This review explores the evolution of dietary protein intake requirements and recommendations, with a focus on skeletal muscle remodelling to support healthy ageing based on presentations at the 2023 Nutrition Society summer conference. In this review, we describe the role of dietary protein for metabolic health and ageing muscle, explain the origins of protein and amino acid (AA) requirements and discuss current recommendations for dietary protein intake, which currently sits at about 0⋅8 g/kg/d. We also critique existing (e.g. nitrogen balance) and contemporary (e.g. indicator AA oxidation) methods to determine protein/AA intake requirements and suggest that existing methods may underestimate requirements, with more contemporary assessments indicating protein recommendations may need to be increased to >1⋅0 g/kg/d. One example of evolution in dietary protein guidance is the transition from protein requirements to recommendations. Hence, we discuss the refinement of protein/AA requirements for skeletal muscle maintenance with advanced age beyond simply the dose (e.g. source, type, quality, timing, pattern, nutrient co-ingestion) and explore the efficacy and sustainability of alternative protein sources beyond animal-based proteins to facilitate skeletal muscle remodelling in older age. We conclude that, whilst a growing body of research has demonstrated that animal-free protein sources can effectively stimulate and support muscle remodelling in a manner that is comparable to animal-based proteins, food systems need to sustainably provide a diversity of both plant and animal source foods, not least for their protein content but other vital nutrients. Finally, we propose some priority research directions for the field of protein nutrition and healthy ageing.

Background: Antibiotics alone are often insufficient to treat recurrent C. difficile infection (rCDI) because they have no activity against C. difficile spores that germinate within a disrupted microbiome. SER-109, an investigational, oral, microbiome therapeutic comprised of purified Firmicutes spores, was designed to reduce rCDI through microbiome repair. We report an integrated efficacy analysis through week 24 for SER-109 from phase 3 studies, ECOSPOR III and ECOSPOR IV. Methods: ECOSPOR III was a randomized, placebo-controlled phase 3 trial conducted at 56 US or Canadian sites that included 182 participants with ≥2 CDI recurrences, confirmed via toxin EIA testing. Participants were stratified by age (<65 years or ≥65 years) and antibiotic regimen (vancomycin, fidaxomicin) and were randomized 1:1 to placebo or SER-109 groups. ECOSPOR IV was an open-label, single-arm study conducted at 72 US or Canadian sites including 263 participants with rCDI enrolled in 2 cohorts: (1) rollover participants from ECOSPOR III who experienced on-study recurrence diagnosed by toxin EIA (n = 29) and (2) participants with ≥1 CDI recurrence (diagnosed by PCR or toxin EIA), inclusive of the current episode (n = 234). In both studies, the investigational product was administered orally as 4 capsules over 3 consecutive days following symptom resolution after standard-of-care antibiotics. The primary efficacy end point was rCDI (recurrent toxin-positive diarrhea requiring treatment) through week 8. Other end points included CDI recurrence rates and safety through 24 weeks. Results: These 349 participants received at least 1 dose of SER-109 in ECOSPOR III or ECOSPOR IV (mean age 64.2; 68.8% female). Overall, 77 participants (22.1%) enrolled with their first CDI recurrence. Four participants received blinded SER-109 in ECOSPOR III followed by a second dose of open-label SER-109 in ECOSPOR IV. Overall, the proportion of participants who received any dose of SER-109 with rCDI at week 8 was 9.5% (33 of 349; 95% CI, 6.6 %–13.0%), and the CDI recurrence rate remained low through 24 weeks (15.2%, 53 of 349; 95% CI, 11.6%–19.4%), corresponding to sustained clinical response rates of 90.5% (95% CI, 87.0%–93.4%) and 84.8% (95% CI, 80.6%–88.4%), respectively (Fig. 1). Most rollover participants (25 of 29, 86.2%) were from the placebo arm; 13.8% had rCDI by week 8. Conclusions: In this integrated analysis, the rates of rCDI were low and durable in participants who received the investigational microbiome therapeutic SER-109, with sustained clinical response rates of 90.5% and 84.8% at weeks 8 and 24, respectively. These data further support the potential benefit of microbiome repair with SER-109 following antibiotics for rCDI to prevent recurrence in high-risk patients.

