Tetanus neurotoxin (TeNT) causes spastic paralysis by inhibiting neurotransmission in spinal inhibitory interneurons. TeNT binds to the neuromuscular junction, leading to its internalisation into motor neurons and subsequent transcytosis into interneurons. While the extracellular matrix proteins nidogens are essential for TeNT binding, the molecular composition of its receptor complex remains unclear. Here, we show that the receptor-type protein tyrosine phosphatases LAR and PTPRδ interact with the nidogen-TeNT complex, enabling its neuronal uptake. Binding of LAR and PTPRδ to the toxin complex is mediated by their immunoglobulin and fibronectin III domains, which we harnessed to inhibit TeNT entry into motor neurons and protect mice from TeNT-induced paralysis. This function of LAR is independent of its role in regulating TrkB receptor activity, which augments axonal transport of TeNT. These findings reveal a multi-subunit receptor complex for TeNT and demonstrate a novel trafficking route for extracellular matrix proteins. Our study offers potential new avenues for developing therapeutics to prevent tetanus and dissecting the mechanisms controlling the targeting of physiological ligands to long-distance axonal transport in the nervous system.

BACKGROUND: Serum lactate dehydrogenase to albumin ratio (LAR) is associated with poor outcomes in malignancy and pneumonia. However, there are few studies suggesting that LAR is associated with the occurrence of acute kidney injury (AKI) in patients with sepsis, which was investigated in this study.
METHODS: We conducted a retrospective cohort study based on the Medical Information Mart for Intensive Care (MIMIC)-IV database. The primary outcome was the occurrence of AKI within 2 days and 7 days. Multivariable logistic regression models were used to calculate odds ratios to validate the association between LAR and AKI, in-hospital mortality, RRT use, and recovery of renal function, respectively.
RESULTS: A total of 4010 participants were included in this study. The median age of the participants was 63.5 years and the median LAR was 10.5. After adjusting for confounding variables, patients in the highest LAR quartile had a higher risk of AKI than those in the lowest LAR quartile within 2 days and 7 days, with odds ratios of 1.37 (95% confidence interval [CI]: 1.23-1.52) and 1.95 (95% CI: 1.72-2.22), respectively. The adjusted odds of AKI within 2 and 7 days were 1.16 (95% CI: 1.12-1.20) and 1.29 (95% CI: 1.24-1.35) for each 1 unit increase in LAR(log2), respectively.
CONCLUSIONS: This study demonstrated that elevated LAR was associated with poor prognosis in patients with sepsis. The risk of AKI and in-hospital mortality increased, the need for RRT increased, and the chance of recovery of renal function decreased with the increase of LAR.

Accurately estimating the prognosis of septic patients on arrival in the emergency department (ED) is clinically challenging. The lactate-to-albumin ratio (LAR) has recently been proposed to improve the predictive performance of septic patients admitted to the ICU.
This study aims to assess whether the LAR could be used as an early prognostic marker of 30-day mortality in patients with sepsis in the ED.
A prospective observational study was conducted in the ED of the Hospital of Merano. All patients with a diagnosis of sepsis were considered. The LAR was recorded on arrival in the ED. The primary outcome measure was mortality at 30 days. The predictive role of the LAR for mortality was evaluated with the area under the ROC curve, logistic regression adjusted for the Charlson Comorbidity Index value, National Early Warning Score, and Sequential Organ Failure score, and with decision tree analysis.
459 patients were enrolled, of whom 17% (78/459) died at 30 days. The median LAR of the patients who died at 30 days (0.78 [0.45-1.19]) was significantly higher than the median LAR of survivors (0.42 [0.27-0.65]) (p < 0.001). The discriminatory ability of the LAR for death at 30 days was 0.738, higher than that of lactate alone (0.692), and slightly lower than that of albumin alone (0.753). The decision trees confirmed the role of the LAR as an independent risk factor for mortality.
The LAR can be used as an index to better predict the 30-day risk of death in septic patients.

