Without surgical repair, flexor tendon injuries do not heal and patients' ability to bend fingers and grip objects is impaired. However, flexor tendon repair surgery also requires optimal ...rehabilitation. There are currently three custom-made splints used in the rehabilitation of zone I/II flexor tendon repairs, each with different assumed harm/benefit profiles: the dorsal forearm and hand-based splint (long), the Manchester short splint (short), and the relative motion flexion splint (mini). There is, however, no robust evidence as to which splint, if any, is most clinical or cost effective. The Flexor Injury Rehabilitation Splint Trial (FIRST) was designed to address this evidence gap.
FIRST is a parallel group, superiority, analyst-blind, multi-centre, individual participant-randomised controlled trial. Participants will be assigned 1:1:1 to receive either the long, short, or mini splint. We aim to recruit 429 participants undergoing rehabilitation following zone I/II flexor tendon repair surgery. Potential participants will initially be identified prior to surgery, in NHS hand clinics across the UK, and consented and randomised at their splint fitting appointment post-surgery. The primary outcome will be the mean post-randomisation score on the patient-reported wrist and hand evaluation measure (PRWHE), assessed at 6, 12, 26, and 52 weeks post randomisation. Secondary outcome measures include blinded grip strength and active range of movement (AROM) assessments, adverse events, adherence to the splinting protocol (measured via temperature sensors inserted into the splints), quality of life assessment, and further patient-reported outcomes. An economic evaluation will assess the cost-effectiveness of each splint, and a qualitative sub-study will evaluate participants' preferences for, and experiences of wearing, the splints. Furthermore, a mediation analysis will determine the relationship between patient preferences, splint adherence, and splint effectiveness.
FIRST will compare the three splints with respect to clinical efficacy, complications, quality of life and cost-effectiveness. FIRST is a pragmatic trial which will recruit from 26 NHS sites to allow findings to be generalisable to current clinical practice in the UK. It will also provide significant insights into patient experiences of splint wear and how adherence to splinting may impact outcomes.
ISRCTN: 10236011.
The aim of the present study was to reach international consensus on the minimum set of outcomes to measure and report in adult traumatic brachial plexus injury care and research. This would ...facilitate comparison of outcomes from different centres and meta-analysis in research. A list of outcomes was developed from a systematic review (n = 54) and patient interviews (n = 12). The outcomes were rated in a three-round online Delphi survey completed by international surgeons, patients and therapists. Two online consensus meetings with patients and clinicians ratified the final core outcome set. A total of 72 people (20 surgeons, 21 patients, 31 therapists) from 19 countries completed all survey rounds. Thirty-eight people from nine countries attended separate patient (n = 13) and clinician consensus (n = 25) meetings. Outcomes were included if recommended by more than 85% of contributors. Pain, voluntary movement and carrying out a daily routine are the core outcome domains that should be assessed and reported when treating and researching adults with a traumatic brachial plexus injury.
Level of evidence
V
Abstract
Introduction
The Achieving Cancer Equity through Identification, Testing, and Screening (ACE‐ITS) program is a community‐engaged framework to improve mammography maintenance and rates of ...genetic risk assessment, counseling, and testing using a multilevel approach that enhances patient navigation through mobile health and community education.
Methods
The ACE‐ITS program is based on the National Institute of Minority Health and Health Disparities research framework focused on the individual (genetic testing, screening navigation) and community (community‐based breast health education) levels and targeted to the biological‐ (genetic risk), behavioral‐ (mammography screening), sociocultural‐ (underserved Black and Hispanic women), and the health care system (patient navigation, automated text messages)–related domains. We further integrate the Practical Robust Implementation and Sustainability Model to describe our program implementation.
Results
In collaboration with genetic counselors and community partners, we created educational modules on mammography maintenance and genetic counseling/testing that have been incorporated into the navigator‐led community education sessions. We also implemented a universal genetic risk assessment tool and automated text message reminders for repeat mammograms into our mammography navigation workflow. Through the ACE‐ITS program implementation, we have collaboratively conducted 22 educational sessions and navigated 585 women to mammography screening over the 2020–2021 calendar years. From January to December 2021, we have also conducted genetic risk assessment on 292 women, of whom 7 have received genetic counseling/testing.
Conclusions
We describe a multilevel, community‐engaged quality improvement program designed to reduce screening‐related disparities in Black and Hispanic women in our catchment area.
This report describes the development and pilot implementation of a community‐engaged quality improvement program to improve mammography maintenance and rates of genetic risk assessment, counseling, and testing in Black and Hispanic women.