Financial support: This study was funded by Seres Therapeutics.

Disclosure: None

Background: Clostridioides difficile infection (CDI) often recurs in patients aged ≥65 years and those with comorbidities. Clinical trials often exclude patients with history of immunosuppression, malignancy, renal insufficiency, or other comorbidities. In a phase 3 trial (ECOSPOR III), SER-109 was superior to placebo in reducing recurrent CDI (rCDI) risk at week 8 and was well tolerated. We report integrated safety data for SER-109 in a broad patient population through week 24 from phase 3 studies: ECOSPOR III and ECOSPOR IV. Methods: ECOSPOR III was a double-blind, placebo-controlled trial conducted in participants with ≥2 CDI recurrences randomized 1:1 to placebo or SER-109. ECOSPOR IV was an open-label, single-arm study conducted in 263 patients with rCDI enrolled in 2 cohorts: (1) rollover participants from ECOSPOR III with on-study recurrence and (2) participants with ≥1 CDI recurrence, inclusive of the current episode. In both studies, the investigational product was administered as 4 oral capsules over 3 days. Treatment-emergent adverse events (TEAEs) were collected through week 8; serious TEAEs and TEAEs of special interest (ie, bacteremia, abscess, meningitis) were collected through week 24. Results: In total, 349 participants received SER-109 in ECOSPOR III and/or ECOSPOR IV (mean age 64.2; 68.8% female). Chronic diseases included cardiac disease (31.2%), immunocompromised or immunosuppressed (21.2%), diabetes (18.9% ), and renal impairment or failure (13.2%). Overall, 221 (63.3%) of 349 participants who received SER-109 experienced TEAEs through week 24. Most were mild to moderate and gastrointestinal. The most common (>5% of participants) treatment related TEAEs were flatulence, abdominal pain and distension, decreased appetite, constipation, nausea, fatigue, and diarrhea. No participants experienced a treatment-related TEAE leading to study withdrawal. Invasive infections were observed in 28 participants (8%); those with identified pathogens were unrelated to SER-109 species, and all were deemed unrelated to treatment by the investigators. There were 11 deaths (3.2%) and 48 participants (13.8%) with serious TEAEs, none of which were deemed treatment related. There were no clinically important differences in the safety profile across subgroups of sex, race, prior antibiotic regimen, or number of CDI recurrences. No safety signals were observed in participants with renal impairment or failure, diabetes, cardiac disease, or immunocompromised or immunosuppressed individuals. Conclusions: In this integrated analysis of phase 3 trials, SER-109, an investigational microbiome therapeutic, was well tolerated in this vulnerable patient population with prevalent comorbidities. No infections, nor those with identified pathogens, were attributed to SER-109 or product species. This safety profile might be expected because this purified product is composed of spore-forming Firmicutes normally abundant in the healthy microbiome.

Financial support: This study was funded by Seres Therapeutics.

