, the associated QA program should be a dynamic process that takes into account the functionalities of the DMS and its application in the clinics. Medical physics experts should ensure the safety and accuracy of DMS's, as an essential component in patient dosimetry - part of their mission. ispartof: PHYSICA MEDICA-EUROPEAN JOURNAL OF MEDICAL PHYSICS vol:99 pages:10-15 ispartof: location:Italy status: published

CD4+Foxp3+ Regulatory T cells (Tregs) are essential for maintaining self-tolerance and are increasingly recognised to have important roles in tissue homeostasis and repair. In the CD8 compartment an analogous Foxp3+ population is present, which shares phenotypic aspects with the more common CD4+Foxp3+Treg population. While oft neglected for their low frequency, there is increasing evidence that these CD8+Foxp3+ cells are bona fide regulatory cells, with both shared and distinct characteristics from their CD4+ analogue. Here we focus on the evidence for a regulatory function of CD8+Foxp3+ cells, and the potential unique role this neglected lineage may play in immune homeostasis and disease prevention. ispartof: IMMUNOLOGY LETTERS vol:247 pages:22-26 ispartof: location:Netherlands status: published

Metallic element release during implant placement can lead to mucositis and peri-implantitis. Here, using ex vivo porcine mandibles, the release of metallic elements into the surrounding bone with different material and geometrical designs was quantified. Implants from BioHorizons® and Straumann® (Bone level, tapered/cylindrical, 3/4 mm body diameter, Ti-CP4/Ti-6Al-4V/Ti-15Zr) systems were used. Micro computed tomography and inductively coupled plasma optical emission spectroscopy was used to visualise and quantify metallic elements in bone, following acid digestion. Implant surfaces were examined with scanning electron microscopy and internalization of implant particles by human gingival fibroblasts (HGFs) and RAW 264.7 macrophages were demonstrated in vitro. Implants with wider body diameters resulted in higher metallic element release. Ti-6Al-4V implants released significantly more metallic elements in comparison to both Ti-CP4 and Ti-15Zr devices with similar design and dimensions. Tapered Ti-CP4 implants released less compared to those with cylindrical design. Al three types of particles were internalized by HGFs and RAW 264.7. Ti-CP4 and Ti-15Zr appear to be more suitable materials, however, further studies are required to elucidate the biological effects of the fine particles and/or metallic species from dental implants. Authors would like to raise the awareness in the dental profession community that careful evaluation of the materials used in dental implants and the potential risks of the individual constituents of any alloy are needed. The potential cytotoxicity of Ti-6Al-4V implant particles should be highlighted. Further investigations on the biological effect of the fine particles or metallic species released from dental implants are also needed. [Abstract copyright: Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.]

BACKGROUND AND AIMS: Pseudoxanthoma elasticum (PXE) is a genetic disorder characterized by systemic calcification of elastin fibers. Additionally, PXE is associated with an increased risk of stroke. It has been hypothesized that this may be caused by accelerated (intracranial) atherogenesis, as a consequence of specific genetic mutations underlying PXE. Hence, we compared the distribution and burden of intracranial atherosclerosis between PXE patients and healthy controls. METHODS: Fifty PXE patients and 40 age-and-sex-matched healthy controls (without previous ischemic cerebrovascular disease) underwent 3T MRI to visualize atherosclerotic intracranial vessel wall lesions (VWLs). We compared the presence and burden of VWLs (total and for the anterior cerebral, middle cerebral, intracranial internal carotid, posterior cerebral, and basilar arteries separately) between PXE patients and healthy controls using logistic (presence versus absence) and negative binomial regression models (VWL count) adjusted for relevant confounders. All regressions included group (PXE patients vs. healthy controls) as independent variable. RESULTS: We found that 34 (68.0%) PXE patients and 28 (70.0%) healthy controls had a VWL (odds ratio for presence 1.06 [95%CI 0.38-2.91]). In addition, the total burden of VWLs was similar between PXE patients (68 VWLs) and healthy controls (73 VWLs, incidence rate ratio for count 0.81 [95%CI 0.55-1.20]). Findings were similar when analyses were stratified for artery. CONCLUSIONS: The distribution and burden of intracranial atherosclerosis were similar between PXE patients and healthy controls. This implies PXE and its underlying mutations do not involve increased (intracranial) atherogenesis and that vascular calcification or other mechanisms explains the increased stroke risk in PXE. ispartof: ATHEROSCLEROSIS vol:350 pages:19-24 ispartof: location:Ireland status: published

CONTEXT: The primary lesion in penile cancer is managed by surgery or radiation. Surgical options include penile-sparing surgery, amputative surgery, laser excision, and Moh's micrographic surgery. Radiation is applied as external beam radiotherapy (EBRT) and brachytherapy. The treatment aims to completely remove the primary lesion and preserve a sufficient functional penile stump. OBJECTIVE: To assess whether the 5-yr recurrence-free rate and other outcomes, such as sexual function, quality of life, urination, and penile preserving length, vary between various treatment options. EVIDENCE ACQUISITION: The EMBASE, MEDLINE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials (CENTRAL; Cochrane HTA, DARE, HEED), Google Scholar, and ClinicalTrials.gov were searched for publications from 1990 through May 2021. Randomized controlled trials, nonrandomized comparative studies (NRCSs), and case series (CSs) were included. EVIDENCE SYNTHESIS: The systematic review included 88 studies, involving 9578 men from 16 NRCSs and 72 CSs. The cumulative mean 5-yr recurrence-free rates were 82.0% for penile-sparing surgery, 83.9% for amputative surgery, 78.6% for brachytherapy, 55.2% for EBRT, 69.4% for lasers, and 88.2% for Moh's micrographic surgery, as reported from CSs, and 76.7% for penile-sparing surgery and 93.3% for amputative surgery, as reported from NRCSs. Penile surgery affects sexual function, but amputative surgery causes more appearance concerns. After brachytherapy, 25% of patients reported sexual dysfunction. Both penile-sparing surgery and amputative surgery affect all aspects of psychosocial well-being. CONCLUSIONS: Despite the poor quality of evidence, data suggest that penile-sparing surgery is not inferior to amputative surgery in terms of recurrence rates in selected patients. Based on the available information, however, broadly applicable recommendations cannot be made; appropriate patient selection accounts for the relative success of all the available methods. PATIENT SUMMARY: We reviewed the evidence of various techniques to treat penile tumor and assessed their effectiveness in oncologic control and their functional outcomes. Penile-sparing as well as amputative surgery is an effective treatment option, but amputative surgery has a negative impact on sexual function. Penile-sparing surgery and radiotherapy are associated with a higher risk of local recurrence, but preserve sexual function and quality of life better. Laser and Moh's micrographic surgery could be used for smaller lesions. ispartof: EUROPEAN UROLOGY OPEN SCIENCE vol:40 pages:58-94 ispartof: location:Netherlands status: published

