Prosthetic Joint Infections Caused by Mycobacterium tuberculosis Complex-An ESGIAI-ESGMYC Multicenter, Retrospective Study and Literature Review.

PURPOSE: While tuberculosis remains a significant global health concern, prosthetic joint infections (PJIs) caused by members of the Mycobacterium tuberculosis complex are exceptionally rare. Our objective is to perform a retrospective search of new cases of this disease and analyze all cases available in the literature of tuberculous PJIs, aiming to detect factors that may influence patient outcomes. METHODS: The ESGIAI and ESGMYC study groups were used to collect information on non-published cases of tuberculous prosthetic joint infections (PJIs). Additionally, a literature review of all published cases of tuberculous PJIs was conducted. All identified cases in the retrospective study and in the literature review were merged and included in the statistical analysis, involving both univariate and multivariate analyses. RESULTS: Fifteen previously unreported cases of tuberculous prosthetic joint infections (PJIs) from four countries were detailed. Among them, ten patients were female, with a median age of 76 years. The hip was affected in 13 cases. Seven patients experienced co-infection with another microorganism. Treatment approaches varied, with 13 patients undergoing implant removal, one treated with DAIR (debridement, antibiotics, and implant retention), and one case was treated with an unknown treatment method. All patients received antibiotic therapy and achieved a cure. The literature review that was conducted detected 155 published cases. Univariate analysis revealed a statistical significance for previous tuberculosis, joint, and no importance of surgery for cure. CONCLUSIONS: Tuberculous prosthetic joint infection (PJI) is a rare condition, typically presenting as a localized chronic infection. Antibiotic treatment is essential for the management of these patients, but neither surgical treatment nor duration of treatment seems to have importance in the outcome.

Primary Hyperparathyroidism: Assessment of the Effects of Parathyroidectomy Using Dual X-Ray Absorptiometry, Trabecular Bone Score, and Dual X-Ray Absorptiometry-Based Three-Dimensional Modeling.

OBJECTIVE: This study aimed to evaluate the bone microstructure to determine whether curative surgery of primary hyperparathyroidism produces changes in bone mineral density (BMD), trabecular bone score (TBS), and three-dimensional (3D) dual x-ray absorptiometry (DXA) parameters and whether these changes are comparable. METHODS: We retrospectively studied 85 patients (60 women and 25 men, 60.4 ± 12.5 years) diagnosed with primary hyperparathyroidism and undergoing parathyroidectomy. Mean percent changes in BMD (lumbar spine [LS], femoral neck [FN], total hip [TH], and 1/3 radius), TBS and 3D-DXA parameters (trabecular volumetric BMD (vBMD), cortical vBMD, integral vBMD, cortical surface density (sBMD), and cortical thickness at TH) after surgery (12, 24, and/or 36 months) were calculated and compared, and we sought the determinants of these changes. RESULTS: After parathyroidectomy, BMD presented statistically significant mean increases in LS, FN, and TH during the first 3 years after surgery (P < .001), accompanied by an improvement in all 3D-DXA parameters, but there were no significant changes in 1/3 radius BMD or TBS. Cortical sBMD, trabecular vBMD, and integral vBMD reached mean increases of similar magnitude to those of FN and TH BMD. Age and preoperative serum levels of parathyroid hormone and carboxy-terminal telopeptide of type 1 collagen were significantly associated with percent changes after surgery. CONCLUSION: We found a benefit of parathyroidectomy for bone, with significant percent increases in LS, FN, and TH BMD up to the third year after surgery, and a qualitative benefit for the hip in both its trabecular and cortical compartments and bone strength.

Moderate-High Blood Eosinophilia Is Associated with Increased Hospitalization and Other Asthma Comorbidities.

(1) Background: Eosinophilia has traditionally been linked to eosinophilic asthma, for which it is the gold-standard prognostic biomarker. However, the association between eosinophilia and the presence of other diseases and comorbidities is yet unclear. (2) Methods: For this retrospective study, we reviewed the electronic medical records of 49,909 subjects with blood eosinophilia to gather data on the presence of asthma, COPD, sleep apnea, tuberculosis, dyslipidemia, hypertension, and other cardiovascular diseases and severe CRSwNP among these subjects. Demographic features including age, sex, and smoking habits were collected, as well as the number of hospitalizations and emergency department visits. T-tests, ANOVA, Fisher test, and logistic regression models were used. (3) Results: For all age groups studied, eosinophilia was significantly more prevalent among asthmatic subjects than nonasthmatics, especially in patients also presenting CRSwNP, hypertension, and dyslipidemia. The likelihood of developing asthma, COPD, and CRSwNP, and hospitalization, was increased when BEC was above 600 eosinophils/µL. The association between asthma, CRSwNP, and BEC was corroborated by multiple logistic regressions models. (4) Conclusions: We demonstrated the association of having over 600 blood eosinophils/µL with a higher number of hospitalizations and comorbidities (CRSwNP and COPD), which proves that BEC is a highly useful parameter to consider in subjects who present blood eosinophilia.

