Search

Background: Respiratory syncytial virus (RSV) causes substantial respiratory disease. Bivalent RSV prefusion F (RSVpreF) vaccine is licensed in ≥60-year-olds. RSVpreF was well tolerated and immunogenic in a phase 1/2 study. We evaluated antibody persistence after initial vaccination and safety and immunogenicity after revaccination from this study., Methods: Healthy adults were randomized to receive initial vaccination and revaccination 12 months later with either placebo or RSVpreF (240 µg with or without aluminum hydroxide). RSV-A and RSV-B geometric mean neutralizing titers (GMTs) were measured through 12 months after both vaccinations. Tolerability and safety were assessed., Results: There were 263 participants revaccinated (18-49 years old, n = 134; 65-85 years old, n = 129). Among 18- to 49-year-olds and 65- to 85-year-olds, geometric mean fold rises (GMFRs) for both RSV subgroups (RSV-A, RSV-B) 1 month after initial RSVpreF vaccination were 13.3 to 20.4 and 8.9 to 15.5, respectively, as compared with levels before initial vaccination; corresponding GMFRs 12 months after initial vaccination were 4.1 to 5.0 and 2.6 to 4.1. GMFRs 1 month after revaccination vs levels before revaccination were 1.4 to 2.3 and 1.4 to 2.2 for 18- to 49-year-olds and 65- to 85-year-olds. Peak GMTs after revaccination were lower than those after initial vaccination. GMTs 12 months after initial vaccination and revaccination were similar, with GMFRs ranging from 0.7 to 1.6. No safety signals occurred., Conclusions: RSVpreF revaccination was immunogenic and well tolerated among adults. Clinical Trials Registration. NCT03529773 (ClinicalTrials.gov)., Competing Interests: Potential conflicts of interest. E. E. W. reports receiving grants from Pfizer, Merck Sharp and Dohme, and Janssen and serving in unpaid consultancy roles for Janssen, Merck, Moderna, and Pfizer. A. R. F. reports receiving grant funding from Pfizer Inc, Merck, Janssen, BioFire Diagnostics, Vax Co, and CyanVac and consulting fees from Gilead, GlaxoSmithKline, Icosavax, and Novavax. A. M. Z., Q. J., A. G., D. R., E. G., D. C., K. U. J., W. C. G., K. A. S., and B. S.-T. are current or former employees of Pfizer Inc and may hold stock or stock options. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Glucocorticoids (GCs) are the leading cause of secondary osteoporosis. The emerging perspective, derived primarily from 2D histological study of trabecular bone, is that GC-induced bone loss arises through the uncoupling of bone formation and resorption at the level of the basic multicellular unit (BMU), which carries out bone remodeling. Here we explore the impact of GCs on cortical bone remodeling in the rabbit model. Based upon the rapid reduction of bone formation and initial elevation of resorption caused by GCs, we hypothesized that the rate of advance (longitudinal erosion rate; LER) of cortical BMUs would be increased. To test this hypothesis we divided 20 female New Zealand White rabbits into four experimental groups: ovariohysterectomy (OVH), glucocorticoid (GC), OVH + GC and SHAM controls (n = 5 animals each). Ten weeks post-surgery (OVH or sham), and two weeks after the initiation of dosing (daily subcutaneous injections of 1.5 mg/kg of methylprednisolone sodium succinate in the GC-treated groups and 1 ml of saline for the others), the right tibiae were scanned in vivo using Synchrotron Radiation (SR) in-line phase contrast micro-CT at the Canadian Light Source. After an additional 2 weeks of dosing, the rabbits were euthanized and ex vivo images were collected using desktop micro-CT. The datasets were co-registered in 3D and LER was calculated as the distance traversed by BMU cutting-cones in the 14-day interval between scans. Counter to our hypothesis, LER was greatly reduced in GC-treated rabbits. Mean LER was lower in GC (4.27 μm/d; p < 0.001) and OVH + GC (4.19 μm/d; p < 0.001), while similar in OVH (40.13 μm/d; p = 0.990), compared to SHAM (40.44 μm/d). This approximately 90 % reduction in LER with GCs was also associated with an overall disruption of BMU progression, with radial expansion of the remodeling space occurring in all directions. This unexpected outcome suggests that GCs do not simply uncouple formation and resorption within cortical BMUs and highlights the value of the time-lapsed 4D approach employed., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: With the future epidemiology and evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uncertain, the use of safe and effective coronavirus disease 2019 (COVID-19) vaccines in pediatric populations remains important., Methods: We report data from two open-label substudies of an ongoing phase 1/2/3 master study (NCT05543616) investigating the safety and immunogenicity of a variant-adapted bivalent COVID-19 vaccine encoding ancestral and Omicron BA.4/BA.5 spike proteins (bivalent BNT162b2). The open-label groups presented here evaluate dose 4 with bivalent BNT162b2 in 6-month- to <12-year-olds who previously received three original (monovalent) BNT162b2 doses. In 6-month- to <5-year-olds, primary immunogenicity objectives were to demonstrate superiority (neutralizing titer) and noninferiority (seroresponse rate) to Omicron BA.4/BA.5 and noninferiority (neutralizing titer and seroresponse rate) to SARS-CoV-2 ancestral strains in participants who received bivalent BNT162b2 dose 4 compared with a matched group who received three doses of original BNT162b2 in the pivotal pediatric study (NCT04816643). In 5- to <12-year-olds, primary immunogenicity comparisons were descriptive. Reactogenicity and safety following vaccination were evaluated., Results: In 6-month- to <5-year-olds, dose 4 with bivalent BNT162b2 met predefined immunogenicity superiority and noninferiority criteria against Omicron BA.4/BA.5 and ancestral strains when compared with dose 3 of original BNT162b2. In 5- to <12-year-olds, bivalent BNT162b2 induced robust Omicron BA.4/BA.5 and ancestral strain neutralizing titers comparable with dose 3 of original BNT162b2. The safety profile for dose 4 of bivalent BNT162b2 given as dose 4 was consistent with that of original BNT162b2 in 6-month- to <12-year-olds. Reactogenicity events were generally mild to moderate. No adverse events led to discontinuation., Conclusions: These safety and immunogenicity data support a favorable benefit-risk profile for a variant-adapted BNT162b2 in children <12 years old., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society.)

