Oligomer Formation Effects on the Separation of Trivalent Lanthanide Fission Products.

The assessment of trivalent lanthanide yields from the fission of uranium-235 is currently achieved using LN (LaNthanide) resin, di(2-ethylhexyl)orthophosphoric acid immobilized on a solid support. However, coelution of lighter lanthanides into terbium (Tb3+) fractions remains a significant problem in recovery of analytically pure fractions. In order to understand how the separation of trivalent lanthanides and yttrium (Ln3+) with LN resin proceeds and how to improve it, their speciation with the organic extractant HDEHP must be fully understood under aqueous conditions. A comprehensive luminescence analysis of aqueous solutions of Ln3+ in contact with HDEHP, along with infrared spectroscopy, elemental combustion analysis, inductively coupled plasma atomic emission spectroscopy (ICP-AES), and mass spectrometry, was used to indicate that an intermediate species is responsible for the coelution; where similar Ln3+ centers (e.g., Eu3+ and Tb3+) are bridged by the O-P-O moiety of deprotonated HDEHP to form large heteronuclear oligomeric structures with the general formula [Ln2(DEHP)6]n. Energy transfer from Tb3+ to Eu3+ in this structure confirms that lanthanide centers are within 10 Å and was used to propose that the oligomeric [Ln2(DEHP)6]n structure is formed rather than a dimeric Ln2(DEHP)6 structure. The effect of this speciation on LN resin column elution is investigated using luminescence spectroscopy, confirming that the oligomeric [Ln2(DEHP)6]n species could disrupt regular elution behavior and cause the problematic bleeding of lighter lanthanides (Sm3+ and Eu3+) into Tb3+ fractions. Resin luminescence measurements were used to propose that the bleeding of the organic extractant HDEHP from its solid support causes the formation of the disruptive oligometallic species.

Dysregulated STAT3 signaling and T cell immunometabolic dysfunction define a targetable, high mortality subphenotype of critically ill children.

Sepsis is the leading cause of death of hospitalized children worldwide. Despite the established link between immune dysregulation and mortality in pediatric sepsis, it remains unclear which host immune factors contribute causally to adverse sepsis outcomes. Identifying modifiable pathobiology is an essential first step to successful translation of biologic insights into precision therapeutics. We designed a prospective, longitudinal cohort study of 88 critically ill pediatric patients with multiple organ dysfunction syndrome (MODS), including patients with and without sepsis, to define subphenotypes associated with targetable mechanisms of immune dysregulation. We first assessed plasma proteomic profiles and identified shared features of immune dysregulation in MODS patients with and without sepsis. We then employed consensus clustering to define three subphenotypes based on protein expression at disease onset and identified a strong association between subphenotype and clinical outcome. We next identified differences in immune cell frequency and activation state by MODS subphenotype and determined the association between hyperinflammatory pathway activation and cellular immunophenotype. Using single cell transcriptomics, we demonstrated STAT3 hyperactivation in lymphocytes from the sickest MODS subgroup and then identified an association between STAT3 hyperactivation and T cell immunometabolic dysregulation. Finally, we compared proteomics findings between patients with MODS and patients with inborn errors of immunity that amplify cytokine signaling pathways to further assess the impact of STAT3 hyperactivation in the most severe patients with MODS. Overall, these results identify a potentially pathologic and targetable role for STAT3 hyperactivation in a subset of pediatric patients with MODS who have high severity of illness and poor prognosis.

Using a Novel Digital Go/No-Go to Dissociate Intra-subject Temporal Fluctuations in Reaction Time and Accuracy.

Impulsivity can be a risk factor for serious complications for those with mood disorders. To understand intra-individual impulsivity variability, we analyzed longitudinal data of a novel gamified digital Go/No-Go (GNG) task in a clinical sample (n=43 mood disorder participants, n=17 healthy controls) and an open-science sample (n=121, self-reported diagnoses). With repeated measurements within-subject, we disentangled two aspects of GNG: reaction time and accuracy in response inhibition (i.e., incorrect No-Go trials) with respect to diurnal and potential learning effects. Mixed-effects models showed diurnal effects in reaction time but not accuracy, with a significant effect of hour on reaction time in the clinical sample and the open-science sample. Moreover, subjects improved on their response inhibition but not reaction time. Additionally, significant interactions emerged between depression symptom severity and time-of-day in both samples, supporting that repeated administration of our GNG task can yield mood-dependent circadian rhythm-aware biomarkers of neurocognitive function.