Biomedical research can generally be categorized into 1 of 3 aims: describing the occurrence of disease; identifying persons with or at increased risk of disease including diagnostic and prognostic studies; and explaining the occurrence of disease including etiologic and efficacy studies. ispartof: WORLD NEUROSURGERY vol:161 pages:240-244 ispartof: location:United States status: published

ispartof: HORTICULTURAL PLANT JOURNAL vol:8 issue:3 pages:289-296 status: published

Emerging clinical data show that three ceramide molecules, Cer d18:1/16:0, Cer d18:1/24:1, and Cer d18:1/24:0, are biomarkers of a fatal outcome in patients with cardiovascular disease. This finding raises basic questions about their metabolic origin, their contribution to disease pathogenesis, and the utility of targeting the underlying enzymatic machinery for treatment of cardiometabolic disorders. Here, we outline the development of a potent N-acetylgalactosamine-conjugated antisense oligonucleotide engineered to silence ceramide synthase 2 specifically in hepatocytes in vivo. We demonstrate that this compound reduces the ceramide synthase 2 mRNA level and that this translates into efficient lowering of protein expression and activity as well as Cer d18:1/24:1 and Cer d18:1/24:0 levels in liver. Intriguingly, we discover that the hepatocyte-specific antisense oligonucleotide also triggers a parallel modulation of blood plasma ceramides, revealing that the biomarkers predictive of cardiovascular death are governed by ceramide biosynthesis in hepatocytes. Our work showcases a generic therapeutic framework for targeting components of the ceramide enzymatic machinery to disentangle their roles in disease causality and to explore their utility for treatment of cardiometabolic disorders. ispartof: MOLECULAR THERAPY vol:30 issue:4 pages:1661-1674 ispartof: location:United States status: published

Aims: Current follow-up for head and neck cancer (HNC) is ineffective, expensive and fails to address patients' needs. The PETNECK2 trial will compare a new model of patient-initiated follow-up (PIFU) with routine scheduled follow-up. This article reports UK clinicians' views about HNC follow-up and PIFU, to inform the trial design. Materials and Methods: Online focus groups with surgeons (ear, nose and throat/maxillofacial), oncologists, clinical nurse specialists and allied health professionals. Clinicians were recruited from professional bodies, mailing lists and personal contacts. Focus groups explored views on current follow-up and acceptability of the proposed PIFU intervention and randomised controlled trial design (presented by the study co-chief investigator), preferences, margins of equipoise, potential organisational barriers and thoughts about the content and format of PIFU. Data were interpreted using inductive thematic analysis. Results: Eight focus groups with 34 clinicians were conducted. Clinicians highlighted already known limitations with HNC follow-up – lack of flexibility to address the wide-ranging needs of HNC patients, expense and lack of evidence – and agreed that follow-up needs to change. They were enthusiastic about the PETNECK2 trial to develop and evaluate PIFU but had concerns that PIFU may not suit disengaged patients and may aggravate patient anxiety/fear of recurrence and delay detection of recurrence. Anticipated issues with implementation included ensuring a reliable route back to clinic and workload burden on nurses and allied health professionals. Conclusions: Clinicians supported the evaluation of PIFU but voiced concerns about barriers to help-seeking. An emphasis on patient engagement, psychosocial issues, symptom reporting and reliable, quick routes back to clinic will be important. Certain patient groups may be less suited to PIFU, which will be evaluated in the trial. Early, meaningful, ongoing engagement with clinical teams and managers around the trial rationale and recruitment process will be important to discourage selective recruitment and address risk-averse behaviour and potential workload burden.

The entactogen 3,4-Methylenedioxymethamphetamine (MDMA) is increasingly being recognized for its therapeutic potential but is also widespread in nightlife settings where it may co-occur with crime. Since previous research detected impaired verbal memory during acute MDMA intoxication, understanding the drug's ramifications in an applied legal context becomes crucial. We conducted a double-blind, placebo-controlled trial to examine acute and delayed effects of MDMA (75 mg) on false memory in 60 healthy volunteers with a history of MDMA use, using three well-established false memory methods: a basic, associative word list (Deese/Roediger-McDermott (DRM)) paradigm and two applied misinformation tasks using a virtual reality crime. Memory was tested immediately (encoding and retrieval under drug influence) and 1 week later (retrieval when sober). Small MDMA-induced impairments of true memory in the word list task were detected at both time points. MDMA increased false memory for related but non-critical lures during the immediate test, and decreased false memory for critical lures after a delay. Episodic memory assessed in the misinformation tasks was not consistently affected. Findings indicate a complex memory profile but no heightened vulnerability to external suggestion in response to MDMA intoxication. Recommendations for future applied legal psychological research include adding measures of recall on top of recognition, using study designs that separate the different memory phases, and potentially testing higher doses. Further research on false memories and suggestibility using imagination procedures can also be relevant for the clinical context. ispartof: EUROPEAN NEUROPSYCHOPHARMACOLOGY vol:57 pages:59-68 ispartof: location:Netherlands status: published

BACKGROUND: Time in range (TIR) goals are rarely met in children with type 1 diabetes, except at the cost of increased hypoglycaemia episodes. Our objective was to evaluate the safety and efficiency of the Diabeloop DBL4K (Diabeloop, Grenoble, France) hybrid closed-loop system in prepubescent children. METHODS: We did a multicentre, open-label, randomised, controlled, non-inferiority, two-session crossover study in the paediatric endocrinology departments of three university hospitals in France and Belgium. Eligible participants were aged 6-12 years with type 1 diabetes for at least 1 year, glycated haemoglobin A1C 9% (75 mmol/mol) or less, and insulin pump treatment for at least 3 months. Participants were randomly assigned (1:1) to a closed-loop device or sensor-augmented pump (open loop) therapy. Randomisation was by a permuted block randomisation scheme, using an interactive web-based response system, and was stratified on centre (block size 6). The assessed closed-loop device, the Diabeloop for Kids DBL4K hybrid closed-loop system, is an automated blood glucose regulation system composed of a handset, insulin pump, and continuous glucose monitor. The open-loop system is defined as a sensor-augmented pump therapy composed of the usual insulin pump used by the patient and a continuous glucose monitor. A 72-h in-patient period was followed by a 6-week home phase. After a 1-week washout period, the participants crossed over to the other device. The primary outcome, assessed in the intention-to-treat population, was the mean proportion of time spent in hypoglycaemia (3·9 mmol/L [

