Systemic vaccination induces CD8+ T cells and remodels the tumor microenvironment.

Therapeutic cancer vaccines are designed to increase tumor-specific T cell immunity. However, suppressive mechanisms within the tumor microenvironment (TME) may limit T cell function. Here, we assessed how the route of vaccination alters intratumoral myeloid cells. Using a self-assembling nanoparticle vaccine that links tumor antigen peptides to a Toll-like receptor 7/8 agonist (SNP-7/8a), we treated tumor-bearing mice subcutaneously (SNP-SC) or intravenously (SNP-IV). Both routes generated antigen-specific CD8+ T cells that infiltrated tumors. However, only SNP-IV mediated tumor regression, dependent on systemic type I interferon at the time of boost. Single-cell RNA-sequencing revealed that intratumoral monocytes expressing an immunoregulatory gene signature (Chil3, Anxa2, Wfdc17) were reduced after SNP-IV boost. In humans, the Chil3+ monocyte gene signature is enriched in CD16- monocytes and associated with worse outcomes. Our results show that the generation of tumor-specific CD8+ T cells combined with remodeling of the TME is a promising approach for tumor immunotherapy.

Intravenous nanoparticle vaccination generates stem-like TCF1+ neoantigen-specific CD8+ T cells.

Personalized cancer vaccines are a promising approach for inducing T cell immunity to tumor neoantigens. Using a self-assembling nanoparticle vaccine that links neoantigen peptides to a Toll-like receptor 7/8 agonist (SNP-7/8a), we show how the route and dose alter the magnitude and quality of neoantigen-specific CD8+ T cells. Intravenous vaccination (SNP-IV) induced a higher proportion of TCF1+PD-1+CD8+ T cells as compared to subcutaneous immunization (SNP-SC). Single-cell RNA sequencing showed that SNP-IV induced stem-like genes (Tcf7, Slamf6, Xcl1) whereas SNP-SC enriched for effector genes (Gzmb, Klrg1, Cx3cr1). Stem-like cells generated by SNP-IV proliferated and differentiated into effector cells upon checkpoint blockade, leading to superior antitumor response as compared to SNP-SC in a therapeutic model. The duration of antigen presentation by dendritic cells controlled the magnitude and quality of CD8+ T cells. These data demonstrate how to optimize antitumor immunity by modulating vaccine parameters for specific generation of effector or stem-like CD8+ T cells.

mTORC1 Controls Phase Separation and the Biophysical Properties of the Cytoplasm by Tuning Crowding.

Macromolecular crowding has a profound impact on reaction rates and the physical properties of the cell interior, but the mechanisms that regulate crowding are poorly understood. We developed genetically encoded multimeric nanoparticles (GEMs) to dissect these mechanisms. GEMs are homomultimeric scaffolds fused to a fluorescent protein that self-assemble into bright, stable particles of defined size and shape. By combining tracking of GEMs with genetic and pharmacological approaches, we discovered that the mTORC1 pathway can modulate the effective diffusion coefficient of particles ≥20 nm in diameter more than 2-fold by tuning ribosome concentration, without any discernable effect on the motion of molecules ≤5 nm. This change in ribosome concentration affected phase separation both in vitro and in vivo. Together, these results establish a role for mTORC1 in controlling both the mesoscale biophysical properties of the cytoplasm and biomolecular condensation.

The prevalence of genital injuries in post-pubertal females presenting for forensic examination after reported sexual violence: a systematic review.

BACKGROUND: Sexual violence is a prevalent issue in contemporary society requiring a robust forensic healthcare response. It is critically important that forensic examiners put clinical examination findings into an appropriate evidence-based context. The presence of genital injuries has been shown to increase the likelihood of successful criminal prosecution and report the crime. However, the reported rates of genital injury vary widely in published studies. AIMS AND OBJECTIVES: We aim to critically evaluate and synthesize existing literature on the prevalence of genital injuries in post-pubertal females, examined following sexual violence, with a view to describing the prevalence and characteristics of genital injuries as well as the range of forensic practices employed. METHODS: Three online databases (PubMed, Embase, and Scopus) were systematically searched with key terms. RESULTS: Of the 1224 studies screened, 141 full-text publications met the inclusion criteria. Reported injury prevalence rates varied widely. Details pertaining to forensic examinations included in each study, such as grade of the examiner, type of examination, location of examination, and time interval from assault to examination also varied widely. Injury prevalence was highest in studies where enhanced visualization techniques were utilized. CONCLUSIONS: This systematic review demonstrates that there is no universally agreed standard for documenting genital injuries in cases of sexual violence and highlights the need for standardized approaches and guidelines for assessing, documenting, and reporting these injuries. The review provides robust evidence to support a call for establishing consistent context, terminology, classification systems, and data collection methods to improve the comparability and reliability of future research findings.