Sport-related concussions in baseball and softball: do mechanisms of injury affect recovery?

OBJECTIVE: Baseball and softball pose unique risks for sport-related concussion (SRC). Although these are not collision sports, concussions in baseball and softball can nonetheless involve high-speed impacts. In a regional, single-institution cohort of baseball and softball athletes who sustained an SRC, the current study sought to 1) describe the mechanisms of injury that led to SRC, and 2) compare initial symptom burden and recovery metrics across mechanisms, including time to return to learn (RTL), time to symptom resolution, and time to return to play (RTP) by mechanism of injury. METHODS: A retrospective cohort study was performed of baseball and softball athletes 12 to 23 years old who sustained an SRC between November 2017 and April 2022. Mechanisms of injury were divided into two categories: 1) contact mechanism (i.e., what initiated contact with the injured player, such as head-to-ball), and 2) player mechanism (i.e., the action the injured player was performing at the time of injury, such as fielding). The recovery outcomes of time to RTL, symptom resolution, and RTP were compared between mechanisms using bivariate analysis and multivariable regression analysis, controlling for sex, age, time to present to concussion clinic, and initial total symptom score. RESULTS: The sample included 58 baseball and softball players (60.3% female, mean age 16.0 ± 1.9 years). Most SRCs (62.1%) occurred during competition. Head-to-ball (50.0%) was the most common contact mechanism, followed by head-to-head/body (31.0%) and head-to-wall/ground/equipment (17.2%). Fielding (63.8%) was the most common player mechanism, followed by drills (20.7%) and running (13.8%). SRCs sustained in practice had significantly longer RTL (median 10.0 [interquartile range (IQR) 3.3-16.3] vs 4.0 [IQR 2.0-8.0] days; U = 421.5, p = 0.031) and symptom resolution (37.0 [IQR 18.0-90.0] vs 14.0 [IQR 7.0-41.0] days; U = 406.5, p = 0.025) compared with SRCs sustained in competition. Multivariable regression analysis revealed that head-to-wall/ground/equipment contact mechanism was associated with longer RTL (ß = 0.30, 95% CI 0.07-0.54, p = 0.013). CONCLUSIONS: The current study found that SRCs in baseball and softball occurred more often in competition than in practice. Head-to-ball and fielding were the most common contact and player mechanisms, respectively. SRCs sustained in practice were associated with longer time to RTL and symptom resolution, and head-to-wall/ground/equipment was associated with longer RTL in multivariable regression analysis. These results provide empirical data to improve concussion safety in baseball/softball.

Acute psychological symptom profiles in high school athletes following sport-related concussion.

OBJECTIVE: Psychological symptoms following a sport-related concussion may affect recovery in adolescent athletes. Therefore, the aims of this study were to 1) describe the proportion of athletes with acute psychological symptoms, 2) identify potential predictors of higher initial psychological symptoms, and 3) determine whether psychological symptoms affect recovery in a cohort of concussed high school athletes. METHODS: A retrospective cohort study of high school athletes (14-18 years of age) who sustained a sport-related concussion from November 2017 to April 2022 and presented to a multidisciplinary concussion center was performed. The main independent variable was psychological symptom cluster score, calculated by summing the four affective symptoms on the initial Post-Concussion Symptom Scale (PCSS) (i.e., irritability, sadness, nervousness, feeling more emotional). The psychological symptom ratio was defined as the ratio of the psychological symptom cluster score divided by the total initial PCSS score. The outcomes included time to return to learn (RTL), symptom resolution, and time to return to play (RTP). Univariable and multivariable regressions were performed to adjust for demographic factors and health history. RESULTS: A total of 431 athletes (58.0% female, mean age 16.2 ± 1.3 years) were included. Nearly half of the sample (45%) reported at least one psychological symptom, with a mean psychological symptom cluster score of 4.2 ± 5.2 and psychological symptom cluster ratio of 0.10 ± 0.11. Irritability was the most commonly endorsed psychological symptom (38.1%), followed by feeling more emotional (30.2%), nervousness (25.3%), and sadness (22.0%). Multivariable regression showed that female sex (B = 2.15, 95% CI 0.91-3.39; p < 0.001), loss of consciousness (B = 1.91, 95% CI 0.11-3.72; p = 0.037), retrograde/anterograde amnesia (B = 1.66, 95% CI 0.20-3.11; p = 0.026), and psychological history (B = 2.96, 95% CI 1.25-4.70; p < 0.001) predicted an increased psychological symptom cluster score. Female sex (B = 0.03, 95% CI 0.00-0.06; p = 0.031) and psychological history (B = 0.06, 95% CI 0.02-0.10; p = 0.002) predicted an increased psychological symptom ratio. Multivariable linear regression showed that both higher psychological symptom cluster score and ratio were associated with longer times to RTL, symptom resolution, and RTP. CONCLUSIONS: In a cohort of high school athletes, 45% reported at least one psychological symptom, with irritability being most common. Female sex, loss of consciousness, amnesia, and a psychological history were significantly associated with an increased psychological symptom cluster score. Higher psychological symptom cluster score and psychological symptom ratio independently predicted longer recovery. These results reinforce the notion that psychological symptoms after concussion are common and may negatively impact recovery.

