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We propose a new method for the rapid determination of five volatile compounds described in the literature as possible biomarkers of lung cancer in urine samples. The method is based on the coupling of a headspace sampler, a programmed temperature vaporizer in solvent-vent injection mode, and a mass spectrometer (HS-PTV-MS). This configuration is known as an electronic nose based on mass spectrometry. Once the method was developed, it was used for the analysis of urine samples from lung cancer patients and healthy individuals. Multivariate calibration models were employed to quantify the biomarker concentrations in the samples. The detection limits ranged between 0.16 and 21 μg/L. For the assignment of the samples to the patient group or the healthy individuals, the Wilcoxon signed-rank test was used, comparing the concentrations obtained with the median of a reference set of healthy individuals. To date, this is the first time that multivariate calibration and non-parametric methods have been combined to classify biological samples from profile signals obtained with an electronic nose. When significant differences in the concentration of one or more biomarkers were found with respect to the reference set, the sample is considered as a positive one and a new analysis was performed using a chromatographic method (HS-PTV-GC/MS) to confirm the result. The main advantage of the proposed HS-PTV-MS methodology is that no prior chromatographic separation and no sample manipulation are required, which allows an increase of the number of samples analyzed per hour and restricts the use of time-consuming techniques to only when necessary. Graphical abstract Schematic diagram of the developed methodology

Prosthetic valve endocarditis (PVE) is a serious infection associated with high mortality that often requires surgical treatment. Study on clinical characteristics and prognosis of a large contemporary prospective cohort of prosthetic valve endocarditis (PVE) that included patients diagnosed between January 2008 and December 2020. Univariate and multivariate analysis of factors associated with in-hospital mortality was performed. The study included 1354 cases of PVE. The median age was 71 years with an interquartile range of 62-77 years and 66.9% of the cases were male. Patients diagnosed during the first year after valve implantation (early onset) were characterized by a higher proportion of cases due to coagulase-negative staphylococci and Candida and more perivalvular complications than patients detected after the first year (late onset). In-hospital mortality of PVE in this series was 32.6%; specifically, it was 35.4% in the period 2008-2013 and 29.9% in 2014-2020 (p = 0.031). Variables associated with in-hospital mortality were: Age-adjusted Charlson comorbidity index (OR: 1.15, 95% CI: 1.08-1.23), intracardiac abscess (OR:1.78, 95% CI:1.30-2.44), acute heart failure related to PVE (OR: 3. 11, 95% CI: 2.31-4.19), acute renal failure (OR: 3.11, 95% CI:1.14-2.09), septic shock (OR: 5.56, 95% CI:3.55-8.71), persistent bacteremia (OR: 1.85, 95% CI: 1.21-2.83) and surgery indicated but not performed (OR: 2.08, 95% CI: 1.49-2.89). In-hospital mortality in patients with surgical indication according to guidelines was 31.3% in operated patients and 51.3% in non-operated patients (p<0.001). In the latter group, there were more cases of advanced age, comorbidity, hospital acquired PVE, PVE due to Staphylococcus aureus, septic shock, and stroke. Not performing cardiac surgery in patients with PVE and surgical indication, according to guidelines, has a significant negative effect on in-hospital mortality. Strategies to better discriminate patients who can benefit most from surgery would be desirable.

Alberto Cascón, Mercedes Robledo and colleagues show that MAX germline mutations confer susceptibility to hereditary pheochromocytoma. This finding supports a key role for MAX and its interaction partners in tumors of neural crest cell origin. Hereditary pheochromocytoma (PCC) is often caused by germline mutations in one of nine susceptibility genes described to date 1 , 2 , 3 , 4 , but there are familial cases without mutations in these known genes. We sequenced the exomes of three unrelated individuals with hereditary PCC (cases) and identified mutations in MAX , the MYC associated factor X gene. Absence of MAX protein in the tumors and loss of heterozygosity caused by uniparental disomy supported the involvement of MAX alterations in the disease. A follow-up study of a selected series of 59 cases with PCC identified five additional MAX mutations and suggested an association with malignant outcome and preferential paternal transmission of MAX mutations. The involvement of the MYC-MAX-MXD1 network in the development and progression of neural crest cell tumors is further supported by the lack of functional MAX in rat PCC (PC12) cells 5 and by the amplification of MYCN in neuroblastoma 6 and suggests that loss of MAX function is correlated with metastatic potential.