PFAS mixtures in the environment are common and identifying PFAS constituents, bioaccumulation, and biological impacts of mixtures remains a challenge. Here, an omics-based ecosurveillance approach ...was taken to investigate the impacts of PFAS pollution in freshwater turtles (Emydura macquariimacquarii). Four turtles were collected from an impacted waterway downstream from an industrial source of PFAS contamination in Queensland, Australia and analysed for 49 different PFAS. One turtle was collected from a suitable control site. PFAS concentrations were quantified in turtle serum using an established targeted methodology. The serum PFAS concentration was ten-fold greater at the impacted site (Σ49 PFAS 1933 ± 481 ng/mL) relative to the control sample (Σ49 PFAS 140 ng/mL). Perfluorooctane sulfonate (PFOS; 889 ± 56 ng/mL) was 235 times higher in turtle serum than in the water that they were collected from (ΣPFAS 32.0 μg/L). Perfluorobutane sulfonamide (FBSA; 403 ± 83 ng/mL) and perfluorohexane sulfonamide (FHxSA; 550 ± 330 ng/mL) were also reported at substantial concentrations in the serum of impacted turtles. Biochemical profiles were analysed using a mixture of liquid chromatography triple quadrupole (QqQ) and quadrupole time-of-flight (QToF) mass spectrometry methodologies. These profiles demonstrated a positive correlation in the impacted turtles exposed to elevated PFAS with an enhanced purine metabolism, glycerophosphocholines and an innate immune response, which suggest an inflammation response, metabolic preservation and re-routing of central carbon metabolites. Conversely, lipid transport and binding activity were negatively correlated. Using these preliminary data, we were able to demonstrate the negative metabolic impact from PFAS mixtures on turtle metabolic health. With further research on a larger turtle cohort, omics-based data will contribute towards linking adverse outcome pathways for turtle populations exposed to PFAS mixtures. Moreover, expanding the use of ecosurveillance tools will inform mechanistic toxicological data for risk assessment and regulatory applications.
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•First ecosurveillance assessment of PFAS mixtures on freshwater turtles.•First report of FBSA and FHxSA in Australian freshwater turtles.•Bioaccumulation of PFOS in turtle serum 235 times higher than water concentrations.•Positive PFAS correlation with purine/lipid metabolism related to immune responses.•Negative PFAS correlation with lipid transport and binding activity.
Per and Polyfluoroalkyl Substances (PFAS) are a diverse group of man-made chemicals with a range of industrial applications and which are widespread in the environment. They are structurally diverse ...but comprise a common chemical feature of at least one (though usually more) perfluorocarbon moiety (–CnF2n–) attached to a functional group such as a carboxylic or sulphonic acid. The strength of the Carbon-Fluorine bond means the compounds do not break down easily and can thus bioaccumulate. PFAS are of high concern to regulators and the public due to their potential toxicity and high persistence. At high exposure levels, PFAS have been implicated in a range of harmful effects on human and environmental health, particularly problems in/with development, cholesterol and endocrine disruption, immune system function, and oncogenesis. However, most environmental toxicology studies use far higher levels of PFAS than are generally found in the environment. Additionally, since the type of exposure, the PFAS used, and the organisms tested all vary between studies, so do the results. Traditional ecotoxicology studies may thus not identify PFAS effects at environmentally relevant exposures. Here we conduct a review of omics-based PFAS exposure studies using laboratory ecotoxicological methodologies and environmentally relevant exposure levels and show that common biochemical response pathways are identified in multiple studies. A major pathway identified was the pentose phosphate shunt pathway. Such molecular markers of sublethal PFAS exposure will greatly benefit accurate and effective risk assessments to ensure that new PFAS regulations can consider the full effects of PFAS exposure on environmental and human health receptors.
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•Effects of PFAS at multiple omic levels reviewed.•Common biochemical responses to exposure identified.•New insights into PFAS mechanistic toxicity generated.•Pentose phosphate shunt identified as a major pathway affected.•Results are useful for future PFAS regulation.
