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Abstract The characterization of soil microbial communities at different depths is essential to understand their impact on nutrient availability, soil fertility, plant growth and stress tolerance. We analyzed the microbial community at three depths (3 cm, 12 cm, and 30 cm) in the native fruit trees Annona cherimola (cherimoya) and Pouteria lucuma (lucuma), which provide fruits in vitamins, minerals, and antioxidants. We used PacBio-HiFi, a long-read high-throughput sequencing to explore the composition, diversity and putative functionality of rhizosphere bacterial communities at different soil depths. Bacterial diversity, encompassing various phyla, families, and genera, changed with depth. Notable differences were observed in the alpha diversity indices, especially the Shannon index. Beta diversity also varied based on plant type and depth. In cherimoya soils, positive correlations with Total Organic Carbon (TOC) and Cation Exchange Capacity (CEC) were observed, but negative ones with certain cations. In lucuma soils, indices like the Shannon index exhibited negative correlations with several metals and specific soil properties. We proposed that differences between the plant rhizosphere environments may explain the variance in their microbial diversity. This study provides insights into the microbial communities present at different soil depths, highlighting the prevalence of decomposer bacteria. Further research is necessary to elucidate their specific metabolic features and overall impact on crop growth and quality.

Abstract Parkinson’s disease is increasingly prevalent. It progresses from the pre-motor stage (characterised by non-motor symptoms like REM sleep behaviour disorder), to the disabling motor stage. We need objective biomarkers for early/pre-motor disease stages to be able to intervene and slow the underlying neurodegenerative process. Here, we validate a targeted multiplexed mass spectrometry assay for blood samples from recently diagnosed motor Parkinson’s patients (n = 99), pre-motor individuals with isolated REM sleep behaviour disorder (two cohorts: n = 18 and n = 54 longitudinally), and healthy controls (n = 36). Our machine-learning model accurately identifies all Parkinson patients and classifies 79% of the pre-motor individuals up to 7 years before motor onset by analysing the expression of eight proteins—Granulin precursor, Mannan-binding-lectin-serine-peptidase-2, Endoplasmatic-reticulum-chaperone-BiP, Prostaglaindin-H2-D-isomaerase, Interceullular-adhesion-molecule-1, Complement C3, Dickkopf-WNT-signalling pathway-inhibitor-3, and Plasma-protease-C1-inhibitor. Many of these biomarkers correlate with symptom severity. This specific blood panel indicates molecular events in early stages and could help identify at-risk participants for clinical trials aimed at slowing/preventing motor Parkinson’s disease.

Abstract During the preparation of fixed prosthesis (including individual bridges and crowns) it is important to select the materials that have the best features and properties to predict a successful clinical treatment. The objective of this study was to determine if the chemical and structural characteristics could cause to increase the fracture resistance, we used four bis-acryl resins Luxatemp, Protemp, Structur and Telio. Three-points bending by Flexural test were performed in ten bars and they were carried out to compare with Anova test. In addition, the bis-acryl resins were analyzed by scanning electron microscopy, to analyze microstructure and morphology and the molecular structure were performed by Infrared Spectroscopy through Attenuated Total Reflectance. A higher flexural strength was found in Luxatemp and Structur with, no significant differences between this study groups. Regarding Protemp and Telio, these study groups showed a lower flexural strength when were compared with Luxatemp and Structur. These results corroborate SEM and ATR analysis because Luxatemp sample showed a regular size particle on the surface and chemically presents a long cross-linkage polymer chain. The presence of CO3, SiO2 and N–H groups as a fillers particle interacting with OH groups cause a higher flexural strength compared with another groups.

Fusarium verticillioides represents a major phytopathogenic threat to maize crops worldwide. In this study, we present genomic sequence data of a phytopathogen isolated from a maize stem that shows obvious signs of vascular rot. Using rigorous microbiological identification techniques, we correlated the disease symptoms observed in an affected maize region with the presence of the pathogen. Subsequently, the pathogen was cultured in a suitable fungal growth medium and extensive morphological characterization was performed. In addition, a pathogenicity test was carried out in a DCA model with three treatments and seven repetitions. De novo assembly from Illumina Novaseq 6000 sequencing yielded 456 contigs, which together constitute a 42.8 Mb genome assembly with a GC % content of 48.26. Subsequent comparative analyses were performed with other Fusarium genomes available in the NCBI database.

Antecedentes: La aplicación exclusiva de fertilizantes sintéticos u orgánicos sigue generando polémica. La evidencia muestra que su aplicación conjunta puede mejorar la nutrición de los cultivos, evitar el uso excesivo de fertilizantes sintéticos y amortiguar su efecto contaminante en el suelo. Objetivo: Evaluar el uso de dosis de fertilización orgánica y mineral sobre el crecimiento y rendimiento del maíz amarillo duro Megahíbrido 619 INIA empleando un biofertilizante líquido derivado de la fermentación de residuos de camal. Metodología: Mediante un diseño experimental de bloques completos al azar con arreglo factorial 4x2, se ensayaron cuatro dosis de fertilización química NPK y la aplicación del biofertilizante. La fertilización mineral se fraccionó en dos partes, mientras que las aplicaciones del biofertilizante fermentado de residuos de camal se realizaron vía drench durante el crecimiento vegetativo y entre las etapas de panojamiento y llenado de grano a una dosis de 50 L.ha-1 de producto. Resultados: El uso del biofertilizante líquido (K1) tuvo un impacto positivo en el crecimiento, con un efecto equiparable en la altura y área foliar de la planta al aplicar una dosis media de fertilización química (F2_K1). La dosis más baja de fertilización química en combinación con el biofertilizante (F1_K1) obtuvo un índice de cosecha estadísticamente superior (+14%) en comparación con el la fertilización completa (F3_K1). Implicaciones: Si bien las fertilizaciones más altas no produjeron rendimientos superiores, es posible que en otras condiciones y con otros híbridos de maíz sí se observendiferencias significativas. Conclusión: La aplicación del biofertilizante líquido junto con una dosis reducida de fertilización mineral permite obtener un mayor índice de cosecha y rendimientos comparables con el uso de una fertilización mineral completa en el maíz amarillo.

This perspective provides strong evidence that the aims set forth when Frontiers in Dental Medicine (FDMED) was launched in 2020, to advance the integration of dental, oral, and craniofacial research with mainstream biomedical practice, underscored the value of interprofessional research collaborations, encouraging studies, publications, and commentaries in this area ripe for continued innovation. The momentum gained toward these aims must continue to inform the public, healthcare providers, researchers, educators, and policymakers so that they can apply the knowledge gained to improve the overall health needs of all our communities.

Stem cells are critical for replenishment of cells lost to death, damage or differentiation. Drosophila testes are a key model system for elucidating mechanisms regulating stem cell maintenance and differentiation. An intriguing gene identified through such studies is the transcription factor, chronologically inappropriate morphogenesis (Chinmo). Chinmo is a downstream effector of the Jak-STAT signaling pathway that acts in testis somatic stem cells to ensure maintenance of male stem cell fate and sexual identity. Defects in these processes can lead to infertility and the formation of germ cell tumors. While Chinmo’s effect on testis stem cell behavior has been investigated in detail, there is still much to be learned about its structure, function, and interactions with other proteins. Using a two-hybrid screen, we find that Chinmo interacts with itself, the small ubiquitin-like modifier SUMO, the novel protein CG11180, and four other proteins (CG4318, Ova (ovaries absent), Taf3 (TBP-associated factor 3), and CG18269). Since both Chinmo and CG11180 contain sumoylation sites and SUMO-interacting motifs (SIMs), we analyzed their interaction in more detail. Using site-directed mutagenesis of a unique SIM in CG11180, we demonstrate that Chinmo’s interaction with CG11180 is SUMO-dependent. Furthermore, to assess the functional relevance of both SUMO and CG11180, we performed RNAi-mediated knockdown of both proteins in somatic cells of the Drosophila testis. Using this approach, we find that CG11180 and SUMO are required in somatic cells of adult testes, and that reduction of either protein causes formation of germ cell tumors. Overall, our work suggests that SUMO may be involved in the interaction of Chinmo and CG11180 and that these genes are required in somatic cells of the adult Drosophila testis. Consistent with the CG11180 knockdown phenotype in male testes, and to underscore its connection to Chinmo, we propose the name Chigno (Childless Gambino) for CG11180.

