Signal transduction at GPCRs: Allosteric activation of the ERK MAPK by ß-arrestin.

ß-arrestins are multivalent adaptor proteins that bind active phosphorylated G protein-coupled receptors (GPCRs) to inhibit G protein signaling, mediate receptor internalization, and initiate alternative signaling events. ß-arrestins link agonist-stimulated GPCRs to downstream signaling partners, such as the c-Raf-MEK1-ERK1/2 cascade leading to ERK1/2 activation. ß-arrestins have been thought to transduce signals solely via passive scaffolding by facilitating the assembly of multiprotein signaling complexes. Recently, however, ß-arrestin 1 and 2 were shown to activate two downstream signaling effectors, c-Src and c-Raf, allosterically. Over the last two decades, ERK1/2 have been the most intensely studied signaling proteins scaffolded by ß-arrestins. Here, we demonstrate that ß-arrestins play an active role in allosterically modulating ERK kinase activity in vitro and within intact cells. Specifically, we show that ß-arrestins and their GPCR-mediated active states allosterically enhance ERK2 autophosphorylation and phosphorylation of a downstream ERK2 substrate, and we elucidate the mechanism by which ß-arrestins do so. Furthermore, we find that allosteric stimulation of dually phosphorylated ERK2 by active-state ß-arrestin 2 is more robust than by active-state ß-arrestin 1, highlighting differential capacities of ß-arrestin isoforms to regulate effector signaling pathways downstream of GPCRs. In summary, our study provides strong evidence for a new paradigm in which ß-arrestins function as active "catalytic" scaffolds to allosterically unlock the enzymatic activity of signaling components downstream of GPCR activation.

A neural circuit architecture for angular integration in Drosophila.

Many animals keep track of their angular heading over time while navigating through their environment. However, a neural-circuit architecture for computing heading has not been experimentally defined in any species. Here we describe a set of clockwise- and anticlockwise-shifting neurons in the Drosophila central complex whose wiring and physiology provide a means to rotate an angular heading estimate based on the fly's angular velocity. We show that each class of shifting neurons exists in two subtypes, with spatiotemporal activity profiles that suggest different roles for each subtype at the start and end of tethered-walking turns. Shifting neurons are required for the heading system to properly track the fly's heading in the dark, and stimulation of these neurons induces predictable shifts in the heading signal. The central features of this biological circuit are analogous to those of computational models proposed for head-direction cells in rodents and may shed light on how neural systems, in general, perform integration.

Mismatch repair deficiency, next-generation sequencing-based microsatellite instability, and tumor mutational burden as predictive biomarkers for immune checkpoint inhibitor effectiveness in frontline treatment of advanced stage endometrial cancer.

OBJECTIVE: Molecular profiling is developing to inform treatment in endometrial cancer. Using real world evidence, we sought to evaluate frontline immune checkpoint inhibitor vs chemotherapy effectiveness in advanced endometrial cancer, stratified by Tumor Mutational Burden (TMB) ≥10 mut/MB and microsatellite instability (MSI). METHODS: Patients with advanced endometrial cancer in the US-based de-identified Flatiron Health-Foundation Medicine Clinico-Genomic Database were included. Data originated from patients treated between January 2011- March 2022 at 280 US clinics. Next-generation sequencing assays were performed via FoundationOne or FoundationOneCDx. Longitudinal clinical data were derived from electronic health records. Immune checkpoint inhibitor treatment included pembrolizumab, dostarlimab, and nivolumab monotherapies. Time to next treatment, time to treatment discontinuation, and overall survival were assessed with the log-rank test and Cox proportional hazard models with adjusted hazard ratios (aHR) for known prognostic factors. We used the Likelihood ratio test to compare biomarker performance. RESULTS: A total of 343 patients received chemotherapy and 28 received immune checkpoint inhibitor monotherapy as frontline treatment. Patients who received monotherapy were more likely to be stage III at diagnosis (immune checkpoint inhibitor: 54.6% vs chemotherapy: 15.0%; p<0.001) and more likely to test MSI-high via next-generation sequencing (immune checkpoint inhibitor: 53.6% vs chemotherapy: 19.2%; p<0.001). In MSI-high cancers, single-agent immune checkpoint inhibitor had a more favorable time to next treatment (aHR: 0.18, p=0.001) and overall survival (aHR 0.29, p=0.045). Additional analyses on 70 unique tumor specimens revealed mismatch repair deficiency (dMMR) via immunohistochemistry and MSI-high via next-generation sequencing concordance (91%), with nominal improvement of MSI over dMMR to predict time to treatment discontinuation (p=0.030), time to next treatment (p=0.032), and overall survival (p=0.22). MSI status was concordant with tumor mutational burden ≥10 in 94.3% of cases. CONCLUSION: Immune checkpoint inhibitors may have improved efficacy over chemotherapy in frontline treatment for advanced endometrial cancer defined by MSI-high using next-generation sequencing as a nominally better predictor of outcomes than dMMR with immunohistochemistry. This provides the biologic rationale of active phase III trials.