LT and SOX9 expression are associated with gene sets that distinguish Merkel cell polyomavirus (MCPyV)-positive and MCPyV-negative Merkel cell carcinoma.

BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive malignant neuroendocrine tumour. There are two subsets of MCC, one related to Merkel cell polyomavirus (MCPyV) and the other to ultraviolet radiation (UVR). MCPyV-positive and MCPyV-negative MCCs have been considered to be different tumours, as the former harbour few DNA mutations and are not related to UVR, and the latter usually arise in sun-exposed areas and may be found in conjunction with other keratinocytic tumours, mostly squamous cell carcinomas. Two viral oncoproteins, large T antigen (LT; coded by MCPyV_gp3) and small T antigen (sT; coded by MCPyV_gp4), promote different carcinogenic pathways. OBJECTIVES: To determine which genes are differentially expressed in MCPyV-positive and MCPyV-negative MCC; to describe the mutational burden and the most frequently mutated genes in both MCC subtypes; and to identify the clinical and molecular factors that may be related to patient survival. METHODS: Ninety-two patients with a diagnosis of MCC were identified from the medical databases of participating centres. To study gene expression, a customized panel of 172 genes was developed. Gene expression profiling was performed with nCounter technology. For mutational studies, a customized panel of 26 genes was designed. Somatic single nucleotide variants (SNVs) were identified following the GATK Best Practices workflow for somatic mutations. RESULTS: The expression of LT enabled the series to be divided into two groups (LT positive, n = 55; LT negative, n = 37). Genes differentially expressed in LT-negative patients were related to epithelial differentiation, especially SOX9, or proliferation and the cell cycle (MYC, CDK6), among others. Congruently, LT displayed lower expression in SOX9-positive patients, and differentially expressed genes in SOX9-positive patients were related to epithelial/squamous differentiation. In LT-positive patients, the mean SNV frequency was 4.3; in LT-negative patients it was 10 (P = 0.03). On multivariate survival analysis, the expression of SNAI1 [hazard ratio (HR) 1.046, 95% confidence interval (CI) 1.007-1.086; P = 0.02] and CDK6 (HR 1.049, 95% CI 1.020-1.080; P = 0.001) were identified as risk factors. CONCLUSIONS: Tumours with weak LT expression tend to co-express genes related to squamous differentiation and the cell cycle, and to have a higher mutational burden. These findings are congruent with those of earlier studies.

Merkel cell carcinoma (MCC) is an aggressive form of skin tumour. There are two subtypes of MCC: one of them is related to a virus called Merkel cell polyomavirus (MCPyV); the other one is related to persistent exposure to sunlight. The aim of this research was to find differences between these subtypes in their molecular behaviour (the genes that are expressed and the mutations that may be found). To do this, we carried out two studies, one to investigate gene expression (the process cells use to convert the instructions in our DNA into a functional product such as a protein) and one to look at gene mutations (changes in the DNA sequence). We found that the tumours that were not related to MCPyV expressed genes related to epithelial differentiation (the process by which unspecialized cells gain features characteristics of epithelial cells, which, among other things, make up the outer surface of the body), which means that the origin of both MCC subtypes may be different. We also found that MCPyV-related tumours had fewer mutations. Our findings are important because they help us to understand the biology of the MCC subtypes and could help with the development of new treatments for people diagnosed with skin tumours.

Patient Characteristics Associated with Growth of Patient-Derived Tumor Implants in Mice (Patient-Derived Xenografts).