One-dimensional nanomechanical resonators based on nanowires and nanotubes have emerged as promising candidates for mass sensors 1 , 2 , 3 , 4 , 5 , 6 . When the resonator is clamped at one end and the atoms or molecules being measured land on the other end (which is free to vibrate), the resonance frequency of the device decreases by an amount that is proportional to the mass of the atoms or molecules. However, atoms and molecules can land at any position along the resonator, and many biomolecules have sizes that are comparable to the size of the resonator, so the relationship between the added mass and the frequency shift breaks down 7 , 8 , 9 , 10 . Moreover, whereas resonators fabricated by top-down methods tend to vibrate in just one dimension because they are usually shaped like diving boards, perfectly axisymmetric one-dimensional nanoresonators can support flexural vibrations with the same amplitude and frequency in two dimensions 11 . Here, we propose a new approach to mass sensing and stiffness spectroscopy based on the fact that the nanoresonator will enter a superposition state of two orthogonal vibrations with different frequencies when this symmetry is broken. Measuring these frequencies allows the mass, stiffness and azimuthal arrival direction of the adsorbate to be determined. A silicon nanowire vibrating in two dimensions can be used to measure the mass and stiffness of atoms and molecules deposited on it.

Background/Objectives: Adult acute lymphoblastic leukemia (ALL) often has poor outcomes, especially after relapse or treatment failure. Many patients eventually become ineligible for curative treatment and require only supportive care or low-intensity chemotherapy. However, data on prognosis and predictive factors in this context are limited. The study aim was to evaluate survival and identify prognostic factors in patients with relapsed/refractory ALL receiving supportive care. Methods: We conducted a retrospective observational study of 59 patients at two tertiary hospitals in Mexico. All patients had exhausted curative treatment options. Clinical variables at diagnosis and relapse were analyzed, including age, leukocyte counts, relapse timing, prior treatment lines, transfusion needs, and use of prognostic scores. Kaplan–Meier analysis was used to estimate survival, and multivariate models were applied to identify predictors of overall survival. Results: Fifty-nine patients were included (median age 31 years, balanced gender). Most received two prior high-intensity chemotherapy lines. Median overall survival was 137 days, with transfusion requirements being the only significant prognostic factor; neither the Palliative Prognostic Index nor the Charlson Comorbidity Index demonstrated predictive value. Conclusions: In patients with relapsed/refractory ALL managed with supportive care, survival remains limited. Transfusion dependence is a strong adverse prognostic factor, likely reflecting disease burden and logistical barriers to outpatient care. These findings highlight the need for earlier integration of palliative care and the development of tailored prognostic tools for this population.

Sialic acids and heparan sulfates make up the outermost part of the cell membrane and the extracellular matrix. Both structures are characterized by being negatively charged, serving as receptors for various pathogens, and are highly expressed in the respiratory and digestive tracts. Numerous viruses use heparan sulfates as receptors to infect cells; in this group are HSV, HPV, and SARS-CoV-2. Other viruses require the cell to express sialic acids, as is the case in influenza A viruses and adenoviruses. This review aims to present, in a general way, the participation of glycoconjugates in viral entry, and therapeutic strategies focused on inhibiting the interaction between the virus and the glycoconjugates. Interestingly, there are few studies that suggest the participation of both glycoconjugates in the viruses addressed here. Considering the biological redundancy that exists between heparan sulfates and sialic acids, we propose that it is important to jointly evaluate and design strategies that contemplate inhibiting the interactions of both glycoconjugates. This approach will allow identifying new receptors and lead to a deeper understanding of interspecies transmission.

Objectives Autoimmune diseases (AID) follow a complex, probably polygenic, pattern of inheritance and often cluster in families of patients with multiple sclerosis (MS). Our objective was to analyze family patterns and characteristics in families including more than one patient with MS. Materials and Methods We analyzed personal and family history of neurological, systemic, and autoimmune diseases in 84 MS patients from 40 different families. Families were classified in two groups: families with cases of MS in at least two different generations (15 families) and families in which cases of MS belonged to only one generation (25 families). Results The two previously established groups presented different clinical patterns and frequency of association with another AID. In one group, the second generation displayed a higher annual relapse rate than the first generation, higher frequency of progressive forms of MS, and more patients with another AID in addition to MS. Relapsing‐remitting forms of MS (RRMS) were more frequent in the other group. Conclusions Families that include more than one MS patient may show two distinct patterns. This finding seems important for the compression and analysis of genetic information on MS. In families of MS patients, there is a high frequency of other autoimmune diseases. Two main patterns of distribution of MS cases between generations were observed. In these families, more cases with concomitant autoimmune diseases were observed.

