Predicting blood-brain barrier permeability of molecules with a large language model and machine learning.

Predicting the blood-brain barrier (BBB) permeability of small-molecule compounds using a novel artificial intelligence platform is necessary for drug discovery. Machine learning and a large language model on artificial intelligence (AI) tools improve the accuracy and shorten the time for new drug development. The primary goal of this research is to develop artificial intelligence (AI) computing models and novel deep learning architectures capable of predicting whether molecules can permeate the human blood-brain barrier (BBB). The in silico (computational) and in vitro (experimental) results were validated by the Natural Products Research Laboratories (NPRL) at China Medical University Hospital (CMUH). The transformer-based MegaMolBART was used as the simplified molecular input line entry system (SMILES) encoder with an XGBoost classifier as an in silico method to check if a molecule could cross through the BBB. We used Morgan or Circular fingerprints to apply the Morgan algorithm to a set of atomic invariants as a baseline encoder also with an XGBoost classifier to compare the results. BBB permeability was assessed in vitro using three-dimensional (3D) human BBB spheroids (human brain microvascular endothelial cells, brain vascular pericytes, and astrocytes). Using multiple BBB databases, the results of the final in silico transformer and XGBoost model achieved an area under the receiver operating characteristic curve of 0.88 on the held-out test dataset. Temozolomide (TMZ) and 21 randomly selected BBB permeable compounds (Pred scores = 1, indicating BBB-permeable) from the NPRL penetrated human BBB spheroid cells. No evidence suggests that ferulic acid or five BBB-impermeable compounds (Pred scores < 1.29423E-05, which designate compounds that pass through the human BBB) can pass through the spheroid cells of the BBB. Our validation of in vitro experiments indicated that the in silico prediction of small-molecule permeation in the BBB model is accurate. Transformer-based models like MegaMolBART, leveraging the SMILES representations of molecules, show great promise for applications in new drug discovery. These models have the potential to accelerate the development of novel targeted treatments for disorders of the central nervous system.

Effects of different protein sources on amino acid absorption and plasma appearance of tryptophan, large neutral amino acids, and tryptophan metabolites in pigs.

BACKGROUND: Absorption of tryptophan (TRP) across the gut epithelium is potentially modulated by competing large neutral amino acids (LNAAs), which could affect the appearance of TRP and its metabolites in the bloodstream. OBJECTIVES: This study aimed to determine, in a growing pig model of an adult human, the absorption of TRP and other LNAAs from the gastrointestinal tract, and plasma appearance of TRP, LNAAs and TRP metabolites , in response to dietary proteins varying in TRP content. METHODS: Pigs were adapted for seven days to each of four diets that differed in their protein source and TRP content: 1) alpha-lactalbumin (AL; 9.95mg TRP/g diet DM), 2) whey protein (6.59mg TRP/g), 3) casein (3.73mg TRP/g), or 4) zein (0.14mg TRP/g). On day 8, after a 12h fast, pigs received a test meal consisting of 45g protein, or a protein-free meal, and were euthanized 0 (baseline), 1, 2, 3, 4, or 6h later (n=6 pigs at each time in each meal group). Tryptophan and LNAA absorption from the small intestine, and appearance of TRP, LNAAs and TRP metabolites (melatonin, serotonin, kynurenine pathway metabolites), in the portal vein and systemic circulation, were determined. RESULTS: AL intake resulted in sustained elevated plasma TRP concentrations after an overnight fast. The amount of TRP absorbed was dose-dependently related to protein TRP content (p=0.028), with fastest rates for pigs fed AL (371mg/h). Portal and systemic plasma TRP, TRP/LNAA and the TRP metabolites were highest (p≤0.05) after AL intake , and remained above baseline levels for ∼4h postprandially. Absorption rates of TRP correlated with postprandial plasma TRP and TRP metabolites(p≤0.05). CONCLUSIONS: In adult humans, postprandial plasma TRP and TRP metabolite concentrations can likely be modulated by the TRP content of the meal.

Influence of long-term supplementation of a formulated botanical blend on growth performance and carcass traits in feedlot steers.