Here we use off-axis electron holography combined with advanced transmission electron microscopy techniques to understand the opto-electronic properties of AlGaN tunnel junction (TJ)-light-emitting diode (LED) devices for ultraviolet emission. Four identical AlGaN LED devices emitting at 290 nm have been grown by metal-organic chemical vapour deposition. Then Ge doped n-type regions with and without InGaN or GaN interlayers (IL) have been grown by molecular beam epitaxy onto the top Mg doped p-type layer to form a TJ and hence a high quality ohmic metal contact. Off-axis electron holography has then been used to demonstrate a reduction in the width of the TJ from 9.5 to 4.1 nm when an InGaN IL is used. As such we demonstrate that off-axis electron holography can be used to reproducibly measure nm-scale changes in electrostatic potential in highly defected and challenging materials such as AlGaN and that systematic studies of devices can be performed. The LED devices are then characterized using standard opto-electric techniques and the improvements in the performance of the LEDs are correlated with the electron holography results., (Creative Commons Attribution license.)

A hexanucleotide (G 4 C 2 ) repeat expansion (HRE) within intron one of C9ORF72 is the leading genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). C9ORF72 haploinsufficiency, formation of RNA foci, and production of dipeptide repeat (DPR) proteins have been proposed as mechanisms of disease. Here, we report the first example of disease-modifying siRNAs for C9ORF72 driven ALS/FTD. Using a combination of reporter assay and primary cortical neurons derived from a C9-ALS/FTD mouse model, we screened a panel of more than 150 fully chemically stabilized siRNAs targeting different C9ORF72 transcriptional variants. We demonstrate the lack of correlation between siRNA efficacy in reporter assay versus native environment; repeat-containing C9ORF72 mRNA variants are found to preferentially localize to the nucleus, and thus C9ORF72 mRNA accessibility and intracellular localization have a dominant impact on functional RNAi. Using a C9-ALS/FTD mouse model, we demonstrate that divalent siRNAs targeting C9ORF72 mRNA variants specifically or non-selectively reduce the expression of C9ORF72 mRNA and significantly reduce DPR proteins. Interestingly, siRNA silencing all C9ORF72 mRNA transcripts was more effective in removing intranuclear mRNA aggregates than targeting only HRE-containing C9ORF72 mRNA transcripts. Combined, these data support RNAi-based degradation of C9ORF72 as a potential therapeutic paradigm., Competing Interests: J.W.G., B.MDC.G., and A.K. are named as inventors on a patent application filed (OLIGONUCLEOTIDE-BASED MODULATION OF C9orf72). A.K. is a founder of Atalanta Therapeutics., (© 2024 The Author(s).)

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition, with 20% of familial and 2-3% of sporadic cases linked to mutations in the cytosolic superoxide dismutase (SOD1) gene. Mutant SOD1 protein is toxic to motor neurons, making SOD1 gene lowering a promising approach, supported by preclinical data and the 2023 FDA approval of the GapmeR ASO targeting SOD1, tofersen. Despite the approval of an ASO and the optimism it brings to the field, the pharmacodynamics and pharmacokinetics of therapeutic SOD1 modulation can be improved. Here, we developed a chemically stabilized divalent siRNA scaffold (di-siRNA) that effectively suppresses SOD1 expression in vitro and in vivo . With optimized chemical modification, it achieves remarkable CNS tissue permeation and SOD1 silencing in vivo . Administered intraventricularly, di-siRNA SOD1 extended survival in SOD1-G93A ALS mice, surpassing survival previously seen in these mice by ASO modalities, slowed disease progression, and prevented ALS neuropathology. These properties offer an improved therapeutic strategy for SOD1-mediated ALS and may extend to other dominantly inherited neurological disorders., Competing Interests: Competing interests: AK is a co-founder, on the scientific advisory board, and holds equities of Atalanta Therapeutics; AK is a founder of Comanche Pharmaceuticals, and on the scientific advisory board of Aldena Therapeutics, AlltRNA, Prime Medicine, and EVOX Therapeutics; Select authors hold patents or on patent applications relating to the divalent siRNA, SOD1-targeting oligonucleotides, and the methods described in this report. NH received compensation for other services from Myrobalan Inc. and General Dynamics during the conduct of this study, unrelated to the present work.

Divalent short-interfering RNA (siRNA) holds promise as a therapeutic approach allowing for the sequence-specific modulation of a target gene within the central nervous system (CNS). However, an siRNA modality capable of simultaneously modulating gene pairs would be invaluable for treating complex neurodegenerative disorders, where more than one pathway contributes to pathogenesis. Currently, the parameters and scaffold considerations for multi-targeting nucleic acid modalities in the CNS are undefined. Here, we propose a framework for designing unimolecular 'dual-targeting' divalent siRNAs capable of co-silencing two genes in the CNS. We systematically adjusted the original CNS-active divalent siRNA and identified that connecting two sense strands 3' and 5' through an intra-strand linker enabled a functional dual-targeting scaffold, greatly simplifying the synthetic process. Our findings demonstrate that the dual-targeting siRNA supports at least two months of maximal distribution and target silencing in the mouse CNS. The dual-targeting divalent siRNA is highly programmable, enabling simultaneous modulation of two different disease-relevant gene pairs (e.g. Huntington's disease: MSH3 and HTT; Alzheimer's disease: APOE and JAK1) with similar potency to a mixture of single-targeting divalent siRNAs against each gene. This work enhances the potential for CNS modulation of disease-related gene pairs using a unimolecular siRNA., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

The mechanical quality of trabecular bone is influenced by its mineral content and spatial distribution, which is controlled by bone remodelling and mineralisation. Mineralisation kinetics occur in two phases: a fast primary mineralisation and a secondary mineralisation that can last from several months to years. Variations in bone turnover and mineralisation kinetics can be observed in the bone mineral density distribution (BMDD). Here, we propose a statistical spatio-temporal bone remodelling model to study the effects of bone turnover (associated with the activation frequency Ac . f ) and mineralisation kinetics (associated with secondary mineralisation T sec ) on BMDD. In this model, individual basic multicellular units (BMUs) are activated discretely on trabecular surfaces that undergo typical bone remodelling periods. Our results highlight that trabecular BMDD is strongly regulated by Ac . f and T sec in a coupled way. Ca wt% increases with lower Ac . f and short T sec . For example, a Ac . f = 4 BMU/year/mm 3 and T sec = 8 years result in a mean Ca wt% of 25, which is in accordance with Ca wt% values reported in quantitative backscattered electron imaging (qBEI) experiments. However, for lower Ac . f and shorter T sec (from 0.5 to 4 years) one obtains a high Ca wt% and a very narrow skew BMDD to the right. This close link between Ac . f and T sec highlights the importance of considering both characteristics to draw meaningful conclusion about bone quality. Overall, this model represents a new approach to modelling healthy and diseased bone and can aid in developing deeper insights into disease states like osteoporosis., (© 2024. The Author(s).)

