Pharmacokinetics and pharmacological target attainment of standard temocillin dosing in non-critically ill patients with complicated urinary tract infections.

OBJECTIVES: Temocillin, a carbapenem-sparing ß-lactam antibiotic, is commonly used at the standard 4 g/day dosage for treating complicated urinary tract infections (cUTIs). However, pharmacokinetic/pharmacodynamic (PK/PD) data supporting this regimen is limited. This study evaluated the plasma pharmacokinetics (PK) and PTA of temocillin in non-critically ill cUTI patients with varying degrees of renal insufficiency (RI). METHODS: In this single-centre clinical study, 22 cUTI patients received a fixed 4 g/day (2 g q12h, intravenously) temocillin dose, irrespective of renal function (no RI: n = 5, mild RI: n = 8, moderate RI: n = 9). Plasma samples were collected post-dosing for LC-MS analysis of total and unbound temocillin levels. Monte Carlo simulations were performed based on the established PK/PD target of ≥35% fT > MIC (minimal inhibitory concentration). RESULTS: Among patients, the highest plasma drug exposure and PK/PD target attainment were observed in those with moderate RI (median AUC0-12h = 1143 h.mg/L and %fT > MIC = 68%), followed by mild RI patients (median AUC0-12h = 918 h.mg/L and %fT > MIC = 34%), and the lowest in those with healthy kidney function (median AUC0-12h = 692 h.mg/L and %fT > MIC = 26%). Simulations indicated that the 4 g/day temocillin dose achieves 90% PTA only for glomerular filtration rate < 60 mL/min and MIC ≤ 8 mg/L. CONCLUSION: The standard temocillin dose may need to be increased from 4 to 6 g/day to treat non-critically ill cUTI patients, in line with recent EUCAST recommendations. For patients with moderate RI, who experience higher exposure due to reduced renal drug clearance, 4 g/day temocillin remains appropriate.

Three-Dimensional Imaging of Bioinspired Lipidic Mesophases Using Multicolored Light-Emitting Carbon Nanodots.

Recent progress in the design of carbon nanostructures exhibiting strong multiphoton-excited emission opens new pathways to explore the self-organization of lipids found in living organisms. Phospholipid-based lyotropic myelin figures (MFs) are promising materials as simplified models of biomembranes due to their structural resemblance to a multilamellar sheath insulating the axon. This study demonstrates the possibility of selective labeling of MFs by strongly emitting multicolor phloroglucinol-derived carbon nanodots (PG CNDs). Such dopants are efficiently excited by visible and near-infrared light; therefore, one- and two-photon fluorescence microscopies are incorporated to gain 3D insights into the MFs. Combining nondestructive fluorescence microscopy and spectroscopy techniques along with polarized light microscopy gives details on the stability and morphology of lipidic mesophases. Our findings suggest that PG CNDs can be a viable and simple alternative to conventional fluorescent lipid stains to image biologically relevant phospholipid-based structures.

Systematic review of long-term effectiveness of endoscopic gastrojejunostomy in patients presenting with gastric outlet obstruction from periampullary malignancies.

BACKGROUND: Recently, endoscopic ultrasound-guided (EUS) gastrojejunostomy (GJ) has emerged as an alternative option to surgical palliation and endoscopic duodenal stenting for malignant gastric outlet obstruction (GOO). Although early success rates are commonly reported with the technique, there is a paucity of data regarding the long-term efficacy of this approach. In this study, we investigated long-term outcomes in patients that underwent EUS-guided GJ for palliation of periampullary malignancies. METHODS: From a total of 192 studies that were reviewed, 6 studies with a follow-up time frame of a minimum of 5 months were analyzed, totaling 238 patients. Outcome variables included technical success rate, clinical success rate, adverse events, symptom recurrence, and re-intervention rates. RESULTS: The cohort of 238 patients had a technical success rate of 93.7% and a clinical success rate of 92.9%. A total of 25 patients (10.5%) experienced adverse events associated with EUS-GJ. A total of 14 patients (5.9%) experienced recurrence of GOO symptoms within 5 months. A total of 14 patients (5.9%) underwent re-intervention with the first 5 months. CONCLUSIONS: This systematic review shows that data are scarce regarding long-term effectiveness of EUS-guided GJ. Even though early success rates have been reported, further studies are needed to focus on long-term efficacy of this approach. Until such studies become available, surgical palliation should continue to be the treatment of choice for patients with malignant GOO with a prolonged life expectancy.