Objective: The objective of this study was to determine if a formulated blend of capsicum oleoresin, clove essential oil, and garlic essential oil (Fytera® Advance - Selko® USA, Indianapolis IN; CCG) influences measures of cattle growth, efficiency, or carcass traits, during the finishing phase in steers fed a concentrate-based diet. Methods: Charolais × Angus steers (n = 96; initial shrunk BW = 391± 34.0 kg) were used in a 144-d (16 February 2023 to 9 July 2023) finishing feedlot experiment in Brookings, SD. Steers were individually weighed and allotted to one of 14 pens (6 to 7 steers; 7 pens/treatment) in a randomized complete block design and randomly assigned to 1 of 2 treatments: control diet without the test product (CON) or a diet including CCG at 500 mg/steer daily (CCG). Steers were fed twice daily, and bunks were managed according to a slick bunk system. Results: There were no differences (P ≥ 0.10) in any growth performance outcomes from d 1 to 35, 36 to 70, or 71 to 98. From d 99 to 144 steers from CCG tended to have 5% greater ADG (P = 0.09) and 8% improved G:F (P = 0.01). No differences (P ≥ 0.15) were noted for cumulative growth performance measures. No differences were noted for any carcass measurements or categorical carcass outcomes, nor lung or liver health outcomes (P ≥ 0.15). Conclusion: The use of CCG had no influence on cumulative growth performance responses. However, the use of CCG improved G:F during the late feeding period.

Evaluation of long-term supplementation of a Bacillus subtilis direct-fed microbial and enzymatically hydrolyzed yeast cell culture product used alone or in combination on Clostridia, Clostridium perfringens, Escherichia coli, and Salmonella prevalence in beef steers.

The objective was to determine the influence of long-term supplementation (258 d) of a direct-fed microbial (DFM) and/or yeast cell wall (YCW) product on bacterial populations in beef steers. Single-sourced Charolais × Red Angus steers (n = 256; body weight = 246 ±â€…1.68 kg) were used in a randomized complete block design and blocked by location into one of four treatments: 1) fed no DFM and no YCW (Control); 2) fed only the DFM (DFM; Certillus CP B1801 Dry, 28 g/steer d-1 ); 3) fed only the YCW (YCW; Celmanax; 18 g/steer d-1 ); and 4) fed the DFM and the YCW (DFM+YCW). Steers were vaccinated for respiratory and clostridial diseases and treated for internal and external parasites at processing and individually weighed on days 1, 14, 42, 77, 105, 133, 161, 182, 230, and 258. To determine bacterial prevalence, fecal samples were collected on days 1, 14, 77, 133, 182, and 230 and environmental (pen area, feed, and water) samples were collected at the beginning of the week when cattle were weighed. No treatment × day interactions or treatment effects (P > 0.05) were observed between treatment groups at any sampling days for the bacterial populations. Samples on days 1, 133, and 182 had greater (P < 0.05) Clostridia levels compared to the other sampling points but were not different from each other. Clostridia levels were also greater (P < 0.05) on day 77 compared to days 14 and 230. Samples on days 77 and 230 had greater (P < 0.05) Clostridium perfringens levels compared to the other sampling points but were not different (P > 0.05) from each other. Samples on days 1 and 14 had lower (P < 0.05) total Escherichia coli levels compared to the other sampling points but were not different (P > 0.05) from each other. Escherichia coli levels on day 77 were higher (P < 0.05) compared to days 133, 182, and 230. Little Salmonella prevalence (1.5%) was observed throughout the study. This study had greater levels of Clostridia compared to small and large commercial feedlots in the Church and Dwight research database, but C. perfringens, total and pathogenic E. coli, and Salmonella prevalence were notably lower. Collectively, there were no appreciable treatment influences on bacterial populations. These data further indicate a low pathogenic bacterial challenge at the trial site, which could partially explain the lack of differences with DFM or YCW supplementation. The DFM and YCW used alone or in combination cannot be expected to show additional benefits when animals are relatively unstressed with a low pathogenic bacterial challenge.

The objective of this research was to determine the influence of long-term supplementation (258 d) of a direct-fed microbial (DFM) and/or yeast cell wall (YCW) product on bacterial populations in beef steers. Collectively, there were no appreciable treatment influences on bacterial populations. These data further indicate a low pathogenic bacterial challenge at the trial site, which could further explain the reasons for little differences. The DFM and YCW used alone or in combination cannot be expected to show productive benefits when animals are relatively unstressed with a low pathogenic bacterial challenge.

Mechanisms and Barriers in Nanomedicine: Progress in the Field and Future Directions.

In recent years, steady progress has been made in synthesizing and characterizing engineered nanoparticles, resulting in several approved drugs and multiple promising candidates in clinical trials. Regulatory agencies such as the Food and Drug Administration and the European Medicines Agency released important guidance documents facilitating nanoparticle-based drug product development, particularly in the context of liposomes and lipid-based carriers. Even with the progress achieved, it is clear that many barriers must still be overcome to accelerate translation into the clinic. At the recent conference workshop "Mechanisms and Barriers in Nanomedicine" in May 2023 in Colorado, U.S.A., leading experts discussed the formulation, physiological, immunological, regulatory, clinical, and educational barriers. This position paper invites open, unrestricted, nonproprietary discussion among senior faculty, young investigators, and students to trigger ideas and concepts to move the field forward.

