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Chimeric antigen receptor (CAR) T cells from allogeneic donors promise "off-the-shelf" availability by overcoming challenges associated with autologous cell manufacturing. However, recipient immunologic rejection of allogeneic CAR-T cells may decrease their in vivo lifespan and limit treatment efficacy. Here, we demonstrate that the immunosuppressants rapamycin and tacrolimus effectively mitigate allorejection of HLA-mismatched CAR-T cells in immunocompetent humanized mice, extending their in vivo persistence to that of syngeneic humanized mouse-derived CAR-T cells. In turn, genetic knockout (KO) of FKBP prolyl isomerase 1A (FKBP1A), which encodes a protein targeted by both drugs, was necessary to confer CD19-specific CAR-T cells (19CAR) robust functional resistance to these immunosuppressants. FKBP1AKO 19CAR-T cells maintained potent in vitro functional profiles and controlled in vivo tumor progression similarly to untreated 19CAR-T cells. Moreover, immunosuppressant treatment averted in vivo allorejection permitting FKBP1AKO 19CAR-T cell-driven B cell aplasia. Thus, we demonstrate that genome engineering enables immunosuppressant treatment to improve the therapeutic potential of universal donor-derived CAR-T cells.

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Decades of neuroimaging studies have shown modest differences in brain structure and connectivity in depression, hindering mechanistic insights or the identification of risk factors for disease onset1. Furthermore, whereas depression is episodic, few longitudinal neuroimaging studies exist, limiting understanding of mechanisms that drive mood-state transitions. The emerging field of precision functional mapping has used densely sampled longitudinal neuroimaging data to show behaviourally meaningful differences in brain network topography and connectivity between and in healthy individuals2-4, but this approach has not been applied in depression. Here, using precision functional mapping and several samples of deeply sampled individuals, we found that the frontostriatal salience network is expanded nearly twofold in the cortex of most individuals with depression. This effect was replicable in several samples and caused primarily by network border shifts, with three distinct modes of encroachment occurring in different individuals. Salience network expansion was stable over time, unaffected by mood state and detectable in children before the onset of depression later in adolescence. Longitudinal analyses of individuals scanned up to 62 times over 1.5 years identified connectivity changes in frontostriatal circuits that tracked fluctuations in specific symptoms and predicted future anhedonia symptoms. Together, these findings identify a trait-like brain network topology that may confer risk for depression and mood-state-dependent connectivity changes in frontostriatal circuits that predict the emergence and remission of depressive symptoms over time.

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This study aimed to characterize the prevalence of irritability among U.S. adults, and the extent to which it co-occurs with major depressive and anxious symptoms. A non-probability internet survey of individuals 18 and older in 50 U.S. states and the District of Columbia was conducted between November 2, 2023, and January 8, 2024. Regression models with survey weighting were used to examine associations between the Brief Irritability Test (BITe5) and sociodemographic and clinical features. The survey cohort included 42,739 individuals, mean age 46.0 (SD 17.0) years; 25,001 (58.5%) identified as women, 17,281 (40.4%) as men, and 457 (1.1%) as nonbinary. A total of 1218(2.8%) identified as Asian American, 5971 (14.0%) as Black, 5348 (12.5%) as Hispanic, 1775 (4.2%) as another race, and 28,427 (66.5%) as white. Mean irritability score was 13.6 (SD 5.6) on a scale from 5 to 30. In linear regression models, irritability was greater among respondents who were female, younger, had lower levels of education, and lower household income. Greater irritability was associated with likelihood of thoughts of suicide in logistic regression models adjusted for sociodemographic features (OR 1.23, 95% CI 1.22-1.24). Among 1979 individuals without thoughts of suicide on the initial survey assessed for such thoughts on a subsequent survey, greater irritability was also associated with greater likelihood of thoughts of suicide being present (adjusted OR 1.17, 95% CI 1.12-1.23). The prevalence of irritability and its association with thoughts of suicide suggests the need to better understand its implications among adults outside of acute mood episodes.