Examining for gender differences in return to learn following sport-related concussion in high school student athletes.

OBJECTIVE: Prior studies have investigated associations between gender, symptom resolution, and time to return to play following sport-related concussion (SRC). However, there is a notable gap in research regarding the association between gender and return to learn (RTL) in adolescents. Therefore, this study 1) compared the patterns of RTL between boys and girls who are high school student athletes, and 2) evaluated the possible association between gender and time to RTL after adjusting for covariates. METHODS: A retrospective cohort study of a prospective surveillance program that monitored concussion recovery of athletes in high schools throughout the state of Maine between February 2015 and January 2023 was performed. The primary independent variable was gender, dichotomized as boys and girls. The primary outcome was time to RTL, defined by the number of days for an athlete to return to school without accommodations. Mann-Whitney U-tests were used to compare RTL between the boys and girls. Each athlete's RTL status was dichotomized (i.e., returned vs had not returned) at several time points following injury (i.e., 1, 2, 3, and 4 weeks), and chi-square tests were performed to compare the proportions who achieved RTL between groups. Multivariable linear regression analyses were performed to evaluate the predictive value of gender on RTL. Covariates included age, number of previous concussions, history of learning disability or attention-deficit disorder or attention-deficit/hyperactivity disorder, history of a psychological condition, history of headaches or migraines, initial Sport Concussion Assessment Tool (SCAT3/SCAT5) score, and days to evaluation. RESULTS: Of 895 high school athletes, 488 (54.5%) were boys and 407 (45.5%) were girls. There was no statistically significant difference in median [IQR] days to RTL between genders (6.0 [3.0-11.0] vs 6.0 [3.0-12.0] days; U = 84,365.00, p < 0.375). A greater proportion of boys successfully returned to learn without accommodations by 3 weeks following concussion (93.5% vs 89.4%; χ2 = 4.68, p = 0.030), but no differences were found at 1, 2, or 4 weeks. A multivariable model predicting days to RTL showed that gender was not a significant predictor of RTL (p > 0.05). Longer days to evaluation (ß = 0.10, p = 0.021) and higher initial SCAT3/SCAT5 scores (ß = 0.15, p < 0.001) predicted longer RTL. CONCLUSIONS: In a cohort of high school athletes, RTL did not differ between boys and girls following SRC. Gender was not a significant predictor of RTL. Longer days to evaluation and higher initial symptom scores were associated with longer RTL.

Age of First Exposure to Contact Sports Is Not Associated With Worse Later-In-Life Brain Health in a Cohort of Community-Dwelling Older Men.