Heat Treatment and Homogenization Influence the Gastric Digestion of Bovine Milk Protein in Growing Pigs as an Adult Human Model.

BACKGROUND: Bovine milk processing influences the structure of the curd formed during gastric digestion, which may alter gastric protein hydrolysis and impact amino acid (AA) release into the small intestine. OBJECTIVES: This study aimed to determine the influence of heat treatment and homogenization on the gastric protein digestion and AA emptying of bovine milk. METHODS: Nine-wk-old pigs (n = 144) consumed either raw, pasteurized nonhomogenized (PNH), pasteurized homogenized (PH), or ultra-high-temperature homogenized (UHT) bovine milk for 10 d. On day 11, fasted pigs received the milk treatment (500 mL) before gastric contents were collected at 0, 20, 60, 120, 180, and 300 min postprandially. The apparent degree of gastric protein hydrolysis (based on the release of free amino groups), apparent gastric disappearance of individual proteins [based on sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) gel band intensity], and the gastric emptying of digested protein and AA were determined. RESULTS: During the first 60 min, the rate of apparent gastric protein hydrolysis was fastest in pigs fed UHT milk (0.29%/min compared with on average 0.07%/min in pigs fed raw, PNH, and PH milk). Differences in the apparent degree of gastric protein hydrolysis and emptying were reflected in the rate of digested protein entering the small intestine. The AA gastric emptying half-time was generally shorter in pigs fed PH and UHT milk than in pigs fed raw and PNH milk. For example, the gastric release of total essential AA was >2-fold faster (P < 0.01) in pigs fed PH or UHT milk than that in pigs fed raw or PNH milk (i.e., homogenized compared with nonhomogenized milk). CONCLUSIONS: Heat treatment and homogenization increased the apparent gastric degree of protein hydrolysis and the release of digested protein into the small intestine. However, the rate of AA entering the small intestine was mainly increased by homogenization.

The impact of heat-set milk protein gel textures modified by pH on circulating amino acid appearance and gastric function in healthy female adults: a randomised controlled trial.

Modification of dairy proteins during processing impacts structural assemblies, influencing textural and nutritional properties of dairy products, and release and availability of amino acids during digestion. By modifying only pH, acid heat-set bovine dairy gels with divergent textural properties were developed to alter protein digestion. In vitro assay confirmed faster digestion of protein from a firm gel (pH 5.65) versus a soft gel (pH 6.55). We hypothesised that firm gel (FIRM-G; pH 5.6) would result in greater indispensable amino acid (IAA) appearance in circulation over 5 h and corresponding differences in gastric myoelectrical activity relative to soft gel (SOFT-G; pH 6.2). In a randomised, single-blind cross-over trial, healthy females (n = 20) consumed 150 g of each gel; plasma amino acid appearance was assessed over 5 hours. Iso-nitrogenous, iso-caloric gels were prepared from identical mixtures of bovine milk and whey protein concentrates; providing 17.7 g (FIRM-G) and 18.9 g (SOFT-G) of protein per serving. Secondary outcomes included gastric myoelectrical activity measured by body surface gastric mapping, glycaemic, triglyceridaemic, and subjective appetite and digestive responses. Overall plasma IAA (area under the curve) did not differ between gels. However, plasma IAA concentrations were higher, and increased more rapidly over time after SOFT-G compared with FIRM-G (1455 ± 53 versus 1350 ± 62 µmol L-1 at 30 min, p = 0.024). Similarly, total, branched-chain and dispensable amino acids were higher at 30 min with SOFT-G than FIRM-G (total: 3939 ± 97 versus 3702 ± 127 µmol L-1, p = 0.014; branched-chain: 677 ± 30 versus 619 ± 34 µmol L-1, p = 0.047; dispensable: 2334 ± 53 versus 2210 ± 76 µmol L-1, p = 0.032). All other measured parameters were similar between gels. Peak postprandial aminoacidaemia was higher and faster following ingestion of SOFT-G. Customised plasma amino acid appearance from dairy is achievable by altering gel coagulum structure using pH during processing and may have minimal influence on related postprandial responses, with implications for targeting food design for optimal health. The Clinical Trial Registry number is ACTRN12622001418763 (https://www.anzctr.org.au) registered November 7, 2022.

Engineering a Rigid Nucleic Acid Structure to Improve the Limit of Detection for Genetic Assays.