Background: Respiratory syncytial virus (RSV) and influenza are both typically seasonal diseases, with winter peaks in temperate climates. Coadministration of an RSV vaccine and influenza vaccine could be a benefit, requiring 1 rather than 2 visits to a healthcare provider for individuals receiving both vaccines., Methods: The primary immunogenicity objective of this phase 3, 1:1 randomized, double-blind, placebo-controlled study in healthy adults aged ≥65 years in Australia was to demonstrate noninferiority of immune responses with coadministration of the stabilized RSV prefusion F protein-based vaccine (RSVpreF) and seasonal inactivated influenza vaccine (SIIV) versus SIIV or RSVpreF administered alone, using a 1.5-fold noninferiority margin (lower bound 95% confidence interval >.667). Safety and tolerability were evaluated by collecting reactogenicity and adverse event data., Results: Of 1403 participants randomized, 1399 received vaccinations (median age, 70; range, 65‒91 years). Local reactions and systemic events were mostly mild or moderate when RSVpreF was coadministered with SIIV or administered alone. No vaccine-related serious adverse events were reported. Geometric mean ratios were 0.86 for RSV-A and 0.85 for RSV-B neutralizing titers at 1 month after RSVpreF administration and 0.77 to 0.90 for strain-specific hemagglutination inhibition assay titers at 1 month after SIIV. All comparisons achieved the prespecified 1.5-fold noninferiority margin., Conclusions: The primary study objectives were met, demonstrating noninferiority of RSVpreF and SIIV immune responses when RSVpreF was coadministered with SIIV and that RSVpreF had an acceptable safety and tolerability profile when coadministered with SIIV. The results of this study support coadministration of RSVpreF and SIIV in an older-adult population., Clinical Trials Registration: https://clinicaltrials.gov/study/NCT05301322., Competing Interests: Potential conflicts of interest. E. A. reports receiving consulting fees from Moderna for vaccine advisory meeting. R. J. S. reports being an investigator for Pfizer (consultant doctor/medical investigator for the University of the Sunshine Coast Clinical Trials team; received consulting fees to work as a medical investigator; and was involved with the conduct of the clinical trial for Pfizer RSVpreF vaccine at the clinical trial site in Queensland, Australia). A. G. reports patents planned, issued, or pending: WO2017/1096729. All authors (except E. A. and R. J. S.) are employees of Pfizer, Inc, and may hold stock or stock options. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Protection against contemporary severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants requires sequence-adapted vaccines., Methods: In this ongoing phase 2/3 trial, 12-17-year-olds (n = 108), 18-55-year-olds (n = 313), and >55-year-olds (n = 306) who previously received 3 original BNT162b2 30-µg doses, received a fourth dose (second booster) of 30-µg bivalent original/Omicron-BA.4/BA.5-adapted BNT162b2 (BNT162b2-Omi.BA.4/BA.5). For comparisons with original BNT162b2, participants were selected from another phase 3 trial. Immunologic superiority 1 month after vaccination, with respect to 50% neutralizing titers (lower bound [LB] of 2-sided 95% confidence interval [CI] for geometric mean ratio [GMR], >1), and noninferiority with respect to seroresponse rates (LB of 2-sided 95% CI for rate difference, greater than -5%), for Omicron BA.4/BA.5 were assessed in >55-year-olds versus original BNT162b2 as a second booster. Noninferiority with respect to neutralizing titer level (LB of 2-sided 95% CI for GMR, > 0.67) and seroresponse rate (LB of 2-sided 95% CI for rate difference, greater than -10%) of Omicron BA.4/BA.5 immune response for BNT162b2-Omi.BA.4/BA.5 in 18-55 versus >55-year-olds was assessed., Results: One month after vaccination in >55-year-olds, the model-adjusted GMR of Omicron BA.4/BA.5 neutralizing titers for the BNT162b2-Omi.BA.4/BA.5 versus BNT162b2 groups (2.91 [95% CI, 2.45-3.44]) demonstrated the superiority of BNT162b2-Omi.BA.4/BA.5. Adjusted difference in the percentages of >55-year-olds with seroresponse (26.77% [95% CI, 19.59-33.95]) showed noninferiority of BNT162b2-Omi.BA.4/BA.5 to BNT162b2. Noninferiority of BNT162b2-Omi.BA.4/BA.5 in 18-55-year-olds compared with >55-year-olds was met for model-adjusted GMR and seroresponse. Geometric mean titers in 12-17-year-olds increased from baseline to 1 month after vaccination. The BNT162b2-Omi.BA.4/BA.5 safety profile was similar to the profiles for booster doses of bivalent Omicron BA.1-modified BNT162b2 and original BNT162b2 reported in previous studies., Conclusions: Based on immunogenicity and safety data up to 1 month after vaccination in participants who previously received 3 original BNT162b2 doses, a BNT162b2-Omi.BA.4/BA.5 30-µg booster has a favorable benefit-risk profile., Clinical Trials Registration: NCT05472038., Competing Interests: Potential conflicts of interest . L. U. reports consulting fees made to institution from Pfizer Survey and a role as Memphis Medical Society President. S. P., X. X., D. Y. L., H. W., F. S. L., C. L., D. C., K. K., A. S. A., K. A. S., W. C. G., and N. K. are employees of Pfizer and may hold stock or stock options. H. R. reports consulting fees from Moderna for Vaccine advisory meeting. D. F. received funding from Pfizer for conducting research trials. F. J. M., Ö. T., and U. Ş. are employees of BioNTech and may hold stock or stock options. Ö. T. reports grants or contracts for joint development from Pfizer, is a coauthor on various issued or pending patents related to RNA technology and coronavirus disease 2019 (COVID-19) vaccines from BioNTech, and is a cofounder and chief executive officer of BioNTech. U. Ş. reports grants or contracts for joint development from Pfizer, is a coauthor on various issued or pending patents related to RNA technology and COVID-19 vaccines from BioNTech, and is a cofounder and chief executive officer of BioNTech. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Bivalent RSV prefusion F subunit vaccine (RSVpreF), comprised of equal quantities of stabilized prefusion F antigens from the major circulating subgroups (RSV A, RSV B), is licensed for prevention of RSV-associated lower respiratory tract illness (LRTI) in older adults and for maternal vaccination for prevention of RSV-associated LRTI in infants. To support licensure and large-scale manufacturing, this lot consistency study was conducted to demonstrate equivalence in immunogenicity across 3 RSVpreF lots., Methods: This phase 3, multicenter, parallel-group, placebo-controlled, randomized (1:1:1:1), double-blind study evaluated immunogenicity, safety, and tolerability of RSVpreF in healthy 18-49-year-old adults. Participants received a single 120-µg injection of 1 of 3RSVpreF lots or placebo. Geometric mean ratio (GMR) of RSV serum 50 % neutralizing geometric mean titers obtained 1 month after vaccination were compared between each vaccine lot for RSV A and RSV B, separately. Equivalence between lots was defined using a 1.5-fold criterion (GMR 95 % CIs for every lot pair within the 0.667-1.5 interval). Safety and tolerability were assessed., Results: Of 992participants vaccinated, 948 were included in the evaluable immunogenicity population. All 3 RSVpreF lots elicited strong immune responses, meeting the 1.5-fold equivalence criterion for all between-lot comparisons for both RSV A and RSV B. Across the 3 lots, RSV A and RSV B 50 % neutralizing geometric mean titers substantially increased from baseline (RSV A, 1671-1795; RSV B 1358-1429) to 1 month after RSVpreF vaccination (RSV A, 24,131-25,238; RSV B, 19,238-21,702), corresponding to ≥14-fold increases in 50 % neutralizing titers for both RSV A and RSV B from before to 1 month after vaccination. Single doses of RSVpreF were safe and well tolerated, with similar safety profiles across the 3 RSVpreF lots., Conclusions: These findings support the reproducibility of RSVpreF vaccine manufacturing with similar safety and reactogenicity profiles (NCT05096208)., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jeffrey Baker received funding from Pfizer as an investigator for this study. Negar Aliabadi, Iona Munjal, Qin Jiang, Ye Feng, Linda G. Brock, David Cooper, Annaliesa S. Anderson, Kena A. Swanson, William C. Gruber, and Alejandra Gurtman received salary from their employment at Pfizer Inc and may hold Pfizer stock or stock options. Negar Aliabadi reports a relationship with Pfizer that includes: equity or stocks. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Iona Munjal reports financial support was provided by Pfizer. Iona Munjal reports a relationship with Pfizer Inc that includes: employment and equity or stocks. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Qin Jiang reports financial support was provided by Pfizer Inc. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Ye Feng declares that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. David Cooper reports a relationship with Pfizer Inc that includes: employment and equity or stocks. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Annaliesa S. Anderson reports a relationship with Pfizer Inc that includes: employment and equity or stocks. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Kena A. Swanson reports writing assistance was provided by ICON. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. William C. Gruber reports financial support was provided by Pfizer Inc. William C. Gruber reports a relationship with Pfizer Inc that includes: employment and equity or stocks. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Alejandra Gurtman reports financial support was provided by Pfizer Inc. Alejandra Gurtman reports a relationship with Pfizer Inc that includes: employment and equity or stocks. I am a Pfizer employee. If there are other authors, they 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 © 2024 The Authors. Published by Elsevier India Pvt Ltd. All rights reserved.)