OBJECTIVE: To evaluate whether early age of first exposure to contact sports (AFE-CS) is associated with worse long-term brain health outcomes. DESIGN: A cross-sectional, survey study of older men with a history of contact sport participation was completed. SETTING: Tertiary care facility. PARTICIPANTS: A cohort of community-dwelling older men dichotomized by using AFE-CS (<12 years vs ≥12 years). INTERVENTIONS: Independent variables included a dichotomized group of AFE-CS (<12 years vs ≥12 years). MAIN OUTCOME MEASURES: Brain health outcomes measured by depression, anxiety, cognitive difficulties, and neurobehavioral symptoms. Endorsements of general health problems, motor symptoms, and psychiatric history were also collected. Age of first exposure groups was compared using t tests, χ2 tests, and multivariable linear regressions, which included the following covariates: age, number of prior concussions, and total years of contact sport. RESULTS: Of 69 men aged 70.5 ± 8.0 years, approximately one-third of the sample (34.8%) reported AFE-CS before age 12 years. That group had more years of contact sports (10.8 ± 9.2 years) compared with those with AFE-CS ≥12 (5.6 ± 4.5 years; P = 0.02). No differences were found after univariate testing between AFE-CS groups on all outcomes (P-values >0.05). Multivariable models suggest that AFE-CS is not a predictor of depression or anxiety. Those in the AFE-CS <12 group had fewer cognitive difficulties (P = 0.03) and fewer neurobehavioral symptoms (P = 0.03). CONCLUSIONS: Those with AFE-CS <12 to contact sports did not have worse long-term brain health outcomes compared with those with AFE-CS ≥12. Individuals with AFE-CS <12 had significantly lower British Columbia Cognitive Complaints Inventory and Neurobehavioral Symptom Inventory scores compared with those with AFE-CS ≥12. CLINICAL RELEVANCE: The benefits of earlier AFE-CS may outweigh the risks of head strikes and result in comparable long-term brain health outcomes.

Dental care access for children in the United States.

OBJECTIVES: To evaluate access to dental care for children in the United States. METHODS: The study population included children in 48 states and the District of Columbia. Using multiple data sources, dental care access was estimated at the community level by matching dental care supply and demand using mathematical modeling accounting for access constraints. Outcome measures included percent-met demand, travel distance, and percentage of underserved and unserved communities. Multiple scenarios to improve Medicaid/CHIP participation of dentists were evaluated. RESULTS: Medicaid-insured and CHIP-insured children exhibited lower access compared to those privately insured. The percent-met demand was lower than 50% for Medicaid-insured children and CHIP-insured children for 42 and 34 states, respectively. Percent-met demand was higher than 50% for private-insured children except for Texas and West Virginia. Increasing Medicaid/CHIP participation of dentists resulted in improving access for public-insured children. At 100% Medicaid/CHIP participation, all states exhibited different degrees of percent-met demand increase for publicly insured children, from 7% to 46%. The percent-met demand across all children ranged in 23.8%-82.9% under 70% participation rate versus 22%-83% under 100% participation rate. No single participation rate improved access for all children uniformly across all states. CONCLUSIONS: This study found that dental care access was lower for children with public insurance than those with private access across all states, although states responded differently to changes in Medicaid/CHIP participation. Increasing access for children with public insurance would reduce disparities, but overall children's access to dental care would be better improved by expanding the oral health workforce.

Impact of Targeted Systemic Therapy and Radiotherapy on Patients Undergoing Spine Surgery for Metastatic Renal Cell Carcinoma.

BACKGROUND: In patients undergoing spine surgery for renal cell carcinoma (RCC), we sought to: (1) describe patterns of postoperative targeted systemic therapy and radiotherapy (RT), (2) compare perioperative outcomes among those treated with targeted systemic therapy to those without, and (3) evaluate the impact of targeted systemic therapy and/or RT on overall survival (OS) and local recurrence (LR). METHODS: A single-institution, retrospective cohort study of patients undergoing spine surgery for metastatic RCC from 2010 to 2021 was undertaken. Treatment groups were RT alone, targeted systemic therapy alone, dual therapy consisting of RT and targeted systemic therapy, and neither therapy. Multivariable Cox regression controlled for age, race, sex, insurance, and preoperative targeted systemic therapy. RESULTS: Forty-nine patients underwent spine surgery for RCC. Postoperatively, 4 patients (8%) received RT alone, 19 (38.8%) targeted systemic therapy alone, 12 (24.5%) dual therapy, and 13 (28.6%) neither. All groups were similar in demographics, preoperative Karnofsky Performance Score (P = 0.372), tumor size (P = 0.413), readmissions (P = 0.884), complications (P = 0.272), Karnofsky Performance Score (P = 0.466), and Modified McCormick Scale (P = 0.980) at last follow-up. Higher 1-year survival was found in dual therapy (83.3%) compared with other therapies. OS was significantly longer in patients with dual therapy compared with other therapies (log-rank; P = 0.010). Multivariate Cox regression (HR = 0.08, 95% CI = 0.02-0.31, P < 0.001) showed longer OS in dual therapy compared with other therapies. Seven patients (14.3%) experienced LR, and a similar time to LR was found between groups (log-rank; P = 0.190). CONCLUSION: In patients undergoing metastatic spine surgery for RCC, postoperative dual therapy demonstrated significantly higher 1-year survival and OS compared with other therapies. CLINICAL RELEVANCE: Multidisciplinary management of metastatic RCC is necessary to ensure timely implementation of targeted systemic therapy and RT to improve outcomes.