The use of andexanet alfa and 4-factor prothrombin complex concentrate in intracranial hemorrhage.

OBJECTIVE: to describe the clinical and safety outcomes between andexanet alfa (AA) and 4-factor prothrombin complex concentrate (4F-PCC) for the reversal of apixaban or rivaroxaban in the setting of an intracranial hemorrhage (ICH). METHODS: A retrospective, multicentered descriptive study was conducted in hospitalized patients 18 years of age or older from June 2018 to October 2019 who received AA or 4F-PCC for the reversal of apixaban or rivaroxaban in the setting of ICH. Patients were excluded if they had received 4F-PCC prior to AA after its addition to the institution wide formulary. Other exclusion criteria were history or presence of heparin-induced thrombocytopenia or disseminated intravascular coagulation, estimated hematoma volume of >60 mL, Glasgow Coma Scores <7, or no repeat CT head scan. Information was collected from the electronic medical records. The primary outcome was the achievement of excellent or good hemostatic efficacy upon the repeat computer tomography (CT) scan performed after the infusion of study drugs. Secondary outcomes included disposition, survival to hospital discharge, 30-day readmission, length of hospital stay, length of ICU stay, incidence of thromboembolic events. RESULTS: A total of 24 patients were included in the study, of which 9 received AA and 15 received 4F-PCC. The achievement of excellent or good hemostatic efficacy upon repeat CT scan occurred in 7 (77.8%) patients in the AA group and in 14 (93.3%) patients in the 4-F PCC group. All patients in the AA group survived to hospital discharge with no 30-day morality and 86.7% patients in the 4F-PCC group. CONCLUSION: This study suggests that real-world clinical and safety outcomes between andexanet alfa and 4F-PCC for the reversal of factor Xa inhibitors in the setting of ICH are similar to ones reported in clinical trials.

5-FU-miR-15a Inhibits Activation of Pancreatic Stellate Cells by Reducing YAP1 and BCL-2 Levels In Vitro.

Chronic pancreatitis is characterized by chronic inflammation and fibrosis, processes heightened by activated pancreatic stellate cells (PSCs). Recent publications have demonstrated that miR-15a, which targets YAP1 and BCL-2, is significantly downregulated in patients with chronic pancreatitis compared to healthy controls. We have utilized a miRNA modification strategy to enhance the therapeutic efficacy of miR-15a by replacing uracil with 5-fluorouracil (5-FU). We demonstrated increased levels of YAP1 and BCL-2 (both targets of miR-15a) in pancreatic tissues obtained from Ptf1aCreERTM and Ptf1aCreERTM;LSL-KrasG12D mice after chronic pancreatitis induction as compared to controls. In vitro studies showed that delivery of 5-FU-miR-15a significantly decreased viability, proliferation, and migration of PSCs over six days compared to 5-FU, TGFß1, control miR, and miR-15a. In addition, treatment of PSCs with 5-FU-miR-15a in the context of TGFß1 treatment exerted a more substantial effect than TGFß1 alone or when combined with other miRs. Conditioned medium obtained from PSC cells treated with 5-FU-miR-15a significantly inhibits the invasion of pancreatic cancer cells compared to controls. Importantly, we demonstrated that treatment with 5-FU-miR-15a reduced the levels of YAP1 and BCL-2 observed in PSCs. Our results strongly suggest that ectopic delivery of miR mimetics is a promising therapeutic approach for pancreatic fibrosis and that 5-FU-miR-15a shows specific promise.

miR-132 suppresses transcription of ribosomal proteins to promote protective Th1 immunity.