Background: patient-derived xenografts (PDXs) have defined the field of translational cancer research in recent years, becoming one of the most-used tools in early drug development. The process of establishing cancer models in mice has turned out to be challenging, since little research focuses on evaluating which factors impact engraftment success. We sought to determine the clinical, pathological, or molecular factors which may predict better engraftment rates in PDXs. Methods: between March 2017 and January 2021, tumor samples obtained from patients with primary or metastatic cancer were implanted into athymic nude mice. A full comprehensive evaluation of baseline factors associated with the patients and patients' tumors was performed, with the goal of potentially identifying predictive markers of engraftment. We focused on clinical (patient factors) pathological (patients' tumor samples) and molecular (patients' tumor samples) characteristics, analyzed either by immunohistochemistry (IHC) or next-generation sequencing (NGS), which were associated with the likelihood of final engraftment, as well as with tumor growth rates in xenografts. Results: a total of 585 tumor samples were collected and implanted. Twenty-one failed to engraft, due to lack of malignant cells. Of 564 tumor-positive samples, 187 (33.2%) grew at time of analysis. The study was able to find correlation and predictive value for engraftment for the following: the use of systemic antibiotics by the patient within 2 weeks of sampling (38.1% (72/189) antibiotics- group vs. 30.7% (115/375) no-antibiotics) (p = 0.048), and the administration of systemic steroids to the patients within 2 weeks of sampling (41.5% (34/48) steroids vs. 31.7% (153/329), no-steroids) (p = 0.049). Regarding patient's baseline tests, we found certain markers could help predict final engraftment success: for lactate dehydrogenase (LDH) levels, 34.1% (140/411) of tumors derived from patients with baseline blood LDH levels above the upper limit of normality (ULN) achieved growth, against 30.7% (47/153) with normal LDH (p = 0.047). Histological tumor characteristics, such as grade of differentiation, were also correlated. Grade 1: 25.4% (47/187), grade 2: 34.8% (65/187) and grade 3: 40.1% (75/187) tumors achieved successful growth (p = 0.043), suggesting the higher the grade, the higher the likelihood of success. Similarly, higher ki67 levels were also correlated with better engraftment rates: low (Ki67 < 15%): 8.9% (9/45) achieved growth vs. high (Ki67 ≥ 15%): 31% (35/113) (p: 0.002). Other markers of aggressiveness such as the presence of lymphovascular invasion in tumor sample of origin was also predictive: 42.2% (97/230) with lymphovascular vs. 26.9% (90/334) of samples with no invasion (p = 0.0001). From the molecular standpoint, mismatch-repair-deficient (MMRd) tumors showed better engraftment rates: 62.1% (18/29) achieved growth vs. 40.8% (75/184) of proficient tumors (p = 0.026). A total of 84 PDX were breast models, among which 57.9% (11/19) ER-negative models grew, vs. 15.4% (10/65) of ER-positive models (p = 0.0001), also consonant with ER-negative tumors being more aggressive. BRAFmut cancers are more likely to achieve engraftment during the development of PDX models. Lastly, tumor growth rates during first passages can help establish a cutoff point for the decision-making process during PDX development, since the higher the tumor grades, the higher the likelihood of success. Conclusions: tumors with higher grade and Ki67 protein expression, lymphovascular and/or perineural invasion, with dMMR and are negative for ER expression have a higher probability of achieving growth in the process of PDX development. The use of steroids and/or antibiotics in the patient prior to sampling can also impact the likelihood of success in PDX development. Lastly, establishing a cutoff point for tumor growth rates could guide the decision-making process during PDX development.

Frailty assessment to individualize treatment in older patients with lymphoma.

PURPOSE: A study analyzing the application of a protocol of comprehensive geriatric assessment (CGA) in older patients with lymphoma was carried out to allow frailty-based patient classification and individualized treatment. METHODS: Lymphoma patients older than 70 years referred to the Geriatric Clinic at a tertiary hospital between May 2016 and March 2021 were included. The assessment protocol included comorbidity, polypharmacy, nutritional, functional, and mental status, geriatric syndromes, and life expectancy. CGA enabled patient classification into four groups (Type I to Type IV) based on frailty assessment instrument scoring and clinical, functional, and mental status. Variables were compared using parametric and non-parametric statistical tests and Kaplan-Meier survival curves. RESULTS: Ninety-three patients (55.9% women) were included. Median age was 81.1 years (± 5.7). 23 patients (24.7%) were classified as robust (type I), 30 (32.3%) as pre-frail (type II) with potentially reversable deficits, 38 (40.9%) as frail (type III), and 2 (2.2%) as requiring palliative care (type IV). Patients received oncospecific treatment with modifications carried out in 64.5% of cases based on CGA results. Differences in overall survival (p = 0.002), response to treatment (p < 0.001) and likelihood of increased frailty (p = 0.024) were observed, with type III-IV patients showing significantly worse outcomes. CONCLUSION: Performance of standardized, systematic CGA by geriatricians permits older lymphoma patients to be classified according to frailty, with significant differences in terms of clinical outcomes across groups. We propose incorporating CGA performed by geriatricians as part of the multidisciplinary care team to optimize therapeutic strategy for these patients.

Risk of Intraocular Lens Opacification After Endothelial Keratoplasty for Different Intraocular Lens Models: A Retrospective Single-Center Cohort Study.