Detecting nucleic acids at ultralow concentrations is critical for research and clinical applications. Particle-based assays are commonly used to detect nucleic acids. However, DNA hybridization on particle surfaces is inefficient due to the instability of tethered sequences, which negatively influences the assay's detection sensitivity. Here, we report a method to stabilize sequences on particle surfaces using a double-stranded linker at the 5' end of the tethered sequence. We termed this method Rigid Double Stranded Genomic Linkers for Improved DNA Analysis (RIGID-DNA). Our method led to a 3- and 100-fold improvement of the assays' clinical and analytical sensitivity, respectively. Our approach can enhance the hybridization efficiency of particle-based assays without altering existing assay workflows. This approach can be adapted to other platforms and surfaces to enhance the detection sensitivity.

Operative treatment of Mason Type III radial head fractures - A comparative analysis using PROMIS.

Objectives: The purpose of this study is to evaluate the outcomes of operatively treated Mason Type III radial head fractures. Additionally, this project seeks to assess efficacy of PROMIS in evaluating post-operative outcomes for this patient population. Methods: A total of 143 patients who underwent operative treated Mason Type III radial head fractures were analyzed retrospectively. PROMIS physical function (PF), PROMIS upper extremity (UE), PROMIS pain interference (PI), demographic variables, and range of motion were collected and analyzed over 12-month follow-up. Results: Radial head arthroplasty (RHA) was performed on 89 patients, open reduction and internal fixation (ORIF) was performed on 47 patients, and radial head excision was performed on 7 patients. Among the RHA patients, PROMIS PF, PI and UE demonstrated a change of -1.33 (p < 0.05), -1.48 (p < 0.05), and 2.23 (p < 0.05) respectively from injury to 12-months. Among the ORIF patients, PROMIS PF, PI and UE demonstrated a change of 3.22 (p < 0.05), -1.56 (p < 0.05), and 2.09 (p < 0.05) respectively from injury to 12-months. At the pre-operative and 12-month visits, the RHA group demonstrated lower PROMIS PF scores 34.75 vs 38.02 (p < 0.05) and 33.42 vs 41.24 (p < 0.05) respectively. Ther was no difference in PROMIS PI, UE, or elbow range of motion between the two groups at 6- or 12-month follow-up (p > 0.05). Conclusion: Comparing the RHA and ORIF groups, there was no difference in PROMIS PI or UE scores nor was there a clinically significant improvement at the 6- or 12-month mark. The ORIF group demonstrated improved PROMIS PF at all follow-up periods and did show a clinically significant improvement. Patient Acceptable Symptom State (PASS) correlated only with PROMIS UE at 6- and 12- months for both groups.

The spatial and social correlates of neighborhood morphology: Evidence from building footprints in five U.S. metropolitan areas.

Recent advances in quantitative tools for examining urban morphology enable the development of morphometrics that can characterize the size, shape, and placement of buildings; the relationships between them; and their association with broader patterns of development. Although these methods have the potential to provide substantial insight into the ways in which neighborhood morphology shapes the socioeconomic and demographic characteristics of neighborhoods and communities, this question is largely unexplored. Using building footprints in five of the ten largest U.S. metropolitan areas (Atlanta, Boston, Chicago, Houston, and Los Angeles) and the open-source R package, foot, we examine how neighborhood morphology differs across U.S. metropolitan areas and across the urban-exurban landscape. Principal components analysis, unsupervised classification (K-means), and Ordinary Least Squares regression analysis are used to develop a morphological typology of neighborhoods and to examine its association with the spatial, socioeconomic, and demographic characteristics of census tracts. Our findings illustrate substantial variation in the morphology of neighborhoods, both across the five metropolitan areas as well as between central cities, suburbs, and the urban fringe within each metropolitan area. We identify five different types of neighborhoods indicative of different stages of development and distributed unevenly across the urban landscape: these include low-density neighborhoods on the urban fringe; mixed use and high-density residential areas in central cities; and uniform residential neighborhoods in suburban cities. Results from regression analysis illustrate that the prevalence of each of these forms is closely associated with variation in socioeconomic and demographic characteristics such as population density, the prevalence of multifamily housing, and income, race/ethnicity, homeownership, and commuting by car. We conclude by discussing the implications of our findings and suggesting avenues for future research on neighborhood morphology, including ways that it might provide insight into issues such as zoning and land use, housing policy, and residential segregation.

Effects of Green and Gold Kiwifruit Varieties on Antioxidant Neuroprotective Potential in Pigs as a Model for Human Adults.