BACKGROUND: The prognostic evaluation of the septic patient has recently been enriched by some predictive indices such as albumin concentration, lactate/albumin ratio (LAR) and C-reactive protein/albumin ratio (CAR). The performance of these indices has been evaluated in septic patients in intensive care, but until now their performance in infected patients in the Emergency Department (ED) has not been evaluated.
OBJECTIVE: To investigate the potential prognostic role of albumin, LAR and CAR in patients with infection in the ED.
METHODS: Single-centre prospective study performed between 1 January 2021 and 31 December 2021 at the ED of the Merano Hospital (Italy). All patients with infection were enrolled. The study outcome was death within 30 days. The predictive ability of albumin, LAR and CAR was assessed by area under the receiver operating characteristic curves (AUROCs). A multivariate logistic regression model was used to examine the association of the indices with 30-day mortality, with comorbidity, acute urgency and severity of infection as covariates.
RESULTS: The study enrolled 962 patients with an infectious status. The overall 30-day mortality rate was 8.9% (86/962). The AUROC of albumin was 0.831 (95% CI 0.795-868), while for LAR this was 0.773 (CI95% 0.719-0.827) and for CAR 0.718 (CI95% 0.664-0.771). The odds ratio for 30-day mortality for albumin was 3.362 (95% CI 1.904-5.936), for ln(LAR) 2.651 (95% CI 1.646-4.270) and for ln(CAR) 1.739 (95% CI 1.326-2.281).
CONCLUSIONS: All three indices had a good discriminatory ability for the risk of short-term death in patients with infection, indicating their promising use in the ED as well as in the ICU. Further studies are needed to confirm the better performance of albumin compared to LAR and CAR.

Patients subjected to low anterior resection for rectal cancers experience a constellation of symptoms of disordered bowel function which leads to a detriment in the quality of life. The LAR syndrome (LARS) score is a self-administered questionnaire to identify and assess disordered bowel function after resective surgery. The objective of this study was to validate the Urdu version of the LARS score. The translation process was carried out in a fashion outlined by the original authors of the LARS score after obtaining proper permission. The validation of the translated version included the assessment of its reliability, convergent and discriminant validities, internal consistency, and confirmatory analyses. A total of 60 patients were enrolled in the study with a 95% power of study. The translated questionnaire was initially administered to a random subgroup of patients to verify the adequacy and degree of comprehension of questions. Then reproducibility was investigated by a test-retest procedure. An analysis was then done to determine the correlation between Urdu LARS score and a quality of life related question that was included along with the questionnaire. The Urdu version of the LARS score demonstrates a high convergent validity in terms of its correlation with self-reported quality of life. It also demonstrated its efficacy to discriminate between clinical variables expected to differ with regards to LARS. There was almost perfect agreement in the test and retest values demonstrating good reliability across all instruments. The Urdu version of the LARS score has proven to be a reliable and a valid tool for measuring LARS in the Urdu speaking population of the Indian subcontinent.
UNASSIGNED: The online version contains supplementary material available at 10.1007/s13193-023-01801-0.

(1) Background: Metastasis is a complex process in which the primary cancer cells spread to a distant organ or organs, creating a secondary tumor location, which in many patients leads to treatment failure and death. The aim of the present study was to assess the association of endothelial markers (i.e., sP-selectin, sE-selectin and von Willebrand factor) with the leptin-to-adiponectin ratio (LAR) and to perform an analysis of the predictive value on the survival of patients with luminal A and B invasive breast cancer (IBrC). (2) Methods: The trial included 70 treatment-naïve early-stage IBrC patients with a median age of 54.5 years and a median tumor diameter of 1.5 cm. The median duration of follow-up was 5.7 years, with a relapse rate of 15.71%. Specific immunoenzymatic kits were used to determine pre- and post-treatment concentrations of analyzed factors. (3) Results: Regardless of the treatment pattern, endothelial marker concentrations and the LAR increased after adjuvant treatment. The follow-up showed a significantly higher relapse rate in patients with IBrC who had higher pre-treatment sP-selectin and post-treatment LAR levels. According to receiver operating characteristic (ROC) analysis, a post-treatment LAR with a sensitivity of 88.9% and specificity of 57.9% discriminating cases with or without disease relapse. Additionally, a higher risk of breast cancer relapse was associated with a lower post-treatment sP-selectin concentration. (4) Conclusions: Our results showed mainly that pre-treatment sP-selectin levels and post-treatment LAR may have value as prognostic indicators and may contribute to predicting the future outcomes in patients with early-stage IBrC.

