Expression and characterization of a novel ß-1,4-endoglucanase from Bacillus subtilis strain isolated from a pulp and paper mill wastewater.

The production of fermentable sugars from lignocellulosic biomass is achieved by the synergistic action of a group of enzymes called cellulases. Cellulose is a long chain of chemically linked glucoses by ß-1,4 bonds. The enzyme ß-1,4-endoglucanase is the first cellulase involved in the degradation, breaking the bond of the amorphous regions. A ß-1,4-endoglucanase enzyme with high activity was obtained from a Bacillus subtilis strain isolated from wastewater of a pulp and paper mill. Sequencing and bioinformatic analysis showed that the gene amplified by PCR consisting of 1407 nucleotides and coding for a ß-1,4-endoglucanase enzyme of approximately 55 kDa. The open reading frame (ORF) encoding the mature endoglucanase (eglS) was successfully inserted in a modified cloning plasmid (pITD03) and into the pYD1 plasmid used for its expression in yeast. Carboxymethylcellulose (CMC) plate assay, SDS-PAGE, and zymogram confirmed the production and secretion by the transformed E. coli BL21-SI strain of a 39 kDa ß-1,4-endoglucanase consistent with the catalytic domain without the cellulose-binding module (CBM). The results showed that the truncated ß-1,4-endoglucanase had higher activity and stability.

SOCS3 regulates pathological retinal angiogenesis through modulating SPP1 expression in microglia and macrophages.

Pathological ocular angiogenesis has long been associated with myeloid cell activation. However, the precise cellular and molecular mechanisms governing the intricate crosstalk between the immune system and vascular changes during ocular neovascularization formation remain elusive. In this study, we demonstrated that the absence of the suppressor of cytokine signaling 3 (SOCS3) in myeloid cells led to a substantial accumulation of microglia and macrophage subsets during the neovascularization process. Our single-cell RNA sequencing data analysis revealed a remarkable increase in the expression of the secreted phosphoprotein 1 (Spp1) gene within these microglia and macrophages, identifying subsets of Spp1-expressing microglia and macrophages during neovascularization formation in angiogenesis mouse models. Notably, the number of Spp1-expressing microglia and macrophages exhibited further elevation during neovascularization in mice lacking myeloid SOCS3. Moreover, our investigation unveiled the Spp1 gene as a direct transcriptional target gene of signal transducer and activator of transcription 3. Importantly, pharmaceutical activation of SOCS3 or blocking of SPP1 resulted in a significant reduction in pathological neovascularization. In conclusion, our study highlights the pivotal role of the SOCS3/STAT3/SPP1 axis in the regulation of pathological retinal angiogenesis.

Degradation kinetics of veterinary antibiotics and estrogenic hormones in a claypan soil.

Veterinary antibiotics and estrogens are excreted in livestock waste before being applied to agricultural lands as fertilizer, resulting in contamination of soil and adjacent waterways. The objectives of this study were to 1) investigate the degradation kinetics of the VAs sulfamethazine and lincomycin and the estrogens estrone and 17ß-estradiol in soil mesocosms, and 2) assess the effect of the phytochemical DIBOA-Glu, secreted in eastern gamagrass (Tripsacum dactyloides) roots, on antibiotic degradation due to the ability of DIBOA-Glu to facilitate hydrolysis of atrazine in solution assays. Mesocosm soil was a silt loam representing a typical claypan soil in portions of Missouri and the Central United States. Mesocosms (n = 133) were treated with a single target compound (antibiotic concentrations at 125 ng g-1 dw, estrogen concentrations at 1250 ng g-1 dw); a subset of mesocosms treated with antibiotics were also treated with DIBOA-Glu (12,500 ng g-1 dw); all mesocosms were kept at 60% water-filled pore space and incubated at 25 °C in darkness. Randomly chosen mesocosms were destructively sampled in triplicate for up to 96 days. All targeted compounds followed pseudo first-order degradation kinetics in soil. The soil half-life (t0.5) of sulfamethazine ranged between 17.8 and 30.1 d and ranged between 9.37 and 9.90 d for lincomycin. The antibiotics results showed no significant differences in degradation kinetics between treatments with or without DIBOA-Glu. For estrogens, degradation rates of estrone (t0.5 = 4.71-6.08 d) and 17ß-estradiol (t0.5 = 5.59-6.03 d) were very similar; however, results showed that estrone was present as a metabolite in the 17ß-estradiol treated mesocosms and vice-versa within 24 h. The antibiotics results suggest that sulfamethazine has a greater potential to persist in soil than lincomycin. The interconversion of 17ß-estradiol and estrone in soil increased their overall persistence and sustained soil estrogenicity. This study demonstrates the persistence of these compounds in a typical claypan soil representing portions of the Central United States.