Synergistic effects of sulopenem in combination with cefuroxime or durlobactam against Mycobacterium abscessus.

Mycobacterium abscessus (Mab) affects patients with immunosuppression or underlying structural lung diseases such as cystic fibrosis (CF). Additionally, Mab poses clinical challenges due to its resistance to multiple antibiotics. Herein, we investigated the synergistic effect of dual ß-lactams [sulopenem and cefuroxime (CXM)] or the combination of sulopenem and CXM with ß-lactamase inhibitors [BLIs-avibactam (AVI) or durlobactam (DUR)]. The sulopenem-CXM combination yielded low minimum inhibitory concentration (MIC) values for 54 clinical Mab isolates and ATCC19977 (MIC50 and MIC90 ≤0.25 µg/mL). Similar synergistic effects were observed in time-kill studies conducted at concentrations achievable in clinical settings. Sulopenem-CXM outperformed monotherapy, yielding ~1.5 Log10 CFU/mL reduction during 10 days. Addition of BLIs enhanced this antibacterial effect, resulting in an additional reduction of CFUs (~3 Log10 for sulopenem-CXM and AVI and ~4 Log10 for sulopenem-DUR). Exploration of the potential mechanisms of the synergy focused on their interactions with L,D-transpeptidases (Ldts; LdtMab1-LdtMab4), penicillin-binding-protein B (PBP B), and D,D-carboxypeptidase (DDC). Acyl complexes, identified via mass spectrometry analysis, demonstrated the binding of sulopenem with LdtMab2-LdtMab4, DDC, and PBP B and CXM with LdtMab2 and PBP B. Molecular docking and mass spectrometry data suggest the formation of a covalent adduct between sulopenem and LdtMab2 after the nucleophilic attack of the cysteine residue at the ß-lactam carbonyl carbon, leading to the cleavage of the ß-lactam ring and the establishment of a thioester bond linking the LdtMab2 with sulopenem. In conclusion, we demonstrated the biochemical basis of the synergy of sulopenem-CXM with or without BLIs. These findings potentially broaden the selection of oral therapeutic agents to combat Mab. IMPORTANCE: Treating infections from Mycobacterium abscessus (Mab), particularly those resistant to common antibiotics like macrolides, is notoriously difficult, akin to a never-ending struggle for healthcare providers. The rate of treatment failure is even higher than that seen with multidrug-resistant tuberculosis. The role of combination ß-lactams in inhibiting L,D-transpeptidation, the major peptidoglycan crosslink reaction in Mab, is an area of intense investigation, and clinicians have utilized this approach in the treatment of macrolide-resistant Mab, with reports showing clinical success. In our study, we found that cefuroxime and sulopenem, when used together, display a significant synergistic effect. If this promising result seen in lab settings, translates well into real-world clinical effectiveness, it could revolutionize current treatment methods. This combination could either replace the need for more complex intravenous medications or serve as a "step down" to an oral medication regimen. Such a shift would be much easier for patients to manage, enhancing their comfort and likelihood of sticking to the treatment plan, which could lead to better outcomes in tackling these tough infections. Our research delved into how these drugs inhibit cell wall synthesis, examined time-kill data and binding studies, and provided a scientific basis for the observed synergy in cell-based assays.

Sleep functional connectivity, hyperexcitability, and cognition in Alzheimer's disease.