Determining the mechanisms that distinguish protective immunity from pathological chronic inflammation remains a fundamental challenge. miR-132 has been shown to play largely immunoregulatory roles in immunity; however, its role in CD4+ T cell function is poorly understood. Here, we show that CD4+ T cells express high levels of miR-132 and that T cell activation leads to miR-132 up-regulation. The transcriptomic hallmark of splenic CD4+ T cells lacking the miR-132/212 cluster during chronic infection is an increase in mRNA levels of ribosomal protein (RP) genes. BTAF1, a co-factor of B-TFIID and novel miR-132/212-3p target, and p300 contribute towards miR-132/212-mediated regulation of RP transcription. Following infection with Leishmania donovani, miR-132-/- CD4+ T cells display enhanced expression of IL-10 and decreased IFNγ. This is associated with reduced hepatosplenomegaly and enhanced pathogen load. The enhanced IL-10 expression in miR-132-/- Th1 cells is recapitulated in vitro following treatment with phenylephrine, a drug reported to promote ribosome synthesis. Our results uncover that miR-132/212-mediated regulation of RP expression is critical for optimal CD4+ T cell activation and protective immunity against pathogens.

Comparison of a predefined dose increment nomogram with a percentage adjustment nomogram in patients receiving argatroban therapy.

OBJECTIVE: To determine the compliance with a predefined dose increment (PDI) nomogram compared with a percentage adjustment (PA) nomogram for the dose titration of argatroban therapy. DESIGN: This was a single-center, retrospective chart review. SETTING AND PARTICIPANTS: This study was conducted in a tertiary care teaching hospital. Patients were included if they received argatroban from 2013 to 2016. OUTCOME MEASURES: The primary safety outcome was the percentage of appropriate dose titrations. The secondary safety and efficacy outcomes included the median time to therapeutic activated partial thromboplastin time (aPTT), the median argatroban dose once therapeutic, and the median time in the therapeutic, subtherapeutic, and supratherapeutic aPTT ranges, as well as the bleeding and thrombotic events during hospitalization. RESULTS: Seventy-seven patients were included in the study. There was no statistically significant difference in the percentage of titrations performed appropriately (P = 0.17). The median time to goal aPTT, the dose when first therapeutic, and the time aPTT was subtherapeutic were similar in both the arms. The patients in the PDI arm were on argatroban for a median time of 55 hours compared with 110.5 hours for the patients in the PA arm (P = 0.001). The patients in the PA arm spent more time in the therapeutic range (P < 0.05) and less time in the supratherapeutic range (P < 0.005). CONCLUSION: Although there was no difference in the percentage of appropriate dose titrations, the patients in the PA arm spent more time on argatroban, had greater time in the therapeutic aPTT range, and had less time in the supratherapeutic aPTT range. Future studies that include a larger sample size, matching therapeutic aPTT ranges, and similar initial infusion rates would help evaluate further the outcomes between the PDI and PA nomograms.

MicroRNA-155 induction via TNF-α and IFN-γ suppresses expression of programmed death ligand-1 (PD-L1) in human primary cells.

Programmed death ligand-1 (PD-L1) is a critical regulator of T cell function contributing to peripheral immune tolerance. Although it has been shown that posttranscriptional regulatory mechanisms control PD-L1 expression in cancer, it remains unknown whether such regulatory loops operate also in non-transformed cells. Here we studied PD-L1 expression in human dermal lymphatic endothelial cells (HDLECs), which play key roles in immunity and cancer. Treatment of HDLECs with the pro-inflammatory cytokines IFN-γ and TNF-α synergistically up-regulated PD-L1 expression. IFN-γ and TNF-α also affected expression of several microRNAs (miRNAs) that have the potential to suppress PD-L1 expression. The most highly up-regulated miRNA following IFN-γ and TNF-α treatment in HDLECs was miR-155, which has a central role in the immune system and cancer. Induction of miR-155 was driven by TNF-α, the effect of which was significantly enhanced by IFN-γ. The PD-L1 3'-UTR contains two functional miR-155-binding sites. Endogenous miR-155 controlled the kinetics and maximal levels of PD-L1 induction upon IFN-γ and TNF-α treatments. We obtained similar findings in dermal fibroblasts, demonstrating that the IFN-γ/TNF-α/miR-155/PD-L1 pathway is not restricted to HDLECs. These results reveal miR-155 as a critical component of an inflammation-induced regulatory loop controlling PD-L1 expression in primary cells.

Targeted Robotic Assisted Microsurgical Denervation of the Spermatic Cord for the Treatment of Chronic Orchialgia or Groin Pain: A Single Center, Large Series Review.