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Importance: Anxiety disorders are prevalent and undertreated among young adults. Digital mental health interventions for anxiety are promising but limited by a narrow range of therapeutic components and low user engagement. Objective: To investigate the efficacy of and engagement with Maya, a scalable, self-guided, comprehensive mobile cognitive behavioral therapy (CBT) intervention with embedded engagement features, comparing the effects of 3 incentive conditions. Design, Setting, and Participants: This randomized clinical trial recruited young adults aged 18 to 25 years with anxiety disorders through online advertisements and outpatient psychiatry clinics at Weill Cornell Medicine. Enrollment was between June 16, 2021, and November 11, 2022. Data analysis was performed from December 21, 2022, to June 14, 2024. Intervention: Participants received a 6-week program of the intervention and were randomized to 1 of 3 different text message-based incentive conditions (gain-framed, loss-framed, or gain-social support). Main Outcomes and Measures: The primary outcome was change in anxious symptoms from baseline to end of treatment, as measured by the Hamilton Anxiety Rating Scale (HAM-A). The Anxiety Sensitivity Index and the Leibowitz Social Anxiety Scale scores were secondary measures. Results: The sample consisted of 59 participants (mean [SD] age, 23.1 [1.9] years; 46 [78%] female; 22 [37%] Asian, 3 [5%] Black, 5 [8%] Hispanic or Latino, 1 [2%] American Indian or Alaska Native, 25 [42%] White, and 6 [10%] >1 race; 32 [54%] college-educated and 12 [20%] graduate or professional school-educated; mean [SD] baseline HAM-A score, 15.0 [6.5]). Anxiety, measured by HAM-A, decreased across conditions from baseline to end of the intervention (mean difference, -5.64; 95% CI, -7.23 to -4.05), and symptomatic improvement was maintained at the week 12 follow-up (baseline to follow-up mean difference, -5.67; 95% CI, -7.29 to -4.04). However, there was no evidence that change in anxiety differed by incentive condition (loss-framed vs gain-social support mean difference, -1.40; 95% CI, -4.72 to 1.93; gain-framed vs gain-social support mean difference, 1.38; 95% CI, -1.19 to 3.96). Secondary anxiety measures (Anxiety Sensitivity Index and Liebowitz Social Anxiety Scale scores) showed a similar pattern of improvement, with no evidence of differences between incentive conditions. Participants completed most of the 12 sessions (mean [SD], 10.8 [2.1]; 95% CI, 10.3-11.4), and User Mobile Application Rating Scale app quality ratings exceeded the published threshold for acceptability at all study visits. There was no evidence that either session completion or app quality ratings differed by incentive condition. Conclusions and Relevance: In this randomized clinical trial of an app-based intervention for anxiety, the primary hypothesis that improvement in anxiety would be greatest in the condition using gain of points plus social incentives was not supported; however, the results suggest that a CBT application incorporating a full suite of CBT skills and embedded user engagement features was efficacious in improving symptoms in young adults with anxiety disorders. Given these findings, digital interventions represent a promising step toward wider dissemination of high-quality, evidence-based interventions. Trial Registration: ClinicalTrials.gov Identifier: NCT05130281.