OBJECTIVES: Universal adhesives (UAs) can optionally be applied in either an etch-and-rinse (E&R) or self-etch (SE) bonding mode. As the preferred bonding mode differs for enamel versus dentin, a universal conditioner for both enamel and dentin in replacement of the relatively aggressive phosphoric-acid etchant remains desirable. This study aimed to test if a metal salt-based etchant (ZrO(NO3)2) provides as durable bonding to dentin as a classic E&R or SE bonding mode METHODS: Before applying the UA Adhese Universal ('AdU'; Ivoclar Vivadent) to bur-cut dentin of 24 teeth (n = 8), dentin was conditioned with either (1) an experimental metal salt-based conditioner ('ZON'; Ivoclar Vivadent) or (2) 37% phosphoric acid (Total Etch gel, Ivoclar Vivadent), representing a classic 'E&R' mode; (3) a third experimental group involved AdU applied in SE mode. Bonding effectiveness was determined in terms of immediate ('1w') and aged ('50k' TC) micro-tensile bond strength (μTBS) to bur-cut dentin. Adhesive-conditioned dentin interfacial interactions were characterized by S/TEM. RESULTS: Linear mixed-effects modeling revealed significantly higher immediate μTBS to dentin of ZON_AdU than E&R_AdU, while ZON_AdU performed not significantly different from SE_AdU. No significant differences were found between the three experimental groups after 50k TC (aged μTBS). S/TEM disclosed less exposure of dentinal collagen fibrils when AdU was bonded upon ZON etching than when applied in E&R mode. Moreover, ZON resulted in more hydroxyapatite (HAp) crystals remaining at the bottom of the hybrid layer, while dentinal tubule orifices remained nearly fully closed, by which hardly any resin tags were formed. SIGNIFICANCE: The alternative metal salt-based conditioner revealed at dentin a more HAp-protected hybrid layer with less exposure of collagen fibrils, while a comparable bond strength was obtained to that with a phosphoric-acid E&R as well as with an SE (no conditioner) bonding mode. These findings confirm that the metal salt-based conditioner can be considered as a suitable alternative (enamel/)dentin conditioner to classic phosphoric acid employed in an E&R bonding mode. ispartof: DENTAL MATERIALS vol:38 issue:3 pages:554-567 ispartof: location:England status: published

Hypogonadism can be present in up to 40% in men who present with couple infertility. Testosterone is the major androgen regulating-spermatogenesis in men; as a result, men with either primary or secondary hypogonadism may be subfertile because of impaired spermatogenesis. The clinical impact of hypogonadism on fertility potential depends on the timing of its onset (fetal, prepubertal, or postpubertal) and effect on semen parameters. Treatment pathways and success rates differ according to the cause of hypogonadism and the time of its onset. When medical therapy fails to induce sufficient sperm, assisted reproductive technologies are considered.

The opinion on the mechanisms underlying the pathogenesis of preeclampsia still divides scientists and clinicians. This common complication of pregnancy has long been viewed as a disorder linked primarily to placental dysfunction, which is caused by abnormal trophoblast invasion, however, evidence from the previous two decades has triggered and supported a major shift in viewing preeclampsia as a condition that is caused by inherent maternal cardiovascular dysfunction, perhaps entirely independent of the placenta. In fact, abnormalities in the arterial and cardiac functions are evident from the early subclinical stages of preeclampsia and even before conception. Moving away from simply observing the peripheral blood pressure changes, studies on the central hemodynamics reveal two different mechanisms of cardiovascular dysfunction thought to be reflective of the early-onset and late-onset phenotypes of preeclampsia. More recent evidence identified that the underlying cardiovascular dysfunction in these phenotypes can be categorized according to the presence of coexisting fetal growth restriction instead of according to the gestational period at onset, the former being far more common at early gestational ages. The purpose of this review is to summarize the hemodynamic research observations for the two phenotypes of preeclampsia. We delineate the physiological hemodynamic changes that occur in normal pregnancy and those that are observed with the pathologic processes associated with preeclampsia. From this, we propose how the two phenotypes of preeclampsia could be managed to mitigate or redress the hemodynamic dysfunction, and we consider the implications for future research based on the current evidence. Maternal hemodynamic modifications throughout pregnancy can be recorded with simple-to-use, noninvasive devices in obstetrical settings, which require only basic training. This review includes a brief overview of the methodologies and techniques used to study hemodynamics and arterial function, specifically the noninvasive techniques that have been utilized in preeclampsia research.

There are over 7 million people worldwide suffering from Parkinson's disease, and this number will double in the next decade. Causative mutations and risk variants in >20 genes that predominantly act at synapses have been linked to Parkinson's disease. Synaptic defects precede neuronal death. However, we are only now beginning to understand which molecular mechanisms contribute to this synaptic dysfunction. In this review, we discuss recent data demonstrating that Parkinson proteins act centrally to various protein quality control pathways at the synapse, and we argue that disturbed synaptic proteostasis is an early driver of neurodegeneration in Parkinson's disease. ispartof: CURRENT OPINION IN NEUROBIOLOGY vol:72 pages:72-79 ispartof: location:England status: published

INTRODUCTION: Interventional radiology procedures are associated with high skin dose exposure. The 2013/59/EURATOM Directive establishes that the equipment used for interventional radiology must have a device or a feature informing the practitioner of relevant parameters for assessing patient dose at the end of the procedure. This work presents and validates PyMCGPU-IR, a patient dose monitoring tool for interventional cardiology and radiology procedures based on MC-GPU. MC-GPU is a freely available Monte Carlo (MC) code of photon transport in a voxelized geometry which uses the computational power of commodity Graphics Processing Unit cards (GPU) to accelerate calculations. METHODOLOGIES: PyMCGPU-IR was validated against two different experimental set-ups. The first one consisted of skin dose measurements for different beam angulations on an adult Rando Alderson anthropomorphic phantom. The second consisted of organ dose measurements in three clinical procedures using the Rando Alderson phantom. RESULTS: The results obtained for the skin dose measurements show differences below 6%. For the clinical procedures the differences are within 20% for most cases. CONCLUSIONS: PyMCGPU-IR offers both, high performance and accuracy for dose assessment when compared with skin and organ dose measurements. It also allows the calculation of dose values at specific positions and organs, the dose distribution and the location of the maximum doses per organ. In addition, PyMCGPU-IR overcomes the time limitations of CPU-based MC codes. ispartof: PHYSICA MEDICA-EUROPEAN JOURNAL OF MEDICAL PHYSICS vol:93 pages:29-37 ispartof: location:Italy status: published