BACKGROUND: Local allergic rhinitis (LAR) is a condition involving a localized nasal allergic response in absence of systemic atopy. Most studies on LAR have been performed in adults. We aimed to describe clinical characteristics of LAR pediatric patients, its clinical evolution over a 7-year follow-up period and to study the role of basophil activation test (BAT), for its diagnosis.
METHODS: Forty-four children with non-allergic rhinitis (NAR) were included (24 males, 20 females, aged under 15 years). Nasal allergen provocation test (NAPT) and BAT were performed with Dermatophagoides pteronyssinus and Phleum pratense.
RESULTS: Seven patients (16%) were diagnosed of LAR. Six reacted to D pteronyssinus and one to P pratense. All LAR and 86% of NAR patients presented perennial symptoms. Fifty-seven percent of NAR and LAR patients referred persistent symptoms. Around half of NAR and LAR patients reported mild-moderate clinical manifestations. Three LAR patients associated conjunctival symptoms, proportionally more than NAR patients (19%, 7 out of 37). NAR patients presented bronchial asthma (n = 10) more frequently than LAR children (n = 1). More than half of LAR and NAR patients presented family history of atopy. BAT was negative in all LAR patients. On follow-up, 3 LAR patients and 10 of the 25 NAR patients who agreed to be retested, presented systemic sensitization. Dust mites were the most frequent allergen involved.
CONCLUSIONS: LAR should be ruled out in children with NAR. Almost half of children with LAR develop systemic sensitization over time. BAT shows low sensitivity for the diagnosis of LAR in children.

Leukocyte common antigen-related protein tyrosine phosphatase (LAR) is a member of the protein tyrosine phosphatase family that serves as a key regulator of cellular survival. It is also involved in neurodevelopment and brain disorders. This study was designed to investigate the role of LAR in a cell-based model of Parkinson\'s disease (PD) in which U251 and SH-SY5Y cells were used as models of astrocytes and dopaminergic neurons, respectively. Cell viability, cell death, cell morphology, protein phosphorylation and expression, ATP levels, reactive oxygen species (ROS) generation, and mitochondrial membrane potential were analyzed in the wild-type (WT) and heterozygous LAR-knockout astrocytoma U251 cells to assess the cell state, signal transduction, and mitochondrial function. LAR downregulation showed a protective effect in rotenone-exposed U251 cells by increasing cell viability, reducing cell mortality, and restoring appropriate cellular morphology. LAR downregulation enhanced IGF-1R phosphorylation and downstream signal transduction as evidenced by increases in the Akt and GSK-3β phosphorylation, as well as the upregulation of NRF2 and HO-1. The downregulation of LAR also augmented DJ-1 levels in these cells. The enhanced Akt and GSK-3β phosphorylation contributed to a reduced Bax/Bcl2 ratio and suppressed apoptosis after rotenone exposure. Heterozygous LAR-knockout U251 cells exhibited higher mitochondrial function evidenced by increased mitochondrial membrane potential, ATP contents, and reduced ROS production compared to the WT cells following rotenone exposure. Further studies showed that the astrocytic protection mediated by the heterozygous knockout of LAR was associated with the activation of Akt. A specific Akt inhibitor, MK2206, reduced the cell viability, Akt and GSK3β phosphorylation, and HO-1 and NRF2 expression in U251 cells exposed to rotenone. Astrocytes provide structural and metabolic support to maintain neuronal health. Astrocytic glial cell-derived neurotrophic factor (GDNF) production is vital for dopaminergic neuron survival. Heterozygous LAR-knockout U251 cells produced higher amounts of GDNF than the WT cells. The SH-SY5Y cells cocultured with heterozygous LAR-knockout U251 cells exhibited greater viability than that of cells cocultured with WT U251 cells in response to rotenone. Together, these findings demonstrate that the heterozygous knockout of LAR in astrocytes can play a key role in protecting both astrocytic cells and cocultured neurons in a rotenone-induced cell-based model of PD. This neuroprotective effect is attributable to the augmentation of IGF1R-Akt-GDNF signaling and the maintenance of astrocytic mitochondrial function.