A mapped dataset of surface ocean acidification indicators in large marine ecosystems of the United States.

Mapped monthly data products of surface ocean acidification indicators from 1998 to 2022 on a 0.25° by 0.25° spatial grid have been developed for eleven U.S. large marine ecosystems (LMEs). The data products were constructed using observations from the Surface Ocean CO2 Atlas, co-located surface ocean properties, and two types of machine learning algorithms: Gaussian mixture models to organize LMEs into clusters of similar environmental variability and random forest regressions (RFRs) that were trained and applied within each cluster to spatiotemporally interpolate the observational data. The data products, called RFR-LMEs, have been averaged into regional timeseries to summarize the status of ocean acidification in U.S. coastal waters, showing a domain-wide carbon dioxide partial pressure increase of 1.4 ± 0.4 µatm yr-1 and pH decrease of 0.0014 ± 0.0004 yr-1. RFR-LMEs have been evaluated via comparisons to discrete shipboard data, fixed timeseries, and other mapped surface ocean carbon chemistry data products. Regionally averaged timeseries of RFR-LME indicators are provided online through the NOAA National Marine Ecosystem Status web portal.

The interaction of size-selected Ru3 clusters with TiO2: depth-profiling of encapsulated clusters.

Ru is a metal of interest in catalysis. Monodisperse Ru3 clusters as catalytic sites are relevant for the development of catalysts because clusters use significantly lower amounts of precious materials for forming active sites due to the small size of the cluster. However, retaining the mono-dispersity of the cluster size after deposition is a challenge because surface energy could drive both agglomeration and encapsulation of the clusters. In the present work Ru3 clusters are deposited by chemical vapor deposition (CVD) of Ru3(CO)12 and cluster source depositions of bare Ru3 onto radio frequency sputter-deposited TiO2 (RF-TiO2) substrates, TiO2(100), and SiO2. When supported on RF-TiO2, bare Ru3 is encapsulated by a layer of titania substrate material during deposition with a cluster source. Ligated Ru3(CO)12 is also encapsulated by a layer of titania when deposited onto sputter-treated RF-TiO2, but only through heat treatment which is required to remove most of the ligands. The titania overlayer thickness was determined to be 1-2 monolayers for Ru3(CO)12 clusters on RF-TiO2, which is thin enough for catalytic or photocatalytic reactions to potentially occur even without clusters being part of the very outermost layer. The implication for catalysis of the encapsulation of Ru3 into the RF-TiO2 is discussed. Temperature-dependent X-ray photoelectron spectroscopy (XPS), angle-resolved XPS, and temperature-dependent low energy ion scattering (TD-LEIS) are used to probe how the cluster-surface interaction changes due to heat treatment and scanning transmission electron microscopy (STEM) was used to image the depth of the surface from side-on.

What are the Protocols and Resources for Sport-Related Concussion Among Top National Collegiate Athletic Association Football Programs? A Cross-Sectional Survey of A5 Schools.