Differences in trauma care between district and regional hospitals and impact of a trauma intake form with decision support prompts in Ghana: A stepped-wedge cluster randomized trial.

BACKGROUND: We sought to determine the achievement of key performance indicators (KPIs) of initial trauma care at district (first-level) and regional (second-level) hospitals in Ghana and to assess the effectiveness of a standardized trauma intake form (TIF) to improve care. METHODS: A stepped-wedge cluster randomized trial was performed with direct observations of trauma management before and after introducing the TIF at emergency units of eight hospitals for 17.5 months. Differences in KPIs were assessed using multivariable logistic regression and generalized linear mixed regression. RESULTS: Management of 4077 patients was observed; 30% at regional and 70% at district hospitals. Eight of 20 KPIs were performed significantly more often at regional hospitals. TIF improved care at both levels. Fourteen KPIs improved significantly at district and eight KPIs improved significantly at regional hospitals. After TIF, regional hospitals still performed better with 18 KPIs being performed significantly more often than district hospitals. After TIF, all KPIs were performed in >90% of patients at regional hospitals. Examples of KPIs for which regional performed better than district hospitals after TIF included: assessment for oxygen saturation (83% vs. 98%) and evaluation for intra-abdominal bleeding (82% vs. 99%, all p < 0.001). Mortality decreased among seriously injured patients (injury severity score ≥9) at both district (15% before vs. 8% after, p = 0.04) and regional (23% vs. 7%, p = 0.004) hospitals. CONCLUSIONS: TIF improved care and lowered mortality at both hospital levels, but KPIs remained lower at district hospitals. Further measures are needed to improve initial trauma care at this level. CLINICAL TRIALS REGISTRATION: Clinicaltrials.gov (NCT04547192).

The Environmental Influences on Child Health Outcomes (ECHO)-Wide Cohort.

The Environmental Influences on Child Health Outcomes (ECHO)-Wide Cohort Study (EWC), a collaborative research design comprising 69 cohorts in 31 consortia, was funded by the National Institutes of Health (NIH) in 2016 to improve children's health in the United States. The EWC harmonizes extant data and collects new data using a standardized protocol, the ECHO-Wide Cohort Data Collection Protocol (EWCP). EWCP visits occur at least once per life stage, but the frequency and timing of the visits vary across cohorts. As of March 4, 2022, the EWC cohorts contributed data from 60,553 children and consented 29,622 children for new EWCP data and biospecimen collection. The median (interquartile range) age of EWCP-enrolled children was 7.5 years (3.7-11.1). Surveys, interviews, standardized examinations, laboratory analyses, and medical record abstraction are used to obtain information in 5 main outcome areas: pre-, peri-, and postnatal outcomes; neurodevelopment; obesity; airways; and positive health. Exposures include factors at the level of place (e.g., air pollution, neighborhood socioeconomic status), family (e.g., parental mental health), and individuals (e.g., diet, genomics).

Resilience in adolescence during the COVID-19 crisis in Canada.

BACKGROUND: The COVID-19 pandemic constitutes a social crisis that will have long-term health consequences for much of the global population, especially for adolescents. Adolescents are triply affected as they: 1) are experiencing its immediate, direct effects, 2) will carry forward health habits they develop now into adulthood, and 3) as future parents, will shape the early life health of the next generation. It is therefore imperative to assess how the pandemic is influencing adolescent wellbeing, identify sources of resilience, and outline strategies for attenuating its negative impacts. METHODS: We report the results of longitudinal analyses of qualitative data from 28 focus group discussions (FGDs) with 39 Canadian adolescents and of cross-sectional analyses of survey data from 482 Canadian adolescents gathered between September 2020 and August 2021. FGD participants and survey respondents reported on their: socio-demographic characteristics; mental health and wellbeing before and during the pandemic; pre- and during-pandemic health behaviours; experiences living through a crisis; current perceptions of their school, work, social, media, and governmental environments; and ideas about pandemic coping and mutual aid. We plotted themes emerging from FGDs along a pandemic timeline, noting socio-demographic variations. Following assessment for internal reliability and dimension reduction, quantitative health/wellbeing indicators were analyzed as functions of composite socio-demographic, health-behavioural, and health-environmental indicators. RESULTS: Our mixed methods analyses indicate that adolescents faced considerable mental and physical health challenges due to the pandemic, and were generally in poorer health than expected in non-crisis times. Nevertheless, some participants showed significantly better outcomes than others, specifically those who: got more exercise; slept better; were food secure; had clearer routines; spent more time in nature, deep in-person social relationships, and leisure; and spent less time on social media. CONCLUSIONS: Support for youth during times of crisis is essential to future population health because adolescence is a period in the life course which shapes the health behaviours, socio-economic capacities, and neurophysiology of these future parents/carers and leaders. Efforts to promote resilience in adolescents should leverage the factors identified above: helping them find structure and senses of purpose through strong social connections, well-supported work and leisure environments, and opportunities to engage with nature.