Current human Single Amino acid Variants (SAVs) databases provide a link between a SAVs and their effect on the carrier individual phenotype, often dividing them into Deleterious/Neutral variants. This is a very coarse-grained description of the genotype-to-phenotype relationship because it relies on un-realistic assumptions such as the perfect Mendelian behavior of each SAV and considers only dichotomic phenotypes. Moreover, the link between the effect of a SAV on a protein (its molecular phenotype) and the individual phenotype is often very complex, because multiple level of biological abstraction connect the protein and individual level phenotypes. Here we present HPMPdb, a manually curated database containing human SAVs associated with the detailed description of the molecular phenotype they cause on the affected proteins. With particular regards to machine learning (ML), this database can be used to let researchers go beyond the existing Deleterious/Neutral prediction paradigm, allowing them to build molecular phenotype predictors instead. Our class labels describe in a succinct way the effects that each SAV has on 15 protein molecular phenotypes, such as protein-protein interaction, small molecules binding, function, post-translational modifications (PTMs), sub-cellular localization, mimetic PTM, folding and protein expression. Moreover, we provide researchers with all necessary means to re-producibly train and test their models on our database. The webserver and the data described in this paper are available at hpmp.esat.kuleuven.be. ispartof: CURRENT RESEARCH IN STRUCTURAL BIOLOGY vol:4 pages:167-174 ispartof: location:Netherlands status: published

Background Given the importance of flexible use of different COVID-19 vaccines within the same schedule to facilitate rapid deployment, we studied mixed priming schedules incorporating an adenoviral-vectored vaccine (ChAdOx1 nCoV-19 [ChAd], AstraZeneca), two mRNA vaccines (BNT162b2 [BNT], Pfizer–BioNTech, and mRNA-1273 [m1273], Moderna) and a nanoparticle vaccine containing SARS-CoV-2 spike glycoprotein and Matrix-M adjuvant (NVX-CoV2373 [NVX], Novavax). Methods Com-COV2 is a single-blind, randomised, non-inferiority trial in which adults aged 50 years and older, previously immunised with a single dose of ChAd or BNT in the community, were randomly assigned (in random blocks of three and six) within these cohorts in a 1:1:1 ratio to receive a second dose intramuscularly (8–12 weeks after the first dose) with the homologous vaccine, m1273, or NVX. The primary endpoint was the geometric mean ratio (GMR) of serum SARS-CoV-2 anti-spike IgG concentrations measured by ELISA in heterologous versus homologous schedules at 28 days after the second dose, with a non-inferiority criterion of the GMR above 0·63 for the one-sided 98·75% CI. The primary analysis was on the per-protocol population, who were seronegative at baseline. Safety analyses were done for all participants who received a dose of study vaccine. The trial is registered with ISRCTN, number 27841311. Findings Between April 19 and May 14, 2021, 1072 participants were enrolled at a median of 9·4 weeks after receipt of a single dose of ChAd (n=540, 47% female) or BNT (n=532, 40% female). In ChAd-primed participants, geometric mean concentration (GMC) 28 days after a boost of SARS-CoV-2 anti-spike IgG in recipients of ChAd/m1273 (20 114 ELISA laboratory units [ELU]/mL [95% CI 18 160 to 22 279]) and ChAd/NVX (5597 ELU/mL [4756 to 6586]) was non-inferior to that of ChAd/ChAd recipients (1971 ELU/mL [1718 to 2262]) with a GMR of 10·2 (one-sided 98·75% CI 8·4 to ∞) for ChAd/m1273 and 2·8 (2·2 to ∞) for ChAd/NVX, compared with ChAd/ChAd. In BNT-primed participants, non-inferiority was shown for BNT/m1273 (GMC 22 978 ELU/mL [95% CI 20 597 to 25 636]) but not for BNT/NVX (8874 ELU/mL [7391 to 10 654]), compared with BNT/BNT (16 929 ELU/mL [15 025 to 19 075]) with a GMR of 1·3 (one-sided 98·75% CI 1·1 to ∞) for BNT/m1273 and 0·5 (0·4 to ∞) for BNT/NVX, compared with BNT/BNT; however, NVX still induced an 18-fold rise in GMC 28 days after vaccination. There were 15 serious adverse events, none considered related to immunisation. Interpretation Heterologous second dosing with m1273, but not NVX, increased transient systemic reactogenicity compared with homologous schedules. Multiple vaccines are appropriate to complete primary immunisation following priming with BNT or ChAd, facilitating rapid vaccine deployment globally and supporting recognition of such schedules for vaccine certification. Funding UK Vaccine Task Force, Coalition for Epidemic Preparedness Innovations (CEPI), and National Institute for Health Research. NVX vaccine was supplied for use in the trial by Novavax.

Summary Background Diabetes leads to a wide range of established vascular and metabolic complications that has resulted in the implementation of diverse prevention programmes across high-income countries. Diabetes has also been associated with an increased risk of a broader set of conditions including cancers, liver disease, and common infections. We aimed to examine the trends in a broad set of cause-specific hospitalisations in individuals with diabetes in England from 2003 to 2018. Methods In this epidemiological analysis, we identified 309 874 individuals 18 years or older with diabetes (type 1 or 2) in England from the Clinical Practice Research Datalink linked to Hospital Episode Statistics inpatient data from 2003 to 2018. We generated a mixed prevalent and incident diabetes study population through serial cross sections and follow-up over time. We used a discretised Poisson regression model to estimate annual cause-specific hospitalisation rates in men and women with diabetes across 17 cause groupings. We generated a 1:1 age-matched and sex-matched population of individuals without diabetes to compare cause-specific hospitalisation rates in those with and without diabetes. Findings Hospitalisation rates were higher for all causes in persons with diabetes than in those without diabetes throughout the study period. Diabetes itself and ischaemic heart disease were the leading causes of excess (defined as absolute difference in the rate in the populations with and without diabetes) hospitalisation in 2003. By 2018, non-infectious and non-cancerous respiratory conditions, non-diabetes-related cancers, and ischaemic heart disease were the most common causes of excess hospitalisation across men and women. Hospitalisation rates of people with diabetes declined and causes of hospitalisation changed. Almost all traditional diabetes complication groups (vascular diseases, amputations, and diabetes) decreased, while conditions non-specific to diabetes (cancers, infections, non-infectious and non-cancerous respiratory conditions) increased. These differing trends represented a change in the cause of hospitalisation, such that the traditional diabetes complications accounted for more than 50% of hospitalisation in 2003, but only approximately 30% in 2018. In contrast, the proportion of hospitalisations due to respiratory infections between the same time period increased from 3% to 10% in men and from 4% to 12% in women. Interpretations Changes in the composition of excess risk and hospitalisation burden in those with diabetes means that preventative and clinical measures should evolve to reflect the diverse set of causes that are driving persistent excess hospitalisation in those with diabetes. Funding Wellcome Trust.