OBJECTIVE: This study summarizes findings from a cross-sectional survey conducted among National Collegiate Athletic Association (NCAA) Division 1 football programs, focusing on sport-related concussion (SRC) protocols for the 2018 season. DESIGN: Cross-sectional survey study. SETTING: 65 football programs within the Autonomy Five (A5) NCAA conferences. PARTICIPANTS: Athletic trainers and team physicians who attended a football safety meeting at the NCAA offices June 17 to 18, 2019, representing their respective institutions. INTERVENTION: Electronic surveys were distributed on June 14, 2019, before the football safety meeting. MAIN OUTCOME MEASURES: Results for 16 unique questions involving SRC protocols and resources were summarized and evaluated. RESULTS: The survey garnered responses from 46 of 65 programs (response rate = 71%). For baseline testing, 98% measured baseline postural stability and balance, 87% used baseline neurocognitive testing, while only 61% assessed baseline vestibular and/or ocular function. Regarding concussion prevention, 51% did not recommend additional measures, while 4% and 24% recommended cervical compression collars and omega-3 supplementation, respectively. In postconcussion treatment, 26% initiated aerobic exercise 1 day postconcussion if symptoms were stable, 24% waited at least 48 hours, 4% waited for the athlete to return to baseline, 11% waited until the athlete became asymptomatic, and 35% determined procedures on a case-by-case basis. CONCLUSIONS: Most institutions assessed postural stability/balance and neurocognitive functioning at baseline and introduced light aerobic exercise within 48 h postconcussion. There was variation in baseline assessment methods and concussion prevention recommendations. These survey findings deepen our understanding of diverse SRC protocols in NCAA football programs.

Liver tissue engineering using decellularized scaffolds: Current progress, challenges, and opportunities.

Liver transplantation represents the only definitive treatment for patients with end-stage liver disease. However, the shortage of liver donors provokes a dramatic gap between available grafts and patients on the waiting list. Whole liver bioengineering, an emerging field of tissue engineering, holds great potential to overcome this gap. This approach involves two main steps; the first is liver decellularization and the second is recellularization. Liver decellularization aims to remove cellular and nuclear materials from the organ, leaving behind extracellular matrices containing different structural proteins and growth factors while retaining both the vascular and biliary networks. Recellularization involves repopulating the decellularized liver with appropriate cells, theoretically from the recipient patient, to reconstruct the parenchyma, vascular tree, and biliary network. The aim of this review is to identify the major advances in decellularization and recellularization strategies and investigate obstacles for the clinical application of bioengineered liver, including immunogenicity of the designed liver extracellular matrices, the need for standardization of scaffold fabrication techniques, selection of suitable cell sources for parenchymal repopulation, vascular, and biliary tree reconstruction. In vivo transplantation models are also summarized for evaluating the functionality of bioengineered livers. Finally, the regulatory measures and future directions for confirming the safety and efficacy of bioengineered liver are also discussed. Addressing these challenges in whole liver bioengineering may offer new solutions to meet the demand for liver transplantation and improve patient outcomes.

Clinical and genetic risk factors for progressive fibrosis in metabolic dysfunction-associated steatotic liver disease.

BACKGROUND: Fibrosis-4 (FIB4) is a recommended noninvasive test to assess hepatic fibrosis among patients with metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we used FIB4 trajectory over time (ie, "slope" of FIB4) as a surrogate marker of liver fibrosis progression and examined if FIB4 slope is associated with clinical and genetic factors among individuals with clinically defined MASLD within the Million Veteran Program Cohort. METHODS: In this retrospective cohort study, FIB4 slopes were estimated through linear regression for participants with clinically defined MASLD and FIB4 <2.67 at baseline. FIB4 slope was correlated with demographic parameters and clinical outcomes using logistic regression and Cox proportional hazard models. FIB4 slope as a quantitative phenotype was used in a genome-wide association analysis in ancestry-specific analysis and multiancestry meta-analysis using METAL. RESULTS: FIB4 slopes, generated from 98,361 subjects with MASLD (16,045 African, 74,320 European, and 7996 Hispanic), showed significant associations with sex, ancestry, and cardiometabolic risk factors (p < 0.05). FIB4 slopes also correlated strongly with hepatic outcomes and were independently associated with time to cirrhosis. Five genetic loci showed genome-wide significant associations (p < 5 × 10-8) with FIB4 slope among European ancestry subjects, including 2 known (PNPLA3 and TM6SF2) and 3 novel loci (TERT 5.1 × 10-11; LINC01088, 3.9 × 10-8; and MRC1, 2.9 × 10-9). CONCLUSIONS: Linear trajectories of FIB4 correlated significantly with time to progression to cirrhosis, with liver-related outcomes among individuals with MASLD and with known and novel genetic loci. FIB4 slope may be useful as a surrogate measure of fibrosis progression.