Influence of lactation stage on heat production and macronutrient oxidation in dairy cows during a 24-hour fasting period.

Understanding nutrient utilization and partitioning is essential for advancing the efficiency of dairy cattle. Our objective was to determine if dairy cows exposed to a 24-h fasting period differ in heat production (HP) and macronutrient oxidation at different stages of lactation. Twelve primiparous, lactating German Holstein dairy cows were used in a longitudinal study design spanning from 2013 to 2014. Dairy cows were housed in respiration chambers during 3 stages of the lactation cycle: early (mean ± SD; 28.8 ± 6.42 d), mid- (89.4 ± 4.52 d), and late (293 ± 7.76 d) lactation. Individual CO2, O2, and CH4 gas exchanges were measured every 6 min for two 24-h periods, an ad libitum period and fasting period (RES). Blood was sampled at the start and end of the RES period. Gas measurements were used to calculate HP, net carbohydrate oxidation (COX), and net fat oxidation (FOX). Measurements were corrected with metabolic BW (kg of BW0.75; cBW). The RES period for each stage of lactation was further subdivided into the start (RESstart) and end (RESend) by averaging the first and last 2 h of the RES period. The net change was calculated as RESend - RESstart. All energy variables differed among lactation stage within the RES period except for HP/cBW. As expected, COX, COX/cBW, COX/HP, HP, and HP/cBW, were greater at the RESstart compared with RESend, whereas FOX, FOX/cBW, and FOX/HP were greater at the RESend except for FOX and FOX/cBW during mid lactation, which was only a tendency for a difference. The net change for COX, COX/cBW, HP, HP/cBW, and FOX/cBW did not differ among stages of lactation. Despite detecting a tendency for a difference among stage of lactation for FOX, pairwise analysis revealed no differences. Plasma triglyceride, urea, and nonesterified fatty acid concentrations were greater at RESend than RESstart. The net change for plasma glucose, urea, ß-hydroxybutyrate, and nonesterified fatty acid concentrations were greater in early than late lactation. Our results demonstrate that despite differences in absolute measurements of energy variables and plasma metabolites, the change in whole-body macronutrient oxidation and HP as cows' transition from a fed-like state to a starvation-like state during a 24-h fasting period is consistent throughout lactation.

Outcomes of subacromial balloon spacer implantation for irreparable rotator cuff tears: a systematic review and meta-analysis.

BACKGROUND: The management of irreparable rotator cuff tears remains a topic of considerable debate among orthopedic surgeons. Currently, there is little consensus regarding the gold-standard treatment; however, an emerging option involves the use of a biodegradable subacromial spacer. The purpose of this study, therefore, was to systematically review and synthesize the current literature reporting on the clinical outcomes following implantation of a subacromial balloon spacer (SABS) for the treatment of patients with irreparable rotator cuff tears. METHODS: A systematic review of the PubMed Central, MEDLINE, Embase, Scopus, and Cochrane Library databases from inception through December 2022 was performed. Clinical outcome studies reporting on functional and clinical outcomes, as well as postoperative complications, were included. RESULTS: A total of 127 studies were initially identified, of which 28 were deemed eligible for inclusion in our review. Of these studies, 17 reported adequate preoperative and postoperative data (mean and a measure of variance) and thus were included in the meta-analysis. Among the included studies, a total of 894 shoulders (886 patients) were included; the mean age was 67.4 years (range, 61.7-76.2 years). The average follow-up period was 30.4 months (range, 12-56 months). All postoperative patient-reported outcomes improved significantly from baseline, including the Constant score (mean difference, 33.53; P < .001), American Shoulder and Elbow Surgeons score (mean difference, 40.38; P < .001), Oxford Shoulder Score (mean difference, 12.05; P = .004), and visual analog scale pain score or Numeric Pain Rating Scale score (mean difference, -3.79; P < .001). Forward elevation (mean difference, 24°; P < .001), abduction (mean difference, 52°; P = .02), and external rotation (mean difference, 15°; P < .001) improved. Device-related complications occurred at a rate of 3.6%, the most common of which were balloon migration (1.0%) and synovitis (0.6%). Ultimately, 5% of patients required salvage reverse shoulder arthroplasty. CONCLUSION: Short-term outcomes suggest that SABS implantation can be a safe and effective treatment and appears to be associated with early improvements in postoperative pain and function. Clinical heterogeneity, use of concomitant procedures, and variations in patient selection limit our ability to conclusively interpret the available evidence. We do not yet know the potential therapeutic value of SABS implantation relative to other currently accepted treatment strategies, the length of symptomatic improvement that can be expected, or the long-term implications of SABS use on the outcomes of further salvage procedures.