Drying processes reduce the amount of available essential nutrients in dried plant-based foods to a large extent compared to fresh produce. This reduction is much larger than the differences in the final quality of products dried using various processing parameters and, in most cases, different drying methods. This aspect is, however, rarely highlighted. Here, the extent to which different convective drying methods reduce the nutritional content, namely vitamin C, carotenoids and phenolic content of dried fruits and vegetables, compared to fresh produce was quantified using literature data. The impact of different drying process parameters, such as air temperature, airspeed and relative humidity on the nutritional content of fruits and vegetables were compared. Results revealed that convective drying reduced the amount of vitamin C, carotenoids and the phenolic content of dried fruits and vegetables by up to 70%. The reduction in the residual vitamin C and carotenoid content of dried fruits and vegetables due to differences in air temperature (∼40%), airspeed (∼20%), and relative humidity (∼20%) is much less than the nutritional quality losses due to the drying process. The residual vitamin C, carotenoids and phenolic contents in convective-dried fruits and vegetables are ∼30% less than those in freeze-dried products. This study confirms that little absolute gains in nutritional quality can be achieved by opting for either an alternative drying method or optimizing processing parameters since the drying process already results in a low nutritional quality of dried products. As such, the remaining micronutrient concentration of dried products should not necessarily be a decisive criterion in selecting the most appropriate drying method or processing parameters for fruits and vegetables. Instead, other key performance indicators such as the drying time, energy consumption, or sensory properties such as color, texture, and rehydration capacity could eventually have a greater influence on the decision-making process., Food and Bioproducts Processing, 131, ISSN:0960-3085, ISSN:1744-3571

Graphical abstract, After oral administration, a drug’s solubility in intestinal fluid is an important parameter influencing bioavailability and if the value is known it can be applied to estimate multiple biopharmaceutical parameters including the solubility limited absorbable dose. Current in vitro measurements may utilise fasted human intestinal fluid (HIF) or simulated intestinal fluid (SIF) to provide an intestinal solubility value. This single point value is limited since its position in relation to the fasted intestinal solubility envelope is unknown. In this study we have applied a nine point fasted equilibrium solubility determination in SIF, based on a multi-dimensional analysis of fasted human intestinal fluid composition, to seven drugs that were previously utilised to investigate the developability classification system (ibuprofen, mefenamic acid, furosemide, dipyridamole, griseofulvin, paracetamol and acyclovir). The resulting fasted equilibrium solubility envelope encompasses literature solubility values in both HIF and SIF indicating that it measures the same solubility space as current approaches with solubility behaviour consistent with previous SIF design of experiment studies. In addition, it identifies that three drugs (griseofulvin, paracetamol and acyclovir) have a very narrow solubility range, a feature that single point solubility approaches would miss. The measured mid-point solubility value is statistically equivalent to the value determined with the original fasted simulated intestinal fluid recipe, further indicating similarity and that existing literature results could be utilised as a direct comparison. Since the multi-dimensional approach covered greater than ninety percent of the variability in fasted intestinal fluid composition, the measured maximum and minimum equilibrium solubility values should represent the extremes of fasted intestinal solubility and provide a range. The seven drugs all display different solubility ranges and behaviours, a result also consistent with previous studies. The dose/solubility ratio for each measurement point can be plotted using the developability classification system to highlight individual drug behaviours. The lowest solubility represents a worst-case scenario which may be useful in risk-based quality by design biopharmaceutical calculations than the mid-point value. The method also permits a dose/solubility ratio frequency distribution determination for the solubility envelope which permits further risk-based refinement, especially where the drug crosses a classification boundary. This novel approach therefore provides greater in vitro detail with respect to possible biopharmaceutical performance in vivo and an improved ability to apply risk-based analysis to biopharmaceutical performance. Further studies will be required to expand the number of drugs measured and link the in vitro measurements to in vivo results.

CTGrepeat expansion (CTGexp) is associated with aberrant alternate splicing that contributes to cardiac dysfunction in myotonic dystrophy type 1 (DM1). Excision of thisCTGexprepeat using CRISPR-Cas resulted in the disappearance of punctate ribonuclear foci in cardiomyocyte-like cells derived from DM1-induced pluripotent stem cells (iPSCs). This was associated with correction of the underlying spliceopathy as determined byRNA sequencingand alternate splicing analysis. Certain genes were of particular interest due to their role in cardiac development, maturation, and function (TPM4,CYP2J2,DMD,MBNL3,CACNA1H,ROCK2,ACTB) or their association with splicing (SMN2,GCFC2,MBNL3). Moreover, while comparing isogenic CRISPR-Cas9-corrected versus non-corrected DM1 cardiomyocytes, a prominent difference in the splicing pattern for a number of candidate genes was apparent pertaining to genes that are associated with cardiac function (TNNT,TNNT2,TTN,TPM1,SYNE1,CACNA1A,MTMR1,NEBL,TPM1),cellular signaling(NCOR2,CLIP1,LRRFIP2,CLASP1,CAMK2G), and other DM1-related genes (i.e.,NUMA1,MBNL2,LDB3) in addition to the disease-causingDMPKgene itself. Subsequent validation using a selected gene subset, includingMBNL1,MBNL2,INSR,ADD3, andCRTC2, further confirmed correction of the spliceopathy followingCTGexprepeat excision. To our knowledge, the present study provides the first comprehensive unbiased transcriptome-wide analysis of the differential splicing landscape in DM1 patient-derived cardiac cells after excision of theCTGexprepeat using CRISPR-Cas9, showing reversal of the abnormal cardiac spliceopathy in DM1.

BACKGROUND: Women with bipolar I disorder are at high risk for severe episodes after childbirth, but there is no study that provides an overview on bipolar episode risk both during pregnancy and after childbirth, miscarriage and induced abortion. The aim of this study was to determine the episode risk during all pregnancy outcomes subdivided by first and subsequent pregnancies. METHODS: Participants were 436 women with bipolar I disorder from the Dutch Bipolar Cohort, having 919 pregnancies of which 762 resulted in a live childbirth, 118 ended in a miscarriage and 39 ended in induced abortion. Women reported on the occurrence of manic or depressed episodes during the perinatal period. Information about medication use was obtained by questionnaires. RESULTS: Episode risk was 5.2% during pregnancy, and 30.1% in the postpartum period, with a peak in the early postpartum period. Risk of an episode was highest after live birth (34.4%), and lower after miscarriage (15.2%) and induced abortion (27.8%). Women with an episode during pregnancy or postpartum were less likely to have a second child compared to women with an uneventful first pregnancy (cOR=0.34; 95%CI: 0.22-0.51; p

