Controlled dual drug release from adhesive electrospun patches for prevention and treatment of alveolar osteitis.

Approximately one in five individuals experience alveolar osteitis (AO) following wisdom tooth extraction. AO is characterised by loss of the blood clot from the tooth extraction socket leading to infection and pain, resulting in repeated hospital visits that impose a substantial burden on healthcare systems. Current treatments are sub-optimal; to address this we developed a novel drug-loaded mucoadhesive patch composed of dual electrospun polyvinyl pyrrolidone/Eudragit RS100 (PVP/RS100) and poly(N-isopropylacrylamide) (PNIPAM) fibres protected by a poly(ε-caprolactone) (PCL) backing layer. These patches demonstrated controlled release of the long-acting analgesic bupivacaine HCl and the anti-inflammatory drug prednisolone. Topical application of patches to tissue-engineered gingival mucosa showed that patch-released bupivacaine and prednisolone achieved sustained tissue permeation with 54.8 ±â€¯3.3 % bupivacaine HCl and 65.8 ±â€¯5.1 % prednisolone permeating the epithelium after 24 h. The drugs retained their functionality after release; bupivacaine HCl significantly (p < 0.05) inhibited veratridine-induced intracellular calcium flux in SH-SY5Y neuronal cells, while prednisolone significantly reduced gene expression of IL-6 (2-fold; p < 0.001), CXCL8 (5.1-fold; p < 0.01) and TNF-α (1.5-fold; p < 0.001) in stimulated THP-1 monocytes. Taken together, these data show that dual electrospun patches have the potential to provide a mucoadhesive covering to prevent blood clot loss while delivering pain relief and anti-inflammatory therapeutics at tooth extraction sites to prevent and treat AO. This study not only offers a future therapeutic pathway for AO but also contributes valuable insights into future advancements in drug delivery devices for periodontal or oral mucosal tissue.

Towards clinically relevant dose ratios for Cabamiquine and Pyronaridine combination using P. falciparum field isolate data.

The selection and combination of dose regimens for antimalarials involve complex considerations including pharmacokinetic and pharmacodynamic interactions. In this study, we use immediate ex vivo P. falciparum field isolates to evaluate the effect of cabamiquine and pyronaridine as standalone treatments and in combination therapy. We feed the data into a pharmacometrics model to generate an interaction map and simulate meaningful clinical dose ratios. We demonstrate that the pharmacometrics model of parasite growth and killing provides a detailed description of parasite kinetics against cabamiquine-susceptible and resistant parasites. Pyronaridine monotherapy provides suboptimal killing rates at doses as high as 720 mg. In contrast, the combination of a single dose of 330 mg cabamiquine and 360 mg pyronaridine provides over 90% parasite killing in most of the simulated patients. The described methodology that combines a rapid, 3R-compliant in vitro method and modelling to set meaningful doses for new antimalarials could contribute to clinical drug development.

Systematic Evaluation of Isometric Maximal Muscle Strength in an Orthopaedic Cohort.

BACKGROUND: Although the lower extremities are essential for movement function and human gait, no normalized isometric maximum strength values, which include the factors gender, age, weight, height, and body mass index (BMI), have been defined to date for orthopaedic patients. OBJECTIVE: To systematically analyze the isometric maximal muscle strength of a cohort in an orthopaedic outpatient clinic and to evaluate its relation to gender, age, weight, height, BMI, and the differences between diseases. STUDY DESIGN: Cross-sectional study. LEVEL OF EVIDENCE: Level 4. METHODS: Isometric maximal muscle strength of knee extension, knee flexion, hip abduction, and hip adduction was measured in orthopaedic patients of an outpatient clinic using a specific muscle strength measurement device. Correlation analysis was performed for age, gender, height, weight, and BMI. Patients were grouped by disease characteristics. RESULTS: The cohort consisted of 311 subjects (sex: 164 male, 147 female; age: 48.63 years, SD = 16.595; BMI: 26.56 kg/m², SD = 4.9). Age correlated significantly with maximal isometric muscle strength. At the age of 54 years onward, based on 133 patients, a decline in maximum isometric muscle strength was detected. Gender showed a strong influence on maximal isometric muscle strength, with significantly higher values for male patients. Furthermore, weight and height, but not BMI, correlated significantly with muscle strength. CONCLUSION: For clinical studies comparing different evidence-based training interventions for rehabilitation, it is important to consider determinants such as gender, age, weight, and height for isometric maximum strength measurement. For further validation, follow-up examinations taking into account the performance level, other target groups, and other muscle groups are required to avoid the wide dispersion of isometric maximum strength values. These results and associated determinants are highly clinically relevant and can be used as a reference for further studies in the field of musculoskeletal regeneration.