Tracking the source of contaminant lead in children's blood.

Pb isotope ratios are used for apportioning the sources of Pb in the blood of children (ages 1-6) screened for high blood Pb levels (>5 µg/dL) surrounding urban areas of Kansas City, MO. We compared Pb isotope ratios measured in the child's blood with those of the most likely sources of Pb in that child's home environment. The environmental sources sampled consisted of topsoils, paints, occupational sources (e.g., oil rig workers' uniforms, mechanics' clothes), indoor air filters, dusts, and dietary sources (e.g., spices). Blood lead levels (BLL) ranged from 2.9 to 12.7 µg/dL in children from the five homes participating in this study. Measurements of 206Pb/204Pb, 207Pb/204Pb and 208Pb/204Pb isotope ratios were made by multi-collector ICP-MS. Comparison of the Pb isotope ratios in home environment samples versus those in the child's blood in each home allowed the identification of possible sources of a child's Pb exposure in three homes. In five homes investigated, children's blood Pb levels were most likely to be derived from dusts inside, and topsoil outside, the homes, or a mixture thereof. In one case, blood Pb was derived from turmeric spice and, in another, the Pb was derived from paint. It is not always possible to directly link high BLLs to the environmental sources collected when Pb isotope ratios of the environmental samples did not overlap with those of the blood.

Mycobactericidal Effects of Different Regimens Measured by Molecular Bacterial Load Assay among People Treated for Multidrug-Resistant Tuberculosis in Tanzania.

Rifampin or multidrug-resistant tuberculosis (RR/MDR-TB) treatment has largely transitioned to regimens free of the injectable aminoglycoside component, despite the drug class' purported bactericidal activity early in treatment. We tested whether Mycobacterium tuberculosis killing rates measured by tuberculosis molecular bacterial load assay (TB-MBLA) in sputa correlate with composition of the RR/MDR-TB regimen. Serial sputa were collected from patients with RR/MDR- and drug-sensitive TB at days 0, 3, 7, and 14, and then monthly for 4 months of anti-TB treatment. TB-MBLA was used to quantify viable M. tuberculosis 16S rRNA in sputum for estimation of colony forming units per ml (eCFU/ml). M. tuberculosis killing rates were compared among regimens using nonlinear-mixed-effects modeling of repeated measures. Thirty-seven patients produced 296 serial sputa and received treatment as follows: 13 patients received an injectable bedaquiline-free reference regimen, 9 received an injectable bedaquiline-containing regimen, 8 received an all-oral bedaquiline-based regimen, and 7 patients were treated for drug-sensitive TB with conventional rifampin/isoniazid/pyrazinamide/ethambutol (RHZE). Compared to the adjusted M. tuberculosis killing of -0.17 (95% confidence interval [CI] -0.23 to -0.12) for the injectable bedaquiline-free reference regimen, the killing rates were -0.62 (95% CI -1.05 to -0.20) log10 eCFU/ml for the injectable bedaquiline-containing regimen (P = 0.019), -0.35 (95% CI -0.65 to -0.13) log10 eCFU/ml for the all-oral bedaquiline-based regimen (P = 0.054), and -0.29 (95% CI -0.78 to +0.22) log10 eCFU/ml for the RHZE regimen (P = 0.332). Thus, M. tuberculosis killing rates from sputa were higher among patients who received bedaquiline but were further improved with the addition of an injectable aminoglycoside.

TB or not TB? Definitive determination of species within the Mycobacterium tuberculosis complex in unprocessed sputum from adults with presumed multidrug-resistant tuberculosis.