INTRODUCTION: Sleep disturbances are common in Alzheimer's disease (AD) and may reflect pathologic changes in brain networks. To date, no studies have examined changes in sleep functional connectivity (FC) in AD or their relationship with network hyperexcitability and cognition. METHODS: We assessed electroencephalogram (EEG) sleep FC in 33 healthy controls, 36 individuals with AD without epilepsy, and 14 individuals with AD and epilepsy. RESULTS: AD participants showed increased gamma connectivity in stage 2 sleep (N2), which was associated with longitudinal cognitive decline. Network hyperexcitability in AD was associated with a distinct sleep connectivity signature, characterized by decreased N2 delta connectivity and reversal of several connectivity changes associated with AD. Machine learning algorithms using sleep connectivity features accurately distinguished diagnostic groups and identified "fast cognitive decliners" among study participants who had AD. DISCUSSION: Our findings reveal changes in sleep functional networks associated with cognitive decline in AD and may have implications for disease monitoring and therapeutic development. HIGHLIGHTS: Brain functional connectivity (FC) in Alzheimer's disease is altered during sleep. Sleep FC measures correlate with cognitive decline in AD. Network hyperexcitability in AD has a distinct sleep connectivity signature.

Torque forces of expandable titanium vertebral body replacement cages during expansion and subsidence in the osteoporotic lumbar spine.

BACKGROUND: The application of expandable titanium-cages has gained widespread use in vertebral body replacement for indications such as burst fractures, tumors and infectious destruction. However, torque forces necessary for a satisfactory expansion of these implants and for subsidence of them into the adjacent vertebrae are unknown within the osteoporotic spine. METHODS: Six fresh-frozen human, osteoporotic, lumbar spines were dorsally instrumented with titanium implants (L2-L4) and a partial corpectomy of L3 was performed. An expandable titanium-cage was inserted ventrally and expanded by both residents and senior surgeons until fixation was deemed sufficient, based on haptic feedback. Torque forces for expansion were measured in Nm. Expansion was then continued until cage subsidence occurred. Torque forces necessary for subsidence were recorded. Strain of the dorsal rods during expansion was measured with strain gauges. FINDINGS: The mean torque force for fixation of cages was 1.17 Nm (0.9 Nm for residents, 1.4 Nm for senior surgeons, p = .06). The mean torque force for subsidence of cages was 3.1 Nm (p = .005). Mean peak strain of the dorsal rods was 970 µm/m during expansion and 1792 µm/m at subsidence of cages (p = .004). INTERPRETATION: The use of expandable titanium-cages for vertebral body replacement seems to be a primarily safe procedure even within the osteoporotic spine as torque forces required for subsidence of cages are nearly three times higher than those needed for fixation. Most of the expansion load is absorbed by straining of the dorsal instrumentation. Rod materials other than titanium may alter the torque forces found in this study.

Best Practice for Therapeutic Drug Monitoring of Infliximab: Position Statement from the International Association of Therapeutic Drug Monitoring and Clinical Toxicology.

BACKGROUND: Infliximab, an anti-tumor necrosis factor monoclonal antibody, has revolutionized the pharmacological management of immune-mediated inflammatory diseases (IMIDs). This position statement critically reviews and examines existing data on therapeutic drug monitoring (TDM) of infliximab in patients with IMIDs. It provides a practical guide on implementing TDM in current clinical practices and outlines priority areas for future research. METHODS: The endorsing TDM of Biologics and Pharmacometrics Committees of the International Association of TDM and Clinical Toxicology collaborated to create this position statement. RESULTS: Accumulating data support the evidence for TDM of infliximab in the treatment of inflammatory bowel diseases, with limited investigation in other IMIDs. A universal approach to TDM may not fully realize the benefits of improving therapeutic outcomes. Patients at risk for increased infliximab clearance, particularly with a proactive strategy, stand to gain the most from TDM. Personalized exposure targets based on therapeutic goals, patient phenotype, and infliximab administration route are recommended. Rapid assays and home sampling strategies offer flexibility for point-of-care TDM. Ongoing studies on model-informed precision dosing in inflammatory bowel disease will help assess the additional value of precision dosing software tools. Patient education and empowerment, and electronic health record-integrated TDM solutions will facilitate routine TDM implementation. Although optimization of therapeutic effectiveness is a primary focus, the cost-reducing potential of TDM also merits consideration. CONCLUSIONS: Successful implementation of TDM for infliximab necessitates interdisciplinary collaboration among clinicians, hospital pharmacists, and (quantitative) clinical pharmacologists to ensure an efficient research trajectory.