Device-aided therapies (DATs) are treatments indicated for people with Parkinson's disease (PwP) experiencing clinical fluctuations that remain suboptimal despite conventional medication. New DATs have recently emerged such as levodopa-entacapone-carbidopa intestinal gel infusion (LECIG) and subcutaneous infusion of foslevodopa/foscarbidopa (fLD/fCD). Understanding the differences between various DATs is essential. We present here the protocol study of the DATs-PD GETM Spanish Registry. This is a descriptive, observational, prospective, multicenter, open study that is proposed as a clinical registry with progressive inclusion of PwP treated with a DAT in daily clinical practice conditions in more 40 centers from Spain for 10 years. The principal aim is to know the type of DAT that PwP in our country (Spain) receive. Specific objectives are to compare the clinical characteristics of the patients, the effectiveness, safety and tolerability, to identify predictors of a good response and to analyze the response by groups (gender, disease duration, phenotype, etc.). There is a baseline visit (V1; indication of the therapy), start visit (V2; initiation of the therapy) and follow-up visits at 6 months ± 3 months (V3_6M) and after this annually ± 3 months for 10 years (V3_12M, V3_24M, etc.). The registry is on going. The first patient was included on April 10, 2024. Patient recruitment and follow-up will be conducted until 31/DEC/2033. It is estimated that the registry will include a minimum of 3,000 patients. The present study will help improve the care of PD patients treated with a DAT.

Background and objective Device-aided therapies (DATs) are treatments indicated for people with Parkinson's disease (PwP) experiencing clinical fluctuations that remain suboptimal despite conventional medication. New DATs have recently emerged such as levodopa-entacapone-carbidopa intestinal gel infusion (LECIG) and subcutaneous infusion of foslevodopa/foscarbidopa (fLD/fCD). Understanding the differences between various DATs is essential. Patients and Methods We present here the protocol study of the DATs-PD GETM Spanish Registry. This is a descriptive, observational, prospective, multicenter, open study that is proposed as a clinical registry with progressive inclusion of PwP treated with a DAT in daily clinical practice conditions in more 40 centers from Spain for 10 years. The principal aim is to know the type of DAT that PwP in our country (Spain) receive. Specific objectives are to compare the clinical characteristics of the patients, the effectiveness, safety and tolerability, to identify predictors of a good response and to analyze the response by groups (gender, disease duration, phenotype, etc.). There is a baseline visit (V1; indication of the therapy), start visit (V2; initiation of the therapy) and follow-up visits at 6 months ± 3 months (V3_6M) and after this annually ± 3 months for 10 years (V3_12M, V3_24M, etc.). Results The registry is on going. The first patient was included on April 10, 2024. Patient recruitment and follow-up will be conducted until 31/DEC/2033. It is estimated that the registry will include a minimum of 3,000 patients. Conclusion The present study will help improve the care of PD patients treated with a DAT.

All metazoans depend on the consumption of O 2 by the mitochondrial oxidative phosphorylation system (OXPHOS) to produce energy. In addition, the OXPHOS uses O 2 to produce reactive oxygen species that can drive cell adaptations 1 – 4 , a phenomenon that occurs in hypoxia 4 – 8 and whose precise mechanism remains unknown. Ca 2+ is the best known ion that acts as a second messenger 9 , yet the role ascribed to Na + is to serve as a mere mediator of membrane potential 10 . Here we show that Na + acts as a second messenger that regulates OXPHOS function and the production of reactive oxygen species by modulating the fluidity of the inner mitochondrial membrane. A conformational shift in mitochondrial complex I during acute hypoxia 11 drives acidification of the matrix and the release of free Ca 2+ from calcium phosphate (CaP) precipitates. The concomitant activation of the mitochondrial Na + /Ca 2+ exchanger promotes the import of Na + into the matrix. Na + interacts with phospholipids, reducing inner mitochondrial membrane fluidity and the mobility of free ubiquinone between complex II and complex III, but not inside supercomplexes. As a consequence, superoxide is produced at complex III. The inhibition of Na + import through the Na + /Ca 2+ exchanger is sufficient to block this pathway, preventing adaptation to hypoxia. These results reveal that Na + controls OXPHOS function and redox signalling through an unexpected interaction with phospholipids, with profound consequences for cellular metabolism. Na + controls the function of the mitochondrial oxidative phosphorylation system and hypoxic redox signalling through an unexpected interaction with phospholipids.