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Salmonella Dublin latent carrier cows represent a high risk for infection of newborn calves via intrauterine transmission and shedding of bacteria in feces and colostrum at calving. Vaccination of these latent carrier dams during late gestation boosts immunity against S. Dublin. This could reduce the activation of the dormant bacteria during the periparturient immune dysfunction period, thereby reducing the risk of early-life infection in the offspring. Thus, the objective of this study was to evaluate the extent to which vaccinating S. Dublin latent carrier cows at dry-off with a commercial live culture vaccine reduces bacterial shedding at calving and intrauterine infection to calves. To identify latent carriers, we screened 1,084 cows in 4 Michigan commercial dairy farms with a history of S. Dublin. Cows were defined as latent carriers when they showed 3 consecutive positive milk antibody ELISA tests conducted every 2 mo. Subsequently, 148 latent carriers were randomly allocated to the vaccine or control group. Vaccine cows received a commercial live culture vaccine subcutaneously (SC) at dry-off and a booster 2 weeks later. Control cows received saline SC at the same times. At calving, we collected fecal and colostrum samples from the dam and a pre-colostral serum sample from the calf. Bacterial shedding was evaluated in feces and colostrum both qualitatively and quantitatively through bacterial culture and qPCR, respectively. Intrauterine transmission was defined when a calf was positive for serum antibody ELISA at birth. Vaccination decreased the likelihood of calves being born S. Dublin seropositive (Relative Risk [95%CI]) = 0.19 [0.04 - 0.84]). However, no S. Dublin positive isolates were identified through either bacteriological culture or qPCR in feces or colostrum. Vaccination of S. Dublin latent-carrier cows at dry-off reduced intrauterine transmission to calves. Further research is warranted into the potential of vaccination to decrease vertical transmission of S. Dublin in dairy farms. Additionally, the absence of S. Dublin positive fecal and colostrum samples warrants further evaluation of the detection methods for identifying latent carriers or S. Dublin isolation, as well as the role of latent carriers in infecting newborn calves in the maternity area at birth.

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BACKGROUND: Catastrophic injury has a low incidence but leads to the death of many Thoroughbred racehorses. OBJECTIVES: To determine sensitivity, specificity, and reliability for third metacarpal condylar stress fracture risk assessment from digital radiographs (DR) and standing computed tomography (sCT). STUDY DESIGN: Controlled ex vivo experiment. METHODS: A blinded set of metacarpophalangeal joint DR and sCT images were prepared from 31 Thoroughbreds. Four observers evaluated the condyles and parasagittal grooves (PSG) of the third metacarpal bone for the extent of dense bone and lucency/fissure and assigned a risk assessment grade for condylar stress fracture based on imaging features. Sensitivity and specificity for detection of subchondral structural changes in the condyles and PSG, and for risk assessment for condylar stress fracture were determined by comparison with a reference assessment based on sCT and joint surface examination. Agreement between observers and the reference assessment and reliability between observers were determined. Intra-observer repeatability was also assessed. RESULTS: Sensitivity for detection of structural change was lower than specificity for both imaging methods and all observers. For agreement with the reference assessment of structural change, correlation coefficients were generally below 0.5 for DR and 0.49-0.82 for sCT. For horses categorised as normal risk on reference assessment, observer assessment often agreed with the reference. Sensitivity for risk assessment was lower than specificity for all observers. For horses with a reference assessment of high risk of injury, observers generally underestimated risk. Diagnostic sensitivity of risk assessment was improved with sCT imaging, particularly for horses categorised as having elevated risk of injury from the reference assessment. Assessment repeatability and reliability was better with sCT than DR. MAIN LIMITATIONS: The ex vivo study design influenced DR image sets. CONCLUSIONS: Risk assessment through screening with diagnostic imaging is a promising approach to improve injury prevention in racing Thoroughbreds. Knowledge of sensitivity and specificity of fetlock lesion detection provides the critical guidance needed to improve racehorse screening programs. We found improved detection of MC3 subchondral structural change and risk assessment for condylar stress fracture with sCT ex vivo.

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BACKGROUND: Repetitive negative thinking (RNT) is a transdiagnostic process involving perseverative, unproductive, and uncontrollable thoughts. Although RNT may impede adaptive psychosocial functioning by prolonging negative mood states, strengthening cognitive biases, and preventing effective problem-solving, the extent to which RNT is associated with risk for poor psychosocial outcomes is unclear. Given that this has clear transdiagnostic treatment implications, the present study aimed to isolate the unique relationship of RNT with social functioning and life satisfaction in a mixed clinical and non-clinical sample. METHODS: In 201 mid-to-later life adult participants (27 with primary diagnoses of bipolar disorder, 84 with major depressive disorder, and 90 healthy volunteers), we measured RNT, social functioning, life satisfaction, trait rumination, DSM-5 diagnoses, depressive symptoms, manic symptoms, cognitive control performance, and global cognitive functioning. RESULTS: Linear regression models revealed that RNT, but not rumination, was significantly associated with poorer social functioning (ß = 0.42 p < .001) and reduced life satisfaction (ß = -0.42, p < .001) after controlling for clinical and cognitive covariates. LIMITATIONS: Limited demographic diversity, cross-sectional design, self-reporting of outcomes. CONCLUSIONS: Results suggest that RNT may confer risk for key psychosocial outcomes during middle to later adulthood, over and above the effects of clinical and cognitive variables and independent of diagnostic status. Findings lend support to the notion of RNT as a transdiagnostic process and suggest that RNT may be an important therapeutic target for adults with poor social functioning and/or reduced life satisfaction.