Nucleic acid-based drugs for patients with solid tumours.

The treatment of patients with advanced-stage solid tumours typically involves a multimodality approach (including surgery, chemotherapy, radiotherapy, targeted therapy and/or immunotherapy), which is often ultimately ineffective. Nucleic acid-based drugs, either as monotherapies or in combination with standard-of-care therapies, are rapidly emerging as novel treatments capable of generating responses in otherwise refractory tumours. These therapies include those using viral vectors (also referred to as gene therapies), several of which have now been approved by regulatory agencies, and nanoparticles containing mRNAs and a range of other nucleotides. In this Review, we describe the development and clinical activity of viral and non-viral nucleic acid-based treatments, including their mechanisms of action, tolerability and available efficacy data from patients with solid tumours. We also describe the effects of the tumour microenvironment on drug delivery for both systemically administered and locally administered agents. Finally, we discuss important trends resulting from ongoing clinical trials and preclinical testing, and manufacturing and/or stability considerations that are expected to underpin the next generation of nucleic acid agents for patients with solid tumours.

Durlobactam, a Diazabicyclooctane ß-Lactamase Inhibitor, Inhibits BlaC and Peptidoglycan Transpeptidases of Mycobacterium tuberculosis.

Peptidoglycan synthesis is an underutilized drug target in Mycobacterium tuberculosis (Mtb). Diazabicyclooctanes (DBOs) are a class of broad-spectrum ß-lactamase inhibitors that also inhibit certain peptidoglycan transpeptidases that are important in mycobacterial cell wall synthesis. We evaluated the DBO durlobactam as an inhibitor of BlaC, the Mtb ß-lactamase, and multiple Mtb peptidoglycan transpeptidases (PonA1, LdtMt1, LdtMt2, LdtMt3, and LdtMt5). Timed electrospray ionization mass spectrometry (ESI-MS) captured acyl-enzyme complexes with BlaC and all transpeptidases except LdtMt5. Inhibition kinetics demonstrated durlobactam was a potent and efficient DBO inhibitor of BlaC (KI app 9.2 ± 0.9 µM, k2/K 5600 ± 560 M-1 s-1) and similar to clavulanate (KI app 3.3 ± 0.6 µM, k2/K 8400 ± 840 M-1 s-1); however, durlobactam had a lower turnover number (tn = kcat/kinact) than clavulanate (1 and 8, respectively). KI app values with durlobactam and clavulanate were similar for peptidoglycan transpeptidases, but ESI-MS captured durlobactam complexes at more time points. Molecular docking and simulation demonstrated several productive interactions of durlobactam in the active sites of BlaC, PonA1, and LdtMt2. Antibiotic susceptibility testing was conducted on 11 Mtb isolates with amoxicillin, ceftriaxone, meropenem, imipenem, clavulanate, and durlobactam. Durlobactam had a minimum inhibitory concentration (MIC) range of 0.5-16 µg/mL, similar to the ranges for meropenem (1-32 µg/mL) and imipenem (0.5-64 µg/mL). In ß-lactam + durlobactam combinations (1:1 mass/volume), MICs were lowered 4- to 64-fold for all isolates except one with meropenem-durlobactam. This work supports further exploration of novel ß-lactamase inhibitors that target BlaC and Mtb peptidoglycan transpeptidases.

Preoperative Performance Status Threshold for Favorable Surgical Outcome in Metastatic Spine Disease.