Splenic flexure mobilization (SFM) may be indicated during anterior resection to provide a tension-free anastomosis. However, to date, no score allows identifying patients who may benefit from SFM.
Patients who underwent robotic anterior resection for rectal cancer were identified from a prospective register. Demographic and cancer-related variables were extracted, and predictors of SFM were identified using regression models. Thereafter, 20 patients with SFM and 20 patients without SFM were randomly selected and their pre-operative CTscan were reviewed. The radiological index was defined as 1/(sigmoid length/pelvis depth). The optimal cut-off value for predicting SFM was identified using ROC curve analysis.
Five hundred and twenty-four patients were included. SFM was performed in 121 patients (27.8%) and increased operative time by 21.8 min (95% CI: 11.3 to 32.4, p < 0.001). The incidence of postoperative complications did not differ between patient with or without SFM. Realization of an anastomosis was the main predictor for SFM (OR: 42.4, 95% CI: 5.8 to 308.5, p < 0.001). In patients with colorectal anastomosis, both sigmoid length (15 ± 5.1 cm versus 24.2 ± 80.9 cm, p < 0.001) and radiological index (1 ± 0.3 versus 0.6 ± 0.2, p < 0.001) differed between patients who had SFM and patients who did not. ROC curve analysis of the radiological index indicated an optimal cut-off value of 0.8 (sensitivity: 75%, specificity: 90%).
SFM was performed in 27.8% of patients who underwent robotic anterior resection, and increased operative time by 21.8 min. For optimal surgical planning, patients requiring SFM can be identified based on pre-operative CT using the index 1/(sigmoid length/pelvis depth) with a cut-off value set at 0.8.

Leukocyte common antigen-related phosphatase (LAR) is widely expressed in the central nervous system and is known to regulate a variety of processes including cell growth, differentiation, and inflammation. However, little is currently known about LAR signaling mediated neuroinflammation after intracerebral hemorrhage (ICH). The objective of this study was to investigate the role of LAR in ICH using autologous blood injection-induced ICH mouse model. Expression of endogenous proteins, brain edema and neurological function after ICH were evaluated. Extracellular LAR peptide (ELP), an inhibitor of LAR, was administered to ICH mice and outcomes were evaluated. LAR activating-CRISPR or IRS inhibitor NT-157 was administered to elucidate the mechanism. The results showed that expressions of LAR, its endogenous agonist chondroitin sulfate proteoglycans (CSPGs) including neurocan and brevican, and downstream factor RhoA increased after ICH. Administration of ELP reduced brain edema, improved neurological function, and decreased microglia activation after ICH. ELP decreased RhoA and phosphorylated serine-IRS1, increased phosphorylated tyrosine-IRS1 and p-Akt, and attenuated neuroinflammation after ICH, which was reversed by LAR activating-CRISPR or NT-157. In conclusion, this study demonstrated that LAR contributed to neuroinflammation after ICH via RhoA/IRS-1 pathway, and ELP may be a potential therapeutic strategy to attenuate LAR mediated neuroinflammation after ICH.