PURPOSE: Microsurgical denervation of the spermatic cord is a treatment option for chronic orchialgia refractory to conservative treatment. A recent study showed specific nerve fibers as the possible cause of chronic orchialgia. Our goal was to present the outcomes of ligation of these nerves using a technique of targeted robotic assisted microsurgical denervation of the spermatic cord. MATERIALS AND METHODS: We retrospectively reviewed the records of 772 patients who underwent targeted robotic assisted microsurgical denervation of the spermatic cord from October 2007 to July 2016. Selection criteria were chronic testicular pain more than 3 months in duration, failed conservative treatments, negative neurological and urological workup, and temporary resolution of pain with a local anesthetic spermatic cord block. Targeted robotic assisted microsurgical denervation of the spermatic cord was performed. Pain was assessed preoperatively and postoperatively using a subjective visual analog scale and objectively with the standardized and validated PIQ-6 (Pain Impact Questionnaire-6) score. RESULTS: Followup data were available on 860 cases. During a median followup of 24 months (range 1 to 70) 718 cases (83%) showed a significant reduction in pain and 142 (17%) had no change in pain by subjective visual analog scale scoring. Of cases with a significant reduction in pain 426 (49%) had complete resolution and 292 (34%) had a 50% or greater reduction. Objective PIQ-6 analysis showed a significant reduction in pain in 67% of patients 6 months postoperatively, in 68% at 1 year, in 77% at 2 years, in 86% at 3 years and in 83% at 4 years. CONCLUSIONS: Targeted robotic assisted microsurgical denervation of the spermatic cord is an effective, minimally invasive approach with potential long-term durability in patients with refractory chronic orchialgia.

Gradient nanocomposite hydrogels for interface tissue engineering.

Two-dimensional (2D) nanomaterials are an emerging class of materials with unique physical and chemical properties due to their high surface area and disc-like shape. Recently, these 2D nanomaterials have been investigated for a range of biomedical applications including tissue engineering, therapeutic delivery and bioimaging, due to their ability to physically reinforce polymeric networks. Here, we present a facile fabrication of a gradient scaffold with two natural polymers (gelatin methacryloyl (GelMA) and methacrylated kappa carrageenan (MκCA)) reinforced with 2D nanosilicates to mimic the native tissue interface. The addition of nanosilicates results in shear-thinning characteristics of prepolymer solution and increases the mechanical stiffness of crosslinked gradient structure. A gradient in mechanical properties, microstructures and cell adhesion characteristics was obtained using a microengineered flow channel. The gradient structure can be used to understand cell-matrix interactions and to design gradient scaffolds for mimicking tissue interfaces.

Quantification of Serial Cerebral Blood Flow in Acute Stroke Using Arterial Spin Labeling.

BACKGROUND AND PURPOSE: Perfusion-weighted imaging is used to select patients with acute ischemic stroke for intervention, but knowledge of cerebral perfusion can also inform the understanding of ischemic injury. Arterial spin labeling allows repeated measurement of absolute cerebral blood flow (CBF) without the need for exogenous contrast. The aim of this study was to explore the relationship between dynamic CBF and tissue outcome in the month after stroke onset. METHODS: Patients with nonlacunar ischemic stroke underwent ≤5 repeated magnetic resonance imaging scans at presentation, 2 hours, 1 day, 1 week, and 1 month. Imaging included vessel-encoded pseudocontinuous arterial spin labeling using multiple postlabeling delays to quantify CBF in gray matter regions of interest. Receiver-operator characteristic curves were used to predict tissue outcome using CBF. Repeatability was assessed in 6 healthy volunteers and compared with contralateral regions of patients. Diffusion-weighted and T2-weighted fluid attenuated inversion recovery imaging were used to define tissue outcome. RESULTS: Forty patients were included. In contralateral regions of patients, there was significant variation of CBF between individuals, but not between scan times (mean±SD: 53±42 mL/100 g/min). Within ischemic regions, mean CBF was lowest in ischemic core (17±23 mL/100 g/min), followed by regions of early (21±26 mL/100 g/min) and late infarct growth (25±35 mL/100 g/min; ANOVA P<0.0001). Between patients, there was marked overlap in presenting and serial CBF values. CONCLUSIONS: Knowledge of perfusion dynamics partially explained tissue fate. Factors such as metabolism and tissue susceptibility are also likely to influence tissue outcome.

Supplemental Screening for Breast Cancer in Women With Dense Breasts: A Systematic Review for the U.S. Preventive Services Task Force.