Soil organic carbon (SOC) is a soil health indicator and understanding dynamics changing SOC stocks will help achieving net zero goals. Here we present four datasets featuring 11,750 data points covering co-located aboveground and below-ground metrics for exploring ecosystem SOC dynamics. Five sites across England with an established land use contrast, grassland and woodland next to each other, were rigorously sampled for aboveground (n = 109), surface (n = 33 soil water release curves), topsoil, and subsoil metrics. Commonly measured soil metrics were analysed in five soil increments for 0-1 metre (n = 4550). Less commonly measured soil metrics which were assumed to change across the soil profile were measured on a subset of samples only (n = 3762). Additionally, we developed a simple method for soil organic matter fractionation using density fractionation which is part of the less common metrics. Finally, soil metrics which may impact SOC dynamics, but with less confidence as to their importance across the soil profile were only measured on topsoil (~5-15 cm = mineral soil) and subsoil (below 50 cm) samples (n = 2567)., (© 2024. The Author(s).)

Purpose: For lung stereotactic body radiation therapy, 4-dimensional computed tomography is often used to delineate target volumes, whereas organs at risk (OARs) are typically outlined on either average intensity projection (AIP) or midventilation (MidV = 30% phase) images. AIP has been widely adopted as it represents a true average, but image blurring often precludes accurate contouring of critical structures such as central airways. Here, we compare AIP versus MidV planning for centrally located tumors via respiratory motion-inclusive (RMI) plans to better evaluate dose delivered throughout the breathing cycle., Methods and Materials: Independently contoured and optimized AIP and MidV plans were created for 16 treatments and rigidly copied to each of the 10 breathing phase-specific computed tomography image sets. Resulting dose distributions were deformably registered back to the MidV image set (used as reference because of clearer depiction of anatomy compared with motion-blurred AIP) and averaged to create RMI plans. Doses to central OARs were compared between plans., Results: Mean absolute dose differences were low for all comparisons (range, 0.01-2.87 Gy); however, individual plans exhibited differences >20 Gy. Dose differences >5 Gy were observed most often for plan comparisons involving AIP-based plans (MidV vs AIP 23, AIP RMI vs AIP 12, MidV RMI vs AIP RMI 7, and MidV RMI vs MidV 8 times). Inclusion of respiratory motion reduced large dose differences. Standard OAR thresholds were exceeded up to 5 times for each plan comparison scenario and always involved proximal bronchial tree D4 cc tolerance dose. AIP-based contours were larger by, on average, 3% to 15%., Conclusions: Large dose differences were observed when plans with AIP-based contours were compared with MidV-based contours, indicating that observed dose differences were likely due to contoured volume differences rather than the effect of motion. Because of blurring with AIP images, MidV RMI-based planning may offer a more accurate method to determine dose to critical OARs in the presence of respiratory motion., (© 2024 The Authors.)