Kiwifruit (KF) has shown neuroprotective potential in cell-based and rodent models by augmenting the capacity of endogenous antioxidant systems. This study aimed to determine whether KF consumption modulates the antioxidant capacity of plasma and brain tissue in growing pigs. Eighteen male pigs were divided equally into three groups: (1) bread, (2) bread + Actinidia deliciosa cv. 'Hayward' (green-fleshed), and (3) bread + A. chinensis cv. 'Hort16A' (yellow-fleshed). Following consumption of the diets for eight days, plasma and brain tissue (brain stem, corpus striatum, hippocampus, and prefrontal cortex) were collected and measured for biomarkers of antioxidant capacity, enzyme activity, and protein expression assessments. Green KF significantly increased ferric-reducing antioxidant potential (FRAP) in plasma and all brain regions compared with the bread-only diet. Gold KF increased plasma ascorbate concentration and trended towards reducing acetylcholinesterase activity in the brain compared with the bread-only diet. Pearson correlation analysis revealed a significant positive correlation between FRAP in the brain stem, prefrontal cortex, and hippocampus with the total polyphenol concentration of dietary interventions. These findings provide exploratory evidence for the benefits of KF constituents in augmenting the brain's antioxidant capacity that may support neurological homeostasis during oxidative stress.

Comparison of Low-Dose Computed Tomography Versus Conventional-Dose Computed Tomography in the Evaluation of Distal Radius Fractures.

BACKGROUND: Distal radius fractures (DRFs) are common upper extremity fractures and often require surgical fixation when they are intraarticular. Preoperative computed tomography (CT) has emerged as a surgical planning tool to evaluate intraarticular DRFs. Although CT affords additional details, patients receive higher radiation doses than standard radiographs. We aim to develop a low-dose CT (LDCT) protocol, relative to the institutional standard-dose CT wrist for intraarticular DRFs although providing adequate detail for surgical decision-making. METHODS: A single-institution prospective study was conducted on patients with intraarticular DRFs who underwent closed reduction and below-elbow splinting who otherwise would undergo wrist CT. Observations were defined as total measurements taken, with each view undergoing 44 measurements. Patients underwent 2 scans with a standard dose and a 10× dose reduction. Articular step and gap measurements were recorded in the sagittal and coronal images. RESULTS: A total of 11 patients were enrolled (7 women and 4 men). The mean age was 55 years (SD = 20.1). There were a total of 4 reviewers: 1 attending surgeon, 2 resident physicians, and 1 student. When comparing LDCT and conventional-dose CT (CDCT), there were no significant differences in step and gap measurements across all reviewers. CONCLUSION: This study demonstrated that LDCT provides comparable imaging quality for surgical planning as a CDCT without significant diagnostic decay in the setting of DRFs. This comes with the added benefit of a 10-fold reduction in radiation exposure. These results suggest that LDCT is an opportunity to reduce effective radiation in patients although providing beneficial preoperative imaging.

Association between electrodiagnosis and neuromuscular ultrasound in the diagnosis and assessment of severity of carpal tunnel syndrome.

BACKGROUND: Neuromuscular ultrasound plays an increasing role in diagnosing carpal tunnel syndrome (CTS). There are limited data supporting the correlation between the electrodiagnostic studies and ultrasound measurements in CTS. OBJECTIVE: To assess the association between different electrodiagnostic severities and ultrasound measurements of the median nerve in CTS. DESIGN: A retrospective cohort study. SETTING: An academic tertiary care center. PATIENTS: Patients 18 years or older evaluated with upper limb electrodiagnostic studies and neuromuscular ultrasound. MAIN OUTCOME MEASUREMENT: Ultrasound measurements of the median nerve cross-sectional area (CSA) at the wrist and the calculated wrist-to-forearm ratio (WFR) were compared with the electrodiagnostic severity (normal, mild, moderate, and severe). Mean analysis and analysis of variance test (α = 0.05) were performed to assess the association. RESULTS: A total of 1359 limbs were identified. There was a statistically significant association between electrodiagnostic severity of CTS and median nerve CSA at the wrist (p < .001), as well as the WFR (p < .001). The mean median nerve CSA at the wrist and WFR were 7.01 ± 2.06 mm2 (95% CI: 6.80-7.20) and 1.24 ± 0.36 (95% CI: 1.16-1.24) in electrodiagnostically normal median nerves, 10.47 ± 2.82 mm2 (95% CI: 10.25-10.75) and 2.06 ± 0.67 (95% CI: 2.04-2.16) in electrodiagnostically mild CTS, 12.95 ± 4.74 mm2 (95% CI: 12.41-13.59) and 2.49 ± 1.04 (95% CI: 2.37, 2.63) in electrodiagnostically moderate CTS, and 14.69 ± 5.38 mm2 (95% CI: 13.95-15.44) and 2.71 ± 1.02 (95% CI: 2.56-2.84) in electrodiagnostically severe CTS, respectively. CONCLUSION: This study suggests a direct association between electrodiagnostic severity and ultrasound measurements of the median nerve in patients with suspected CTS.