PURPOSE: The aims of this study were to calculate the specific risk of opacification for different intraocular lens (IOL) models and to determine whether differences exist, even between lenses made of similar acrylic materials. METHODS: This is a retrospective cohort study of all patients who underwent endothelial keratoplasty (EK), either after or in conjunction with cataract surgery, from June 2009 to October 2020 at Fundación Jiménez Díaz Hospital. RESULTS: Three hundred seventy-two eyes of 308 patients with a median follow-up of 856 days [interquartile range (IQR): 384-1570] were included, of which 128 IOLs were hydrophobic, 120 hydrophilic, and 124 unknown. 12.9% of IOLs opacified after a median of 466 days (IQR: 255-743). Visual acuity (VA) was significantly lower in the opacified IOL group [0.51 (IQR: 0.36-1.13)] compared with the nonopacified group [0.22 (IQR: 0.11-0.65)] ( P < 0.001). IOL explantation and exchange was performed in 10 eyes, in which VA improved markedly, from 1.75 (IQR: 0.99-3.00) to 0.60 (IQR: 0.36-0.86) ( P = 0.004). IOL material and opacification events were not independent ( P < 0.001). Significant differences were found between the Akreos ADAPT AO and MI60P models and the Asphina 409M model ( P = 0.022). No significant differences were found in the opacification ratio for hydrophilic IOLs in the clinical diagnosis ( P = 0.11), the type of EK ( P = 0.25), the rebubbling rate ( P = 0.44), or the tamponade used ( P = 0.36). CONCLUSIONS: Hydrophilic lenses should be avoided in patients at risk of requiring EK. It is important to know the probability of opacification of each IOL model to balance risk and benefits when planning an EK procedure because not all lenses opacify equally. Opacification is an unwanted event with a negative impact on VA, making IOL explantation and exchange the only viable treatment, although one that is not without risks.

Enhanced thrombin generation detected with ST-Genesia analyzer in patients with newly diagnosed multiple myeloma.

The issue of how to identify newly diagnosed multiple myeloma (NDMM) patients requiring thromboprophylaxis remains unsolved. Several changes in thrombin generation (TG)-derived parameters have been described in multiple myeloma (MM) patients recently. Assessment of prothrombotic risk with a fully automated TG analyzer could reduce interlaboratory variability. Our objective was to determine whether ST-Genesia® could reveal a hypercoagulable state in NDMM compared to healthy controls. We conducted a multicenter observational study of NDMM requiring initial treatment to compare TG parameters obtained with ST-Genesia® analyzer and ST-ThromboScreen® reagent with a control group. Clinical data were obtained from medical records and blood samples were collected before initial anti-myeloma therapy. A thrombophilia panel was performed in all patients. Compared to age- and sex-matched controls (n = 83), NDMM patients (n = 83) had significantly higher peak height, higher velocity index, shorter time-to-peak and lower percentage of endogenous thrombin potential (ETP) inhibition after adding thrombomodulin (TM) (ETP%inh). NDMM on prophylactic low molecular weight heparin (LMWH) showed reduced both peak height and velocity index compared to NDMM who had not yet started VTE prophylaxis, similar to that of controls. Moreover, partial correction of ETP%inh was observed in MM patients on LMWH. The presence of a thrombophilia did not modify the TG phenotype. Untreated NDMM patients showed an enhanced TG, regardless of their thrombophilia status. They generate a higher peak of thrombin, take less time to produce it, and exhibit resistance to TM inhibition. Our findings suggest that standard prophylactic dose of LMWH may reduce TG at levels of healthy controls.

Clinical description, molecular delineation and genotype-phenotype correlation in 340 patients with KBG syndrome: addition of 67 new patients.

BACKGROUND: KBG syndrome is a highly variable neurodevelopmental disorder and clinical diagnostic criteria have changed as new patients have been reported. Both loss-of-function sequence variants and large deletions (copy number variations, CNVs) involving ANKRD11 cause KBG syndrome, but no genotype-phenotype correlation has been reported. METHODS: 67 patients with KBG syndrome were assessed using a custom phenotypical questionnaire. Manifestations present in >50% of the patients and a 'phenotypical score' were used to perform a genotype-phenotype correlation in 340 patients from our cohort and the literature. RESULTS: Neurodevelopmental delay, macrodontia, triangular face, characteristic ears, nose and eyebrows were the most prevalentf (eatures. 82.8% of the patients had at least one of seven main comorbidities: hearing loss and/or otitis media, visual problems, cryptorchidism, cardiopathy, feeding difficulties and/or seizures. Associations found included a higher phenotypical score in patients with sequence variants compared with CNVs and a higher frequency of triangular face (71.1% vs 42.5% in CNVs). Short stature was more frequent in patients with exon 9 variants (62.5% inside vs 27.8% outside exon 9), and the prevalence of intellectual disability/attention deficit hyperactivity disorder/autism spectrum disorder was lower in patients with the c.1903_1907del variant (70.4% vs 89.4% other variants). Presence of macrodontia and comorbidities were associated with larger deletion sizes and hand anomalies with smaller deletions. CONCLUSION: We present a detailed phenotypical description of KBG syndrome in the largest series reported to date of 67 patients, provide evidence of a genotype-phenotype correlation between some KBG features and specific ANKRD11 variants in 340 patients, and propose updated clinical diagnostic criteria based on our findings.