Proteomics studies often explore phenotypic differences between whole organs and systems. Within the heart, more subtle variation exists. To date, differences in the underlying proteome are only described between whole cardiac chambers. This study, using the bovine heart as a model, investigates inter-regional differences and assesses the feasibility of measuring detailed, cross-tissue variance in the cardiac proteome. Using a bovine heart, we created a two-dimensional section through a plane going through two chambers. This plane was further sectioned into 4 × 4 mm cubes and analysed using label-free proteomics. We identified three distinct proteomes. When mapped to the extracted sections, the proteomes corresponded largely to the outer wall of the right ventricle and secondly to the outer wall of the left ventricle, right atrial appendage, tricuspid and mitral valves, modulator band, and parts of the left atrium. The third separate proteome corresponded to the inner walls of the left and right ventricles, septum, and left atrial appendage. Differential protein abundancies indicated differences in energy metabolism between regions. Data analyses of the mitochondrial proteins revealed a variable pattern of abundances of complexes I–V between the proteomes, indicating differences in the bioenergetics of the different cardiac sub-proteomes. Mapping of disease-associated proteins interestingly showed desmoglein-2, for which defects in this protein are known to cause Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy, which was present predominantly in the outer wall of the left ventricle. This study highlights that organs can have variable proteomes that do not necessarily correspond to anatomical features.

E. coli is considered one of the most important zoonotic pathogens worldwide. Highly virulent and antimicrobial-resistant strains of E. coli have been reported in recent years, making it essential to understand their ecological origins. In this study, we analyzed the characteristics of E. coli strains present in the natural population of American bison (Bison bison) in Mexico. We sampled 123 individuals and determined the presence of E. coli using standard bacteriological methods. The isolated strains were characterized using molecular techniques based on PCR. To evaluate the diversity of E. coli strains in this population, we analyzed 108 suggestive colonies from each fecal sample. From a total of 13,284 suggestive colonies, we isolated 33 E. coli strains that contained at least one virulence gene. The virotypes of these strains were highly varied, including strains with atypical patterns or combinations compared to classical pathotypes, such as the presence of escV, eae, bfpB, and ial genes in E. coli strain LMA-26-6-6, or stx2, eae, and ial genes in E. coli strain LMA-16-1-32. Genotype analysis of these strains revealed a previously undescribed phylogenetic group. Serotyping of all strains showed that serogroups O26 and O22 were the most abundant. Interestingly, strains belonging to these groups exhibited different patterns of virulence genes. Finally, the isolated E. coli strains demonstrated broad resistance to antimicrobials, including various beta-lactam antibiotics.

ABSTRACT Clustered regularly interspaced short palindromic repeats (CRISPR) are prokaryotic adaptive immune systems regularly utilized as DNA-editing tools. While Neisseria gonorrhoeae does not have an endogenous CRISPR, the commensal species Neisseria lactamica encodes a functional Type I-C CRISPR-Cas system. We have established an isopropyl β-d-1-thiogalactopyranoside added (IPTG)-inducible, CRISPR interference (CRISPRi) platform based on the N. lactamica Type I-C CRISPR missing the Cas3 nuclease to allow locus-specific transcriptional repression. As proof of principle, we targeted a non-phase-variable version of the opaD gene. We show that CRISPRi can downregulate opaD gene and protein expression, resulting in bacterial inability to stimulate neutrophil oxidative responses and to bind to an N-terminal fragment of CEACAM1. Importantly, we used CRISPRi to effectively knockdown all the transcripts of all 11 opa genes using a five-spacer CRISPR array, allowing control of the entire phase-variable opa family in strain FA1090. We also report that repression is reversible following IPTG removal. Finally, we showed that the Type I-C CRISPRi system can conditionally reduce the expression of two essential genes. This CRISPRi system will allow the interrogation of every Gc gene, essential and non-essential, to study physiology and pathogenesis and aid in antimicrobial development.IMPORTANCEClustered regularly interspaced short palindromic repeats (CRISPR)-Cas systems have proven instrumental in genetically manipulating many eukaryotic and prokaryotic organisms. Despite its usefulness, a CRISPR system had yet to be developed for use in Neisseria gonorrhoeae (Gc), a bacterium that is the main etiological agent of gonorrhea infection. Here, we developed a programmable and IPTG-inducible Type I-C CRISPR interference (CRISPRi) system derived from the commensal species Neisseria lactamica as a gene repression system in Gc. As opposed to generating genetic knockouts, the Type I-C CRISPRi system allows us to block transcription of specific genes without generating deletions in the DNA. We explored the properties of this system and found that a minimal spacer array is sufficient for gene repression while also facilitating efficient spacer reprogramming. Importantly, we also show that we can use CRISPRi to knockdown genes that are essential to Gc that cannot normally be knocked out under laboratory settings. Gc encodes ~800 essential genes, many of which have no predicted function. We predict that this Type I-C CRISPRi system can be used to help categorize gene functions and perhaps contribute to the development of novel therapeutics for gonorrhea.

Education for public health is at a critical inflection point, and either transforms for success or fails to remain relevant. In 2020, the Association for Schools and Programs of Public Health launched an initiative, Framing the Future 2030: Education for Public Health (FTF 2030) to develop a resilient educational system for public health that promotes scientific inquiry, connects research, education, and practice, eliminates inequities, incorporates anti-racism principles, creates and sustains diverse and inclusive teaching and learning communities, and optimizes systems and resources to prepare graduates who are clearly recognizable for their population health perspectives, knowledge, skills, attitudes, and practices. Three expert panels: (1) Inclusive excellence through an anti-racism lens; (2) Transformative approaches to teaching and learning; and (3) Expanding the reach, visibility, and impact of the field of academic public health are engaged in ongoing deliberations to generate recommendations to implement the necessary change. The article describes the panels’ work completed thus far, a “Creating an Inclusive Workspace” guide, and work planned, including questions for self-evaluation, deliberation, and reflection toward actions that support academe in developing a resilient education system for public health, whether beginning or advancing through a process of change. The FTF 2030 steering committee asserts its strong commitment to structural and substantial change that strengthens academic public health as an essential component of a complex socio-political system. Lastly, all are called to join the effort as collaboration is essential to co-develop an educational system for public health that ensures health equity for all people, everywhere.

Background: The differential responses of the myokine irisin, in combination with changes in markers and regulators of bone remodeling to high-intensity interval exercise of high and low impact, were examined in 18 young adult females (22.5 ± 2.7 years). Methods: Participants performed two high-intensity interval exercise trials in random order: running on a treadmill and cycling on a cycle ergometer. Trials consisted of eight 1 min running or cycling intervals at ≥ 90% of maximal heart rate, separated by 1 min passive recovery intervals. Blood samples were collected at rest (pre-exercise) and 5 min, 1 h, and 24 h following each exercise trial. Irisin, osteocalcin, sclerostin, osteoprotegerin (OPG), receptor activator nuclear factor kappa-β ligand (RANKL), and parathyroid hormone (PTH) were analyzed in serum, with post-exercise concentrations being corrected for exercise-induced changes in plasma volume. Results: Irisin was elevated 24 h post-exercise compared to its resting values in both trials (20%, p < 0.05) and was higher after cycling compared to running (exercise mode effect, p < 0.05) with no interaction. Osteocalcin, sclerostin, PTH, and RANKL increased from pre- to 5 min post-exercise (18%, 37%, 83%, and 33%, respectively, p < 0.05), returning to baseline levels in 1 h, with no trial or interaction effects. OPG showed a time effect (p < 0.05), reflecting an overall increase at 5 min and 1 h post-exercise, which was not significant after the Bonferroni adjustment. Conclusions: In young adult females, high-intensity interval exercise induced an immediate response in markers and regulators of bone remodeling and a later response in irisin concentrations, which was independent of the gravitational impact.