Effect of bone and analytical method on assessment of bone mineralization in response to dietary phosphorus, phytase, and vitamin D in finishing pigs.

A total of 882 pigs (PIC TR4 × [Fast LW × PIC L02]; initially 33.2 ±â€…0.31 kg) were used in a 112-d study to evaluate the effects of different bones and analytical methods on the assessment of bone mineralization response to changes in dietary P, phytase, and vitamin D in growing pigs. Pens of pigs (20 pigs per pen) were randomized to one of five dietary treatments with nine pens per treatment. Dietary treatments were designed to create differences in bone mineralization and included: 1) P at 80% of NRC (2012) standardized total tract digestible (STTD) P requirement, 2) NRC STTD P with no phytase, 3) NRC STTD P with phytase providing an assumed release of 0.14% STTD P from 2,000 FYT/kg, 4) high STTD P (128% of the NRC P) using monocalcium phosphate and phytase, and 5) diet 4 with additional vitamin D3 from 25(OH)D3. On day 112, one pig per pen was euthanized for bone, blood, and urine analysis. Additionally, 11 pigs identified as having poor body condition which indicated a history of low feed intake (unhealthy) were sampled. There were no differences between treatments for final body weight, average daily gain, average daily feed intake, gain to feed, or bone ash measurements (treatment × bone interaction) regardless of bone ash method. The response to treatment for bone density and bone mineral content was dependent upon the bone sampled (density interaction, P = 0.053; mineral interaction, P = 0.078). For 10th rib bone density, pigs fed high levels of P had increased (P < 0.05) bone density compared with pigs fed NRC levels with phytase, with pigs fed deficient P, NRC levels of P with no phytase, and high STTD P with extra 25(OH)D3 intermediate, with no differences for metacarpals, fibulas, or 2nd ribs. Pigs fed extra vitamin D from 25(OH)D3 had increased (P < 0.05) 10th rib bone mineral content compared with pigs fed deficient P and NRC levels of P with phytase, with pigs fed industry P and vitamin D, and NRC P with monocalcium intermediate. Healthy pigs had greater (P < 0.05) serum Ca, P, vitamin D concentrations, and defatted bone ash than those unhealthy, with no difference between the two health statuses for non-defatted bone ash. In summary, differences between bone ash procedures were more apparent than differences between diets. Differences in bone density and mineral content in response to dietary P and vitamin D were most apparent with 10th ribs.

Lameness is defined as impaired movement or deviation from normal gait. The evaluation of bone mineralization can be an important component of a diagnostic investigation of lameness. Lameness in growing pigs can cause an increase in morbidity and mortality, which leads to economic losses and animal welfare concerns for producers. Calcium and P are the primary minerals in skeletal tissue and their deficiency is considered to be one of the causes of lameness. To evaluate bone mineralization, it is important to know the differences between methodologies used to determine bone ash and the expected differences between the bones analyzed. Furthermore, there has been limited data comparing bone mineralization and serum Ca and P concentrations between healthy pigs and those exhibiting clinical signs of illness (unhealthy). By removing the lipid in the bone (defatting) before the bone is ashed, variation across bones is decreased compared with not removing lipid before ashing (non-defatted). The reduction in variation across bones allows for more differences to be detected among dietary treatments and health statuses of pigs. The 10th rib is more sensitive to detect dietary differences using bone density than metacarpals, fibulas, and 2nd ribs. When comparing healthy vs. unhealthy pigs exhibiting clinical signs of illness, healthy pigs have increased defatted percentage bone ash and serum Ca, P, and vitamin D.

An unbiased ranking of murine dietary models based on their proximity to human metabolic dysfunction-associated steatotic liver disease (MASLD).