Galectin-1, a novel promising target for outcome prediction and treatment in SCLC.

INTRODUCTION: small-cell lung cancer (SCLC) is one of the most lethal malignancies. Its management is complex due to the lack of biomarkers and limited therapies. Galectin-1 (Gal-1) plays a major role in cancer development and progression. The aim of this study is to assess whether Gal-1 has a predictive role in the disease evolution and its therapeutic potential. MATERIAL AND METHODS: The expression level of Gal-1 was examined by using a public RNA-sequencing (77 SCLC patients) and in-house immunohistochemistry (IHC) performed on biopsies from 81 patients. Survival curves and Cox regression analysis were used to assess the prognostic potential of Gal-1. In addition, a SCLC-PDX model was carried out and treated with either OTX008, an inhibitor of Gal-1, or vehicle to assess the effects of Gal-1 inhibition on this disease in vivo. RESULTS: Galectin-1 gene (LGALS1) expression showed a strong negative correlation with outcome in SCLC patients with advanced disease (p = 0.007). IHC unveiled that overall survival (OS) was significantly lower among extensive-stage SCLC (ES-SCLC) patient group with increased level of Gal-1 and platelet-to-lymphocyte ratio (PLR) (HR=3.07, 95% CI: 1.62, 5.79, p < 0.001). The SCLC-PDX model showed a significant reduction in tumor size (tumor growth inhibition [TGI] index 73%) without side effects. DISCUSSION: in this study, high levels of Gal-1 and PLR were associated with poorer OS in SCLC patients, supporting their utility as clinical prognostic biomarkers. Moreover, the in vivo model suggests the inhibition of Gal-1 as a novel potential therapy for this disease with very poor prognosis.

An integrated prognostic model for diffuse large B-cell lymphoma treated with immunochemotherapy.

Diffuse large B-cell lymphoma (DLBCL), the most frequent non-Hodgkin's lymphoma subtype, is characterized by strong biological, morphological, and clinical heterogeneity, but patients are treated with immunochemotherapy in a relatively homogeneous way. Here, we have used a customized NanoString platform to analyze a series of 197 homogeneously treated DLBCL cases. The platform includes the most relevant genes or signatures known to be useful for predicting response to R-CHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone) in DLBCL cases. We generated a risk score that combines the International Prognostic Index with cell of origin and double expression of MYC/BCL2, and stratified the series into three groups, yielding hazard ratios from 0.15 to 5.49 for overall survival, and from 0.17 to 5.04 for progression-free survival. Group differences were highly significant (p < 0.0001), and the scoring system was applicable to younger patients (<60 years of age) and patients with advanced or localized stages of the disease. Results were validated in an independent dataset from 166 DLBCL patients treated in two distinct clinical trials. This risk score combines clinical and biological data in a model that can be used to integrate biological variables into the prognostic models for DLBCL cases.

Sialolithiasis: mineralogical composition, crystalline structure, calculus site, and epidemiological features.

The purpose of this paper was to describe the characteristics of salivary calculi and their relationship to epidemiological factors, through a cross-sectional study. We analysed 100 calculi obtained in 2017-2021. Patient data including age, time since onset of symptoms, gland involved, and site of location in the salivary system were studied. The calculi were studied to determine their morphological features using scanning electron microscopy and energy dispersive plain radiographic analysis. Most of the calculi had formed in the submandibular gland (SG) (82%). The mean age of patients at onset was 45.83 years; patients presenting parotid gland (PG) stones were somewhat older (p = 0.031). The mean time since the onset of symptoms was longer in PG calculi (p = 0.038). The most common lithiasis site was the main duct (74%), followed by the hilum (22%). Hilar stones were the largest (p < 0.05) and heaviest (p = 0.028). Octacalcium phosphate (OCP) was the most common crystalline phase (Cp) founded, followed by hydroxyapatite (HA) and whitlockite (WH). Specifically, OCP had a higher presence in PG calculi (p = 0.029) and WH was the most common phase in SG calculi (p = 0.017). The most prevalent site of lithiasis was the main duct, and the largest and heaviest calculi were found in the SG. PG stones were associated with a longer history of symptoms and older age. OCP was the most frequent Cp of the calculi studied, and the main Cp in PG stones. WH was the predominant Cp in SG stones. The Cp of the calculi was not influenced by location, patient age, or time of symptoms.