Abstract Background The purpose of this study was to examine the association of sacroiliac joint (SIJ) dysfunction and pain with overuse and acute lower limb and pelvic girdle injuries of Iranian basketball players. Methods In this cross-sectional study, basketball-related injury data were collected during 2019–2020 from 204 basketball players of the Iranian league using the online Information Retrospective Injury Questionnaire. A researcher then performed ten clinical tests to assess SIJ dysfunction and pain (five tests for dysfunction and five tests for pain). Data analysis was performed by logistic regression at the confidence interval of 95%. Results Within our sample (n = 204), injury rates were calculated across sub-groups of athletes that had only SIJ pain (n = 19), only SIJ dysfunction (n = 67), both SIJ pain and dysfunction (n = 15) or no SIJ complaints (n = 103). Across these groups, a total of 464 injuries were reported. SIJ pain group reported 80 injuries (17.2%), SIJ dysfunction group reported 210 injuries (45.2%), both SIJ pain and dysfunction group reported 58 injuries (12.5%, and the no SIJ pain or SIJ dysfunction group reported 116 injuries (25.0%). Participants with SIJ pain were more likely to report previous pelvic girdle injuries (overuse: odds ratio (OR): 0.017; 95% CI: 0.005–0.56; p

Consistent with the biochemistry of coronaviruses as well established over decades, SARS-CoV-2 makes its initial attachment to host cells through the binding of its spike protein (SP) to sialylated glycans (containing the monosaccharide sialic acid) on the cell surface. The virus can then slide over and enter via ACE2. SARS-CoV-2 SP attaches particularly tightly to the trillions of red blood cells (RBCs), platelets and endothelial cells in the human body, each cell very densely coated with sialic acid surface molecules but having no ACE2 or minimal ACE2. These interlaced attachments trigger the blood cell aggregation, microvascular occlusion and vascular damage that underlie the hypoxia, blood clotting and related morbidities of severe COVID-19. Notably, the two human betacoronaviruses that express a sialic acid-cleaving enzyme are benign, while the other three—SARS, SARS-CoV-2 and MERS—are virulent. RBC aggregation experimentally induced in several animal species using an injected polysaccharide caused most of the same morbidities of severe COVID-19. This glycan biochemistry is key to disentangling controversies that have arisen over the efficacy of certain generic COVID-19 treatment agents and the safety of SP-based COVID-19 vaccines. More broadly, disregard for the active physiological role of RBCs yields unreliable or erroneous reporting of pharmacokinetic parameters as routinely obtained for most drugs and other bioactive agents using detection in plasma, with whole-blood levels being up to 30-fold higher. Appreciation of the active role of RBCs can elucidate the microvascular underpinnings of other health conditions, including cardiovascular disease, and therapeutic opportunities to address them.

Rationale & Objective: Little is known about hospital admissions in nondialysis patients with chronic kidney disease (CKD) before death or starting kidney replacement therapy (KRT). Study Design: Retrospective observational cohort study Setting & Participants: Hospitalizations among 7,201 patients with CKD from 10 public renal clinics in Queensland (QLD), enrolled in the CKD.QLD registry starting in May 2011, were followed for 25,496.34 person-years until they started receiving KRT or died, or until June 30, 2018. Predictors: Demographic and clinical characteristics of patients with CKD. Outcomes: Hospital admissions. Analytical Approach: We evaluated the association of demographic and clinical features with hospitalizations, length of hospital stay, and cost. Results: Approximately 81.5% of the patients were admitted at least once, with 42,283 admissions, costing Australian dollars (AUD) 231 million. The average number of admissions per person-year was 1.7, and the cost was AUD 9,060, 10 times and 2 times their Australian averages, respectively. Single (1-day) admissions constituted 59.2% of all the hospital episodes, led by neoplasms (largely chemotherapy), anemia, CKD-related conditions and eye conditions (largely cataract extractions), but only 14.8% of the total costs. Approximately 41% of admissions were >1-day admissions, constituting 85.2% of the total costs, with cardiovascular conditions, respiratory conditions, CKD-related conditions, and injuries, fractures, or poisoning being the dominant causes. Readmission within 30 days of discharge constituted >42% of the admissions and 46.8% costs. Admissions not directly related to CKD constituted 90% of the admissions and costs. More than 40% of the admissions and costs were through the emergency department. Approximately 19% of the hospitalized patients and 27% of the admissions did not have kidney disease mentioned as either principal or associate causes. Limitations: Variable follow-up times because of different dates of consent. Conclusions: The hospital burden of patients with CKD is mainly driven by complex multiday admissions and readmissions involving comorbid conditions, which may not be directly related to their CKD. Strategies to prevent these complex admissions and readmissions should minimize hospital costs and outcomes. Plain-Language Summary: We analyzed primary causes, types, and costs of hospitalizations among 7,201 patients with chronic kidney disease (CKD) from renal speciality clinics across Queensland, Australia, over an average follow-up of 3.54 years. The average annual cost per person was $9,060, and was the highest in those with more advanced CKD, higher age, and with diabetes. More than 85% of costs were driven by more complex hospitalizations with longer length of stay. Cardiovascular disease was the single largest contributor for hospitalizations, length of hospital stay, and total costs. Readmission within 30 days of discharge, particularly for the same disorder, and multiday admissions should be the main targets for mitigation of hospital costs in this population.

Introduction: Obstructive Sleep Apnea (OSA) is the total or partial limitation of the passage of air through the upper respiratory tract during sleep, it has two forms of presentation: central and obstructive (related to anatomical profile). Objective: To determine the relationship between the anatomical profile and severity of Obstructive Sleep Apnea in adult patients of a Private Clinic in Lima Norte, Lima, 2020-2022. Methods: Cross-sectional analytical study. We used medical records of patients diagnosed with OSA during the period 2020-2022 in a private clinic in Lima, Peru. Our variable was the severity of OSA, in addition to apnea-hypopnea per hour (AHI), in addition we also took oxygen desaturation index (ODI), Epworth Scale, CT90%, body mass index (BMI), minimum saturation and snoring and of the newborn reported in the clinical history. The response variable was OSA . Results: a total of 120 clinical histories were studied. The predominant OSA was mild (29.2%), followed by very severe (26.7%). In very severe OSA, patients with retrognathia had 3.0 higher frequency, those with long face had 30.0 lower frequency and those with short face had 4.0 higher frequency, compared to patients with normal face (40 vs 7 vs 41 vs 37; p

Abstract Typically, athletes alter movement mechanics in the presence of back pain, but the effect of these changes on lower extremity injury risk is not well understood. This study aimed to compare the effect of fatigue on electromechanical response times during a choice reaction task in basketball players with and without persistent low back pain. Twenty-four male basketball players participated. Total reaction time (TRT), premotor time (PMT), and electromechanical delay (EMD data were recorded before and after fatigue. The chronic low back pain (CLBP) group had significantly longer EMD in Med gastrocnemius (p = 0.001) and Tibialis anterior (p = 0.001), and shorter EMD in Vastus Lateralis (p = 0.001), Vastus Medialis Oblique (p = 0.003), and Semitendinosus (p = 0.025) muscles after fatigue. PMT in the CLBP group had longer than the Non-CLBP in Vastus Lateralis (p = 0.010), Vastus Medialis Oblique (p = 0.017), Semitendinosus (p = 0.002). Also, TRT was longer in knee flexion (p = 0.001) and ankle plantarflexion (p = 0.001) muscle groups. The different effects of fatigue on electromechanical response times of the knee and ankle in people with CLBP may represent the effect of an axial injury on lower extremity injury risk factors in situations of higher cognitive load, similar to competitive play.

Abstract Background The molecular drivers of early sporadic Parkinson’s disease (PD) remain unclear, and the presence of widespread end stage pathology in late disease masks the distinction between primary or causal disease-specific events and late secondary consequences in stressed or dying cells. However, early and mid-stage Parkinson’s brains (Braak stages 3 and 4) exhibit alpha-synuclein inclusions and neuronal loss along a regional gradient of severity, from unaffected-mild-moderate-severe. Here, we exploited this spatial pathological gradient to investigate the molecular drivers of sporadic PD. Methods We combined high precision tissue sampling with unbiased large-scale profiling of protein expression across 9 brain regions in Braak stage 3 and 4 PD brains, and controls, and verified these results using targeted proteomic and functional analyses. Results We demonstrate that the spatio-temporal pathology gradient in early-mid PD brains is mirrored by a biochemical gradient of a changing proteome. Importantly, we identify two key events that occur early in the disease, prior to the occurrence of alpha-synuclein inclusions and neuronal loss: (i) a metabolic switch in the utilisation of energy substrates and energy production in the brain, and (ii) perturbation of the mitochondrial redox state. These changes may contribute to the regional vulnerability of developing alpha-synuclein pathology. Later in the disease, mitochondrial function is affected more severely, whilst mitochondrial metabolism, fatty acid oxidation, and mitochondrial respiration are affected across all brain regions. Conclusions Our study provides an in-depth regional profile of the proteome at different stages of PD, and highlights that mitochondrial dysfunction is detectable prior to neuronal loss, and alpha-synuclein fibril deposition, suggesting that mitochondrial dysfunction is one of the key drivers of early disease.

Summary: We examined the effects of ∼30 days of spaceflight on glycogen synthase kinase 3 (GSK3) content and inhibitory serine phosphorylation in murine muscle and bone samples from four separate missions (BION-M1, rodent research [RR]1, RR9, and RR18). Spaceflight reduced GSK3β content across all missions, whereas its serine phosphorylation was elevated with RR18 and BION-M1. The reduction in GSK3β was linked to the reduction in type IIA fibers commonly observed with spaceflight as these fibers are particularly enriched with GSK3. We then tested the effects of inhibiting GSK3 before this fiber type shift, and we demonstrate that muscle-specific Gsk3 knockdown increased muscle mass, preserved muscle strength, and promoted the oxidative fiber type with Earth-based hindlimb unloading. In bone, GSK3 activation was enhanced after spaceflight; and strikingly, muscle-specific Gsk3 deletion increased bone mineral density in response to hindlimb unloading. Thus, future studies should test the effects of GSK3 inhibition during spaceflight.