Disclosures: None

Background: Carbapenem-resistant Acinetobacter baumannii (CRAB) has emerged as a major cause of bloodstream infection among hospitalized patients in low- and middle-income countries (LMICs). CRAB infections can be difficult to treat and are devastating in neonates (~30% mortality). CRAB outbreaks are hypothesized to arise from reservoirs in the hospital environment, but outbreak investigations in LMICs seldom incorporate whole-genome sequencing (WGS). Methods: WGS (Illumina NextSeq) was performed at the National Institute for Communicable Diseases (South Africa) on 43 preserved A. baumannii isolates from a 530-bed referral hospital in Gaborone, Botswana, from March 2021–August 2022. This included 23 blood-culture isolates from 21 unique patients (aged 2 days–69 years) and 20 environmental isolates collected at the 36-bed neonatal unit in April–June 2021. Infections were considered healthcare-associated if the culture was obtained >72 hours after hospital arrival (or sooner in inborn infants). Blood cultures were incubated using an automated system (BACT/ALERT, BioMérieux) and were identified using manual methods. Environmental isolates were identified using selective or differential chromogenic media (CHROMagarTM). Taxonomic assignment, multilocus sequence typing (MLST), antimicrobial resistance gene identification, and phylogenetic analyses were performed using publicly accessible analysis pipelines. Single-nucleotide polymorphism (SNP) matrices were used to assess clonal lineage. Results: All 23 blood isolates and 5 (25%) of 20 environmental isolates were confirmed as A. baumannii; thus, 28 A. baumannii isolates were included in the phylogenetic analysis. MLST revealed that 22 (79%) of 28 isolates were sequence type 1 (ST1), including all 19 healthcare-associated blood isolates and 3 (60%) of 5 environmental isolates. Genes encoding for carbapenemases (blaNDM-1, blaOXA-23) and biocide resistance (qacE) were present in all 22 ST1 isolates; colistin resistance genes were not identified. Phylogenetic analysis of the ST1 clade demonstrated spatial clustering by hospital unit. Related isolates spanned wide ranges in time (>1 year), suggesting ongoing transmission from environmental sources (Fig. 1). An exclusively neonatal clade (0–2 SNPs) containing all 8 neonatal blood isolates was closely associated with 3 environmental isolates from the neonatal unit: a sink drain, bed rail, and a healthcare worker’s hand. Conclusions: WGS analysis of clinical and environmental A. baumannii revealed the presence of unit-specific CRAB clones, with evidence of ongoing transmission likely driven by persistent environmental reservoirs. This research highlights the potential of WGS to detect hospital outbreaks and reaffirms the importance of environmental sampling to identify and remediate reservoirs (eg, sinks) and vehicles (eg, hands and equipment) within the healthcare environment.

Disclosures: None

Knowledge graphs have become a common approach for knowledge representation. Yet, the application of graph methodology is elusive due to the sheer number and complexity of knowledge sources. In addition, semantic incompatibilities hinder efforts to harmonize and integrate across these diverse sources. As part of The Biomedical Translator Consortium, we have developed a knowledge graph–based question-answering system designed to augment human reasoning and accelerate translational scientific discovery: the Translator system. We have applied the Translator system to answer biomedical questions in the context of a broad array of diseases and syndromes, including Fanconi anemia, primary ciliary dyskinesia, multiple sclerosis, and others. A variety of collaborative approaches have been used to research and develop the Translator system. One recent approach involved the establishment of a monthly “Question-of-the-Month (QotM) Challenge” series. Herein, we describe the structure of the QotM Challenge; the six challenges that have been conducted to date on drug-induced liver injury, cannabidiol toxicity, coronavirus infection, diabetes, psoriatic arthritis, and ATP1A3-related phenotypes; the scientific insights that have been gleaned during the challenges; and the technical issues that were identified over the course of the challenges and that can now be addressed to foster further development of the prototype Translator system. We close with a discussion on Large Language Models such as ChatGPT and highlight differences between those models and the Translator system.

Newcastle disease (ND) is a notifiable disease affecting chickens and other avian species caused by virulent strains of Avian paramyxovirus type 1 (APMV-1). While outbreaks of ND can have devastating consequences, avirulent strains of APMV-1 generally cause subclinical infections or mild disease. However, viruses can cause different levels of disease in different species and virulence can evolve following cross-species transmission events. This report describes the detection of three cases of avirulent APMV-1 infection in Great Britain (GB). Case 1 emerged from the ‘testing to exclude’ scheme in chickens in Shropshire while cases 2 and 3 were made directly from notifiable avian disease investigations in chicken broilers in Herefordshire and on premises in Wiltshire containing ducks and mixed species, respectively). Class II/genotype I.1.1 APMV-1 from case 1 shared 99.94% identity to the Queensland V4 strain of APMV-1. Class II/genotype II APMV-1 was detected from case 2 while the class II/genotype I.2 virus from case 3 aligned closely with strains isolated from Anseriformes. Exclusion of ND through rapid detection of avirulent APMV-1 is important where clinical signs caused by avirulent or virulent APMV-1s could be ambiguous. Understanding the diversity of APMV-1s circulating in GB is critical to understanding disease threat from these adaptable viruses.