Epidemiologic, radiologic, and sialendoscopic aspects in chronic obstructive sialadenitis.

PURPOSE: Chronic obstructive sialadenitis (COS) is a recurring inflammation of the salivary gland. To date, there are no known predisposing factors for COS. Given the advances seen in radiology and sialendoscopy, we must update our knowledge of COS, analyzing factors that can favor its development. METHODS: We prospectively analyzed 333 patients who underwent sialendoscopy between 2012 and 2021. Epidemiologic, radiologic, and sialendoscopy-related factors were correlated. Suspected diagnosis was established based on the clinical and radiologic data. The final diagnosis was determined on the basis of sialendoscopic findings. RESULTS: The most common etiology of COS was stricture (40.8%). Lack of papilla distensibility (LPD) was also described as an etiology. COS was related to patient gender and age. Submandibular gland involvement was significantly more associated with lithiasis and LPD, while COS of the parotid gland was most frequently caused by stricture. Radioiodine sialadenitis and Sjögren's syndrome were significantly associated with stricture. MR sialography (MR-Si) showed the best overall sensitivity and specificity. CONCLUSION: In our series, stricture was the most common cause of COS. We describe LPD as a frequent cause of COS in this series; ours is the first study to report this finding. There was a significant association between the salivary gland involved, patient sex and age, and the cause of COS. MR-Si showed the greatest diagnostic yield.

Prognostic factors of trochanteric bursitis in surgical-staged patients: a prospective study.

BACKGROUND: Trochanteric bursitis or greater trochanteric pain syndrome is a common disorder and frequent cause of lateral hip pain. It can lead to severe functional impairment with increase morbidity and poor quality of life.The purpose of the current study was to identify and evaluate relationship between health-related factors, as prognostic indicators, and clinical outcomes. METHODS: A single-centre, prospective study was conducted and 60 patients (62 hips) were included with a minimum 12 months of follow-up. Clinical outcomes were evaluated using Hip Outcome Scale, Single Assessment Numeric Evaluation and Visual Analogue Scale. Radiological assessments and health-related factors were documented in an attempt to understand their validity as predictors of clinical outcomes. Complications and recurrence rates were also analyzed. RESULTS: Univariate model revealed that an increased BMI (p = 0.001; OR = 1.05; 95% CI, 1.02-1.07); number of previous corticosteroid infiltrations (p = 0.001; OR = 1.28, 95% CI, 1.11-1.48); longer time from symptom onset to surgery (p = 0.001; OR = 1.19; 95% CI, 1.12-1.28); smoker status (p = 0.001; OR 11.2; 95% CI, 3.30-44.2); and the presence of prior lumbosacral fusion (LSF) (p = 0.001; OR 13.8; 95% CI, 2.96-101); were prognostic factors predisposing for poor clinical outcomes.Among prognostic health-related factors were medical comorbidities such as emotional distress (p < 0.001; OR 26.1; 95% CI, 5.71-192); fibromyalgia (p = 0.026; OR 3.56; 95% CI, 1.16-11.7); and hyporthyroidism (p = 0.005, OR = 6.55, 95% CI, 1.73-28.7). CONCLUSIONS: Better overall physical function was predicted by lower number of corticosteroid infiltrations, shorter time span from symptom onset to surgery, non-smoker status and the absence of prior lumbosacral fusion. Obesity, smoking, the presence of emotional distress, fibromyalgia and hypothyroidism seem to increase the risk of poor clinical outcomes. A proper selection and/or correction of modifiable prognostic factors could reduce the incidence of endoscopic treatment failure and, as a consequence, improve patient outcomes and quality of life. However, future efforts should focus on experimental and randomised studies to fully determine these associations.

N-Terminal Pro-Brain Natriuretic Peptide Plasma Levels Are Associated with Intermediate-Term Follow-Up Cancer in Coronary Patients.