We demonstrate the use of both pixelated differential phase contrast (DPC) scanning transmission electron microscopy (STEM) and off-axis electron holography (EH) for the measurement of electric fields and assess the advantages and limitations of each technique when applied to technologically relevant samples. Three different types of samples are examined, firstly a simple highly-doped Si pn junction. Then a SiGe superlattice is examined to evaluate the effects of the mean inner potential on the measured signal. Finally, an InGaN/GaN microwire light-emitting diode (LED) device is examined which has a polarization field, variations of mean inner potential and a wurtzite crystal lattice. We discuss aspects such as spatial resolution and sensitivity, and the concept of pseudo-field is defined. However, the most important point is the need to limit the influence of diffraction contrast to obtain accurate measurements. In this respect, the use of a plane electron wave for EH is clearly beneficial when compared to the use of a convergent beam for pixelated DPC STEM., 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 © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Terrigenous carbon in aquatic systems is increasingly recognised as an important part of the global carbon cycle. Despite this, the fate and distribution of terrigenous dissolved organic carbon (tDOC) in coastal and oceanic systems is poorly understood. We have implemented a theoretical framework for the degradation of tDOC across the land to ocean continuum in a 3D hydrodynamical-biogeochemical model on the North West European Shelf. A key feature of this model is that both photochemical and bacterial tDOC degradation rates are age dependant constituting an advance in our ability to describe carbon cycling in the marine environment. Over the time period 1986-2015, 182±17 Gmol yr -1 of riverine tDOC is input to the shelf. Results indicate that bacterial degradation is by far the most important process in removing tDOC on the shelf, contributing to 73±6 % (132±11 Gmol yr -1 ) of the total removal flux, while 21±3 % (39±6 Gmol yr -1 ) of riverine tDOC was advected away from the shelf and photochemical degradation removing 5±0.5 % of the riverine flux. Explicitly including tDOC in the model decreased the air-sea carbon dioxide (CO 2 ) flux by 112±8 Gmol yr -1 (4±0.4 %), an amount approximately equivalent to the CO 2 released by the UK chemical industry in 2020. The reduction is equivalent to 62 % of the riverine tDOC input to the shelf while approximately 17 % of riverine input is incorporated into the foodweb. This work can improve the assumptions of the fate of tDOC by Earth System Models and demonstrates that the inclusion of tDOC in models can impact ecosystem dynamics and change predicted global carbon budgets for the ocean., 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 The Authors. Published by Elsevier B.V. All rights reserved.)

Guide RNAs offer programmability for CRISPR-Cas9 genome editing but also add challenges for delivery. Chemical modification, which has been key to the success of oligonucleotide therapeutics, can enhance the stability, distribution, cellular uptake, and safety of nucleic acids. Previously, we engineered heavily and fully modified SpyCas9 crRNA and tracrRNA, which showed enhanced stability and retained activity when delivered to cultured cells in the form of the ribonucleoprotein complex. In this study, we report that a short, fully stabilized oligonucleotide (a 'protecting oligo'), which can be displaced by tracrRNA annealing, can significantly enhance the potency and stability of a heavily modified crRNA. Furthermore, protecting oligos allow various bioconjugates to be appended, thereby improving cellular uptake and biodistribution of crRNA in vivo. Finally, we achieved in vivo genome editing in adult mouse liver and central nervous system via co-delivery of unformulated, chemically modified crRNAs with protecting oligos and AAV vectors that express tracrRNA and either SpyCas9 or a base editor derivative. Our proof-of-concept establishment of AAV/crRNA co-delivery offers a route towards transient editing activity, target multiplexing, guide redosing, and vector inactivation., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Vaccination remains an important mitigation tool against COVID-19. We report 1-month safety and preliminary immunogenicity data from a substudy of an ongoing, open-label, phase 2/3 study of monovalent Omicron XBB.1.5-adapted BNT162b2 (single 30-μg dose). Healthy participants ≥12 years old ( N = 412 (12-17 years, N = 30; 18-55 years, N = 174; >55 years, N = 208)) who previously received ≥3 doses of a US-authorized mRNA vaccine, the most recent being an Omicron BA.4/BA.5-adapted bivalent vaccine ≥150 days before study vaccination, were vaccinated. Serum 50% neutralizing titers against Omicron XBB.1.5, EG.5.1, and BA.2.86 were measured 7 days and 1 month after vaccination in a subset of ≥18-year-olds (N = 40) who were positive for SARS-CoV-2 at baseline. Seven-day immunogenicity was also evaluated in a matched group who received bivalent BA.4/BA.5-adapted BNT162b2 in a previous study (ClinicalTrials.gov Identifier: NCT05472038). There were no new safety signals; local reactions and systemic events were mostly mild to moderate in severity, adverse events were infrequent, and none led to study withdrawal. The XBB.1.5-adapted BNT162b2 induced numerically higher titers against Omicron XBB.1.5, EG.5.1, and BA.2.86 than BA.4/BA.5-adapted BNT162b2 at 7 days and robust neutralizing responses to all three sublineages at 1 month. These data support a favorable benefit-risk profile of XBB.1.5-adapted BNT162b2 30 μg. ClinicalTrials.gov Identifier: NCT05997290.