HairNet2: deep learning to quantify cotton leaf hairiness, a complex genetic and environmental trait.

BACKGROUND: Cotton accounts for 80% of the global natural fibre production. Its leaf hairiness affects insect resistance, fibre yield, and economic value. However, this phenotype is still qualitatively assessed by visually attributing a Genotype Hairiness Score (GHS) to a leaf/plant, or by using the HairNet deep-learning model which also outputs a GHS. Here, we introduce HairNet2, a quantitative deep-learning model which detects leaf hairs (trichomes) from images and outputs a segmentation mask and a Leaf Trichome Score (LTS). RESULTS: Trichomes of 1250 images were annotated (AnnCoT) and a combination of six Feature Extractor modules and five Segmentation modules were tested alongside a range of loss functions and data augmentation techniques. HairNet2 was further validated on the dataset used to build HairNet (CotLeaf-1), a similar dataset collected in two subsequent seasons (CotLeaf-2), and a dataset collected on two genetically diverse populations (CotLeaf-X). The main findings of this study are that (1) leaf number, environment and image position did not significantly affect results, (2) although GHS and LTS mostly correlated for individual GHS classes, results at the genotype level revealed a strong LTS heterogeneity within a given GHS class, (3) LTS correlated strongly with expert scoring of individual images. CONCLUSIONS: HairNet2 is the first quantitative and scalable deep-learning model able to measure leaf hairiness. Results obtained with HairNet2 concur with the qualitative values used by breeders at both extremes of the scale (GHS 1-2, and 5-5+), but interestingly suggest a reordering of genotypes with intermediate values (GHS 3-4+). Finely ranking mild phenotypes is a difficult task for humans. In addition to providing assistance with this task, HairNet2 opens the door to selecting plants with specific leaf hairiness characteristics which may be associated with other beneficial traits to deliver better varieties.

The impact of heat treatment of bovine milk on gastric emptying and nutrient appearance in peripheral circulation in healthy females: a randomized controlled trial comparing pasteurized and ultra-high temperature milk.

BACKGROUND: Heat treatments of dairy, including pasteurization and ultra-high temperature (UHT) processing, alter milk macromolecular structures, and ultimately affect digestion. In vitro, animal, and human studies show faster nutrient release or circulating appearance after consuming UHT milk (UHT-M) compared with pasteurized milk (PAST-M), with a faster gastric emptying (GE) rate proposed as a possible mechanism. OBJECTIVES: To investigate the impact of milk heat treatment on GE as a mechanism of faster nutrient appearance in blood. We hypothesized that GE and circulating nutrient delivery following consumption would be faster for UHT-M than PAST-M. METHODS: In this double-blind randomized controlled cross-over trial, healthy female (n = 20; 27.3 ± 1.4 y, mean ± SD) habitual dairy consumers, consumed 500 mL of either homogenized bovine UHT-M or PAST-M (1340 compared with 1320 kJ). Gastric content volume (GCV) emptying half-time (T50) was assessed over 3 h by magnetic resonance imaging subjective digestive symptoms, plasma amino acid, lipid and B vitamin concentrations, and gastric myoelectrical activity were measured over 5 h. RESULTS: Although GCV T50 did not differ (102 ± 7 min compared with 89 ± 8 min, mean ± SEM, UHT-M and PAST-M, respectively; P = 0.051), GCV time to emptying 25% of the volume was 31% longer following UHT-M compared with PAST-M (42 ± 2 compared with 32 ± 4 min, P = 0.004). Although GCV remained larger for a longer duration following UHT-M (treatment × time interaction, P = 0.002), plasma essential amino acid AUC was greater following UHT-M than PAST-M (55,324 ± 3809 compared with 36,598 ± 5673 µmol·min·L-1, P = 0.006). Heat treatment did not impact gastric myoelectrical activity, plasma appetite hormone markers or subjective appetite scores. CONCLUSIONS: Contrary to expectations, GE was slower with UHT-M, yet, as anticipated, aminoacidemia was greater. The larger GCV following UHT-M suggests that gastric volume may poorly predict circulating nutrient appearance from complex food matrices. Dairy heat treatment may be an effective tool to modify nutrient release by impacting digestion kinetics. CLINICAL TRIAL REGISTRY: www.anzctr.org.au (ACTRN12620000172909).

Acquired Aquagenic Syringeal Keratoderma Following COVID-19 Infection.