BACKGROUND: Screening mammography has lower sensitivity and specificity in women with dense breasts, who experience higher breast cancer risk. PURPOSE: To perform a systematic review of reproducibility of Breast Imaging Reporting and Data System (BI-RADS) density categorization and test performance and clinical outcomes of supplemental screening with breast ultrasonography, magnetic resonance imaging (MRI), and digital breast tomosynthesis (DBT) in women with dense breasts and negative mammography results. DATA SOURCES: MEDLINE, PubMed, EMBASE, and Cochrane database from January 2000 to July 2015. STUDY SELECTION: Studies reporting BI-RADS density reproducibility or supplemental screening results for women with dense breasts. DATA EXTRACTION: Quality assessment and abstraction of 24 studies from 7 countries; 6 studies were good-quality. DATA SYNTHESIS: Three good-quality studies reported reproducibility of BI-RADS density; 13% to 19% of women were recategorized between "dense" and "nondense" at subsequent screening. Two good-quality studies reported that sensitivity of ultrasonography for women with negative mammography results ranged from 80% to 83%; specificity, from 86% to 94%; and positive predictive value (PPV), from 3% to 8%. The sensitivity of MRI ranged from 75% to 100%; specificity, from 78% to 94%; and PPV, from 3% to 33% (3 studies). Rates of additional cancer detection with ultrasonography were 4.4 per 1000 examinations (89% to 93% invasive); recall rates were 14%. Use of MRI detected 3.5 to 28.6 additional cancer cases per 1000 examinations (34% to 86% invasive); recall rates were 12% to 24%. Rates of cancer detection with DBT increased by 1.4 to 2.5 per 1000 examinations compared with mammography alone (3 studies). Recall rates ranged from 7% to 11%, compared with 7% to 17% with mammography alone. No studies examined breast cancer outcomes. LIMITATIONS: Good-quality evidence was sparse. Studies were small and CIs were wide. Definitions of recall were absent or inconsistent. CONCLUSION: Density ratings may be recategorized on serial screening mammography. Supplemental screening of women with dense breasts finds additional breast cancer but increases false-positive results. Use of DBT may reduce recall rates. Effects of supplemental screening on breast cancer outcomes remain unclear. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.

Targeting Interleukin-5 in Patients With Severe Eosinophilic Asthma: A Clinical Review.

Interleukin-5 (IL-5) is known to play a major role in the growth, differentiation, recruitment, and activation of eosinophils. The authors review the efficacy and safety of two IL-5-targeting agents used in the treatment of eosinophilic asthma.

Heart Failure: A Class Review of Pharmacotherapy.

A recent guideline update for the treatment of heart failure has created the need for a new look at the medication classes and trials related to the disease. The authors focus on pharmacological options available for treating the problem.

Arteriovenous Malformation of the Jaws: a Black Hole for the GDP ­ A Case Report.

We report a case of a mandibular arteriovenous malformation in a 3-year-old child, who attended our department, and have carried out a literature review. Clinical relevance: Arteriovenous malformation (AVM) is a rare condition but clinicians need to be aware of it as this lesion can have potentially life-threatening complications due to massive haemorrhage.

The design and structural characterization of a synthetic pentatricopeptide repeat protein.

Proteins of the pentatricopeptide repeat (PPR) superfamily are characterized by tandem arrays of a degenerate 35-amino-acid α-hairpin motif. PPR proteins are typically single-stranded RNA-binding proteins with essential roles in organelle biogenesis, RNA editing and mRNA maturation. A modular, predictable code for sequence-specific binding of RNA by PPR proteins has recently been revealed, which opens the door to the de novo design of bespoke proteins with specific RNA targets, with widespread biotechnological potential. Here, the design and production of a synthetic PPR protein based on a consensus sequence and the determination of its crystal structure to 2.2 Šresolution are described. The crystal structure displays helical disorder, resulting in electron density representing an infinite superhelical PPR protein. A structural comparison with related tetratricopeptide repeat (TPR) proteins, and with native PPR proteins, reveals key roles for conserved residues in directing the structure and function of PPR proteins. The designed proteins have high solubility and thermal stability, and can form long tracts of PPR repeats. Thus, consensus-sequence synthetic PPR proteins could provide a suitable backbone for the design of bespoke RNA-binding proteins with the potential for high specificity.

Assessment of clinical outcome of percutaneous needle quadriceps tenotomy in the treatment of congenital knee dislocation.