OBJECTIVES: Differences among Mycobacterium tuberculosis complex (MTC) species may predict drug resistance or treatment success. Thus, we optimised and deployed the genotype MTBC assay (gMTBC) to identify MTC to the species level, and then performed comparative genotypic drug-susceptibility testing to anti-tuberculosis drugs from direct sputum of patients with presumed multidrug-resistant tuberculosis (MDR-TB) by the MTBDRplus/sl reference method. METHODS: Patients with positive Xpert® MTB/RIF (Xpert) results were consented to provide early-morning-sputum for testing by the gMTBC and the reference MTBDRplus/sl. Chi-square or Fisher's exact test compared proportions. Modified Poisson regression modelled detection of MTC by gMTBC. RESULTS: Among 73 patients, 53 (73%) were male and had a mean age of 43 (95% CI; 40-45) years. In total, 34 (47%), 36 (49%) and 38 (55%) had positive gMTBC, culture and MTBDR respectively. Forty patients (55%) had low quantity MTC by Xpert, including 31 (78%) with a negative culture. gMTBC was more likely to be positive in patients with chest cavity 4.18 (1.31-13.32, P = 0.016), high-quantity MTC by Xpert 3.03 (1.35-6.82, P = 0.007) and sputum smear positivity 1.93 (1.19-3.14, P = 0.008). The accuracy of gMTBC in detecting MTC was 95% (95% CI; 86-98; κ = 0.89) compared to MTBDRplus/sl. All M. tuberculosis/canettii identified by gMTB were susceptible to fluoroquinolone and aminoglycosides/capreomycin. CONCLUSIONS: The concordance between the gMTBC assay and MTBDRplus/sl in detecting MTC was high but lagged behind the yield of Xpert MTB/RIF. All M. tuberculosis/canettii were susceptible to fluoroquinolones, a core drug in MDR-TB treatment regimens.

Differences in net fat oxidation, heat production, and liver mitochondrial DNA copy numbers between high and low feed-efficient dairy cows.

Improving feed utilization efficiency in dairy cattle could have positive economic and environmental effects that would support the sustainability of the dairy industry. Identifying key differences in metabolism between high and low feed-efficient animals is vital to enhancing feed conversion efficiency. Therefore, our objectives were (1) to determine whether cows grouped by either high or low feed efficiency have measurable differences in net fat and carbohydrate metabolism that account for differences in heat production (HP), and if so, whether these differences also exists under conditions of feed withdrawal when the effect of feeding on HP is minimized, and (2) to determine whether the abundance of mitochondria in the liver can be related to the high or low feed-efficient groups. Ten dairy cows from a herd of 15 (parity = 2) were retrospectively grouped into either a high (H) or a low (L) feed-efficient group (n = 5 per group) based on weekly energy-corrected milk (ECM) divided by dry mater intake (DMI) from wk 4 through 30 of lactation. Livers were biopsied at wk -4, 2, and 12, and blood was sampled weekly from wk -3 to 12 relative to parturition. Blood was subset to be analyzed for the transition period (wk -3 to 3) and from wk 4 to 12. In wk 5.70 ± 0.82 (mean ± SD) postpartum (PP), cows spent 2 d in respiration chambers (RC), in which CO2, O2, and CH4 gases were measured every 6 min for 24 h. Fatty acid oxidation (FOX), carbohydrate oxidation (COX), metabolic respiratory quotient (RQ), and HP were calculated from gas measurements for 23 h. Cows were fed ad libitum (AD-LIB) on d 1 and had feed withdrawn (RES, restricted diet) on d 2. Additional blood samples were taken at the end of the AD-LIB and RES feeding periods in the RC. During wk 4 to 30 PP, H had greater DMI/kg of metabolic body weight (BW0.75), ECM per kilogram of BW0.75 yield, and ECM/DMI ratio, compared with L, but a lower body condition score between wk 4 and 12 PP. In the RC period, we detected no differences in BW, DMI, or milk yield between groups. We also detected no significant group or group by feeding period interactions for plasma metabolites except for Revised Quantitative Insulin Sensitivity Check Index, which tended to have a group by feeding period interaction. The H group had lower HP and HP per kilogram of BW0.75 compared with L. Additionally, H had lower FOX and FOX per kilogram of BW0.75 compared with L during the AD-LIB period. Methane, CH4 per kilogram of BW0.75, and CH4 per kilogram of milk yield were lower in H compared with L, but, when adjusted for DMI, CH4/DMI did not differ between groups, nor did HP/DMI. Relative mitochondrial DNA copy numbers in the liver were lower in the L than in the H group. These results suggest that lower feed efficiency in dairy cows may result from fewer mitochondria per liver cell as well as a greater whole-body HP, which likely partially results from higher net fat oxidation.

Mapping the Current and Future Noncommunicable Disease Burden in Kenya by Human Immunodeficiency Virus Status: A Modeling Study.