Supervised learning for improving the accuracy of robot-mounted 3D camera applied to human gait analysis.

BACKGROUND AND OBJECTIVE: the use of 3D cameras for gait analysis has been highly questioned due to the low accuracy they have demonstrated in the past. The objective of the study presented in this paper is to improve the accuracy of the estimations made by robot-mounted 3D cameras in human gait analysis by applying a supervised learning stage. METHODS: the 3D camera was mounted in a mobile robot to obtain a longer walking distance. This study shows an improvement in detection of kinematic gait signals and gait descriptors by post-processing the raw estimations of the camera using artificial neural networks trained with the data obtained from a certified Vicon system. To achieve this, 37 healthy participants were recruited and data of 207 gait sequences were collected using an Orbbec Astra 3D camera. There are two basic possible approaches for training and both have been studied in order to see which one achieves a better result. The artificial neural network can be trained either to obtain more accurate kinematic gait signals or to improve the gait descriptors obtained after initial processing. The former seeks to improve the waveforms of kinematic gait signals by reducing the error and increasing the correlation with respect to the Vicon system. The second is a more direct approach, focusing on training the artificial neural networks using gait descriptors directly. RESULTS: the accuracy of the 3D camera to objectify human gait was measured before and after training. In both training approaches, a considerable improvement was observed. Kinematic gait signals showed lower errors and higher correlations with respect to the ground truth. The accuracy of the system to detect gait descriptors also showed a substantial improvement, mostly for kinematic descriptors rather than spatio-temporal. When comparing both training approaches, it was not possible to define which was the absolute best. CONCLUSIONS: supervised learning improves the accuracy of 3D cameras but the selection of the training approach will depend on the purpose of the study to be conducted. This study reveals the great potential of 3D cameras and encourages the research community to continue exploring their use in gait analysis.

Exploring Medical Career Choice to Better Inform Swiss Physician Workforce Planning: Protocol for a National Cohort Study.

BACKGROUND: A medical student's career choice directly influences the physician workforce shortage and the misdistribution of resources. First, individual and contextual factors related to career choice have been evaluated separately, but their interaction over time is unclear. Second, actual career choice, reasons for this choice, and the influence of national political strategies are currently unknown in Switzerland. OBJECTIVE: The overall objective of this study is to better understand the process of Swiss medical students' career choice and to predict this choice. Our specific aims will be to examine the predominately static (ie, sociodemographic and personality traits) and predominately dynamic (ie, learning context perceptions, anxiety state, motivation, and motives for career choice) variables that predict the career choice of Swiss medical school students, as well as their interaction, and to examine the evolution of Swiss medical students' career choice and their ultimate career path, including an international comparison with French medical students. METHODS: The Swiss Medical Career Choice study is a national, multi-institution, and longitudinal study in which all medical students at all medical schools in Switzerland are eligible to participate. Data will be collected over 4 years for 4 cohorts of medical students using questionnaires in years 4 and 6. We will perform a follow-up during postgraduate training year 2 for medical graduates between 2018 and 2022. We will compare the different Swiss medical schools and a French medical school (the University of Strasbourg Faculty of Medicine). We will also examine the effect of new medical master's programs in terms of career choice and location of practice. For aim 2, in collaboration with the Swiss Institute for Medical Education, we will implement a national career choice tracking system and identify the final career choice of 2 cohorts of medical students who graduated from 4 Swiss medical schools from 2010 to 2012. We will also develop a model to predict their final career choice. Data analysis will be conducted using inferential statistics, and machine learning approaches will be used to refine the predictive model. RESULTS: This study was funded by the Swiss National Science Foundation in January 2023. Recruitment began in May 2023. Data analysis will begin after the completion of the first cohort data collection. CONCLUSIONS: Our research will inform national stakeholders and medical schools on the prediction of students' future career choice and on key aspects of physician workforce planning. We will identify targeted actions that may be implemented during medical school and may ultimately influence career choice and encourage the correct number of physicians in the right specialties to fulfill the needs of currently underserved regions. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/53138.

De facto Water Reuse: Investigating the Fate and Transport of Chemicals of Emerging Concern from Wastewater Discharge through Drinking Water Treatment Using Non-targeted Analysis and Suspect Screening.