PURPOSE: Treatment of congenital knee dislocation (CDK) depends on the severity and flexibility of the deformity. Various modalities of treatment ranging from serial cast, open quadricepsplasty and minimally invasive quadricepsplasty have been described. We describe percutaneous needle quadriceps tenotomy for treatment of flexible CDK and present our result of retrospective case series. METHODS: This was a retrospective study of 12 patients (20 knees) with flexible CDK. Eight patients with bilateral and four with unilateral deformities. The mean age of intervention was 14.5 days (range, 4-55 days). None of the patients were syndromic. All procedures were done within eight weeks of age. The outcome was measured using knee evaluation score and complications in view of extensor lag, instability and knee flexion deformity. Ultrasound was performed to check for integrity of quadriceps mechanism. RESULTS: The mean pre-operative hyperextension was 50° (range, 30-70°). All patients were able to achieve >90° flexion intra-operatively. The mean knee flexion at walking age was 135° (range, 130-140°). Knee evaluation score showed good results in nine patients and fair result in three patients. There was no extensor lag, knee flexion deformity or infection. One patient of anterior instability had ACL aplasia which was documented on MRI. Ultrasound performed at walking age showed normal functioning of quadriceps mechanism. CONCLUSIONS: Percutaneous needle tenotomy of quadriceps is a effective, simple and safe procedure for flexible, non syndromic CDK presenting early. It avoids complications associated with the open surgical procedure and causes less extensor scarring. However its effectiveness in stiff/hyperlax variants associated with syndromes is yet to be determined.

Is patient assessment of asthma care delivery associated with publicly reported performance measures?

OBJECTIVE: To determine the association between patient assessment of healthcare delivery and publicly reported asthma performance measures. METHODS: We identified individuals 5-50 years old who had asthma quality measures reported to the Minnesota Community Measurement© (MCM©) by their clinic and sent them a postal survey which included within it the Patient Assessment of Chronic Illness care (PACIC), a validated measure of patient perception of the quality of healthcare delivery. We performed a multivariable analysis to examine the association between PACIC scores and achievement of asthma care quality measures. RESULTS: The response rate for the ACS was 102/367 (28%); a non-response bias analysis revealed no differences between responders and non-responders for age, gender and asthma control. Most responders (73%) reported taking asthma medications daily and most (71%) had poorly controlled asthma. The PACIC score was not associated with any of the asthma quality measures based on the data reported to MCM© by the clinic. A higher PACIC score was, however, associated with having an asthma action plan based on patient-reported data in the ACS (p < 0.0001) but not with patient-reported asthma control or emergency department/hospitalizations for asthma. CONCLUSIONS: Patient assessment of high quality asthma care delivery was associated with patient self-report of having an asthma action plan but was not associated with any of the publicly reported asthma performance measures.

The psychosocial and affective burden of posttraumatic neuropathy following injuries to the trigeminal nerve.

AIMS: To explore the impact of trigeminal nerve injuries on quality of life, including the effect of pain on psychological and affective function. METHODS: An observational, cross-sectional survey design was employed. Fifty-six patients with inferior alveolar nerve injury (IANI) and 33 patients with lingual nerve injury (LNI) completed standardized self-report measures of pain intensity, pain catastrophizing, self-efficacy to cope with pain, and mood, in addition to generic and oral health-related quality of life (HRQoL) indicators. The impact of pain severity on these aspects of psychosocial function was examined. Summary statistics were calculated for all measures and compared with norms or values of other relevant studies, when available, using t tests. The impact of pain severity on these aspects of psychosocial function was examined using analysis of variance and hierarchical multivariate regression models. RESULTS: The majority of patients reported pain associated with their nerve injury (86%). Nerve injury had a significant impact on all investigated domains, and this was closely linked with reported pain levels. Patients with severe pain showed particularly elevated levels of depression and pain catastrophizing, as well as substantially reduced HRQoL and coping efficacy levels. Pain intensity level was a significant predictor in all models except anxiety, uniquely contributing between 17% and 26% of variance to the prediction of pain catastrophizing, depression, coping efficacy, and generic and oral HRQoL. CONCLUSION: Traumatic injury to the trigeminal nerve is associated with a substantial patient burden, particularly in patients who experience severe neuropathic pain as part of their condition. These findings highlight the need to identify, develop, and evaluate more effective treatments for neuropathic pain in trigeminal nerve injury that will not only provide clinically meaningful reductions in pain but also improve patients' quality of life.