BACKGROUND: The noncommunicable disease (NCD) burden in Kenya is not well characterized, despite estimates needed to identify future health priorities. We aimed to quantify current and future NCD burden in Kenya by human immunodeficiency virus (HIV) status. METHODS: Original systematic reviews and meta-analyses of prevalence/incidence of cardiovascular disease (CVD), chronic kidney disease, depression, diabetes, high total cholesterol, hypertension, human papillomavirus infection, and related precancerous stages in Kenya were carried out. An individual-based model was developed, simulating births, deaths, HIV disease and treatment, aforementioned NCDs, and cancers. The model was parameterized using systematic reviews and epidemiological national and regional surveillance data. NCD burden was quantified for 2018-2035 by HIV status among adults. RESULTS: Systematic reviews identified prevalence/incidence data for each NCD except ischemic heart disease. The model estimates that 51% of Kenyan adults currently suffer from ≥1 NCD, with a higher burden in people living with HIV (PLWH) compared to persons not living with HIV (62% vs 51%), driven by their higher age profile and partly by HIV-related risk for NCDs. Hypertension and high total cholesterol are the main NCD drivers (adult prevalence of 20.5% [5.3 million] and 9.0% [2.3 million]), with CVD and cancers the main causes of death. The burden is projected to increase by 2035 (56% in persons not living with HIV; 71% in PLWH), with population growth doubling the number of people needing services (15.4 million to 28.1 million) by 2035. CONCLUSIONS: NCD services will need to be expanded in Kenya. Guidelines in Kenya already support provision of these among both the general and populations living with HIV; however, coverage remains low.

The anti-ageing effects of a natural peptide discovered by artificial intelligence.

OBJECTIVE: As skin ages, impaired extracellular matrix (ECM) protein synthesis and increased action of degradative enzymes manifest as atrophy, wrinkling and laxity. There is mounting evidence for the functional role of exogenous peptides across many areas, including in offsetting the effects of cutaneous ageing. Here, using an artificial intelligence (AI) approach, we identified peptide RTE62G (pep_RTE62G), a naturally occurring, unmodified peptide with ECM stimulatory properties. The AI-predicted anti-ageing properties of pep_RTE62G were then validated through in vitro, ex vivo and proof of concept clinical testing. METHODS: A deep learning approach was applied to unlock pep_RTE62G from a plant source, Pisum sativum (pea). Cell culture assays of human dermal fibroblasts (HDFs) and keratinocytes (HaCaTs) were subsequently used to evaluate the in vitro effect of pep_RTE62G. Distinct activities such as cell proliferation and ECM protein production properties were determined by ELISA assays. Cell migration was assessed using a wound healing assay, while ECM protein synthesis and gene expression were analysed, respectively, by immunofluorescence microscopy and PCR. Immunohistochemistry of human skin explants was employed to further investigate the induction of ECM proteins by pep_RTE62G ex vivo. Finally, the clinical effect of pep_RTE626 was evaluated in a proof of concept 28-day pilot study. RESULTS: In vitro testing confirmed that pep_RTE62G is an effective multi-functional anti-ageing ingredient. In HaCaTs, pep_RTE62G treatment significantly increases both cellular proliferation and migration. Similarly, in HDFs, pep_RTE62G consistently induced the neosynthesis of ECM protein elastin and collagen, effects that are upheld in human skin explants. Lastly, in our proof of concept clinical study, application of pep_RTE626 over 28 days demonstrated anti-wrinkle and collagen stimulatory potential. CONCLUSION: pep_RTE62G represents a natural, unmodified peptide with AI-predicted and experimentally validated anti-ageing properties. Our results affirm the utility of AI in the discovery of novel, functional topical ingredients.