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One of the major challenges in processing rare-earth element (REE) materials arises from the large amounts of radioactive thorium (Th) that are often found within REE minerals, encouraging enhanced metal separation procedures. We report here a study aimed at developing improved systems for REE processing with the goal of efficient extraction of Th(IV) from acidic solution. A tripodal ligand, TRPN-CMPO-Ph, was prepared that utilizes carbamoylmethylphosphine oxide (CMPO) chelators tethered to a tris(3-aminopropyl)amine (TRPN) capping scaffold. The ligand and its metal complexes were characterized by using elemental analysis, NMR, Fourier transform infrared spectroscopy, mass spectrometry, and luminescence spectroscopy. Using a liquid-liquid metal extraction protocol, TRPN-CMPO-Ph selectively extracts Th(IV) at an efficiency of 79% from a mixture of Th(IV), UO22+, and all rare-earth metal cations (except promethium) dissolved in nitric acid into an organic solvent. Th(IV) extraction selectivity is maintained upon extraction from a mixture that approximates a typical monazite leach solution containing several relevant lanthanide ions, including two ions at higher concentration relative to Th(IV). Comparative studies with a tris(2-aminoethyl)amine (TREN)-capped derivative are presented and support the need for a larger TRPN capping scaffold in achieving Th(IV) extraction selectivity.

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BACKGROUND: Late-life depression (LLD) is characterized by a poor response to antidepressant medications and diminished cognitive performance, particularly in executive functioning. There is currently no accepted pharmacotherapy for LLD that effectively treats both mood and cognitive symptoms. This study investigated whether transdermal nicotine augmentation of standard antidepressant medications benefitted mood and cognitive symptoms in LLD. METHODS: Nonsmoking participants aged 60 years or older with unremitted LLD on stable SSRI or SNRI medications (N = 29) received transdermal nicotine patches up to a 21 mg daily dose over 12 weeks. Clinical measures assessed depression severity, secondary affective symptoms, and cognitive performance. Nicotine metabolite concentrations were obtained from blood samples. RESULTS: Depression severity significantly decreased over the trial, with a 76 % response rate and 59 % remission rate. Change in depression severity was positively associated with nicotine exposure. Participants also exhibited improvement in self-reported affective symptoms (apathy, insomnia, rumination, and generalized anxiety symptoms), negativity bias, and disability. Executive function test performance significantly improved, specifically in measures of cognitive control, as did subjective cognitive performance. Adverse events were generally mild, with 75 % of the sample tolerating the maximum dose. CONCLUSION: The current study extends our previous pilot open-label trial in LLD, supporting feasibility and tolerability of transdermal nicotine patches as antidepressant augmentation. Although preliminary, this open-label study supports the potential benefit of transdermal nicotine patches for both mood and cognitive symptoms of LLD. Further research, including definitive randomized, blinded trials, is warranted to confirm these findings and explore long-term risk and benefit. TRIAL REGISTRATION: The study was registered with clinicaltrials.gov (NCT04433767).