Analysis of the different pathways of ectopic recurrence of craniopharyngioma in pediatric patients: presentation of cases and review of the literature.

PURPOSE: Craniopharyngioma is a tumor derived from the squamous epithelium of Rathke's pouch. Despite successful excision, recurrence is common, typically occurring at the original tumor site. More rarely, recurrences can manifest at distant locations. This article reports on three distinct types of ectopic recurrence and reviews the existing literature. METHODS: We reviewed clinical records and neuroimaging data of craniopharyngioma patients at our institution, identifying three cases of ectopic recurrence. Additionally, we conducted a literature review of similar cases published between 1975 and 2023, focusing on historical background, pathophysiology, clinical and radiological features, and treatment options. RESULTS: We identified nineteen articles detailing ectopic recurrence of craniopharyngiomas in pediatric patients. The right frontal lobe was the most frequently reported site of recurrence. The shortest interval to recurrence was 11 months, while the longest was 14 years. Most cases were managed with surgical resection, yielding positive outcomes. In our cases, the recurrence sites were temporal intraparenchymal, intraosseous orbital, and occipital intraventricular. All were successfully treated with surgery, with no subsequent recurrences. CONCLUSION: Although craniopharyngiomas are histologically benign, they can recur locally and, more rarely, at distant sites. Surgical intervention is generally well-tolerated. Further research into tumor cell dissemination mechanisms is essential to develop strategies for preventing ectopic recurrence.

Predictive performance of multi-model approaches for model-informed precision dosing of piperacillin in critically ill patients.

OBJECTIVES: Piperacillin (PIP)/tazobactam is a frequently prescribed antibiotic; however, over- or underdosing may contribute to toxicity, therapeutic failure, and development of antimicrobial resistance. An external evaluation of 24 published PIP-models demonstrated that model-informed precision dosing (MIPD) can enhance target attainment. Employing various candidate models, this study aimed to assess the predictive performance of different MIPD-approaches comparing (i) a single-model approach, (ii) a model selection algorithm (MSA) and (iii) a model averaging algorithm (MAA). METHODS: Precision, accuracy and expected target attainment, considering either initial (B1) or initial and secondary (B2) therapeutic drug monitoring (TDM)-samples per patient, were assessed in a multicentre dataset (561 patients, 11 German centres, 3654 TDM-samples). RESULTS: The results demonstrated a slight superiority in predictive performance using MAA in B1, regardless of the candidate models, compared to MSA and the best single models (MAA, MSA, best single models: inaccuracy ±3%, ±10%, ±8%; imprecision: <25%, <31%, <28%; expected target attainment >77%, >71%, >73%). The inclusion of a second TDM-sample notably improved precision and target attainment for all MIPD-approaches, particularly within the context of MSA and most of the single models. The expected target attainment is maximized (up to >90%) when the TDM-sample is integrated within 24 h. CONCLUSIONS: In conclusion, MAA streamlines MIPD by reducing the risk of selecting an inappropriate model for specific patients. Therefore, MIPD of PIP using MAA implicates further optimisation of antibiotic exposure in critically ill patients, by improving predictive performance with only one sample available for Bayesian forecasting, safety, and usability in clinical practice.

Meropenem pharmacokinetics in cerebrospinal fluid: comparing intermittent and continuous infusion strategies in critically ill patients-a prospective cohort study.