OBJECTIF: À mesure que la peau vieillit, une altération de la synthèse des protéines de la matrice extracellulaire (ECM) et une action accrue des enzymes dégradantes se manifestent par une atrophie, des rides et un laxisme. Il existe de plus en plus de preuves du rôle fonctionnel des peptides exogènes dans de nombreux domaines, y compris pour compenser les effets du vieillissement cutané. Ici, en utilisant une approche d'intelligence artificielle (AI), nous avons identifié le peptide RTE62G (pep_RTE62G), un peptide naturel non modifié avec des propriétés de stimulation ECM. Les propriétés anti-âge prédites par l'IA de pep_RTE62G ont ensuite été validées par des tests cliniques in vitro, ex vivo et de validation de principe. LES MÉTHODES: Une approche d'apprentissage en profondeur a été appliquée pour déverrouiller pep_RTE62G à partir d'une source végétale, Pisum sativum (pois). Des tests de culture cellulaire de fibroblastes dermiques humains (HDF) et de kératinocytes (HaCaTs) ont ensuite été utilisés pour évaluer l'effet in vitro de pep_RTE62G. Des activités distinctes telles que la prolifération cellulaire et les propriétés de production de protéines ECM ont été déterminées par des tests ELISA. La migration cellulaire a été évaluée à l'aide d'un test de cicatrisation des plaies, tandis que la synthèse des protéines ECM et l'expression des gènes ont été analysées, respectivement, par microscopie à immunofluorescence et PCR. L'immunohistochimie des explants de peau humaine a été utilisée pour approfondir l'induction des protéines ECM par pep_RTE62G ex vivo. Enfin, l'effet clinique de pep_RTE626 a été évalué dans une étude pilote de 28 jours de validation de principe. RÉSULTATS: Les tests in vitro ont confirmé que pep_RTE62G est un ingrédient anti-âge multifonctionnel efficace. Dans HaCaTs, le traitement pep_RTE62G augmente de manière significative à la fois la prolifération et la migration cellulaire. De même, dans les HDF, pep_RTE62G a induit de manière cohérente la néosynthèse de la protéine ECM élastine et collagène, effets qui sont maintenus dans les explants de peau humaine. Enfin, dans notre étude clinique de preuve de concept, l'application de pep_RTE626 sur 28 jours a démontré un potentiel stimulant anti-rides et collagène. CONCLUSION: pep_RTE62G représente un peptide naturel, non modifié avec des propriétés anti-âge prédites par l'IA et validées expérimentalement. Nos résultats confirment l'utilité de l'IA dans la découverte de nouveaux ingrédients topiques fonctionnels.

Cochlear compound action potentials from high-level tone bursts originate from wide cochlear regions that are offset toward the most sensitive cochlear region.

Little is known about the spatial origins of auditory nerve (AN) compound action potentials (CAPs) evoked by moderate to intense sounds. We studied the spatial origins of AN CAPs evoked by 2- to 16-kHz tone bursts at several sound levels by slowly injecting kainic acid solution into the cochlear apex of anesthetized guinea pigs. As the solution flowed from apex to base, it sequentially reduced CAP responses from low- to high-frequency cochlear regions. The times at which CAPs were reduced, combined with the cochlear location traversed by the solution at that time, showed the cochlear origin of the removed CAP component. For low-level tone bursts, the CAP origin along the cochlea was centered at the characteristic frequency (CF). As sound level increased, the CAP center shifted basally for low-frequency tone bursts but apically for high-frequency tone bursts. The apical shift was surprising because it is opposite the shift expected from AN tuning curve and basilar membrane motion asymmetries. For almost all high-level tone bursts, CAP spatial origins extended over 2 octaves along the cochlea. Surprisingly, CAPs evoked by high-level low-frequency (including 2 kHz) tone bursts showed little CAP contribution from CF regions ≤ 2 kHz. Our results can be mostly explained by spectral splatter from the tone-burst rise times, excitation in AN tuning-curve "tails," and asynchronous AN responses to high-level energy ≤ 2 kHz. This is the first time CAP origins have been identified by a spatially specific technique. Our results show the need for revising the interpretation of the cochlear origins of high-level CAPs-ABR wave 1. NEW & NOTEWORTHY Cochlear compound action potentials (CAPs) and auditory brain stem responses (ABRs) are routinely used in laboratories and clinics. They are typically interpreted as arising from the cochlear region tuned to the stimulus frequency. However, as sound level is increased, the cochlear origins of CAPs from tone bursts of all frequencies become very wide and their centers shift toward the most sensitive cochlear region. The standard interpretation of CAPs and ABRs from moderate to intense stimuli needs revision.

Candidaemia and a risk predictive model for overall mortality: a prospective multicentre study.

BACKGROUND: Candidaemia is associated with high mortality. Variables associated with mortality have been published previously, but not developed into a risk predictive model for mortality. We sought to describe the current epidemiology of candidaemia in Australia, analyse predictors of 30-day all-cause mortality, and develop and validate a mortality risk predictive model. METHODS: Adults with candidaemia were studied prospectively over 12 months at eight institutions. Clinical and laboratory variables at time of blood culture-positivity were subject to multivariate analysis for association with 30-day all-cause mortality. A predictive score for mortality was examined by area under receiver operator characteristic curves and a historical data set was used for validation. RESULTS: The median age of 133 patients with candidaemia was 62 years; 76 (57%) were male and 57 (43%) were female. Co-morbidities included underlying haematologic malignancy (n = 20; 15%), and solid organ malignancy in (n = 25; 19%); 55 (41%) were in an intensive care unit (ICU). Non-albicans Candida spp. accounted for 61% of cases (81/133). All-cause 30-day mortality was 31%. A gastrointestinal or unknown source was associated with higher overall mortality than an intravascular or urologic source (p < 0.01). A risk predictive score based on age > 65 years, ICU admission, chronic organ dysfunction, preceding surgery within 30 days, haematological malignancy, source of candidaemia and antibiotic therapy for ≥10 days stratified patients into < 20% or ≥ 20% predicted mortality. The model retained accuracy when validated against a historical dataset (n = 741). CONCLUSIONS: Mortality in patients with candidaemia remains high. A simple mortality risk predictive score stratifying patients with candidaemia into < 20% and ≥ 20% 30-day mortality is presented. This model uses information available at time of candidaemia diagnosis is easy to incorporate into decision support systems. Further validation of this model is warranted.