Abstract Background Prevalence of Fabry disease amongst Chronic Kidney Disease (CKD) patients on haemodialysis has been shown to be approximately 0.2%. Methods We undertook a cross-sectional study employing a cascade screening strategy for Fabry Disease amongst 3000 adult, male and female patients affected by CKD stage 1-5D/T at public, specialty renal practices within participating Queensland Hospital and Health Services from October 2017 to August 2019. A multi-tiered FD screening strategy, utilising a combination of dried blood spot (DBS) enzymatic testing, and if low, then lyso-GB3 testing and DNA sequencing, was used. Results Mean (SD) age was 64.0 (15.8) years (n = 2992), and 57.9% were male. Eight participants withrew out of the 3000 who consented. Of 2992 screened, 6 (0.20%) received a diagnosis of FD, 2902 (96.99%) did not have FD, and 84 (2.81%) received inconclusive results. Of the patients diagnosed with FD, mean age was 48.5 years; 5 were male (0.29%) and 1 was female (0.08%); 4 were on kidney replacement therapy (2 dialysis and 2 transplant); 3 were new diagnoses. Conclusions Estimated overall FD prevalence was 0.20%. Screening of the broader CKD population may be beneficial in identifying cases of FD. Trial registration The aCQuiRE Study has been prospectively registered with the Queensland Health Database of Research Activity (DORA, https://dora.health.qld.gov.au ) as pj09946 (Registered 3rd July 2017).

Microbiome modulation, aiming to restore a health-compatible microbiota, is a novel strategy to treat periodontitis. This study evaluated the modulation effects of antimicrobial peptide LL-31 and its D-enantiomer (D-LL-31) on saliva-derived microcosm biofilms, spiked with or without Porphyromonas gingivalis. To this end, one-day-old biofilms were incubated for 24 h with biofilm medium alone, or medium containing 40 µM LL-31 or D-LL-31, after which biofilms were grown for 5 days. Biofilms were assessed at 1 day and 5 days after intervention for the total viable cell counts, dipeptidyl peptidase IV (DPP4) activity, P. gingivalis amount (by qPCR) and microbial composition (by sequencing). The results showed that D-LL-31, not LL-31, significantly reduced the total viable cell counts, the P. gingivalis amount, and the DPP4 activity of the biofilms spiked with P. gingivalis, but only at 1 day after intervention. In the biofilms spiked with P. gingivalis, D-LL-31 tended to reduce the α-diversity and the compositional shift of the biofilms in time as compared to the control and LL-31 groups. In conclusion, D-LL-31 showed a better performance than LL-31 in biofilm modulation. The biofilm modulation function of the peptides could be impaired when the biofilms were in a severely dysbiotic state.

Aim. Anaemia among patients with chronic kidney disease (CKD) leads to poor overall outcomes. This study explores anaemia and its impact on nondialysis CKD (NDD-CKD) patients. Methods. 2,303 adults with CKD from two CKD.QLD Registry sites were characterised at consent and followed until start of kidney replacement therapy (KRT), death, or censor date. Mean follow-up was 3.9 (SD 2.1) years. Analysis explored the impact of anaemia on death, KRT start, cardiovascular events (CVE), admissions, and costs in these NDD-CKD patients. Results. At consent, 45.6% patients were anaemic. Males were more often anaemic (53.6%) than females, and anaemia was significantly more common over the age of 65 years. The prevalence of anaemia was highest among CKD patients with diabetic nephropathy (27.4%) and renovascular disease (29.2%) and lowest in patients with genetic renal disease (3.3%). Patients with admissions for gastrointestinal bleeding had more severe anaemia, but accounted for only the minority of cases overall. Administration of ESAs, iron infusions, and blood transfusions were all correlated with more severe degrees of anaemia. The number of hospital admissions, length of stay, and hospital costs were all strikingly higher with more severe degrees of anaemia. Adjusted hazard ratios (CI 95%) of patients with moderate and severe anaemia vs. no anaemia for subsequent CVE, KRT, and death without KRT were 1.7 (1.4–2.0), 2.0 (1.4–2.9), and 1.8 (1.5–2.3), respectively. Conclusion. Anaemia is associated with higher rates of CVE, progression to KRT and death in NDD- CKD patients, and with greater hospital utilisation and costs. Preventing and treating anaemia should improve clinical and economic outcomes.

Abstract The relationship between ATR/Chk1 activity and replication stress, coupled with the development of potent and tolerable inhibitors of this pathway, has led to the clinical exploration of ATR and Chk1 inhibitors (ATRi/Chk1i) as anticancer therapies for single-agent or combinatorial application. The clinical efficacy of these therapies relies on the ability to ascertain which patient populations are most likely to benefit, so there is intense interest in identifying predictive biomarkers of response. To comprehensively evaluate the components that modulate cancer cell sensitivity to replication stress induced by Chk1i, we performed a synthetic-lethal drop-out screen in a cell line derived from a patient with triple-negative breast cancer (TNBC), using a pooled barcoded shRNA library targeting ~350 genes involved in DNA replication, DNA damage repair, and cycle progression. In addition, we sought to compare the relative requirement of these genes when DNA fidelity is challenged by clinically relevant anticancer breast cancer drugs, including cisplatin and PARP1/2 inhibitors, that have different mechanisms of action. This global comparison is critical for understanding not only which agents should be used together for combinatorial therapies in breast cancer patients, but also the genetic context in which these therapies will be most effective, and when a single-agent therapy will be sufficient to provide maximum therapeutic benefit to the patient. We identified unique potentiators of response to ATRi/Chk1i and describe a new role for components of the cytosolic iron–sulfur assembly (CIA) pathway, MMS19 and CIA2B-FAM96B, in replication stress tolerance of TNBC.

IntroductionRacism is a root cause of ill health for communities of color, and hate incidents are one manifestation of racism. Marginalized racial and ethnic groups, including but not limited to Asian Americans, have been the target of highly publicized violence, hate, and discrimination which has been amplified during the COVID-19 pandemic.ObjectivesThis paper investigates (1) the prevalence of hate incidents across racial and ethnic groups, and (2) the relationship between race and ethnicity and hate incidents during the first year of the COVID-19 pandemic. We also seek to (3) situate study findings within theories of racism.MethodsThis study utilizes national data from the Understanding America Study (UAS) COVID-19 Longitudinal Survey from June 10, 2020 to March 30, 2021 (n = 8,436). Hate incidents in six categories were examined: being treated with less courtesy, receiving poorer service, others acting as if they were not smart, others acting as if they were afraid of them, being threatened or harassed, and experiencing any of the previous categories of hate incidents. Main analyses were conducted via population averaged logistic panel regression.ResultsThe majority of members of all six marginalized racial and ethnic groups reported at least one hate incident during the first year of the COVID-19 pandemic. In addition, all marginalized racial or ethnic groups had statistically significant higher odds of experiencing at least two categories of hate incidents compared to white individuals. Asian, AI/AN, Black, and Multiracial groups had significantly higher odds of experiencing each category of hate incident. All marginalized racial and ethnic groups had significantly higher odds of receiving poorer service and others acting as if they were afraid of them.ConclusionAll marginalized racial and ethnic groups experienced significant levels of hate incidents within the first year of the COVID-19 pandemic. The public health community must continue to research, monitor, treat, and prevent hate incidents as a public health issue while recognizing the social and historical contexts of structural and interpersonal racism in the US.