Aim: To establish, for the first time, the clinically important differences for the ICIQ-UI-SF and ICIQ-FLUTS questionnaires following surgical and conservative treatments for stress-predominant urinary incontinence in women., Methods: Data from the SIMS and OPAL randomised controlled trials were analysed using an anchor-based method. Clinically important difference (CID; score change indicating a successful outcome) and minimal important difference (MID; score change indicating the smallest noticeable difference) were estimated using the PGI-I scale as the anchor., Results: For ICIQ-UI-SF, following surgical management, CIDs were 5.0 (95%CI 4.3, 5.6) at 1 year and 4.9 points (95%CI 4.2, 5.5) at 3 years, while following conservative management, CIDs were 4.0 (95%CI 3.4, 4.5) at 1 year and 4.6 points (95%CI 4.0, 5.2) at 2 years. For ICIQ-FLUTS, the CID was 3.4 points (95%CI 2.9, 4.0) at 1 year for both surgical and conservative management. MIDs for ICIQ-UI-SF, after surgical treatment, were 4.7 (95% CI 3.2, 6.1) at 1 year and 1.6 points (95%CI -0.2, 3.0) at 3 years, and after conservative treatment they were 1.7 (95% CI 1.0, 2.5) at 1 year and 1.9 points (95%CI 1.1, 2.7) at 2 years. For ICIQ-FLUTS, MIDs were 1.8 (95% CI 0.6, 3.1) at 1 year and 3.2 points (95%CI 2.0, 4.4) at 2 years after surgical treatment, and 1.3 (95%CI 0.6, 1.9) at 1 year and 1.9 points (95%CI 1.1, 2.6) at 2 years after conservative treatment., Conclusion: Our study is the first to establish the CID for the ICIQ-UI-SF and ICIQ-FLUTS that women would associate with a successful outcome 3-years post-surgery and 2-years post-conservative treatment of stress-predominant urinary incontinence. The MID was lower following conservative compared to surgical treatment., (© 2023. Crown.)

Objective: To report on the cost-effectiveness of adjustable anchored single-incision mini-slings (mini-slings) compared with tension-free standard mid-urethral slings (standard slings) in the surgical management of female stress urinary incontinence (SUI)., Patients and Methods: Data on resource use and quality were collected from women aged ≥18 years with predominant SUI undergoing mid-urethral sling procedures in 21 UK hospitals. Resource use and quality of life (QoL) data were prospectively collected alongside the Single-Incision Mini-Slings versus standard synthetic mid-urethral slings Randomised Control Trial (SIMS RCT), for surgical treatment of SUI in women. A health service provider's (National Health Service [NHS]) perspective with 3-year follow-up was adopted to estimate the costs of the intervention and all subsequent resource use. A generic instrument, EuroQol EQ-5D-3L, was used to estimate the QoL. Results are reported as incremental costs, quality adjusted life years (QALYs) and incremental cost per QALY., Results: Base case analysis results show that although mini-slings cost less, there was no significant difference in costs: mini-slings versus standard slings: £-6 [95% CI -228-208] or in QALYs: 0.005 [95% CI -0.068-0.073] over the 3-year follow-up. There is substantial uncertainty, with a 56% and 44% probability that mini-slings and standard slings are the most cost-effective treatment, respectively, at a £20 000 willingness-to-pay threshold value for a QALY., Conclusions: At 3 years, there is no significant difference between mini-slings and standard slings in costs and QALYs. There is still some uncertainty over the long-term complications and failure rates of the devices used in the treatment of SUI; therefore, it is important to establish the long-term clinical and cost-effectiveness of these procedures., Competing Interests: Dr. Dwayne Boyers reports grants from UK NIHR during the conduct of the study. Ms. Mary Kilonzo reports grants from UK NIHR during the conduct of the study. Kiron Bhal: I have been a speaker and trainer for the following companies in the past Astellas, Pfizer, AMS, Contura, Allergan and others, where I have received honorariums and sponsorship towards attending scientific conferences. Professor James N'Dow reports HTA General Committee 2016–2018. Professor Graeme MacLennan reports grants from UK NIHR during the conduct of the study. Professor John Norrie reports grants from the University of Edinburgh, outside the submitted work; and past and present member of the following: HTA Commissioning Sub‐Board (EOI), NIHR CTU Standing Advisory Committee, NIHR HTA & EME Editorial Board, Pre‐Exposure Prophylaxis Impact Review Panel, EME Strategy Advisory Committee, EME—Funding Committee Members, EME Funding Committee Sub‐Group Remit & Comp Check, HTA General Committee, HTA Funding Committee Policy Group (formerly CSG) and HTA Commissioning Committee. HTA post‐funding committee teleconference 2016–2019; COVID‐19 reviewing 2020. Professor Mohamed Abdel‐Fattah: None in the last 5 years. Before 2015, I have been a speaker, consultant and/or surgical trainer for a number of industrial companies (Astellas, Ethicon, Bard, Pfizer, AMS, Coloplast and others): I have been reimbursed my travel expenses; and on occasions received personal honorariums; proctorship fees and sponsorship towards attending scientific conferences. Research grant from Coloplast managed by the University of Aberdeen. A limited number of my trainees attended pharmaceutical‐sponsored educational/leadership workshops and/or received assistance in presenting their research work at scientific conferences. Was Chairman of the Scottish Pelvic Floor Network (SPFN), which at the time received financial sponsorship from various industrial companies (including all those mentioned above) and non‐profit organisations for its annual meetings and surgical workshops. The SPFN provided an educational grant funding the PI at the highest recruiting site to attend the International Continence Society annual scientific conference in Brazil in 2014. Ongoing: I receive travel sponsorship and occasionally speaker‘s fees from numerous national and international conferences and non‐profit organisations when invited as a guest speaker and/or expert surgeon. In 2019, and at request from NHS Grampian, I attended 2 educational meetings for setting up sacral nerve stimulation service partially funded by Medtronic. I am the Chief Investigator for four NIHR—HTA‐funded studies. I do not hold (and never held) any shares (or similar) in any of the industrial companies (medical or non‐medical). To the best of my knowledge, none of the above have influenced my research or clinical practice. No other authors declared any potential conflicts of interest., (© 2023 The Authors. BJUI Compass published by John Wiley & Sons Ltd on behalf of BJU International Company.)