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Introduction: This study explored the connection between social determinants and patient self-rated health at Health Ministries Clinic (HMC) in a rural Kansas community. Community health centers, like HMC, strive to deliver comprehensive care that addresses patients' social needs. Methods: The authors employed a convenience sampling method to survey HMC patients with appointments from September to December 2018. The authors analyzed the data using Chi-square tests and descriptive statistics in RStudio, considering p <0.05 as significant. Results: Among 200 patient responses, education, income, employment, and insurance status were negatively correlated with self-rated health. Notably, 86.2% of college or graduate school graduates reported positive health ratings, compared to 40% of those who did not finish high school (χ2(12, N = 185) = 25.75, p = 0.012). Lower income individuals (income <$34,000 per year) consistently rated their health poorer than their higher income counterparts (χ2(12, N = 174) = 23.96, p = 0.021). Patients without insurance or with public insurance (Medicaid/ CHIP) perceived their health as worse than those on private health insurance and Medicare (χ2(12, N = 137) = 35.67, p <0.001). Conclusions: Our findings suggest that low educational attainment, income, and lack of health insurance are associated with barriers to healthcare, resulting in poor health outcomes and chronic disease among those with lower socioeconomic status. This underscores the strong association between social determinants and self-rated health among HMC patients. These results can be used by other clinics to assess the needs of their patient population and enhance community health initiatives.

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The ATPase family AAA+ domain containing 2 (ATAD2) protein and its paralog ATAD2B have a C-terminal bromodomain (BRD) that functions as a reader of acetylated lysine residues on histone proteins. Using a structure-function approach, we investigated the ability of the ATAD2/B BRDs to select acetylated lysine among multiple histone post-translational modifications. The ATAD2B BRD can bind acetylated histone ligands that also contain adjacent methylation or phosphorylation marks, while the presence of these modifications significantly weakened the acetyllysine binding activity of the ATAD2 BRD. Our structural studies provide mechanistic insights into how ATAD2/B BRD-binding pocket residues coordinate the acetyllysine group in the context of adjacent post-translational modifications. Furthermore, we investigated how sequence changes in amino acids of the histone ligands impact the recognition of an adjacent acetyllysine residue. Our study highlights how the interplay between multiple combinations of histone modifications influences the reader activity of the ATAD2/B BRDs, resulting in distinct binding modes.

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In eukaryotes, the ubiquitin-proteasome system is responsible for intracellular protein degradation. Proteins tagged with ubiquitin are recognized by ubiquitin receptors on the 19S regulatory particle (RP) of the 26S proteasome, unfolded, routed through the translocation channel of the RP, and are then degraded in the 20S core particle (CP). Aromatic paddles on the pore-1 loops of the RP's Rpt subunits grip the substrate and pull folded domains into the channel, thereby unfolding them. The sequence that the aromatic paddles grip while unfolding a substrate is therefore expected to influence the extent of unfolding, and low complexity sequences have been shown to interfere with grip. However, the detailed spatial requirements for grip while unfolding proteins, particularly from the N-terminus, remain unknown. We determined how the location of glycine-rich tracts relative to a folded domain impairs unfolding. We find that, in contrast to a previous report, inserting glycine-rich sequences closer to the folded domain reduced unfolding ability more than positioning them further away. Locations that have the biggest effect on unfolding map onto the regions where the aromatic paddles are predicted to interact with the substrate. Effects on unfolding from locations up to 67 amino acids away from the folded domain suggest that there are additional interactions between the substrate and the proteasome beyond the aromatic paddles that facilitate translocation of the substrate. In sum, this study deepens understanding of the mechanical interactions within the substrate channel by mapping the spacing of interactions between the substrate and the proteasome during unfolding.

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[This corrects the article DOI: 10.3389/fvets.2024.1334858.].

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The muscles of mastication derive from a common embryological source, and the presence of accessory muscles in the infratemporal fossa (ITF) is uncommon. Here, we present findings from postmortem dissection of the ITF revealing a unilaterally present muscle extending from the greater wing of the sphenoid to blend inferiorly with the medial and lateral pterygoid muscles before attaching to the lateral pterygoid plate. This muscle is most consistent with the pterygoideus proprius muscle initially described in 1858. Though the exact embryological origin and function of this muscle remain speculative, these topics are nonetheless worth investigating as it may provide insight regarding the ontogeny of muscles descending from the first pharyngeal arch. Additionally, presence of the pterygoideus proprius muscle may have clinical implications and impact surrounding structures such as the mandibular division of the trigeminal nerve, maxillary artery, pterygoid venous plexus, masticatory muscles, and temporomandibular joint (TMJ).