Apicomplexan infections, such as giardiasis and cryptosporidiosis, negatively impact a considerable proportion of human and commercial livestock populations. Despite this, the molecular mechanisms of ...disease, particularly the effect on the body beyond the gastrointestinal tract, are still poorly understood. To highlight host-parasite-microbiome biochemical interactions, we utilised integrated metabolomics-16S rRNA genomics and metabolomics-proteomics approaches in a C57BL/6J mouse model of giardiasis and compared these to
and uropathogenic
(UPEC) infections. Comprehensive samples (faeces, blood, liver, and luminal contents from duodenum, jejunum, ileum, caecum and colon) were collected 10 days post infection and subjected to proteome and metabolome analysis by liquid and gas chromatography-mass spectrometry, respectively. Microbial populations in faeces and luminal washes were examined using 16S rRNA metagenomics. Proteome-metabolome analyses indicated that 12 and 16 key pathways were significantly altered in the gut and liver, respectively, during giardiasis with respect to other infections. Energy pathways including glycolysis and supporting pathways of glyoxylate and dicarboxylate metabolism, and the redox pathway of glutathione metabolism, were upregulated in small intestinal luminal contents and the liver during giardiasis. Metabolomics-16S rRNA genetics integration indicated that populations of three bacterial families-
(Up),
(Up), and
(Down)-were most significantly affected across the gut during giardiasis, causing upregulated glycolysis and short-chained fatty acid (SCFA) metabolism. In particular, the perturbed
population seemed to cause oxidative stress responses along the gut-liver axis. Overall, the systems biology approach applied in this study highlighted that the effects of host-parasite-microbiome biochemical interactions extended beyond the gut ecosystem to the gut-liver axis. These findings form the first steps in a comprehensive comparison to ascertain the major molecular and biochemical contributors of host-parasite interactions and contribute towards the development of biomarker discovery and precision health solutions for apicomplexan infections.
Per- and polyfluoroalkyl substances (PFAS) are persistent synthetic contaminants that are pervasive in the environment. Toxicity resulting from elevated PFAS concentrations in wildlife has been ...studied, yet evidence of their accumulation, developmental toxicity and maternal offloading in egg-laying species is limited. Here we show the maternal offloading of PFAS in freshwater short-necked turtles (Emydura macquarii macquarii) exposed to elevated PFAS and the resulting biological impact on oviducal eggs. Total PFAS concentrations were determined in serum from adult females and harvested oviducal eggs collected from euthanised turtles exposed to low and high levels of PFAS and compared against turtle serum and eggs collected from a suitable reference site. Multi-omics assays were utilised to explore the biochemical impact of elevated PFAS on egg albumen, yolk and eggshell using a range of metabolomics, lipidomics, and proteomics techniques. Eggshells were also screened for metals by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). Analysis of the serum collected from adult female turtles and their oviducal eggs demonstrated PFAS offloading and transference that is 1.6 and 5.3 times higher in the low and high PFAS impacted eggs, respectively, compared to maternal serum concentrations. Oviducal egg yolk comprised >90% of the bioaccumulated PFAS load. Multi-omic analysis of the dissected egg fractions illustrated PFAS impacted eggs are significantly elevated in purine metabolism metabolites, which are tied to potential biological dysfunctional processes. The yolks were significantly depleted in lipids and lipid quality tied to growth and development. The high PFAS impacted oviducal eggshells were lower in calcium, important developmental and immune response proteins, and higher in glycerophosphoethanolamines (PE) lipids and histidine metabolism metabolites that are tied to a weakened physical structure. Further investigation is needed to establish the rate of PFAS offloading and quantify the developmental impact on hatchling and hatchling success to fully demonstrate PFAS-developmental toxicity linkages.
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•Maternal PFAS offloading ~5-fold higher in eggs compared to serum•Impacted oviducal egg yolk comprised >97% of bioaccumulated PFAS.•Down-regulation of developmental and immune response proteins in impacted eggshells•Impacted eggshells: Elevated PE lipids, purine and histidine metabolism metabolites
Per- and polyfluoroalkyl substances (PFAS) are environmentally persistent and pervasive. Understanding the toxicity of PFAS to wildlife is difficult, both due to the complexity of biotic and abiotic ...perturbations in the taxa under study and the practical and ethical problems associated with studying the impacts of environmental pollutants on free living wildlife. One avenue of inquiry into the effects of environmental pollutants, such as PFAS, is assessing the impact on the host gut microbiome. Here we show the microbial composition and biochemical functional outputs from the gut microbiome of sampled faeces from euthanised and necropsied wild-caught freshwater turtles (Emydura macquarii macquarii) exposed to elevated PFAS levels. The microbial community composition was profiled by 16S rRNA gene sequencing using a Nanopore MinION and the biochemical functional outputs of the gut microbiome were profiled using a combination of targeted central carbon metabolism metabolomics using liquid chromatography coupled to a triple quadrupole mass spectrometer (LC-QqQ-MS) and untargeted metabolomics using liquid chromatography coupled to a quadrupole time of flight mass spectrometer (LC-QToF-MS). Total PFAS was measured in the turtle serum using standard methods. These preliminary data demonstrated a 60-fold PFAS increase in impacted turtles compared to the sampled aquatic environment. The microbiome community was also impacted in the PFAS exposed turtles, with the ratio of Firmicutes-to-Bacteroidetes rising from 1.4 at the reference site to 5.5 at the PFAS impacted site. This ratio increase is indicative of host stress and dysfunction of the gut microbiome that was correlated with the biochemical metabolic function data, metabolites observed that are indications of stress and inflammation in the gut microbiome. Utilising the gut microbiome of sampled faeces collected from freshwater turtles provides a non-destructive avenue for investigating the impacts of PFAS in native wildlife, and provides an avenue to explore other contaminants in higher-order taxa within the environment.