The sliding sleeve holds a pivotal role in regulating fluid flow during hydraulic fracturing within shale oil extraction processes. However, concerns persist surrounding its reliability due to repeated attempts at opening the sleeve, resulting in process inefficiencies. While downhole cameras can verify sleeve states, their high cost poses a limitation. This study proposes an alternative approach, leveraging downhole data analysis for sleeve incident detection in lieu of cameras. This study introduces "XGSleeve," a novel machine-learning methodology. XGSleeve amalgamates hidden Markov model-based clustering with the XGBoost model, offering robust identification of sleeve incidents. This method serves as an operator-centric tool, addressing the domains of oil and gas, well completion, sliding sleeves, time series classification, signal processing, XGBoost, and hidden Markov models. The XGSleeve model exhibits a commendable 86% precision in detecting sleeve incidents. This outcome significantly curtails the need for multiple sleeve open-close attempts, thereby enhancing operational efficiency and safety. The successful implementation of the XGSleeve model rectifies existing limitations in sleeve incident detection, consequently fostering optimization, safety, and resilience within the oil and gas sector. This innovation further underscores the potential for data-driven decision-making in the industry. The XGSleeve model represents a groundbreaking advancement in sleeve incident detection, demonstrating the potential for broader integration of AI and machine learning in oil and gas operations. As technology advances, such methodologies are poised to optimize processes, minimize environmental impact, and promote sustainable practices. Ultimately, the adoption of XGSleeve contributes to the enduring growth and responsible management of global oil and gas resources., Competing Interests: DC and PW are employed by Kobold Completion Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Somi, Jubair, Cooper and Wang.)

The optoelectronic properties of a fully processed red emitting AlGaInP micro-diode device is measured using standard I-V and luminescence measurements. A thin specimen is then prepared for in situ transmission electron microscopy analysis by focused ion beam milling, then the changes of electrostatic potential as a function of applied forward bias voltage are mapped by off-axis electron holography. We demonstrate that the quantum wells in the diode sit on a potential gradient until the threshold forward bias voltage for light emission is reached; at which point the quantum wells are aligned at the same potential. From simulations, a similar effect for the band structure can be demonstrated, where the quantum wells are aligned at the same energy level, and contain electrons and holes that are available for radiative recombination at this threshold voltage. We demonstrate that off-axis electron holography can be used to directly measure the potential distribution in optoelectronic devices, and is a powerful tool to help better understand their performance and to improve simulations., (© 2023 The Authors. Small Methods published by Wiley-VCH GmbH.)

Introduction: Vaccination is a critical tool for preventing coronavirus disease 2019 (COVID-19) and influenza illnesses. Coadministration of the COVID-19 vaccine, BNT162b2, with seasonal inactivated influenza vaccine (SIIV) can provide substantial benefits, including streamlining vaccine delivery., Methods: In this phase 3 study, healthy 18- to 64-year-olds who had received three previous doses of BNT162b2 were randomized (1:1) to the coadministration group (month 0, BNT162b2 + SIIV; month 1, placebo) or the separate-administration group (month 0, placebo + SIIV; month 1, BNT162b2). The primary immunogenicity objective was to demonstrate that the immune responses elicited by BNT162b2 and SIIV [measured by full-length S-binding immunoglobulin G (IgG) levels and strain-specific hemagglutination inhibition assay (HAI) titers against four influenza strains 1 month post-vaccination, respectively] when coadministered were noninferior to those elicited by either vaccine administered alone, based on a prespecified 1.5-fold noninferiority margin [lower bound 95% CI for geometric mean ratio (GMR) > 0.67]. Reactogenicity and adverse event (AE) rates were evaluated., Results: Randomized participants who received study vaccination (N = 1128; coadministration group, n = 564; separate-administration group, n = 564) had a median age of 39 years. Model-adjusted GMRs for coadministration to separate administration were 0.83 (95% CI 0.77, 0.89) for full-length S-binding IgG levels and 0.89-1.00 (lower bound of all 95% CIs > 0.67) for the four influenza strain-specific HAI titers, with all endpoints achieving the prespecified noninferiority criterion. Reactogenicity events were mostly mild or moderate when BNT162b2 was coadministered with SIIV. Serious AEs were reported in < 1% of participants within 1 month after any vaccination; none were considered vaccine-related., Conclusions: BNT162b2 coadministered with SIIV elicited immune responses that were noninferior to those elicited by BNT162b2 alone and SIIV alone, and BNT162b2 had an acceptable safety profile when coadministered with SIIV. The results of this study support the coadministration of BNT162b2 and SIIV in adults., Trial Registration: ClinicalTrials.gov registration: NCT05310084., (© 2023. The Author(s).)