N-terminal pro-brain natriuretic peptide (NT-proBNP) plasma levels are increased in patients with cancer. In this paper, we test whether NT-proBNP may identify patients who are going to receive a future cancer diagnosis (CD) in the intermediate-term follow-up. We studied 962 patients with stable coronary artery disease and free of cancer and heart failure at baseline. This sample represents a re-analysis of a previous work expanding the sample size and the follow-up. NT-proBNP, galectin-3, monocyte chemoattractant protein-1, high-sensitivity C-reactive protein, high-sensitivity cardiac troponin I (hsTnI), and calcidiol (vitamin D) plasma levels were assessed. The primary outcome was new CD. After 5.40 (2.81-6.94) years of follow-up, 59 patients received a CD. NT-proBNP [HR 1.036 CI (1.015-1.056) per increase in 100 pg/mL; p = 0.001], previous atrial fibrillation (HR 3.140 CI (1.196-8.243); p = 0.020), and absence of previous heart failure (HR 0.067 CI (0.006-0.802); p = 0.033) were independent predictors of receiving a CD in the first three years of follow-up. None of the variables analyzed predicted a CD beyond this time. The number of patients developing heart failure during follow-up was 0 (0.0%) in patients receiving CD in the first three years of follow-up, 2 (6.9%) in those receiving a CD diagnosis beyond this time, and 40 (4.4%) in patients not developing cancer (p = 0.216). These numbers suggest that future heart failure was not a confounding factor. In patients with coronary artery disease, NT-proBNP was an independent predictor of CD in the first three years of follow-up but not later, suggesting that it could be detecting subclinical undiagnosed cancers.

Efficacy and safety of intramuscular administration of allogeneic adipose tissue derived and expanded mesenchymal stromal cells in diabetic patients with critical limb ischemia with no possibility of revascularization: study protocol for a randomized controlled double-blind phase II clinical trial (The NOMA Trial).

BACKGROUND: Chronic lower limb ischemia develops earlier and more frequently in patients with type 2 diabetes mellitus. Diabetes remains the main cause of lower-extremity non-traumatic amputations. Current medical treatment, based on antiplatelet therapy and statins, has demonstrated deficient improvement of the disease. In recent years, research has shown that it is possible to improve tissue perfusion through therapeutic angiogenesis. Both in animal models and humans, it has been shown that cell therapy can induce therapeutic angiogenesis, making mesenchymal stromal cell-based therapy one of the most promising therapeutic alternatives. The aim of this study is to evaluate the feasibility, safety, and efficacy of cell therapy based on mesenchymal stromal cells derived from adipose tissue intramuscular administration to patients with type 2 diabetes mellitus with critical limb ischemia and without possibility of revascularization. METHODS: A multicenter, randomized double-blind, placebo-controlled trial has been designed. Ninety eligible patients will be randomly assigned at a ratio 1:1:1 to one of the following: control group (n = 30), low-cell dose treatment group (n = 30), and high-cell dose treatment group (n = 30). Treatment will be administered in a single-dose way and patients will be followed for 12 months. Primary outcome (safety) will be evaluated by measuring the rate of adverse events within the study period. Secondary outcomes (efficacy) will be measured by assessing clinical, analytical, and imaging-test parameters. Tertiary outcome (quality of life) will be evaluated with SF-12 and VascuQol-6 scales. DISCUSSION: Chronic lower limb ischemia has limited therapeutic options and constitutes a public health problem in both developed and underdeveloped countries. Given that the current treatment is not established in daily clinical practice, it is essential to provide evidence-based data that allow taking a step forward in its clinical development. Also, the multidisciplinary coordination exercise needed to develop this clinical trial protocol will undoubtfully be useful to conduct academic clinical trials in the field of cell therapy in the near future. TRIAL REGISTRATION: ClinicalTrials.gov NCT04466007 . Registered on January 07, 2020. All items from the World Health Organization Trial Registration Data Set are included within the body of the protocol.

Elevated levels of arginase activity are related to inflammation in patients with COPD exacerbation.

INTRODUCTION: Within the pathogenesis of the chronic obstructive pulmonary disease (COPD) there are interactions between different inflammatory mediators that are enhanced during an exacerbation. Arginase is present in bronchial epithelial cells, endothelial, fibroblasts and alveolar macrophages, which make it a probable key enzyme in the regulation of inflammation and remodelling. We aimed to find a potential relationship between arginase activity, inflammatory mediators in COPD patients in stable phase and during exacerbations. METHODS: We performed a prospective, observational study of cases and controls, with 4 study groups (healthy controls, stable COPD, COPD during an exacerbation and COPD 3 months after exacerbation). We measured arginase, inflammation markers (IL-6, IL-8, TNF-∝, IFN-γ and C reactive protein), and mediators of immunity: neutrophils, monocytes, total TCD3 + lymphocytes (CD3ζ), CD4 + T cells, CD8 + T cells, NK cells. RESULTS: A total of 49 subjects were recruited, average age of 69.73 years (59.18% male). Arginase activity is elevated during an exacerbation of COPD, and this rise is related to an increase in IL-6 production. The levels of IL-6 and IL-8 remained elevated in patients with COPD at 3 months after hospital exacerbation. We did not find a clear relationship between arginase activity, immunity or with the degree of obstruction in COPD patients. CONCLUSIONS: Arginase activity is elevated during an exacerbation of COPD, and it could be related to an increase in the production of IL-6. Levels of IL-6, IL-8, and arginase activity remain elevated in patients with COPD at 3 months after hospital exacerbation. Arginase activity could contribute to the development of COPD.