The impact of providing blood to the scene of an accident on transfusion laboratory practice.

BACKGROUND: Haemorrhage is the leading cause of mortality during trauma. In 2012, London's Air Ambulance introduced Blood on Board (BOB), transfusing group O red cells (RBC) to trauma patients at the scene. OBJECTIVES: This study assessed the impact of BOB on the number of mixed field samples received by the laboratory, the number of group O RBC transfused to non-group O patients and the ratio of RBC to fresh frozen plasma (FFP) transfused in the initial 24 h. METHODS: Three major trauma centres collected data on patients for whom the major haemorrhage protocol was activated between August 2008 and February 2012 pre-BOB and March 2012 and December 2013 post-BOB. RESULTS: A total of 233 trauma patients were identified pre-BOB and 119 post-BOB. There was no significant difference in the percentage of group O units transfused to non-group O patients (75 vs 82%, P = 0·21) or the RBC : FFP ratio (pre-BOB mean 1·6 [interquartile range (IQR) 1·0-2·0]; post-BOB mean 1·7 [IQR 1·1-2·2], P = 0·24). There was no significant difference in the percentage of mixed field samples received (23% vs 27%, P = 0·3). CONCLUSION: The introduction of BOB did not change the proportion of group O RBC transfused or the RBC : FFP ratio; however, the proportion of acceptable samples decreased. This is largely due to an increase in blood samples not received from the post-BOB cohort, which we believe is probably due to patients who died at the scene. We have introduced robust systems to indicate reasons for not obtaining samples.

Point Prevalence of Adult Intestinal Failure in Republic Of Ireland.

Parenteral Nutrition (PN) is a life-saving treatment used for patients with Intestinal Failure (IF). PN is complex and demands highly specialised care to avoid serious complications in the home setting. All tertiary centres in the Republic of Ireland (ROI) were contacted to assess the prevalence of IF requiring PN and complications, over a one year period. Sixty-seven patients were treated across 15 centres: a period prevalence of 14.6 and 9.6 patients per million for long-term PN and home PN respectively. Three-quarters of patients experienced at least one major complication with 18% mortality rate over the study period. There were 2.86 admissions per HPN patient, each lasting mean 13.4 days. One-third experienced catheter-related infections. There was a reduced length of stay during emergency re-admissions in high volume centres (mean 31 v 43 days, p=0.17). The establishment of a National Centre for IF/HPN in ROI is integral to reducing PN-associated complications.

Transvaginal Sonography: perception and attitude of Nigerian women.

BACKGROUND: To assess the attitude to and perception of transvaginal sonography (TVS) among Nigerian women of mixed educational status in order to ascertain factors that may prevent them from submitting to TVS when recommended. METHODS: A Cross-sectional survey was adopted for the study. In all, one missionary, one government and eight private hospitals were enlisted. The instruments for data collection were visual analogue scale (VAS), to ascertain patients' pain/discomfort experience, and a researcher-developed semi-structured questionnaire. The level of pain/discomfort on the VAS was categorized into four on a scale of 100. The categories were: 0-5 (no pain), 6-40 (mild pain), 41-74 (moderate pain), and 75-100 (severe pain). RESULTS: Majority (50.6%) of the respondents who attained secondary education had positive attitude to TVS. Also majority of the respondents (63.1%) preferred female sonographers. Majority of the respondents (54.1%) perceived TVS as not embarrassing, 78% did not consider it stressful, 96.9% reported that the sonographers were professional, 46.7% felt that a chaperon was needed, 98.4% reported there were enough privacy and 84.7% reported they needed prior information. Most of the respondents (82%) were willing to consent to TVS in future, 90.5% reported no pain, 8.6% reported mild pain/discomfort and 0.9% reported moderate pain. CONCLUSIONS: Majority of our respondents had positive attitude to TVS and were willing to consent to TVS in future, hence it was acceptable to them. It was however observed that acceptability increased with increasing academic status.