PURPOSE: To assess the impact of fenfluramine (FFA) on the expected mortality incidence, including sudden unexpected death in epilepsy (SUDEP), in persons with Dravet syndrome (DS). METHODS: In this pooled analysis, total time of exposure for persons with DS who were treated with FFA in phase 3 clinical trials, in United States and European Early Access Programs, and in two long-term open-label observational studies in Belgium was calculated. Literature was searched for reports of SUDEP mortality in DS, which were utilized as a comparison. Mortality rates were expressed per 1000 person-years. RESULTS: A total of 732 persons with DS were treated with FFA, representing a total of 1185.3 person-years of exposure. Three deaths occurred, all in the phase 3 program: one during placebo treatment (probable SUDEP) and two during treatment with FFA (one probable SUDEP and one definite SUDEP). The all-cause and SUDEP mortality rates during treatment with FFA was 1.7 per 1000 person-years (95% CI, 0.4 to 6.7), a value lower than the all-cause estimate of 15.8 per 1000 person-years (95% CI, 9.9 to 25.4) and SUDEP estimate of 9.3 (95% CI, 5.0 to 17.3) reported by Cooper et al. (Epilepsy Res 2016;128:43-7) for persons with DS receiving standard-of-care. CONCLUSION: All-cause and SUDEP mortality rates in DS patients treated with FFA were substantially lower than in literature reports. Further studies are warranted to confirm that FFA reduces SUDEP risk in DS patients and to better understand the potential mechanism(s) by which FFA lowers SUDEP risk. CLINICAL TRIAL REGISTRATION: NCT02926898, NCT02682927, NCT02826863, NCT02823145, NCT03780127. ispartof: SEIZURE-EUROPEAN JOURNAL OF EPILEPSY vol:93 pages:154-159 ispartof: location:England status: published

Objective. To describe molecular and clinical characteristics of patients with high-grade recurrent ovarian carcinoma (HGOC) who had long-term responses to the poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib. Methods. This post hoc analysis pooled patients from Study 10 (NCT01482715; Parts 2A and 2B; n = 54) and ARIEL2 (NCT01891344; Parts 1 and 2; n = 491). Patients with investigator-assessed complete or partial response per RECIST were classified based on duration of response (DOR): long (≥1 year), intermediate (6 months to

OBJECTIVE: As the empirical picture of adults with psychiatric conditions (further referred to as 'patients') requesting euthanasia is still incomplete, this study aims to deepen our understanding of why these patients request euthanasia, how this relates to the option of suicide, and what could have prevented these patients from considering death and requesting euthanasia. METHODS: A qualitative study using in-depth, face-to-face interviews was conducted with 16 patients who had their euthanasia request under assessment in the period 2016-2020. Thematic coding was used. FINDINGS: Most patients were in a state of feeling emotionally worn-out as a result of the many accumulated misfortunes and setbacks, leading to the all-pervasive sense that life is no longer worth living. Whereas some patients reported lifelong adversity, others struggled predominantly in later life. Whereas some patients longed for death strongly, others expressed ambivalence towards death ideation, and some even requested euthanasia to hear of their ineligibility for it, to restore hope and to (re)find meaning in life. patients valued euthanasia over suicide as being more dignified and acceptable, both for themselves and for their inner circle. With regard to preventive factors, patients posited the need for improved accessibility and quality of mental healthcare, as well as a profound change in society's perception of, and support for, these patients. CONCLUSIONS: This study revealed the many complexities of euthanasia in the context of psychiatry, due to the many differences in patients' background characteristics, in their motives for requesting euthanasia, and the multi-layered aspects of mental suffering that go beyond the field of psychiatry. ispartof: JOURNAL OF PSYCHIATRIC RESEARCH vol:144 pages:158-167 ispartof: location:England status: published

Purpose Radiation therapy to the prostate and pelvic lymph nodes (PLNRT) is part of the curative treatment of high-risk prostate cancer. Yet, the broader influence of radiation therapy on patient physiology is poorly understood. We conducted comprehensive global metabolomic profiling of urine, plasma, and stools sampled from patients undergoing PLNRT for high-risk prostate cancer. Methods and Materials Samples were taken from 32 patients at 6 timepoints: baseline, 2 to 3 and 4 to 5 weeks of PLNRT; and 3, 6, and 12 months after PLNRT. We characterized the global metabolome of urine and plasma using 1H nuclear magnetic resonance spectroscopy and ultraperformance liquid chromatography-mass spectrometry, and of stools with nuclear magnetic resonance. Linear mixed-effects modeling was used to investigate metabolic changes between timepoints for each biofluid and assay and determine metabolites of interest. Results Metabolites in urine, plasma and stools changed significantly after PLNRT initiation. Metabolic profiles did not return to baseline up to 1 year post-PLNRT in any biofluid. Molecules associated with cardiovascular risk were increased in plasma. Pre-PLNRT fecal butyrate levels directly associated with increasing gastrointestinal side effects, as did a sharper fall in those levels during and up to 1 year postradiation therapy, mirroring our previous results with metataxonomics. Conclusions We showed for the first time that an overall metabolic effect is observed in patients undergoing PLNRT up to 1 year posttreatment. These metabolic changes may effect on long-term morbidity after treatment, which warrants further investigation.

Polyfluoroalkyl substances (PFAS) have gained increasing negative attention in re-cent years owing to their potential carcinogenicity, neurotoxicity, and ability to bio-accumulate in wildlife, making their rapid and low-cost detection highly desirable. Molecularly Imprinted Polymers (MIPs) were therefore implemented as robust, cost-effective, and highly selective affinity reagent in a thermal sensing platform (the "Heat Transfer Method"), enabling the development of a time-efficient sensor that is capable of analyzing both river water and soil samples. To this end, a MIP was synthesized for the detection of perfluorooctanoic acid (PFOA) with an optimized rebinding capacity of 123 Imol g-1 and an imprinting factor of 2.1 as determined by UV-Vis spectrophotom-etry. Integration of the MIP into the thermal readout platform revealed a calculated limit of detection (LoD) of 22 pM in controlled buffer solutions. The sensor is able to distinguish PFOA from other PFAS and detect the compound in a mixture of PFAS, providing a proof-of-concept towards the desired application, the specific detection of PFOA in complex samples. To further illustrate the performance of the sensor in this sense, it was exposed to spiked (0.1 nM-500 nM) river water and soil samples, with a calculated LoD of 91 pM and 154 pM respectively. These findings highlight that the developed sensor has the potential to operate at a relevant sensitivity for the analysis of both aqueous and solid environmental samples, facilitating a more straightforward method of screening for PFAS against more complex and time-consuming methodologies.(c) 2023 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

ispartof: BRAIN STIMULATION vol:15 issue:4 pages:965-967 ispartof: location:United States status: accepted