Meropenem penetration into the cerebrospinal fluid (CSF) is subject to high interindividual variability resulting in uncertain target attainment in CSF. Recently, several authors recommended administering meropenem as a continuous infusion (CI) to optimize CSF exposure. This study aimed to compare the concentrations and pharmacokinetics of meropenem in CSF after intermittent infusion (II) and CI. This prospective, observational study (NCT04426383) included critically ill patients with external ventricular drains who received either II or CI of meropenem. Meropenem pharmacokinetics in plasma and CSF were characterized using population pharmacokinetic modeling (NONMEM 7.5). The developed model was used to compare the concentration-time profile and probability of target attainment (PTA) between II and CI. A total of 16 patients (8 CI, 8 II; samples: nplasma = 243, nCSF = 263) were recruited, with nine patients (5 CI, 4 II) suffering from cerebral and seven patients from extracerebral infections. A one-compartment model described the plasma concentrations adequately. Meropenem penetration into the CSF (partition coefficient (KP), cCSF/cplasma) was generally low (6.0%), exhibiting substantial between-subject variability (coefficient of variation: 84.0%). There was no correlation between the infusion mode and KP, but interleukin (IL)-6 measured in CSF showed a strong positive correlation with KP (P < 0.001). Dosing simulations revealed no relevant differences in CSF concentrations and PTA in CSF between CI and II. Our study did not demonstrate increased penetration rates or higher concentrations of meropenem in the CSF with CI compared with II. CLINICAL TRIALS: This study is registered with ClinicalTrials.gov as NCT04426383.

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.

Cholesterol-dependent dynamic changes in the conformation of the type 1 cholecystokinin receptor affect ligand binding and G protein coupling.

Development of optimal therapeutics for disease states that can be associated with increased membrane cholesterol requires better molecular understanding of lipid modulation of the drug target. Type 1 cholecystokinin receptor (CCK1R) agonist actions are affected by increased membrane cholesterol, enhancing ligand binding and reducing calcium signaling, while agonist actions of the closely related CCK2R are not. In this work, we identified a set of chimeric human CCK1R/CCK2R mutations that exchange the cholesterol sensitivity of these 2 receptors, providing powerful tools when expressed in CHO and HEK-293 model cell lines to explore mechanisms. Static, low energy, high-resolution structures of the mutant CCK1R constructs, stabilized in complex with G protein, were not substantially different, suggesting that alterations to receptor dynamics were key to altered function. We reveal that cholesterol-dependent dynamic changes in the conformation of the helical bundle of CCK receptors affects both ligand binding at the extracellular surface and G protein coupling at the cytosolic surface, as well as their interrelationships involved in stimulus-response coupling. This provides an ideal setting for potential allosteric modulators to correct the negative impact of membrane cholesterol on CCK1R.

Complications and Outcomes of Surgically Treated Pediatric Supracondylar Humerus Fractures.

This study describes the outcome of supracondylar humerus fractures in children using crossed K-wires after closed or open reduction with the medial, lateral or bilateral approach. Patients treated between January 2000 and December 2019 were classified according to the Von Laer classification, complications were classified according to the Sink classification and clinical outcomes were classified according to modified Flynn criteria. In total, 364 patients with a mean age of 5.23 ± 2.45 years were included. The majority were type IV fractures (156; 42.9%) and 94 (60.3%) needed an open reduction for which the medial approach (53; 56.4%) was predominantly used. Overall, of 50 complications (31 using closed reduction, 19 open reduction), 17/50 (34%) needed revision surgery. An excellent clinical outcome was achieved in 348/364 (95.6%) patients. The approach used for open reduction as such had no influence on the complication rate or clinical outcome. For severely displaced fractures, the data showed that an open approach for crossed K-wires tended to result in fewer complications and better clinical outcomes than a closed reduction. If an open reduction is indicated, the required approach (medial, lateral or bilateral) should be primarily selected according to the requirements of the fracture pattern and eventual cosmetic considerations.

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.

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.

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.

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%.

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.

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.

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.