Household survey data from 27 sites in 22 countries were collected in 2017–2018 in order to construct and validate a cross-cultural household-level water insecurity scale. The resultant Household Water Insecurity Experiences (HWISE) scale presents a useful tool for monitoring and evaluating water interventions as a complement to traditional metrics used by the development community. It can also help track progress toward achievement of Sustainable Development Goal 6 ‘clean water and sanitation for all’. We present HWISE scale scores from 27 sites as comparative data for future studies using the HWISE scale in low- and middle-income contexts. Site-level mean scores for HWISE-12 (scored 0–36) ranged from 1.64 (SD 4.22) in Pune, India, to 20.90 (7.50) in Cartagena, Colombia, while site-level mean scores for HWISE-4 (scored 0–12) ranged from 0.51 (1.50) in Pune, India, to 8.21 (2.55) in Punjab, Pakistan. Scores tended to be higher in the dry season as expected. Data from this first implementation of the HWISE scale demonstrate the diversity of water insecurity within and across communities and can help to situate findings from future applications of this tool. HIGHLIGHTS We present comparison scores of the Household Water Insecurity Experiences (HWISE) scale, a novel household water insecurity index validated for use in low- and middle-income countries.; These scores can aid interpretation of future implementation of the HWISE scale.; The HWISE scale should still be evaluated in new contexts, such as high-income settings.;

Abstract Objective Non‐surgical scaling and root planing (SRP), as an initial form of periodontal treatment, followed by ongoing periodontal maintenance appointments is necessary to manage periodontal disease and prevent tooth loss. Saliva also has an essential role in oral health though the relationship between low salivary flow and periodontal outcomes has not been extensively investigated. This study determined if patients with dry mouth have similar clinical outcomes as patients without dry mouth when receiving regular periodontal maintenance after SRP. Materials and methods This is a retrospective study that investigated clinical periodontal outcomes in patients with (n = 34) or without (n = 85) dry mouth who had undergone SRP 1 to 5 years prior and had routine periodontal maintenance. The presence of dry mouth was established based on a patient's unstimulated salivary flow rate. Results Probing depth for both patients with or without dry mouth was similar between groups and maintained 1 to 5 years following initial SRP. Improved probing depth achieved post‐SRP was sustained regardless of dry mouth status. Conclusion Patients with or without dry mouth did not exhibit different probing depths.

Summary: Background: The majority of those infected by ancestral Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) during the UK first wave (starting March 2020) did not require hospitalisation. Most had a short-lived mild or asymptomatic infection, while others had symptoms that persisted for weeks or months. We hypothesized that the plasma proteome at the time of first infection would reflect differences in the inflammatory response that linked to symptom severity and duration. Methods: We performed a nested longitudinal case-control study and targeted analysis of the plasma proteome of 156 healthcare workers (HCW) with and without lab confirmed SARS-CoV-2 infection. Targeted proteomic multiple-reaction monitoring analysis of 91 pre-selected proteins was undertaken in uninfected healthcare workers at baseline, and in infected healthcare workers serially, from 1 week prior to 6 weeks after their first confirmed SARS-CoV-2 infection. Symptom severity and antibody responses were also tracked. Questionnaires at 6 and 12 months collected data on persistent symptoms. Findings: Within this cohort (median age 39 years, interquartile range 30–47 years), 54 healthcare workers (44% male) had PCR or antibody confirmed infection, with the remaining 102 (38% male) serving as uninfected controls. Following the first confirmed SARS-CoV-2 infection, perturbation of the plasma proteome persisted for up to 6 weeks, tracking symptom severity and antibody responses. Differentially abundant proteins were mostly coordinated around lipid, atherosclerosis and cholesterol metabolism pathways, complement and coagulation cascades, autophagy, and lysosomal function. The proteomic profile at the time of seroconversion associated with persistent symptoms out to 12 months. Data are available via ProteomeXchange with identifier PXD036590. Interpretation: Our findings show that non-severe SARS-CoV-2 infection perturbs the plasma proteome for at least 6 weeks. The plasma proteomic signature at the time of seroconversion has the potential to identify which individuals are more likely to suffer from persistent symptoms related to SARS-CoV-2 infection. Funding information: The COVIDsortium is supported by funding donated by individuals, charitable Trusts, and corporations including Goldman Sachs, Citadel and Citadel Securities, The Guy Foundation, GW Pharmaceuticals, Kusuma Trust, and Jagclif Charitable Trust, and enabled by Barts Charity with support from University College London Hospitals (UCLH) Charity. This work was additionally supported by the Translational Mass Spectrometry Research Group and the Biomedical Research Center (BRC) at Great Ormond Street Hospital.

Summary: Determining the protection an individual has to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants of concern (VoCs) is crucial for future immune surveillance, vaccine development, and understanding of the changing immune response. We devised an informative assay to current ELISA-based serology using multiplexed, baited, targeted proteomics for direct detection of multiple proteins in the SARS-CoV-2 anti-spike antibody immunocomplex. Serum from individuals collected after infection or first- and second-dose vaccination demonstrates this approach and shows concordance with existing serology and neutralization. Our assays show altered responses of both immunoglobulins and complement to the Alpha (B.1.1.7), Beta (B.1.351), and Delta (B.1.617.1) VoCs and a reduced response to Omicron (B1.1.1529). We were able to identify individuals who had prior infection, and observed that C1q is closely associated with IgG1 (r > 0.82) and may better reflect neutralization to VoCs. Analyzing additional immunoproteins beyond immunoglobulin (Ig) G, provides important information about our understanding of the response to infection and vaccination. Motivation: Assays for measuring serum antibody responses are typically limited to measurement of a total or single immunoglobulin isotype. The antibody response is far more complex, with multiple immunoglobulin classes, isotypes, and complement factors involved. This is a potential wealth of information that is typically understudied and missed by existing tests. The global COVID-19 pandemic has highlighted the need to understand better the immune response in respect to vaccine development and emerging new severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants. Using the ability of tandem mass spectrometry to multiplex and directly and accurately measure the antibody complex, we devised an alternative assay to capture this valuable information.

Enteric methane emissions from ruminants account for ∼35% of New Zealand’s greenhouse gas emissions. This poses a significant threat to the pastoral sector. Breeding has been shown to successfully lower methane emissions, and genomic prediction for lowered methane emissions has been introduced at the national level. The long-term genetic impacts of including low methane in ruminant breeding programs, however, are unknown. The success of the New Zealand sheep industry is currently heavily reliant on the prolificacy, fecundity and survival of adult ewes. The objective of this study was to determine genetic and phenotypic correlations between adult maternal ewe traits (live weight, body condition score, number of lambs born, litter survival to weaning, pregnancy scanning and fleece weight), faecal and Nematodirus egg counts and measures of methane in respiration chambers. More than 9,000 records for methane from over 2,200 sheep measured in respiration chambers were collected over 10 years. Sheep were fed on a restricted diet calculated as approximately twice the maintenance. Methane measures were converted to absolute daily emissions of methane measured in g per day (CH4/day). Two measures of methane yield were recorded: the ratio of CH4 to dry matter intake (g CH4/kg DMI; CH4/DMI) and the ratio of CH4 to total gas emissions (CH4/(CH4 + CO2)). Ewes were maintained in the flocks for at least two parities. Non-methane trait data from over 8,000 female relatives were collated to estimate genetic correlations. Results suggest that breeding for low CH4/DMI is unlikely to negatively affect faecal egg counts, adult ewe fertility and litter survival traits, with no evidence for significant genetic correlations. Fleece weight was unfavourably (favourably) correlated with CH4/DMI (rg = −0.21 ± 0.09). Live weight (rg = 0.3 ± 0.1) and body condition score (rg = 0.2 ± 0.1) were positively correlated with methane yield. Comparing the two estimates of methane yield, CH4/DMI had lower heritability and repeatability. However, correlations of both measures with adult ewe traits were similar. This suggests that breeding is a suitable mitigation strategy for lowering methane yield, but wool, live weight and fat deposition traits may be affected over time and should be monitored.

Bacterial adhesion is the first step in the formation of surface biofilms. The number of bacteria that bind to a surface from the solution depends on how many bacteria can reach the surface (bacterial transport) and the strength of interactions between bacterial adhesins and surface receptors (adhesivity). By using microfluidic channels and video microscopy as well as computational simulations, we investigated how the interplay between bacterial transport and adhesivity affects the number of the common human pathogen Escherichia coli that bind to heterogeneous surfaces with different receptor densities. We determined that gravitational sedimentation causes bacteria to concentrate at the lower surface over time as fluid moves over a non-adhesive region, so bacteria preferentially adhere to adhesive regions on the lower, inflow-proximal areas that are downstream of non-adhesive regions within the entered compartments. Also, initial bacterial attachment to an adhesive region of a heterogeneous lower surface may be inhibited by shear due to mass transport effects alone rather than shear forces per se, because higher shear washes out the sedimented bacteria. We also provide a conceptual framework and theory that predict the impact of sedimentation on adhesion between and within adhesive regions in flow, where bacteria would likely bind both in vitro and in vivo, and how to normalize the bacterial binding level under experimental set-ups based on the flow compartment configuration.