Objectives: To elicit and value patient preferences for the processes and outcomes of surgical management of stress urinary incontinence in women., Design: A discrete choice experiment survey to elicit preferences for type of anaesthesia, postoperative recovery time, treatment success, adverse events, impact on daily activities and cost. An experimental design generated 40 choice tasks, and each respondent completed 1 block of 10 and 2 validity tests. Analysis was by multinomial logistical regression., Setting: N=21 UK hospitals., Participants: N=325 adult women who were a subsample of those randomised to the single-incision mini-slings clinical trial., Outcomes: Patient preferences; valuation obtained using willingness to pay., Results: N=227 of 325 (70%) returned a questionnaire, and 94% of those completed all choice tasks. Respondents preferred general anaesthesia, shorter recovery times, improved stress urinary incontinence symptoms and avoidance of adverse events. Women were willing to pay (mean (95% CI)) £76 (£33 to £119) per day of reduction in recovery time following surgery. They valued increases in Patient Global Impression of Improvement, ranging from £8173 (£5459 to £10 887) for 'improved' to £11 706 (£8267 to £15 144) for 'very much improved' symptoms, compared with no symptom improvement. This was offset by negative values attached to the avoidance of complications ranging between £-8022 (£-10 661 to £-5383) and £-10 632 (£-14 077 to £-7187) compared to no complications. Women valued treatments that reduced the need to avoid daily activities, with willingness to pay ranging from £-967 (£-2199 to £266) for rarely avoiding activities to £-5338 (£-7258 to £-3417) for frequently avoiding daily activities compared with no avoidance., Conclusion: This discrete choice experiment demonstrates that patients place considerable value on improvement in stress urinary incontinence symptoms and avoidance of treatment complications. Trade-offs between symptom improvement and adverse event risk should be considered within shared decision-making. The willingness to pay values from this study can be used in future cost-benefit analyses., Trial Registration Number: ISRCTN: 93264234; Post-results., Competing Interests: Competing interests: DB reports grants from UK NIHR during the conduct of the study. KB has been a speaker and trainer for the following companies in the past: Astellas, Pfizer, AMS, Contura, Allergan and others, where he received honoraria and sponsorship towards attending scientific conferences. JN'D reports HTA General Committee 2016–2018. GM reports grants from UK NIHR during the conduct of the study. JN reports grants from University of Edinburgh, outside the submitted work; and past and present member of the following: HTA Commissioning Sub-Board (EOI), NIHR CTU Standing Advisory Committee, NIHR HTA & EME Editorial Board, Pre-Exposure Prophylaxis Impact Review Panel, EME Strategy Advisory Committee, EME-Funding Committee Members, EME Funding Committee Sub-Group Remit & Comp Check, HTA General Committee, HTA Funding Committee Policy Group (formerly CSG), HTA Commissioning Committee, HTA Post-funding committee teleconference 2016–2019 and COVID-19 reviewing 2020. MA-F reports none in the last 5 years. Before 2015, he has been a speaker, consultant and/or surgical trainer for a number of industrial companies (Astellas, Ethicon, Bard, Pfizer, AMS, Coloplast and others); has reimbursed his travel expenses and on occasions received personal honoraria, proctorship fees and sponsorship towards attending scientific conferences; received research grant from Coloplast managed by University of Aberdeen. Moreover, his limited number of trainees attended pharmaceutical sponsored educational/leadership workshops and/or received assistance towards presenting their research work in scientific conferences. He was also Chairman of the Scottish Pelvic Floor Network (SPFN), which at the time, received financial sponsorship from various industrial companies (including all those mentioned above) and non-profit organisations for its annual meetings and surgical workshops. The SPFN provided an educational grant funding the PI at the highest recruiting site to attend the International Continence Society annual scientific conference in Brazil in 2014. At present, he receives travel sponsorship and occasionally speaker’s fees from numerous national and international conferences and non-profit organisations when invited as guest speaker and/or expert surgeon. In 2019, and at the request from NHS Grampian, he attended two educational meetings for setting up sacral nerve stimulation service partially funded by Medtronic. He is the Chief Investigator for four NIHR-HTA-funded studies. He does not hold (and never held) any shares (or similar) in any of the industrial companies (medical or non-medical). To the best of his knowledge, none of the above have influenced his research or clinical practice. No other authors declared any potential conflict of interest., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background/aims: To assess baseline ocular parameters in the prediction of long-term intraocular pressure (IOP) control after clear lens extraction (CLE) or laser peripheral iridotomy (LPI) in patients with primary angle closure (PAC) disease using data from the Effectiveness of Early Lens Extraction for the treatment of primary angle-closure glaucoma (EAGLE) tria., Methods: This study is a secondary analysis of EAGLE data where we define the primary outcome of 'good responders' as those with IOP<21 mm Hg without requiring additional surgery and 'optimal responders' as those who in addition were medication free, at 36-month follow-up. Primary analysis was conducted using a multivariate logistic regression model to assess how randomised interventions and ocular parameters predict treatment response., Results: A total of 369 patients (182 in CLE arm and 187 in LPI arm) completed the 36-month follow-up examination. After CLE, 90% met our predefined 'good response' criterion compared with 67% in the LPI arm, and 66% met 'optimal response' criterion compared with 18% in the LPI arm, with significantly longer drops/surgery-free survival time (p<0.05 for all). Patients randomised to CLE (OR=10.1 (6.1 to 16.8)), Chinese (OR=2.3 (1.3 to 3.9)), and those who had not previously used glaucoma drops (OR=2.8 (1.6 to 4.8)) were more likely to maintain long-term optimal IOP response over 36 months., Conclusion: Patients with primary angle closure glaucoma/PAC are 10 times more likely to maintain drop-free good IOP control with initial CLE surgery than LPI. Non-Chinese ethnicity, higher baseline IOP and using glaucoma drops prior to randomisation are predictors of worse long-term IOP response., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction and Hypothesis: Clinical trials for stress urinary incontinence (SUI) require a robust, reliable, and responsive tool for objective assessment of SUI post-intervention. The Aberdeen Home Continence Stress Test (HCST) is a novel patient-reported objective assessment tool, aimed to be patient-friendly and reduce attrition rates by avoiding hospital appointments and prolonged pad-wearing. We aim to describe the HCST for the first time and evaluate its reliability, diagnostic accuracy, and response to change., Methods: A secondary analysis of the Single-Incision Mini-Slings (SIMS) study (a prospective multicentre randomised control trial (RCT) comparing two surgical treatments of SUI was performed. In SIMS (n = 600 women), the objective outcome was assessed by the 24-h pad test, while the patient-reported success rates were assessed using the Patient Global Impression of Improvement (PGI-I) at 15 months, 2 years and 3 years post-randomisation. Participants were instructed to perform the HCST before and after the 24-h pad test. The HCST was analysed in relation to reliability, validity, and the relationship between the 24-h pad test and HCST results and finally with regard to its responsiveness to change in PGI-I. (Trial registration-number ISRCTN93264234, registration date 14/01/2014)., Results: Compared to the 24-h pad test, the sensitivity of the HCST ranged from 0.81-0.95, specificity was 0.76-0.79, negative predictive value was 0.96-0.99 and positive predictive value was 0.32-0.43. Reliability was indicated by high-performing Cronbach's alpha value (> 0.7). An improvement of ≥ 2 leakage groups on the HCST (for example from Large at baseline to Small leakage at follow-up) was strongly associated with patient-reported success on PGI-I (OR 4.38, 95% CI 2.31, 8.31)., Conclusions: The HCST is a valid and reliable patient-reported objective assessment tool that can be used for assessing SUI in surgical trials with good specificity, sensitivity, and consistency., (© 2023. The Author(s).)