Aquagenic syringeal keratoderma (ASK), rare in males, is characterized by the rapid onset of edematous palmar wrinkling with small white papules after brief contact with water or sweat. A 24-year-old atopic male presented with a 2-week subacute history of bilateral palmar edema with whitish-colored papules after exposure to water, 3 months after having had COVID-19 infection treated with a full course of ritonavir-boosted nirmatrelvir (PAXLOVIDTM). He had received 3 COVID-19 vaccines (Pfizer, New York, NY) about 12 months prior. Workup was negative. Initial spontaneous near-resolution 2 months after onset was temporary, with recurrence 1 month later. Treatment with 12% topical aluminum chloride was ineffective. Botulinum toxin injection to both palms led to resolution of symptoms that has been sustained for 7 months. The association between atopy and ASK remains weak. We present a case of new-onset ASK in an adult male 3 months following COVID-19 infection without a history of excessive handwashing. Our patient may have had a predisposition to recurrent ASK due to his history of atopy including atopic dermatitis and food allergy anaphylaxis combined with prior COVID-19 infection. It is possible that ASK is a novel manifestation of post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (PASC) infection or long COVID.

Validation of a Combined In Vivo/In Vitro Ileal Fermentation Assay in the Growing Pig to be Used as a Model for Adult Humans.

BACKGROUND: An in vivo/in vitro ileal fermentation assay using growing pigs has been developed but not yet formally validated. OBJECTIVES: This study aimed to validate the in vivo/in vitro ileal fermentation assay by comparing in vitro fermentation values with those obtained in vivo in growing pigs. The effect of raising pigs under different environmental conditions was also investigated. METHODS: Thirty piglets (1.59 ± 0.31 kg body weight, mean ± standard deviation) were subjected to 1 of 3 treatments: artificially reared (AR) (nonfarm, laboratory housing conditions) from postnatal day (PND) 7 (AR group), inoculated orally with human infant fecal extracts from birth until PND 8 and AR (AR+ group), or conventionally reared on a farm (control group). Starting at PND 7, the AR and AR+ pigs received human infant formula for 3 wk, followed by a human-type diet for 5 wk. Control pigs were weaned on the farm and, on PND 63, relocated to the laboratory animal facility. From PND 63, all pigs received a human-type diet. On PND 78, pigs were killed, after which ileal digesta were collected to perform an in vitro ileal fermentation (in vitro organic matter [OM] fermentability and organic acid production) and to determine digesta microbial composition and dietary OM fermentability in vivo. RESULTS: The rearing regimen resulted in only a few differences in ileal microbial taxonomic composition. The rearing regimen generally did not affect the in vitro production of individual organic acids. The in vivo and in vitro OM fermentability of proximal ileal digesta (19.7 ± 2.04%; mean ± SEM) was similar (P > 0.05) for the AR and control pigs but not for the AR+ pigs. CONCLUSIONS: The control-rearing regimen was preferred over AR or AR+ because of ease of implementation. The in vitro ileal fermentation assay accurately predicted the in vivo OM fermentability.

Best-Evidence Systematic Review and Meta-Analysis of Mini-Open Carpal Tunnel Release.

Purpose: This study aimed to evaluate the safety and effectiveness of mini-open carpal tunnel release (mOCTR) using best-evidence synthesis methods. Methods: We systematically searched for prospective studies published from January 2013 to July 2023 that reported outcomes from a minimum of 50 mOCTR cases. The outcomes included Quick Disabilities of the Arm, Shoulder, and Hand Questionnaire, Boston Carpal Tunnel Questionnaire Symptom Severity Scale (BCTQ-SSS) and Functional Status Scale (BCTQ-FSS), pain visual analog scale (VAS), complication rate, and reoperation rate. Data analysis was performed using a random-effects meta-analysis, with metaregression to identify the associations between patient- and study-level factors with surgical outcomes. Results: The meta-analysis included 23 studies with 2,303 patients followed for median durations ranging from 6 to 12 months depending on the outcome. Mini-open carpal tunnel release resulted in statistically significant and clinically important improvements in Quick Disabilities of the Arm, Shoulder, and Hand Questionnaire (mean difference = -25.5; 95% confidence interval [CI]: -36.4 to -14.5; P < .001), BCTQ-SSS (mean difference = -2.2; 95% CI: -2.5 to -1.9; P < .001), BCTQ-FSS (mean difference = -2.1; 95% CI: -2.4 to -1.7; P < .001), and pain VAS (mean difference = -5.1; 95% CI: -6.2 to -4.1; P < .001). The sole predictor of improvement in BCTQ-SSS, BCTQ-FSS, and pain VAS was a higher preoperative score for the respective variable (all P < .001). The risk of complications (mainly short-term pillar pain or scar complications) was 8.9% (95% CI: 4.0%-13.8%) and increased with longer incision lengths (P = .008). Revision carpal tunnel release was performed in 0.6% (95% CI: 0.1%-1.0%) of the cases during follow-up. No cases of median nerve transection were reported. Conclusions: Based on a best-evidence meta-analysis of contemporary studies, mOCTR significantly improved function and pain, with a relatively low risk of mainly temporary complications. Patient outcomes after mOCTR were influenced by patient symptomatology and surgical incision length. Clinical relevance: Mini-open carpal tunnel release is an effective surgical option that significantly improves symptoms and function, especially for patients with more severe baseline dysfunction. Surgeons should use the shortest incision that allows adequate visualization to safely divide the transverse carpal ligament.