Abstract Background Periodontal disease is a chronic state of inflammation that can destroy the supporting tissues around the teeth, leading to the resorption of alveolar bone. The initial strategy for treating periodontal disease is non-surgical sanative therapy (ST). Periodontal disease can also induce dysbiosis in the gut microbiota and contribute to low-grade systemic inflammation. Prebiotic fibers such as inulin can selectively alter the intestinal microbiota and support homeostasis by improving gut barrier functions and preventing inflammation. Providing an inulin supplement prior to and post-ST may influence periodontal health while providing insight into the complex relationship between periodontal disease and the gut microbiota. The primary objective is to determine if inulin is more effective than the placebo at improving clinical periodontal outcomes including probing depth (PD) and bleeding on probing (BOP). Secondary objectives include determining the effects of inulin supplementation pre- and post-ST on salivary markers of inflammation and periodontal-associated pathogens, as these outcomes reflect more rapid changes that can occur. Methods We will employ a single-center, randomized, double-blind, placebo-controlled study design and recruit and randomize 170 participants who are receiving ST to manage the periodontal disease to the intervention (inulin) or placebo (maltodextrin) group. A pilot study will be embedded within the randomized controlled trial using the first 48 participants to test the feasibility for the larger, powered trial. The intervention period will begin 4 weeks before ST through to their follow-up appointment at 10 weeks post-ST. Clinical outcomes of periodontal disease including the number of sites with PD ≥ 4 mm and the presence of BOP will be measured at baseline and post-ST. Salivary markers of inflammation, periodontal-associated pathogens, body mass index, and diet will be measured at baseline, pre-ST (after 4 weeks of intervention), and post-ST (after 14 weeks of intervention). Discussion We expect that inulin will enhance the positive effect of ST on the management of periodontal disease. The results of the study will provide guidance regarding the use of prebiotics prior to and as a supportive adjunct to ST for periodontal health. Trial registration ClinicalTrials.gov NCT04670133 . Registered on 17 December 2020.

Abstract Despite the prevalence of large (>5 cm2) articular cartilage defects involving underlying bone, current tissue-engineered therapies only address small defects. Tissue-engineered, anatomically shaped, native-like implants may address the need for off-the-shelf, tissue-repairing therapies for large cartilage lesions. This study fabricated an osteochondral construct of translationally relevant geometry with robust functional properties. Scaffold-free, self-assembled neocartilage served as the chondral phase, and porous hydroxyapatite served as the osseous phase of the osteochondral constructs. Constructs in the shape and size of an ovine femoral condyle (31 × 14 mm) were assembled at day 4 (early) or day 10 (late) of neocartilage maturation. Early osteochondral assembly increased the interfacial interdigitation depth by 244%, interdigitation frequency by 438%, interfacial shear modulus by 243-fold, and ultimate interfacial shear strength by 4.9-fold, compared to late assembly. Toward the development of a bioprosthesis for the repair of cartilage lesions encompassing up to an entire condylar surface, this study generated a large, anatomically shaped osteochondral construct with robust interfacial mechanical properties and native-like neocartilage interdigitation.

The classic model of non-contact ACL injury includes environmental, anatomical, hormonal and biomechanical risk factors which directly impact either the amount of stress placed on the ligament or the relative capacity of ligament to withstand the forces placed on it. However, cognition also clearly plays a role in successful athletic performance, yet diminished cognitive function is rarely considered a risk factor for injury. # Objective To examine the existing literature to determine the extent to which cognitive function (both cognitive ability and task cognitive load) influences non-contact lower extremity injury risk in male and female athletes with a broad variety of athletic expertise. # Study Design Scoping Review # Methods An electronic search was conducted of CINAHL, SPORTDiscus, Google Scholar, and MEDLINE using the PRISMA method. Search terms included Boolean combinations of “cognition”, “concussion”, “ImPACT”, “cognitive deficit”, “mild traumatic brain injury (mTBI)”, and “neuropsychological function” as cognitive descriptors and the terms “injury risk” and “lower extremity injury” as injury descriptors. Inclusion criteria included papers written in English published between 2000-2021. Exclusion criteria included neurological and cognitively atypical populations, except for concussion (included). Included articles were appraised using the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. # Results Fifty-six studies utilizing across the spectrum of levels of evidence met inclusion criteria. Forty-one articles had good, fourteen had fair, and one had poor methodological quality. Studies examined baseline cognitive function in healthy athletes (n=7); performance during dual-task paradigms (n=13); and the impact of concussion on dual-task performance (n=4), LE injury risk (n=22), or post-concussion testing (n=10). Six articles examining cognitive function and all dual-task studies (including concussion studies) found altered biomechanics associated with injury or increased processing demands. Studies related to concussion and injury incidence consistently found an increased risk of LE injury following concussion. Half of the studies that examined concussion and post-concussion cognitive testing demonstrated significant effects. # Discussion Consistent across participant demographics, tasks, and dependent measures, fifty-one of fifty-six assessed articles concluded that decreased cognitive ability or increased cognitive load led to risky LE mechanics or a direct increase in non-contact LE injury risk. # Conclusion The robustness of results across gender, performance level, sport, cognitive ability, task cognitive load suggest that the inclusion of cognitive training in the design of optimal LE injury prevention programs warrants further study. Level of Evidence: Ia

Abstract Objective Diet and dietary supplement use are associated with periodontal health while a cause and effect relationship is less clear. Although associations with specific nutrients and supplements suggest a potential benefit to healing of periodontal tissues after periodontal procedures, this study determined if patients undergoing periodontal surgery currently take dietary supplements to gage whether patients may accept use of such supplements as a potential intervention. Materials and methods Patients who were undergoing implant placement or soft tissue graft surgery completed a questionnaire indicating any dietary supplements they consumed. Patient demographics, such as age, sex, and smoking status, were gathered from patients' charting records. Results Data on dietary supplement usage were collected from 221 patients. More than half (64.7%) the population surveyed reported using one or more dietary supplements. The most commonly used dietary supplements were vitamin D (31%), multivitamin (28%), and B‐complex (17.2%). Females were more likely to be taking calcium, vitamin B12, and magnesium than males. Adults, aged 51 years and older, were more likely to be taking dietary supplements than their younger counterparts. They were also more likely to be taking four or more supplements than those under the age of 50 years. There was no association between supplement use and sex, but when the number of different supplements being used was assessed, females were more likely than males to be taking four or more different supplements. Conclusions The majority of the study population is already taking dietary supplements as part of their routine. Based on this study, future studies to determine if supplement usage, potentially at levels higher than current levels of intake, can be used to maintain or promote periodontal health seem highly feasible.

Abstract Background Both childhood maltreatment (CM) and intimate partner violence (IPV) are public health problems that have been related to a wide range of adverse health consequences. However, studies examining associations between specific types of CM and experiencing IPV in adulthood have yielded conflicting results. Methods Using data from 10,608 men and 11,458 women aged 18 or older from Canada’s 2014 General Social Survey, we examined associations between three types of CM—childhood physical abuse (CPA), childhood sexual abuse (CSA), and childhood exposure to IPV —and subsequent intimate partner violence (IPV) in adulthood (physical, sexual or emotional). Results When potential confounders were controlled, CPA, CSA and childhood exposure to IPV were associated with IPV in adulthood for both sexes (odds ratios, 1.7, 1.8 and 2.0 for men, and 2.2, 2.0 and 2.1 for women). When severity and frequency of CM were examined, a dose-response relationship between all three types of CM and IPV in adulthood was observed among women (meaning that as the severity/frequency of CM increased, the likelihood of reporting IPV also increased); among men, a dose-response relationship was observed only for CPA. Conclusions The association between CM and IPV in adulthood is particularly concerning because experiencing multiple forms of trauma has cumulative effects. Lifespan studies have shown that individuals who experience multiple incidents of abuse exhibit the highest levels of impairment. This underscores the importance of programs to eradicate both CM and IPV. This underscores the importance of programs to eradicate both CM and IPV. Future research should focus on assessing interventions designed to promote healthy relationships and the provision of emotional support and coping mechanisms to children and families in abusive situations.

Because of its proximity to and frequent travelers to and from China, Taiwan faces complex challenges in preventing coronavirus disease (COVID-19). As soon as China reported the unidentified outbreak to the World Health Organization on December 31, 2019, Taiwan assembled a taskforce and began health checks onboard flights from Wuhan. Taiwan’s rapid implementation of disease prevention measures helped detect and isolate the country’s first COVID-19 case on January 20, 2020. Laboratories in Taiwan developed 4-hour test kits and isolated 2 strains of the coronavirus before February. Taiwan effectively delayed and contained community transmission by leveraging experience from the 2003 severe acute respiratory syndrome outbreak, prevalent public awareness, a robust public health network, support from healthcare industries, cross-departmental collaborations, and advanced information technology capacity. We analyze use of the National Health Insurance database and critical policy decisions made by Taiwan’s government during the first 50 days of the COVID-19 outbreak.