The lattice parameters and the crystal and magnetic structures of Fe2SiO4 have been determined from 10 K to 1453 K by high-resolution time-of-flight neutron powder diffraction. Fe2SiO4 undergoes two antiferromagnetic phase transformations on cooling from room temperature: the first, at 65.4 K, is to a collinear antiferromagnet with moments on two symmetry-independent Fe ions; the second transition, at ~23 K, is to a structure in which the moments on one of the sets of Fe ions (those on the ‘M1 site’) become canted. The magnetic unit cell is identical to the crystallographic (chemical) unit cell and the space group remains Pbnm throughout. The magnetic structures have been refined and the results found to be in good agreement with previous studies; however, we have determined the spontaneous magnetostrictive strains, which have not been reported previously. In the paramagnetic phase of Fe2SiO4, at temperatures of 70 K and above, we find that the temperature dependence of the linear thermal expansion coefficient of the b axis takes an unusual form. In contrast to the behaviour of the expansion coefficients of the unit-cell volume and of the a and c axes, which show the expected reduction in magnitude below ~300 K, that of the b axis remains almost constant between ~70 K and 1000 K.

The U.S. Department of Agriculture–Agricultural Research Service (USDA-ARS) has been a leader in weed science research covering topics ranging from the development and use of integrated weed management (IWM) tactics to basic mechanistic studies, including biotic resistance of desirable plant communities and herbicide resistance. ARS weed scientists have worked in agricultural and natural ecosystems, including agronomic and horticultural crops, pastures, forests, wild lands, aquatic habitats, wetlands, and riparian areas. Through strong partnerships with academia, state agencies, private industry, and numerous federal programs, ARS weed scientists have made contributions to discoveries in the newest fields of robotics and genetics, as well as the traditional and fundamental subjects of weed–crop competition and physiology and integration of weed control tactics and practices. Weed science at ARS is often overshadowed by other research topics; thus, few are aware of the long history of ARS weed science and its important contributions. This review is the result of a symposium held at the Weed Science Society of America’s 62nd Annual Meeting in 2022 that included 10 separate presentations in a virtual Weed Science Webinar Series. The overarching themes of management tactics (IWM, biological control, and automation), basic mechanisms (competition, invasive plant genetics, and herbicide resistance), and ecosystem impacts (invasive plant spread, climate change, conservation, and restoration) represent core ARS weed science research that is dynamic and efficacious and has been a significant component of the agency’s national and international efforts. This review highlights current studies and future directions that exemplify the science and collaborative relationships both within and outside ARS. Given the constraints of weeds and invasive plants on all aspects of food, feed, and fiber systems, there is an acknowledged need to face new challenges, including agriculture and natural resources sustainability, economic resilience and reliability, and societal health and well-being.