BACKGROUND AND OBJECTIVES: Surgical treatment is an integral component of multimodality management of metastatic spine disease but must be balanced against the risk of surgery-related morbidity and mortality, making tailored surgical counseling a clinical challenge. The aim of this study was to investigate the potential predictive value of the preoperative performance status for surgical outcome in patients with spinal metastases. METHODS: Performance status was determined using the Karnofsky Performance Scale (KPS), and surgical outcome was classified as "favorable" or "unfavorable" based on postoperative changes in neurological function and perioperative complications. The correlation between preoperative performance status and surgical outcome was assessed to determine a KPS-related performance threshold. RESULTS: A total of 463 patients were included. The mean age was 63 years (range: 22-87), and the mean preoperative KPS was 70 (range: 30-100). Analysis of clinical outcome in relation to the preoperative performance status revealed a KPS threshold between 40% and 50% with a relative risk of an unfavorable outcome of 65.7% in KPS ≤40% compared with the relative chance for a favorable outcome of 77.1% in KPS ≥50%. Accordingly, we found significantly higher rates of preserved or restored ambulatory function in KPS ≥50% (85.7%) than in KPS ≤40% (48.6%; P < .001) as opposed to a significantly higher risk of perioperative mortality in KPS ≤40% (11.4%) than in KPS ≥50% (2.1%, P = .012). CONCLUSION: Our results underline the predictive value of the KPS in metastatic spine patients for counseling and decision-making. The study suggests an overall clinical benefit of surgical treatment of spinal metastases in patients with a preoperative KPS score ≥50%, while a high risk of unfavorable outcome outweighing the potential clinical benefit from surgery is encountered in patients with a KPS score ≤40%.

Bioactive Protein and Peptide Release from a Mucoadhesive Electrospun Membrane.

Protein-based biologics constitute a rapidly expanding category of therapeutic agents with high target specificity. Their clinical use has dramatically increased in recent years, but administration is largely via injection. Drug delivery across the oral mucosa is a promising alternative to injections, in order to avoid the gastrointestinal tract and first-pass metabolism. Current drug delivery formulations include liquid sprays, mucoadhesive tablets and films, which lack dose control in the presence of salivary flow. To address this, electrospun membranes that adhere tightly to the oral mucosa and release drugs locally have been developed. Here, we investigated the suitability of these mucoadhesive membranes for peptide or protein release. Bradykinin (0.1%) or insulin (1, 3, and 5%) were incorporated by electrospinning from ethanol/water mixtures. Immersion of membranes in buffer resulted in the rapid release of bradykinin, with a maximal release of 70 ± 12% reached after 1 h. In contrast, insulin was liberated more slowly, with 88 ± 11, 69.0 ± 5.4, and 63.9 ± 9.0% cumulative release of the total encapsulated dose after 8 h for membranes containing 1, 3, and 5% w/w insulin, respectively. Membrane-eluted bradykinin retained pharmacological activity by inducing rapid intracellular calcium release upon binding to its cell surface receptor on oral fibroblasts, when examined by flow cytometry. To quantify further, time-lapse confocal microscopy revealed that membrane-eluted bradykinin caused a 1.58 ± 0.16 fold-change in intracellular calcium fluorescence after 10 s compared to bradykinin solution (2.13 ± 0.21), relative to placebo. In conclusion, these data show that electrospun membranes may be highly effective vehicles for site-specific administration of biotherapeutic proteins or peptides directly to the oral mucosa for either local or systemic drug delivery applications.

Cationic cholesterol-dependent LNP delivery to lung stem cells, the liver, and heart.

Adding a cationic helper lipid to a lipid nanoparticle (LNP) can increase lung delivery and decrease liver delivery. However, it remains unclear whether charge-dependent tropism is universal or, alternatively, whether it depends on the component that is charged. Here, we report evidence that cationic cholesterol-dependent tropism can differ from cationic helper lipid-dependent tropism. By testing how 196 LNPs delivered mRNA to 22 cell types, we found that charged cholesterols led to a different lung:liver delivery ratio than charged helper lipids. We also found that combining cationic cholesterol with a cationic helper lipid led to mRNA delivery in the heart as well as several lung cell types, including stem cell-like populations. These data highlight the utility of exploring charge-dependent LNP tropism.

The genome of the colonial hydroid Hydractinia reveals that their stem cells use a toolkit of evolutionarily shared genes with all animals.