Abstract Background The T 1 Mapping and Extracellular volume (ECV) Standardization (T1MES) program explored T 1 mapping quality assurance using a purpose-developed phantom with Food and Drug Administration (FDA) and Conformité Européenne (CE) regulatory clearance. We report T 1 measurement repeatability across centers describing sequence, magnet, and vendor performance. Methods Phantoms batch-manufactured in August 2015 underwent 2 years of structural imaging, B 0 and B 1, and “reference” slow T 1 testing. Temperature dependency was evaluated by the United States National Institute of Standards and Technology and by the German Physikalisch-Technische Bundesanstalt. Center-specific T 1 mapping repeatability (maximum one scan per week to minimum one per quarter year) was assessed over mean 358 (maximum 1161) days on 34 1.5 T and 22 3 T magnets using multiple T 1 mapping sequences. Image and temperature data were analyzed semi-automatically. Repeatability of serial T 1 was evaluated in terms of coefficient of variation (CoV), and linear mixed models were constructed to study the interplay of some of the known sources of T 1 variation. Results Over 2 years, phantom gel integrity remained intact (no rips/tears), B 0 and B 1 homogenous, and “reference” T 1 stable compared to baseline (% change at 1.5 T, 1.95 ± 1.39%; 3 T, 2.22 ± 1.44%). Per degrees Celsius, 1.5 T, T 1 (MOLLI 5s(3s)3s) increased by 11.4 ms in long native blood tubes and decreased by 1.2 ms in short post-contrast myocardium tubes. Agreement of estimated T 1 times with “reference” T 1 was similar across Siemens and Philips CMR systems at both field strengths (adjusted R 2 ranges for both field strengths, 0.99–1.00). Over 1 year, many 1.5 T and 3 T sequences/magnets were repeatable with mean CoVs

Abstract Background Fabry disease (FD) is a rare, lysosomal storage disorder caused by the absence or deficiency of the enzyme alpha-galactosidase A (α-Gal A) that leads to the abnormal accumulation of the lipid globotriaosylceramide (GB3) in a variety of cell types and tissues throughout the body. FD has an x-linked inheritance pattern. Previously thought to be only carriers, females can also experience FD symptomatology. Symptoms vary in type and severity from patient to patient and tend to increase in severity with age. FD symptoms are non-specific and may be shared with those of other diseases. Misdiagnoses and diagnostic delays are common, often resulting in progressive, irreversible tissue damage. The estimated prevalence of FD in the general population is 1:40,000 to 1:117,000 individuals. However, it is estimated that the prevalence of FD in the dialysis population is 0.12 to 0.7%. Little is known about the prevalence of FD in the broader Chronic Kidney Disease (CKD) population. Methods This is an epidemiological study of the prevalence of FD in CKD patents identified from the public renal speciality practices in Queensland, Australia. A cascade approach to screening is being employed with dried blood spot testing for blood levels of alpha-galactosidase A (Alpha-Gal), with follow-up testing for patients with abnormal results by plasma levels of globotriaosylsphingosine (Lyso-GB3) for females and non-definitive cases in males. A diagnosis of FD is confirmed through genetic testing of the GLA gene in cases suspected of having FD based upon Alpha-Gal and Lyso-GB3 testing. Discussion Expected outcomes of this study include more information about the prevalence of FD at all stages of CKD, including for both males and females. The study may also provide information about common characteristics of FD to assist with diagnosis and optimal management/treatment. Screening is also available for family members of diagnosed patients, with potential for early diagnosis of FD and intervention for those individuals. Trial registration Queensland Health Database of Research Activity (DORA, https://dora.health.qld.gov.au) pj09946 (Registered 3rd July 2017).

Abstract Background Childhood maltreatment (CM) is an established risk factor for various mental and substance use disorders. This study adds to existing evidence that CM may also be a risk factor for cancer. Methods Based on data from a sample of 9783 men and 12,132 women from the 2012 Canadian Community Health Survey - Mental Health (CCHS-MH), this analysis explores mediated associations between cancer in adulthood and different levels of exposure to three types of CM—childhood physical abuse (CPA), childhood sexual abuse (CSA), and childhood exposure to intimate partner violence (CEIPV). “Cancer” was defined as an affirmative response to either of these questions: “Do you have cancer?” or “Have you ever been diagnosed with cancer?” The potential mediators were: smoking, depression, alcohol abuse/dependence, life stress, obesity, and physical activity. Results For women, but not men, having experienced CM was significantly associated with a cancer diagnosis in adulthood, even when effects due to age and socio-demographic characteristics were controlled. Smoking, life stress, depression, and alcohol abuse/dependence reduced the strength of the association between CM and cancer in women. However, most associations remained statistically significant when controlling for effects due to these behavioural and other mediators. Evidence indicated a “dose-response” relationship, in that the likelihood of reporting cancer increased with the number of abuse types (CPA, CSA, CEIPV) reported, and with the severity of CPA. Conclusions The analyses suggest an association between CM and cancer in women, even when the effects of known risk factors were taken into account. The association was graded, becoming stronger as CM exposure increased. Implications for the provision of cancer screening and other health care services to women with histories of CM to reduce health disparities are discussed.

Classic late infantile neuronal ceroid lipofuscinosis (CLN2 disease) is caused by a deficiency of tripeptidyl-peptidase-1. In 2017, the first CLN2 enzyme replacement therapy (ERT) cerliponase alfa (Brineura) was approved by the FDA and EMA. The CLN2 disease clinical rating scale (CLN2 CRS) was developed to monitor loss of motor function, language and vision as well as frequency of generalised tonic clonic seizures. Using CLN2 CRS in an open label clinical trial it was shown that Brineura slowed down the progression of CLN2 symptoms. Neurofilament light chain (NfL) is a protein highly expressed in myelinated axons. An increase of cerebrospinal fluid (CSF) and blood NfL is found in a variety of neuroinflammatory, neurodegenerative, traumatic, and cerebrovascular diseases. We analysed CSF NfL in CLN2 patients treated with Brineura to establish whether it can be used as a possible biomarker of response to therapy. Newly diagnosed patients had CSF samples collected and analysed at first treatment dose and up to 12 weeks post-treatment to look at acute changes. Patients on a compassionate use programme who were already receiving ERT for approximately 1yr had CSF samples collected and NfL analysed over the following 1.3 years (2.3 years post-initiation of ERT) to look at long-term changes. All newly diagnosed patients we investigated with classical late infantile phenotype had high NfL levels >2000 pg/ml at start of treatment. No significant change was observed in NfL up to 12 weeks post-treatment. After one year of ERT, two out of six patients still had high NfL levels, but all patients showed a continued decrease, and all had low NfL levels after two years on ERT. NfL levels appear to correspond and predict improved clinical status of patients on ERT and could be useful as a biomarker to monitor neurodegeneration and verify disease modification in CLN2 patients on ERT.

Main objective There is limited information on how patient outcomes have changed during the COVID-19 pandemic. This study characterizes changes in mortality, intubation, and ICU admission rates during the first 20 months of the pandemic. Study design and methods University of Wisconsin researchers collected and harmonized electronic health record data from 1.1 million COVID-19 patients across 21 United States health systems from February 2020 through September 2021. The analysis comprised data from 104,590 adult hospitalized COVID-19 patients. Inclusion criteria for the analysis were: (1) age 18 years or older; (2) COVID-19 ICD-10 diagnosis during hospitalization and/or a positive COVID-19 PCR test in a 14-day window (+/- 7 days of hospital admission); and (3) health system contact prior to COVID-19 hospitalization. Outcomes assessed were: (1) mortality (primary), (2) endotracheal intubation, and (3) ICU admission. Results and significance The 104,590 hospitalized participants had a mean age of 61.7 years and were 50.4% female, 24% Black, and 56.8% White. Overall risk-standardized mortality (adjusted for age, sex, race, ethnicity, body mass index, insurance status and medical comorbidities) declined from 16% of hospitalized COVID-19 patients (95% CI: 16% to 17%) early in the pandemic (February-April 2020) to 9% (CI: 9% to 10%) later (July-September 2021). Among subpopulations, males (vs. females), those on Medicare (vs. those on commercial insurance), the severely obese (vs. normal weight), and those aged 60 and older (vs. younger individuals) had especially high mortality rates both early and late in the pandemic. ICU admission and intubation rates also declined across these 20 months. Conclusions Mortality, intubation, and ICU admission rates improved markedly over the first 20 months of the pandemic among adult hospitalized COVID-19 patients although gains varied by subpopulation. These data provide important information on the course of COVID-19 and identify hospitalized patient groups at heightened risk for negative outcomes. Trial registration ClinicalTrials.gov Identifier: NCT04506528 (https://clinicaltrials.gov/ct2/show/NCT04506528).