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease, encompasses steatosis and metabolic dysfunction-associated steatohepatitis (MASH), leading to cirrhosis and hepatocellular carcinoma. Preclinical MASLD research is mainly performed in rodents; however, the model that best recapitulates human disease is yet to be defined. We conducted a wide-ranging retrospective review (metabolic phenotype, liver histopathology, transcriptome benchmarked against humans) of murine models (mostly male) and ranked them using an unbiased MASLD 'human proximity score' to define their metabolic relevance and ability to induce MASH-fibrosis. Here, we show that Western diets align closely with human MASH; high cholesterol content, extended study duration and/or genetic manipulation of disease-promoting pathways are required to intensify liver damage and accelerate significant (F2+) fibrosis development. Choline-deficient models rapidly induce MASH-fibrosis while showing relatively poor translatability. Our ranking of commonly used MASLD models, based on their proximity to human MASLD, helps with the selection of appropriate in vivo models to accelerate preclinical research.

An active machine learning discovery platform for membrane-disrupting and pore-forming peptides.

Membrane-disrupting and pore-forming peptides (PFPs) play a substantial role in bionanotechnology and can determine the life and death of cells. The control of chemical and ion transport through cell membranes is essential to maintaining concentration gradients. Likewise, the delivery of drugs and intracellular proteins aided by pore-forming agents is of interest in treating malfunctioning cells. Known PFPs tend to be up to 50 residues in length, which is commensurate with the thickness of a lipid bilayer. Accordingly, few short PFPs are known. Here we show that the discovery of PFPs can be accelerated via an active machine learning approach. The approach identified 71 potential PFPs from the 25.6 billion octapeptide sequence space; 13 sequences were tested experimentally, and all were found to have the predicted membrane-disrupting ability, with 1 forming highly stable pores. Experimental verification of the predicted pore-forming ability demonstrated that a range of short peptides can form pores in membranes, while the positioning and characteristics of residues that favour pore-forming behaviour were identified. This approach identified more ultrashort (8-residues, unmodified, non-cyclic) PFPs than previously known. We anticipate our findings and methodology will be useful in discovering new pore-forming and membrane-disrupting peptides for a range of applications from nanoreactors to therapeutics.

Invited Commentary: Raising a High-Pressure Alarm About Pediatric Hypertension.

Hypertension is a common "silent killer" in adult medicine, but epidemiologic estimates of elevated blood pressure in children and adolescents are challenged by under-diagnosis and resultant low utilization of relevant administrative or billing codes. In the article by Horgan et al (Am J Epidemiol 2024), children and adolescents with hypertension and elevated blood pressure were identified using direct assessment of blood pressure measurements available in the electronic health record from both inpatient and outpatient visits ("clinical cohort") in comparison to diagnosis codes ("claims-based cohort"). The study population included 3.75 million pediatric healthcare visits available in the US Food and Drug Administration's Sentinel System. While the study applied a relatively novel methodology to interrogate available clinical data within the EHR to better understand the prevalence of pediatric hypertension and raised concern for a higher occurrence of hypertension among children and adolescents than previously realized using claims codes, the utility of the prevalence estimates may be limited by the potential for misclassification bias inherent in EHR data. However, these data raise important concerns about relaying solely on ICD-9-CM/ICD-10-CM codes to quantify the epidemiology of pediatric hypertension and highlight opportunities to address elevated blood pressure in children that could improve long-term cardiovascular health.

FOXA2 rewires AP-1 for transcriptional reprogramming and lineage plasticity in prostate cancer.

FOXA family proteins act as pioneer factors by remodeling compact chromatin structures. FOXA1 is crucial for the chromatin binding of the androgen receptor (AR) in both normal prostate epithelial cells and the luminal subtype of prostate cancer (PCa). Recent studies have highlighted the emergence of FOXA2 as an adaptive response to AR signaling inhibition treatments. However, the role of the FOXA1 to FOXA2 transition in regulating cancer lineage plasticity remains unclear. Our study demonstrates that FOXA2 binds to distinct classes of developmental enhancers in multiple AR-independent PCa subtypes, with its binding depending on LSD1. Moreover, we reveal that FOXA2 collaborates with JUN at chromatin and promotes transcriptional reprogramming of AP-1 in lineage-plastic cancer cells, thereby facilitating cell state transitions to multiple lineages. Overall, our findings underscore the pivotal role of FOXA2 as a pan-plasticity driver that rewires AP-1 to induce the differential transcriptional reprogramming necessary for cancer cell lineage plasticity.