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The production of HbS - an abnormal hemoglobin (Hb) - in sickle cell disease (SCD) results in poorly deformable red blood cells (RBCs) that are prone to microcapillary occlusion, causing tissue ischemia and organ damage. Novel treatments, including gene therapy, may reduce SCD morbidity, but methods to functionally evaluate RBCs remain limited. Previously, we presented the microfluidic impedance red cell assay (MIRCA) for rapid assessment of RBC deformability, employing electrical impedance-based readout to measure RBC occlusion of progressively narrowing micropillar openings. We describe herein the design, development, validation, and clinical utility of the next-generation MIRCA assay, featuring enhanced portability, rapidity, and usability. It incorporates a miniaturized impedance analyzer and features a simplified wash-free operation that yields an occlusion index (OI) within 15 min as a new metric for RBC occlusion. We show a correlation between OI and percent fetal hemoglobin (%HbF), other laboratory biomarkers of RBC hemolysis, and SCD severity. To demonstrate the assay's versatility, we tested RBC samples from treatment-naïve SCD patients in Uganda that yielded OI levels similar to those from hydroxyurea (HU)-treated patients in the U.S., highlighting the role of %HbF in protecting against microcapillary occlusion independent of other pharmacological effects. The MIRCA assay could also identify a subset of HU-treated patients with high occlusion risks, suggesting that they may require treatment adjustments including a second-line therapy to improve their outcomes. This work demonstrates the potential of the MIRCA assay for accelerated evaluation of RBC health, function, and therapeutic effect in an ex vivo model of the microcapillary networks.

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Glycans modify protein, lipid, and even RNA molecules to form the regulatory outer coat on cells called the glycocalyx. The changes in glycosylation have been linked to the initiation and progression of many diseases. Thus, while the significance of glycosylation is well established, a lack of accessible methods to characterize glycans has hindered the ability to understand their biological functions. Mass spectrometry (MS)-based methods have generally been at the core of most glycan profiling efforts; however, modern data-independent acquisition (DIA), which could increase sensitivity and simplify workflows, has not been benchmarked for analyzing glycans. Herein, we developed a DIA-based glycomic workflow, termed GlycanDIA, to identify and quantify glycans with high sensitivity and accuracy. The GlycanDIA workflow combined higher energy collisional dissociation (HCD)-MS/MS and staggered windows for glycomic analysis, which facilitates the sensitivity in identification and the accuracy in quantification compared to conventional data-dependent acquisition (DDA)-based glycomics. To facilitate its use, we also developed a generic search engine, GlycanDIA Finder, incorporating an iterative decoy searching for confident glycan identification and quantification from DIA data. The results showed that GlycanDIA can distinguish glycan composition and isomers from N-glycans, O-glycans, and human milk oligosaccharides (HMOs), while it also reveals information on low-abundant modified glycans. With the improved sensitivity, we performed experiments to profile N-glycans from RNA samples, which have been underrepresented due to their low abundance. Using this integrative workflow to unravel the N-glycan profile in cellular and tissue glycoRNA samples, we found that RNA-glycans have specific forms as compared to protein-glycans and are also tissue-specific differences, suggesting distinct functions in biological processes. Overall, GlycanDIA can provide comprehensive information for glycan identification and quantification, enabling researchers to obtain in-depth and refined details on the biological roles of glycosylation.