Hydractinia is a colonial marine hydroid that shows remarkable biological properties, including the capacity to regenerate its entire body throughout its lifetime, a process made possible by its adult migratory stem cells, known as i-cells. Here, we provide an in-depth characterization of the genomic structure and gene content of two Hydractinia species, Hydractinia symbiolongicarpus and Hydractinia echinata, placing them in a comparative evolutionary framework with other cnidarian genomes. We also generated and annotated a single-cell transcriptomic atlas for adult male H. symbiolongicarpus and identified cell-type markers for all major cell types, including key i-cell markers. Orthology analyses based on the markers revealed that Hydractinia's i-cells are highly enriched in genes that are widely shared amongst animals, a striking finding given that Hydractinia has a higher proportion of phylum-specific genes than any of the other 41 animals in our orthology analysis. These results indicate that Hydractinia's stem cells and early progenitor cells may use a toolkit shared with all animals, making it a promising model organism for future exploration of stem cell biology and regenerative medicine. The genomic and transcriptomic resources for Hydractinia presented here will enable further studies of their regenerative capacity, colonial morphology, and ability to distinguish self from nonself.

Towards a better detection of patients at-risk of linezolid toxicity in clinical practice: a prospective study in three Belgian hospital centers.

Introduction: Linezolid is a last-resort antibiotic for infections caused by multidrug-resistant microorganisms. It is widely used for off-label indications and for longer than recommended treatment durations, exposing patients at higher risk of adverse drug reactions (ADRs), notably thrombocytopenia. This study aimed to investigate ADR incidence and risk factors, identify thrombocytopenia-related trough levels based on treatment duration, and evaluate the performance of predictive scores for ADR development. Methods: Adult in- and outpatients undergoing linezolid therapy were enrolled in three hospitals and ADRs and linezolid trough levels prospectively monitored over time. A population pharmacokinetic (pop-PK model) was used to estimate trough levels for blood samples collected at varying times. Results: A multivariate analysis based on 63 treatments identified treatment duration ≥10 days and trough levels >8 mg/L as independent risk factors of developing thrombocytopenia, with high trough values correlated with impaired renal function. Five patients treated for >28 days did not develop thrombocytopenia but maintained trough values in the target range (<8 mg/L). The Buzelé predictive score, which combines an age-adjusted Charlson comorbidity index with treatment duration, demonstrated 77% specificity and 67% sensitivity to predict the risk of ADR. Conclusion: Our work supports the necessity of establishing guidelines for dose adjustment in patients with renal insufficiency and the systematic use of TDM in patients at-risk in order to keep trough values ≤8 mg/L. The Buzelé predictive score (if ≥7) may help to detect these at-risk patients, and pop-PK models can estimate trough levels based on plasma samples collected at varying times, reducing the logistical burden of TDM in clinical practice.

Substituting Poly(ethylene glycol) Lipids with Poly(2-ethyl-2-oxazoline) Lipids Improves Lipid Nanoparticle Repeat Dosing.

Poly(ethylene glycol) (PEG)-lipids are used in Food-and-Drug-Administration-approved lipid nanoparticle (LNP)-RNA drugs, which are safe and effective. However, it is reported that PEG-lipids may also contribute to accelerated blood clearance and rare cases of hypersensitivity; this highlights the utility of exploring PEG-lipid alternatives. Here, it is shown that LNPs containing poly(2-ethyl-2-oxazoline) (PEOZ)-lipids can deliver messenger RNA (mRNA) to multiple cell types in mice inside and outside the liver. In addition, it is reported that LNPs formulated with PEOZ-lipids show reduced clearance from the bloodstream and lower levels of antistealth lipid immunoglobulin Ms than LNPs formulated with PEG-lipids. These data justify further exploration of PEOZ-lipids as alternatives to PEG-lipids in LNP-RNA formulations.

An artificial intelligence approach of feature engineering and ensemble methods depicts the rumen microbiome contribution to feed efficiency in dairy cows.