AIM: Although nonunions are among the most common complications after long-bone fracture fixation, the definition of fracture nonunion remains controversial and varies widely. The aim of this study was to identify the definitions and diagnostic criteria used in the scientific literature to describe nonunions after long-bone fractures. METHODS: A comprehensive literature search was performed in PubMed, Cochrane Library, Web of Science, and Embase. Prospective clinical studies, in which adult long-bone fracture nonunions were investigated as main subject, were included in this analysis. Data on nonunion definitions described in each study were extracted and collected in a database. RESULTS: Although 148 studies met the inclusion criteria, only 50% (74/148) provided a definition for their main study subject. Nonunion was defined in these studies based on time-related criteria in 85% (63/74), on radiographic criteria in 62% (46/74), and on clinical criteria in 45% (33/74). A combination of clinical, radiographic and time-related criteria for definition was found in 38% (28/74). The time interval between fracture and the time point when authors defined an unhealed fracture as a nonunion showed considerable heterogeneity, ranging from three to twelve months. CONCLUSION: In the current orthopaedic literature, we found a lack of consensus with regard to the definition of long-bone nonunions. Without valid and reliable definition criteria for nonunion, standardization of diagnostic and treatment algorithms as well as the comparison of clinical studies remains problematic. The lack of a clear definition emphasizes the need for a consensus-based approach to the diagnosis of fracture nonunion centred on clinical, radiographical and time-related criteria. pmid: 34531088 ispartof: INJURY-INTERNATIONAL JOURNAL OF THE CARE OF THE INJURED vol:52 issue:11 pages:3200-3205 ispartof: location:Netherlands status: published

BACKGROUND: In the absence of randomised head-to-head trials, we conducted a population-adjusted indirect treatment comparison (PA-ITC) of phase III trial data to evaluate the relative efficacy and safety of maintenance olaparib and bevacizumab alone and in combination in patients with newly diagnosed, advanced ovarian cancer and a BRCA mutation (BRCAm). METHODS: An unanchored PA-ITC was performed on investigator-assessed progression-free survival (PFS) data. Individual patient data from SOLO1 (olaparib versus placebo) and from BRCA-mutated patients in PAOLA-1/ENGOT-ov25 (olaparib plus bevacizumab versus placebo plus bevacizumab) were pooled. Each arm of PAOLA-1 was weighted so that key baseline patient characteristics were similar to the SOLO1 cohort. Analyses were performed in patients with complete baseline data. Weighted Cox regression analysis was used to estimate the comparative efficacy of different maintenance therapy strategies, supplemented by weighted Kaplan-Meier analyses. RESULTS: Data from SOLO1 patients (olaparib, n = 254; placebo, n = 126) were compared with data from BRCA-mutated PAOLA-1 patients (olaparib plus bevacizumab, n = 151; placebo plus bevacizumab, n = 71). Adding bevacizumab to olaparib was associated with a numerical improvement in PFS compared with olaparib alone (hazard ratio [HR] 0.71; 95% confidence interval [CI] 0.45-1.09). Statistically significant improvements in PFS were seen with olaparib alone versus placebo plus bevacizumab (HR 0.48; 95% CI 0.30-0.75), olaparib plus bevacizumab versus placebo (0.23; 0.14-0.34), and placebo plus bevacizumab versus placebo (0.65; 0.43-0.95). CONCLUSIONS: Results of this hypothesis-generating PA-ITC analysis support the use of maintenance olaparib alone or with bevacizumab in patients with newly diagnosed, advanced ovarian cancer and a BRCAm. ispartof: EUROPEAN JOURNAL OF CANCER vol:157 pages:415-423 ispartof: location:England status: published

Summary Background England's COVID-19 roadmap out of lockdown policy set out the timeline and conditions for the stepwise lifting of non-pharmaceutical interventions (NPIs) as vaccination roll-out continued, with step one starting on March 8, 2021. In this study, we assess the roadmap, the impact of the delta (B.1.617.2) variant of SARS-CoV-2, and potential future epidemic trajectories. Methods This mathematical modelling study was done to assess the UK Government's four-step process to easing lockdown restrictions in England, UK. We extended a previously described model of SARS-CoV-2 transmission to incorporate vaccination and multi-strain dynamics to explicitly capture the emergence of the delta variant. We calibrated the model to English surveillance data, including hospital admissions, hospital occupancy, seroprevalence data, and population-level PCR testing data using a Bayesian evidence synthesis framework, then modelled the potential trajectory of the epidemic for a range of different schedules for relaxing NPIs. We estimated the resulting number of daily infections and hospital admissions, and daily and cumulative deaths. Three scenarios spanning a range of optimistic to pessimistic vaccine effectiveness, waning natural immunity, and cross-protection from previous infections were investigated. We also considered three levels of mixing after the lifting of restrictions. Findings The roadmap policy was successful in offsetting the increased transmission resulting from lifting NPIs starting on March 8, 2021, with increasing population immunity through vaccination. However, because of the emergence of the delta variant, with an estimated transmission advantage of 76% (95% credible interval [95% CrI] 69–83) over alpha, fully lifting NPIs on June 21, 2021, as originally planned might have led to 3900 (95% CrI 1500–5700) peak daily hospital admissions under our central parameter scenario. Delaying until July 19, 2021, reduced peak hospital admissions by three fold to 1400 (95% CrI 700–1700) per day. There was substantial uncertainty in the epidemic trajectory, with particular sensitivity to the transmissibility of delta, level of mixing, and estimates of vaccine effectiveness. Interpretation Our findings show that the risk of a large wave of COVID-19 hospital admissions resulting from lifting NPIs can be substantially mitigated if the timing of NPI relaxation is carefully balanced against vaccination coverage. However, with the delta variant, it might not be possible to fully lift NPIs without a third wave of hospital admissions and deaths, even if vaccination coverage is high. Variants of concern, their transmissibility, vaccine uptake, and vaccine effectiveness must be carefully monitored as countries relax pandemic control measures. Funding National Institute for Health Research, UK Medical Research Council, Wellcome Trust, and UK Foreign, Commonwealth and Development Office.

Peptide receptor radionuclide therapy (PRRT) is used for the treatment of patients with unresectable or metastasized somatostatin receptor type 2 (SSTR2)-expressing gastroenteropancreatic neuroendocrine tumours (GEP-NETs). The radiolabelled somatostatin analogue [177Lu]Lu-DOTA-TATE delivers its radiation dose to SSTR2-overexpressing tumour cells, resulting in selective cell killing during radioactive decay. While tumour control can be achieved in many patients, complete remissions remain rare, causing the majority of patients to relapse after a certain period of time. This raises the question whether the currently fixed treatment regime (4 × 7.4 GBq) leaves room for dose escalation as a means of improving therapy efficacy. The kidneys have shown to play an important role in defining a patient's tolerability to PRRT. As a consequence of the proximal tubular reabsorption of [177Lu]Lu-DOTA-TATE, via the endocytic megalin/cubilin receptor complex, the radionuclides are retained in the renal interstitium. This results in extended retention of radioactivity in the kidneys, generating a risk for the development of radiation nephropathy. In addition, a decreased kidney function has shown to be associated with a prolonged circulation of [177Lu]Lu-DOTA-TATE, causing increased irradiation to the bone marrow. This can on its turn lead to myelosuppression and haematological toxicity, owing to the marked radio sensitivity of the rapidly proliferating cells in the bone marrow. In contrast to external beam radiotherapy (EBRT), the exact absorbed dose limits for these critical organs (kidneys and bone marrow) in PRRT with [177Lu]Lu-DOTA-TATE are still unclear. Better insights into these uncertainties, can help in optimizing PRRT to reach its maximum therapeutic potential, while avoiding severe adverse events, like nephropathy and hematologic toxicities. In this review we focus on the nephrotoxic effects of PRRT with [177Lu]Lu-DOTA-TATE for the treatment of GEP-NETs. If the absorbed dose to the kidneys can be lowered, higher activities can be administered, enlarging the therapeutic window for PRRT. Therefore, we evaluated the renal protective potential of current and promising future strategies and discuss the importance of (renal) dosimetry in PRRT. ispartof: NUCLEAR MEDICINE AND BIOLOGY vol:102 pages:1-11 ispartof: location:United States status: published