Effect of Lighter and Heavier Initial Weight on Growth Performance and Carcass Traits of Single-Source Beef Steers.

The objective of the study was to determine the influence that initial BW has on growth performance responses, efficiency of dietary net energy (NE) utilization, and carcass traits in feedlot steers. Charolais×Red Angus steers (n = 70) selected from a larger single-source group were used in a 209-d growing-finishing feedlot experiment. Steers were assigned to two groups based on initial BW (light initial weight, LIW = 273 ± 16.0 kg; heavy initial weight, HIW = 356 ± 14.2 kg) and allotted into 10 pens (n = 7 steers per pen; 5 pens per experimental group) the within pen standard deviation for LIW was from 14.1 kg to 20.9 kg and for HIW was from 13.7 kg to 16.0 kg. Steers were fed a common diet once daily. Experimental data were analyzed as a randomized complete block design with pen as the experimental unit. LIW steers had a greater cumulative HH change (p = 0.04). A treatment × day interaction (p = 0.05) was observed for HH with HIW steers having a greater HH at all time points. Final BW and carcass-adjusted (HCW/0.625) BW were greater for HIW steers by 13.1% and 13.4% respectively (p ≤ 0.01). HIW steers had a greater DMI (p = 0.01) compared to LIW. Cumulative ADG was greater for HIW by 3% (p = 0.04). LIW steers had better feed conversion (p = 0.01). HIW steers had greater (p ≤ 0.05) HCW, marbling scores, and yield grade (YG), with decreased REA/HCW (p = 0.01) compared to LIW. The distribution of USDA Yield Grade was altered by initial BW (p = 0.04). No differences were detected (p ≥ 0.22) for the distribution of Quality grade nor liver abscess prevalence and severity. Regression coefficients did not differ between LIW and HIW for urea space calculations of empty body water, fat, or protein (p ≥ 0.70). A quadratic response was noted for empty body fat (EBF), empty body water (EBH20), and carcass protein (CP). In conclusion, HIW steers had greater growth, but poorer feed efficiency compared to LIW steers. Steers with a HIW produced fatter carcasses with a greater degree of marbling.

Efficacy of novel agents against cellular models of familial platelet disorder with myeloid malignancy (FPD-MM).

Germline, mono-allelic mutations in RUNX1 cause familial platelet disorder (RUNX1-FPD) that evolves into myeloid malignancy (FPD-MM): MDS or AML. FPD-MM commonly harbors co-mutations in the second RUNX1 allele and/or other epigenetic regulators. Here we utilized patient-derived (PD) FPD-MM cells and established the first FPD-MM AML cell line (GMR-AML1). GMR-AML1 cells exhibited active super-enhancers of MYB, MYC, BCL2 and CDK6, augmented expressions of c-Myc, c-Myb, EVI1 and PLK1 and surface markers of AML stem cells. In longitudinally studied bone marrow cells from a patient at FPD-MM vs RUNX1-FPD state, we confirmed increased chromatin accessibility and mRNA expressions of MYB, MECOM and BCL2 in FPD-MM cells. GMR-AML1 and PD FPD-MM cells were sensitive to homoharringtonine (HHT or omacetaxine) or mebendazole-induced lethality, associated with repression of c-Myc, EVI1, PLK1, CDK6 and MCL1. Co-treatment with MB and the PLK1 inhibitor volasertib exerted synergistic in vitro lethality in GMR-AML1 cells. In luciferase-expressing GMR-AML1 xenograft model, MB, omacetaxine or volasertib monotherapy, or co-treatment with MB and volasertib, significantly reduced AML burden and improved survival in the immune-depleted mice. These findings highlight the molecular features of FPD-MM progression and demonstrate HHT, MB and/or volasertib as effective agents against cellular models of FPD-MM.