Genetic selection has remarkably helped U.S. dairy farms to decrease their carbon footprint by more than doubling milk production per cow over time. Despite the environmental and economic benefits of improved feed and milk production efficiency, there is a critical need to explore phenotypical variance for feed utilization to advance the long-term sustainability of dairy farms. Feed is a major expense in dairy operations, and their enteric fermentation is a major source of greenhouse gases in agriculture. The challenges to expanding the phenotypic database, especially for feed efficiency predictions, and the lack of understanding of its drivers limit its utilization. Herein, we leveraged an artificial intelligence approach with feature engineering and ensemble methods to explore the predictive power of the rumen microbiome for feed and milk production efficiency traits, as rumen microbes play a central role in physiological responses in dairy cows. The novel ensemble method allowed to further identify key microbes linked to the efficiency measures. We used a population of 454 genotyped Holstein cows in the U.S. and Canada with individually measured feed and milk production efficiency phenotypes. The study underscored that the rumen microbiome is a major driver of residual feed intake (RFI), the most robust feed efficiency measure evaluated in the study, accounting for 36% of its variation. Further analyses showed that several alpha-diversity metrics were lower in more feed-efficient cows. For RFI, [Ruminococcus] gauvreauii group was the only genus positively associated with an improved feed efficiency status while seven other taxa were associated with inefficiency. The study also highlights that the rumen microbiome is pivotal for the unexplained variance in milk fat and protein production efficiency. Estimation of the carbon footprint of these cows shows that selection for better RFI could reduce up to 5 kg of diet consumed per cow daily, potentially reducing up to 37.5% of CH4. These findings shed light that the integration of artificial intelligence approaches, microbiology, and ruminant nutrition can be a path to further advance our understanding of the rumen microbiome on nutrient requirements and lactation performance of dairy cows to support the long-term sustainability of the dairy community.

Material-Intrinsic NIR-Fluorescence Enables Image-Guided Surgery for Ceramic Fracture Removal.

Hip arthroplasty effectively treats advanced osteoarthritis and is therefore entitled as "operation of the 20th century." With demographic shifts, the USA alone is projected to perform up to 850 000 arthroplasties annually by 2030. Many implants now feature a ceramic head, valued for strength and wear resistance. Nonetheless, a fraction, up to 0.03% may fracture during their lifespan, demanding complex removal procedures. To address this, a radiation-free, fluorescence-based image-guided surgical technique is presented. The method uses the inherent fluorescence of ceramic implant materials, demonstrated through chemical and optical analysis of prevalent implant types. Specifically, Biolox delta implants exhibited strong fluorescence around 700 nm with a 74% photoluminescence quantum yield. Emission tails are identified extending into the near-infrared (NIR-I) biological transparency range, forming a vital prerequisite for the label-free visualization of fragments. This ruby-like fluorescence could be attributed to Cr within the zirconia-toughened alumina matrix, enabling the detection of even deep-seated millimeter-sized fragments via camera-assisted techniques. Additionally, fluorescence microscopy allowed detection of µm-sized ceramic particles, enabling debris visualization in synovial fluid as well as histological samples. This label-free optical imaging approach employs readily accessible equipment and can seamlessly transition to clinical settings without significant regulatory barriers, thereby enhancing the safety, efficiency, and minimally invasive nature of fractured ceramic implant removal procedures.

A giant tyrannosaur from the Campanian-Maastrichtian of southern North America and the evolution of tyrannosaurid gigantism.

Tyrannosaurid dinosaurs dominated as predators in the Late Cretaceous of Laurasia, culminating in the evolution of the giant Tyrannosaurus rex, both the last and largest tyrannosaurid. Where and when Tyrannosaurini (T. rex and kin) originated remains unclear. Competing hypotheses place tyrannosaurin origins in Asia, or western North America (Laramidia). We report a new tyrannosaurin, Tyrannosaurus mcraeensis, from the Campanian-Maastrichtian Hall Lake Formation of New Mexico, based on a fossil previously referred to T. rex. T. mcraeensis predates T. rex by ~ 6-7 million years, yet rivaled it in size. Phylogenetic analysis recovers T. mcraeensis as sister to T. rex and suggests Tyrannosaurini originated in southern Laramidia. Evolution of giant tyrannosaurs in southern North America, alongside giant ceratopsians, hadrosaurs, and titanosaurs suggests large-bodied dinosaurs evolved at low latitudes in North America.