The environmental impacts of food are currently at unsustainable levels. Consumers undoubtedly play a central role in reducing the impacts of the food system to more sustainable levels via dietary changes and food waste reduction. Mathematical optimisation is one approach to identifying less environmentally impactful dietary patterns. A limited number of studies, however, have assessed whether impact reductions offered by optimised diets are enough to remain within planetary boundaries (i.e. attain ‘absolute’ environmental sustainability). Using UK food consumption as a case study, here we employ linear programming to identify nutritionally adequate diets that meet sociocultural acceptability criteria whilst minimising (a) environmental impact transgressions of their allocated share of the safe operating space (SoSOS) for nine planetary boundaries (PBs), (b) cost, or (c) deviation from the current diet. We show that the current diet is unsustainable as it transgresses six or seven PBs, depending on the SoSOS allocation principle. Optimising for minimum SoSOS transgressions yields diets offering significant impact reductions (66 - 95% reduction across all PBs) compared to the current average dietary pattern, but whether they completely mitigate SoSOS transgressions depends on the sharing principle adopted to assign the SoSOS to national food consumption. Additionally, by comparing least-cost and least-transgression solutions, we find a trade-off between cost and environmental sustainability indicating that more sustainable dietary patterns are not currently incentivised by the relative prices of food items in the UK. Our work demonstrates the value in embedding ‘absolute’ sustainability in diet optimisation so that solutions inherently provide a more clear-cut understanding of their broad implications on the environment., Sustainable Production and Consumption, 28, ISSN:2352-5509

BACKGROUND: Several groups have proposed features to identify low-risk patients who may benefit from endoscopic kidney-sparing surgery in upper tract urothelial carcinoma (UTUC). OBJECTIVE: To evaluate standard risk stratification features, develop an optimal model to identify ≥pT2/N+ stage at radical nephroureterectomy (RNU), and compare it with the existing unvalidated models. DESIGN, SETTING, AND PARTICIPANTS: This was a collaborative retrospective study that included 1214 patients who underwent ureterorenoscopy with biopsy followed by RNU for nonmetastatic UTUC between 2000 and 2017. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We performed multiple imputation of chained equations for missing data and multivariable logistic regression analysis with a stepwise selection algorithm to create the optimal predictive model. The area under the curve and a decision curve analysis were used to compare the models. RESULTS AND LIMITATIONS: Overall, 659 (54.3%) and 555 (45.7%) patients had ≤pT1N0/Nx and ≥pT2/N+ disease, respectively. In the multivariable logistic regression analysis of our model, age (odds ratio [OR] 1.02, 95% confidence interval [CI] 1.0-1.03, p = 0.013), high-grade biopsy (OR 1.81, 95% CI 1.37-2.40, p

BACKGROUND: Long-term follow-up (LTFU) care for childhood, adolescent, and young adult (CAYA) cancer survivors is essential to preserve health and quality of life (QoL). Evidence-based guidelines are needed to inform optimal surveillance strategies, but many topics are yet to be addressed by the International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG). Therefore, the PanCareFollowUp Recommendations Working Group collaborated with stakeholders to develop European harmonised recommendations in anticipation of evidence-based IGHG guidelines. METHODS: The PanCareFollowUp Recommendations Working Group, consisting of 23 late effects specialists, researchers, and survivor representatives from nine countries, collaborated in the first Europe-wide effort to provide unified recommendations in anticipation of evidence-based guidelines. A pragmatic methodology was used to define recommendations for topics where no evidence-based IGHG recommendations exist. The objective was to describe the surveillance requirements for high-quality care while balancing the different infrastructures and resources across European health care systems. The process included two face-to-face meetings and an external consultation round involving 18 experts from 14 countries. RESULTS: Twenty-five harmonised recommendations for LTFU care were developed collaboratively and address topics requiring awareness only (n = 6), awareness, history and/or physical examination (n = 9), or additional surveillance tests (n = 10). CONCLUSIONS: The PanCareFollowUp Recommendations, representing a unique agreement across European stakeholders, emphasise awareness among survivors and health care providers in addition to tailored clinical evaluation and/or surveillance tests. They include existing IGHG guidelines and additional recommendations developed by a pragmatic methodology and will be used in the Horizon 2020-funded PanCareFollowUp project to improve health and QoL of CAYA cancer survivors. ispartof: EUROPEAN JOURNAL OF CANCER vol:154 pages:316-328 ispartof: location:England status: published

Self-amplifying mRNA (saRNA) represents a promising platform for nucleic acid delivery of vaccine immunogens. Unlike plasmid DNA, saRNA does not require entry into the nucleus of target cells for expression, having the capacity to drive higher protein expression compared to mRNA as it replicates within the cytoplasm. In this study, we examined the potential of stabilized native-like HIV-1 Envelope glycoprotein (Env) trimers to elicit immune responses when delivered by saRNA polyplexes (PLXs), assembled with linear polyethylenimine. We showed that Venezuelan equine encephalitis virus (VEEV) saRNA induces a stronger humoral immune response to the encoded transgene compared to Semliki Forest virus saRNA. Moreover, we characterized the immunogenicity of the soluble and membrane-bound ConSOSL.UFO Env design in mice and showed a faster humoral kinetic and an immunoglobulin G (IgG)2a skew using a membrane-bound design. The immune response generated by PLX VEEV saRNA encoding the membrane-bound Env was then evaluated in larger animal models including macaques, in which low doses induced high IgG responses. Our data demonstrated that the VEEV saRNA PLX nanoparticle formulation represents a suitable platform for the delivery of stabilized HIV-1 Env and has the potential to be used in a variety of vaccine regimens., Graphical abstract, Aldon, McKay, and colleagues evaluated the potential of formulated VEEV and SFV self-amplifying mRNA (saRNA) for the delivery of HIV-1 Env stabilized trimers. The authors demonstrate great potential for PEI-polyplex formulated VEEV-saRNA platform, which elicits strong humoral responses at low doses in non-human primates.