During pregnancy and lactation, maternal bone mineral density (BMD) is reduced as calcium is mobilized to support offspring bone development. In humans, BMD returns to pre-pregnancy levels shortly after delivery, shifting from a high rate of bone resorption during pregnancy and lactation, into a rapid phase of bone formation post-lactation. This rapid change in bone turnover may provide an opportunity to stimulate a greater gain in BMD and stronger trabecular and cortical structure than present pre-pregnancy. Providing polyphenols present in red rooibos herbal tea may promote such an effect. In vitro, red rooibos polyphenols stimulate osteoblast activity, reduce osteoclastic resorption, and increase mineral production. The study objective was to determine if consuming red rooibos from pre-pregnancy through to 4 months post-lactation resulted in a higher BMD and improved trabecular and cortical bone structure in a commonly used rat model. Female Sprague-Dawley rats (n = 42) were randomized to one of the following groups: PREG TEA (pregnant, received supplemental level of red rooibos in water: ~2.6 g /kg body weight/day in water), PREG WATER (pregnant, received water), or NONPREG CON (age-matched, non-pregnant control, received water) from 2 weeks pre-pregnancy (age 8 weeks) through to 4 months post-lactation. Rats were fed AIN-93G (pre-pregnancy through to the end of lactation) and AIN-93M (post-lactation onwards). BMD and trabecular structure (bone volume fraction, trabecular number, trabecular separation) were improved (p < 0.05) by 1- or 2-months post-lactation when comparing PREG TEA to PREG CON, though neither group recovered to the level of NONPREG CON. Cortical outcomes (cortical area fraction, cortical thickness, tissue mineral density) for PREG TEA and PREG CON were reduced (p < 0.05) following lactation but returned to the level of NONPREG CON by 2-months post-lactation, with the exception of cortical thickness. The lack of recovery of BMD and key outcomes of trabecular bone structure was unexpected. While consumption of red rooibos did not result in stronger bone post-lactation, red rooibos did support the partial recovery of trabecular BMD and bone structure following pregnancy and lactation. The findings also provide insight into the timing and dose of polyphenols to study in future interventions.

Three-dimensional particle tracking is a routine experimental procedure for various biophysical applications including magnetic tweezers. A common method for tracking the axial position of particles involves the analysis of diffraction rings whose pattern depends sensitively on the axial position of the bead relative to the focal plane. To infer the axial position, the observed rings are compared with reference images of a bead at known axial positions. Often the precision or accuracy of these algorithms is measured on immobilized beads over a limited axial range, whereas many experiments are performed using freely mobile beads. This inconsistency raises the possibility of incorrect estimates of experimental uncertainty. By manipulating magnetic beads in a bidirectional magnetic tweezer setup, we evaluated the error associated with tracking mobile magnetic beads and found that the error of tracking a moving magnetic bead increases by almost an order of magnitude compared with the error of tracking a stationary bead. We found that this additional error can be ameliorated by excluding the center-most region of the diffraction ring pattern from tracking analysis. Evaluation of the limitations of a tracking algorithm is essential for understanding the error associated with a measurement. These findings promise to bring increased resolution to three-dimensional bead tracking of magnetic microspheres.

Dentistry and medicine traditionally practice as separate professions despite sharing goals for optimal patient health. Many US residents experience both poor oral and general health, with difficulty accessing care. More efficient collaboration between these professions could enhance health. The COVID-19 pandemic disclosed further disparities while underscoring concerns that physician supply is inadequate for population needs. Hence, enhancing healthcare provider education to better meet the public's health needs is critical. The proposed titles “Oral Physician” or “Oral Health Primary Care Provider” (OP-PCP) acknowledge dentist's capacity to diagnose and manage diseases of the orofacial complex and provide some basic primary healthcare. The US Surgeon General's National Prevention Council and others recommend such models. Medical and dental education already overlap considerably, thus it is plausible that dental graduates could be trained as OP-PCPs to provide primary healthcare such as basic screening and preventive services within existing dental education standards. In 2018, 23 dental and medical educators participated in an expert-opinion elicitation process to review educational competencies for this model. They demonstrated consensus on educational expansion and agreed that the proposed OP-PCP model could work within existing US Commission on Dental Accreditation (CODA) standards for predoctoral education. However, there were broader opinions on scope of practice details. Existing CODA standards could allow interested dental programs to educate OP-PCPs as a highly-skilled workforce assisting with care of medically-complex patients and to helping to reduce health disparities. Next steps include broader stakeholder discussion of OC-PCP competencies and applied studies including patient outcome assessments.

Functional magnetic resonance imaging for presurgical brain mapping enables neurosurgeons to identify viable tissue near a site of operable pathology which might be at risk of surgery-induced damage. However, focal brain pathology (e.g., tumors) may selectively disrupt neurovascular coupling while leaving the underlying neurons functionally intact. Such neurovascular uncoupling can result in false negatives on brain activation maps thereby compromising their use for surgical planning. One way to detect potential neurovascular uncoupling is to map cerebrovascular reactivity using either an active breath-hold challenge or a passive resting-state scan. The equivalence of these two methods has yet to be fully established, especially at a voxel level of resolution. To quantitatively compare breath-hold and resting-state maps of cerebrovascular reactivity, we first identified threshold settings that optimized coverage of gray matter while minimizing false responses in white matter. When so optimized, the resting-state metric had moderately better gray matter coverage and specificity. We then assessed the spatial correspondence between the two metrics within cortical gray matter, again, across a wide range of thresholds. Optimal spatial correspondence was strongly dependent on threshold settings which if improperly set tended to produce statistically biased maps. When optimized, the two CVR maps did have moderately good correspondence with each other (mean accuracy of 73.6%). Our results show that while the breath-hold and resting-state maps may appear qualitatively similar they are not quantitatively identical at a voxel level of resolution.

Objective To explore factors behind inpatient admissions by high-cost users (HCUs) in pre-end-stage chronic kidney disease (CKD).Design Retrospective analysis of CKD.QLD Registry and hospital admissions of the Queensland Government Department of Health recorded between 1 July 2011 and 30 June 2016.Setting Queensland public and private hospitals.Participants 5096 individuals with CKD who consented to the CKD.QLD Registry via 1 of 11 participating sites.Main outcomes Associations of HCU status with patient characteristics, pathways and diagnoses behind hospital admissions at 12 months.Results Age, advanced CKD, primary renal diagnosis, cardiovascular disease and hypertension were predictors of the high-cost outcome. HCUs were more likely than non-HCUs to be admitted by means of episode change (relative risk: 5.21; 95% CI 5.02 to 5.39), 30-day readmission (2.19; 2.13 to 2.25), scheduled readmission (1.29; 1.11 to 1.46) and emergency (1.07; 1.02 to 1.13), for diagnoses of the nervous (1.94; 1.74 to 2.15), circulatory (1.24; 1.14 to 1.34) and respiratory (1.2; 1.03 to 1.37) systems and other factors influencing health status (1.92; 1.74 to 2.09).Conclusions The high relevance of episode change and other factors influencing health status revealed that a substantial part of excess demand for inpatient care was associated with discordant conditions often linked to frailty, decline in psychological health and social vulnerability. This suggests that multidisciplinary models of care that aim to manage discordant comorbidities and address psychosocial determinants of health, such as renal supportive care, may play an important role in reducing inpatient admissions in this population.

Equine herpesvirus 1 (EHV-1) ubiquitously infects horses worldwide and causes respiratory disease, abortion, and equine herpesvirus myeloencephalopathy. Protection against EHV-1 disease is elusive due to establishment of latency and immune-modulatory features of the virus. These include the modulation of interferons, cytokines, chemokines, antigen presentation, and cellular immunity. Because the modulation of immunity likely occurs at the site of first infection—the respiratory epithelium, we hypothesized that the mucosal influenza vaccine Flu Avert® I.N. (Flu Avert), which is known to stimulate strong antiviral responses, will enhance antiviral innate immunity, and that these responses would also provide protection from EHV-1 infection. To test our hypothesis, primary equine respiratory epithelial cells (ERECs) were treated with Flu Avert, and innate immunity was evaluated for 10 days following treatment. The timing of Flu Avert treatment was also evaluated for optimal effectiveness to reduce EHV-1 replication by modulating early immune responses to EHV-1. The induction of interferons, cytokine and chemokine mRNA expression, and protein secretion was evaluated by high-throughput qPCR and multiplex protein analysis. Intracellular and extracellular EHV-1 titers were determined by qPCR. Flu Avert treatment resulted in the modulation of IL-8, CCL2, and CXCL9 starting at days 5 and 6 post-treatment. Coinciding with the timing of optimal chemokine induction, our data also suggested the same timing for reduction of EHV-1 replication. In combination, our results suggest that Flu Avert may be effective at counteracting some of the immune-modulatory properties of EHV-1 at the airway epithelium and the peak for this response occurs 5–8 days post-Flu Avert treatment. Future in vivo studies are needed to investigate Flu Avert as a prophylactic in situations where EHV-1 exposure may occur.