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Introduction: Bladder cancer is a common neoplasia of the urinary tract that holds the highest cost of lifelong treatment per patient, highlighting the need for a continuous search for new therapies for the disease. Current bladder cancer models are either imperfect in their ability to translate results to clinical practice (mouse models), or rare and not inducible (canine models). Swine models are an attractive alternative to model the disease due to their similarities with humans on several levels. The Oncopig Cancer Model has been shown to develop tumors that closely resemble human tumors. However, urothelial carcinoma has not yet been studied in this platform. Methods: We aimed to develop novel Oncopig bladder cancer cell line (BCCL) and investigate whether these urothelial swine cells mimic human bladder cancer cell line (5637 and T24) treatment-responses to cisplatin, doxorubicin, and gemcitabine in vitro. Results: Results demonstrated consistent treatment responses between Oncopig and human cells in most concentrations tested (p>0.05). Overall, Oncopig cells were more predictive of T24 than 5637 cell therapeutic responses. Microarray analysis also demonstrated similar alterations in expression of apoptotic (GADD45B and TP53INP1) and cytoskeleton-related genes (ZMYM6 and RND1) following gemcitabine exposure between 5637 (human) and Oncopig BCCL cells, indicating apoptosis may be triggered through similar signaling pathways. Molecular docking results indicated that swine and humans had similar Dg values between the chemotherapeutics and their target proteins. Discussion: Taken together, these results suggest the Oncopig could be an attractive animal to model urothelial carcinoma due to similarities in in vitro therapeutic responses compared to human cells.

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BACKGROUND AND OBJECTIVES: Implantable telemetric intracranial pressure (ICP) sensors (telesensors) enable routine, noninvasive ICP feedback, aiding clinical decision-making and attribution of pressure-related symptoms in patients with cerebrospinal fluid shunt systems. Here, we aim to explore the impact of these devices on service demand and costs in patients with adult hydrocephalus. METHODS: We performed an observational propensity-matched control study, comparing patients who had an MScio/Sensor Reservoir (Christoph Miethke, GmbH & Co) against those with a nontelemetric reservoir inserted between March 2016 and March 2018. Patients were matched on demographics, diagnosis, shunt-type, and revision status. Service usage was recorded with frequencies of neurosurgical admissions, outpatient clinics, scans, and further surgical procedures in the 2 years before and after shunt insertion. RESULTS: In total, 136 patients, 73 telesensors, and 63 controls were included in this study (48 matched pairs). Telesensor use led to a significant decrease in neurosurgical inpatient admissions, radiographic encounters, and procedures including ICP monitoring. After multivariate adjustment, the mean cumulative saving after 2 years was £5236 ($6338) in telesensor patients (£5498 on matched pair analysis). On break-even analysis, cost-savings were likely to be achieved within 8 months of clinical use, postimplantation. Telesensor patients also experienced a significant reduction in imaging-associated radiation (4 mSv) over 2 years. CONCLUSION: The findings of this exploratory study reveal that telesensor implantation is associated with reduced service demand and provides net financial savings from an institutional perspective. Moreover, telesensor patients required fewer appointments, invasive procedures, and had less radiation exposure, indicating an improvement in both their experience and safety.

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This study aimed to develop a practical semi-mechanistic modeling framework to predict particle size evolution during wet bead milling of pharmaceutical nanosuspensions over a wide range of process conditions and milling scales. The model incorporates process parameters, formulation parameters, and equipment-specific parameters such as rotor speed, bead type, bead size, bead loading, active pharmaceutical ingredient (API) mass, temperature, API loading, maximum bead volume, blade diameter, distance between blade and wall, and an efficiency parameter. The characteristic particle size quantiles, i.e., x10, x50, and x90, were transformed to obtain a linear relationship with time, while the general functional form of the apparent breakage rate constant of this relationship was derived based on three models with different complexity levels. Model A, the most complex and general model, was derived directly from microhydrodynamics. Model B is a simpler model based on a power-law function of process parameters. Model C is the simplest model, which is the pre-calibrated version of Model B based on data collected from different mills across scales, formulations, and drug products. Being simple and computationally convenient, Model C is expected to reduce the amount of experimentation needed to develop and optimize the wet bead milling process and streamline scale-up and/or scale-out.