Lung injury in patients age 75 years and older with the use of polymethylmethacrylate fenestrated pedicle screws.

BACKGROUND CONTEXT: Pulmonary complications in patients age 75 years and older who undergo spinal fusion may have catastrophic consequences. The use of augmentation techniques with polymethylmethacrylate (PMMA) have been associated with pulmonary damage. The use of fenestrated pedicle screws augmented with PMMA may increase the risk of lung injury in this population. PURPOSE: To investigate whether the use of PMMA-augmented screws is correlated with increased lung injury in patients undergoing instrumented lumbar spinal fusion. STUDY DESIGN: A nonrandomized, prospective, case-controlled clinical study was carried out. PATIENT SAMPLE: We included 50 consecutive patients: 25 classifieds as patients who required PMMA-augmented screws in lumbar spinal fusion, and 25 classifieds as control participants because they underwent uncemented instrumented spinal fusion. OUTCOME MEASURES: We compare the incidence of the event, lung damage, in both groups by measuring a series of parameters: arterial blood gas, transesophageal echocardiography, urinary desmosine, and chest radiograph. The epidemiological parameters analyzed were age, sex, body mass index, status as a smoker, and number of cement leaks. METHODS: Changes in pulmonary damage markers were described in both groups of patients, comparing postsurgery values with baseline values. In control participants, each change was evaluated for the total number of patients. All changes are indicated in this report by mean differences for quantitative variables and by differing proportions for qualitative variables, with 95% confidence intervals provided for all values. RESULTS: There was an increase in postinstrumentation PaO2 (arterial partial pressure of oxygen) in both groups, probably related to the use of mechanical ventilation and recruitment maneuvers. Even though the group that required augmentation had lower baseline levels, the difference between groups was not statistically significant. On transesophageal echocardiographs, we observed scattered small, snowflake-like emboli, and bright echo signals appeared in the right atrium during PMMA injection. Signal density was constant but gradually faded away when PMMA injection ended. No participants in the group without augmentation had radiological complications. Overall, desmosine levels increased in both groups, and the rise was similar in both. There was a slight average increase in urine desmosine levels after instrumentation and progressively continues to rise until 24 hours after instrumentation, with a subsequent decrease at 72 hours. Comparing the two groups, we found no statistically significant differences at any time. CONCLUSIONS: We were not able to identify a significant difference in urine desmosine levels associated with the augmentation of with fenestrated pedicle screws with PMMA. Despite comparing patients age 75 years or older with a younger group, we found no clinical, analytical, or gasometric data indicating lung damage in patients who had augmentation.

Bronchiolitis and recurrent wheezing are distinguished by type 2 innate lymphoid cells and immune response.

BACKGROUND: Recurrent wheezing (RW) is frequently developed in infants that have suffered bronchiolitis (BCH) during first months of life, but the immune mechanism underlying is not clear. The goal was to analyze the innate immune response that characterizes BCH and RW. METHODS: Ninety-eight and seventy hospitalized infants with BCH or RW diagnosis, respectively, were included. Nasopharyngeal aspirate (NPA) was processed. Cellular pellet was employed to evaluate type 2 innate lymphoid cells (ILC2) by flow cytometry and mRNA expression assays by semi-quantitative real-time PCR (qRT-PCR). In supernatant, twenty-seven pro-inflammatory and immunomodulatory factors, as well as lipid mediators and nitrites, were evaluated by ELISA and Luminex. RESULTS: Bronchiolitis patients showed higher ILC2 percentage compared with RW (P < .05). Also, ST2+ /ILC2 percentage was higher in the BCH group than in the RW group (P < .01). TLR3, IL33, IFNG, IL10, and FLG mRNA levels were significantly increased in BCH vs RW (P < .05). In supernatant, no significant differences were reached, observing similar levels of parameters linked to vascular damage, monocyte activation, and fibroblast growth. Prostaglandin E2 and cysteinyl leukotrienes C4 were evaluated; a significant difference was only found in their ratio. CONCLUSION: Bronchiolitis is associated with elevated nasal percentage of ILC2. This cellular population could be the key element in the differential immune response between BCH and RW which share some mechanisms such us monocyte activation, vascular damage, and fibroblast repair. Lipid mediators could play a role in the evolution of the disease later in life through innate lymphoid cells.