Being able to characterise objects at low frequencies, but in situations where the modelling error in the eddy current approximation of the Maxwell system becomes large, is important for improving current metal detection technologies. Importantly, the modelling error becomes large as the frequency increases, but the accuracy of the eddy current model also depends on the object topology and on its materials, with the error being much larger for certain geometries compared to others of the same size and materials. Additionally, the eddy current model breaks down at much smaller frequencies for highly magnetic conducting materials compared to non-permeable objects (with similar conductivities, sizes and shapes) and, hence, characterising small magnetic objects made of permeable materials using the eddy current at typical frequencies of operation for a metal detector is not always possible. To address this, we derive a new asymptotic expansion for permeable highly conducting objects that is valid for small objects and holds not only for frequencies where the eddy current model is valid but also for situations where the eddy current modelling error becomes large and applying the eddy approximation would be invalid. The leading-order term we derive leads to new forms of object characterisations in terms of polarizability tensor object descriptions where the coefficients can be obtained from solving vectorial transmission problems. We expect these new characterisations to be important when considering objects at greater stand-off distance from the coils, which is important for safety critical applications, such as the identification of landmines, unexploded ordnance and concealed weapons. We also expect our results to be important when characterising artefacts of archaeological and forensic significance at greater depths than the eddy current model allows and to have further applications parking sensors and improving the detection of hidden, out-of-sight, metallic objects.

Clinical trials face many challenges with meeting projected enrollment and retention goals. A study’s recruitment materials and messaging convey necessary key information and therefore serve as a critical first impression with potential participants. Yet study teams often lack the resources and skills needed to develop engaging, culturally tailored, and professional-looking recruitment materials. To address this gap, the Recruitment Innovation Center recently developed a Recruitment & Retention Materials Content and Design Toolkit, which offers research teams guidance, actionable tips, resources, and customizable templates for creating trial-specific study materials. This paper seeks to describe the creation and contents of this new toolkit.

In the context of an ageing population and longer working lives, the impact of increasing rates of early exit from the labour force on quality of life is a particularly current concern. However, relatively little is known about the impact on quality of life of later-life labour force transitions and various forms of early exit from the labour force, compared to remaining in employment. This paper examines lifecourse labour force trajectories and transitions in relation to change in quality of life prior to the State Pension Age. Lifecourse data on early life circumstances, labour force trajectories and labour force transitions from 3,894 women and 3,528 men in the National Child Development Study (1958 British Birth Cohort) were examined in relation to change in quality of life, measured by a short-form version of CASP, between the ages of 50 and 55. Women and men differed in the types of labour force transition associated with positive change in quality of life, with men more frequent beneficiaries. For both men and women, labour force exit due to being sick or disabled was associated with a negative change in quality of life, whereas joining the labour force was associated with a positive change in quality of life. Moving into retirement was associated with a positive change in men's quality of life, but not women's. Moving from full-time to part-time employment was associated with a positive change in women's quality of life but not men's. The findings that stand out for their policy relevance are: the threat to the quality of life of both women and men from early labour force exit due to limiting longstanding illness; and women are less likely to experience beneficial labour force exit in the later years of their working life, but are more likely to benefit from a reduction in working hours.

Understanding the dynamics of staircases in salt fingering convection presents a long-standing theoretical challenge to fluid dynamicists. Although there has been significant progress, particularly through numerical simulations, there are a number of conflicting theoretical explanations as to the driving mechanism underlying staircase formation. The Phillips effect proposes that layering in stirred stratified flow is due to an antidiffusive process, and it has been suggested that this mechanism may also be responsible for salt fingering staircases. However, the details of this process, as well as mathematical models to predict the evolution and merger dynamics of staircases, have yet to be established. We generalise the theory of the Phillips effect to a three-component system (e.g. temperature, salinity, energy) and demonstrate a regularised nonlinear model of layering based on mixing length parametrisations. The model predicts both the inception of layering and its long-term evolution through mergers, while generalising, and remaining consistent with, previous results for double-diffusive layering based on flux ratios. Our model of salt fingering is formulated using spatial averaging processes, and closed by a mixing length parametrised in terms of the kinetic energy and the ratio of the temperature and salt gradients. The model predicts a layering instability for a bounded range of parameter values in the salt fingering regime. Nonlinear solutions show that an initially unstable linear buoyancy gradient develops into layers, which proceed to merge through a process of stronger interfaces growing at the expense of weaker ones. Our results indicate that these mergers are responsible for the characteristic increase of buoyancy flux through thermohaline staircases.