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•PFAS impacted turtle serum levels >60 times higher than in the sampled aquatic environment.•Firmicutes-to-Bacteroidetes ratios at the PFAS impacted site indicates dysfunction of the gut microbiome.•PFAS impacted turtles were more abundant in anabolic pathway metabolites tied to differences in food protein sources.•Indications of stress and inflammation in the gut microbiome of PFAS impacted turtles.
Although commonly associated with autophagosomes, LC3 can also be recruited to membranes by covalent lipidation in a variety of non-canonical contexts. These include responses to ionophores such as ...the M2 proton channel of influenza A virus. We report a subtractive CRISPR screen that identifies factors required for non-canonical LC3 lipidation. As well as the enzyme complexes directly responsible for LC3 lipidation in all contexts, we show the RALGAP complex is important for M2-induced, but not ionophore drug-induced, LC3 lipidation. In contrast, ATG4D is responsible for LC3 recycling in M2-induced and basal LC3 lipidation. Identification of a vacuolar ATPase subunit in the screen suggests a common mechanism for non-canonical LC3 recruitment. Influenza-induced and ionophore drug-induced LC3 lipidation lead to association of the vacuolar ATPase and ATG16L1 and can be antagonized by Salmonella SopF. LC3 recruitment to erroneously neutral compartments may therefore represent a response to damage caused by diverse invasive pathogens.
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•Subtractive CRISPR screen identifies genes involved in non-canonical LC3 lipidation•v-ATPase regulates LC3 lipidation at erroneously neutral compartments•RALGAP complex involved in M2 proton channel induced LC3 lipidation•ATG4D is responsible for LC3 recycling in M2-induced and basal LC3 lipidation
Ulferts et al. identify v-ATPase as the central regulator of ATG16L1 WD40 domain-dependent of LC3 lipidation. This lipidation can be prevented by Salmonella SopF and counteracted by ATG4D, the predominant ATG4 paralog responsible for LC3 delipidation. The RalGAP complex affects influenza virus M2-induced LC3 lipidation by affecting M2 trafficking.
Cryptosporidiosis is a major human health concern globally. Despite well-established methods, misdiagnosis remains common. Our understanding of the cryptosporidiosis biochemical mechanism remains ...limited, compounding the difficulty of clinical diagnosis. Here, we used a systems biology approach to investigate the underlying biochemical interactions in C57BL/6J mice infected with Cryptosporidium parvum. Faecal samples were collected daily following infection. Blood, liver tissues and luminal contents were collected 10 days post infection. High-resolution liquid chromatography and low-resolution gas chromatography coupled with mass spectrometry were used to analyse the proteomes and metabolomes of these samples. Faeces and luminal contents were additionally subjected to 16S rRNA gene sequencing. Univariate and multivariate statistical analysis of the acquired data illustrated altered host and microbial energy pathways during infection. Glycolysis/citrate cycle metabolites were depleted, while short-chain fatty acids and D-amino acids accumulated. An increased abundance of bacteria associated with a stressed gut environment was seen. Host proteins involved in energy pathways and Lactobacillus glyceraldehyde-3-phosphate dehydrogenase were upregulated during cryptosporidiosis. Liver oxalate also increased during infection. Microbiome–parasite relationships were observed to be more influential than the host–parasite association in mediating major biochemical changes in the mouse gut during cryptosporidiosis. Defining this parasite–microbiome interaction is the first step towards building a comprehensive cryptosporidiosis model towards biomarker discovery, and rapid and accurate diagnostics.
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