Wastewater is a source for many contaminants of emerging concern (CECs), and surface waters receiving wastewater discharge often serve as source water for downstream drinking water treatment plants. Nontargeted analysis and suspect screening methods were used to characterize chemicals in residence-time-weighted grab samples and companion polar organic chemical integrative samplers (POCIS) collected on three separate hydrologic sampling events along a surface water flow path representative of de facto water reuse. The goal of this work was to examine the fate of CECs along the study flow path as water is transported from wastewater effluent through drinking water treatment. Grab and POCIS samples provided a comparison between residence-time-weighted single-point and integrative sample results. This unique and rigorous study design, coupled with advanced analytical chemistry tools, provided important insights into chemicals found in drinking water and their potential sources, which can be used to help prioritize chemicals for further study. K-means clustering analysis was used to identify patterns in chemical occurrences across both sampling sites and sampling events. Chemical features that occurred frequently or survived drinking water treatment were prioritized for identification, resulting in the probable identification of over 100 CECs in the watershed and 28 CECs in treated drinking water.

The Supplementation of Sechium edule var. nigrum spinosum (Chayote) Promotes Nrf2-Mediated Antioxidant Protection in Older Adults with Metabolic Syndrome.

The aim was to determine the effect of Sechium edule var. nigrum spinosum (chayote) on gene expression related to antioxidant protection mechanisms and the inflammatory process in older adults with metabolic syndrome (MetS). A quasi-experimental study was carried out in a convenience sample of 46 older adults diagnosed with MetS: (i) placebo group (PG; n = 20); (ii) experimental group (EG; n = 26). The clinical, biochemical, anthropometric parameters and SOD, GPx, and CAT enzyme activity, alongside total oxidant status (TOS), total antioxidant status (TAS), oxidative stress index (OSI), cytokines (IL-6, IL-8 and TNF-α), and mRNA expression of SOD, GPx, CAT, IL-6, IL-8, TNF-α, Nrf2, NFkB p50, and NFkB p65, were measured at baseline and 6 months post-intervention. A statistically significant decrease was observed in TOS (baseline, 28.9 ± 3.6 vs. post, 23.7 ± 3.4, p < 0.01) and OSI (baseline, 24.1 ± 3.8 vs. post, 17.7 ± 4), as well as an increase in IL-6 (baseline, 10.7 ± 1.1 vs. post, 12.3 ± 2, p = 0.03), SOD activity (baseline, 167.1 ± 11.9 vs. post, 180.6 ± 7.6, p < 0.05), CAT activity (baseline, 1.0 ± 0.2 vs. post, 1.3 ± 0.2, p < 0.01), and TAS (baseline, 1.1 ± 0.1 vs. post, 1.4 ± 0.1, p < 0.01) in the EG compared to the PG. Regarding the expression of Nrf2, SOD, and IL-6, the EG showed a significant increase vs. basal levels (47%, 44%, and 43%, respectively). Our findings suggest that Sechium edule supplementation promotes the antioxidant response and decreases oxidative stress via Nrf2.

Ocular Vascular Diseases: From Retinal Immune Privilege to Inflammation.

The eye is an immune privileged tissue that insulates the visual system from local and systemic immune provocation to preserve homeostatic functions of highly specialized retinal neural cells. If immune privilege is breached, immune stimuli will invade the eye and subsequently trigger acute inflammatory responses. Local resident microglia become active and release numerous immunological factors to protect the integrity of retinal neural cells. Although acute inflammatory responses are necessary to control and eradicate insults to the eye, chronic inflammation can cause retinal tissue damage and cell dysfunction, leading to ocular disease and vision loss. In this review, we summarized features of immune privilege in the retina and the key inflammatory responses, factors, and intracellular pathways activated when retinal immune privilege fails, as well as a highlight of the recent clinical and research advances in ocular immunity and ocular vascular diseases including retinopathy of prematurity, age-related macular degeneration, and diabetic retinopathy.

Evaluation of Dosimetry Formalisms in Intraoperative Radiation Therapy of Glioblastoma.

PURPOSE: The intraoperative radiotherapy in newly diagnosed glioblastoma multiforme (INTRAGO) clinical trial assesses survival in patients with glioblastoma treated with intraoperative radiation therapy (IORT) using the INTRABEAM. Treatment planning for INTRABEAM relies on vendor-provided in-water depth dose curves obtained according to the TARGeted Intraoperative radioTherapy (TARGIT) dosimetry protocol. However, recent studies have shown discrepancies between the estimated TARGIT and delivered doses. This work evaluates the effect of the choice of dosimetry formalism on organs at risk (OAR) doses. METHODS AND MATERIALS: A treatment planning framework for INTRABEAM was developed to retrospectively calculate the IORT dose in 8 INTRAGO patients. These patients received an IORT prescription dose of 20 to 30 Gy in addition to external beam radiation therapy. The IORT dose was obtained using (1) the TARGIT method; (2) the manufacturer's V4.0 method; (3) the CQ method, which uses an ionization chamber Monte Carlo (MC) calculated factor; (4) MC dose-to-water; and (5) MC dose-to-tissue. The IORT dose was converted to 2 Gy fractions equivalent dose. RESULTS: According to the TARGIT method, the OAR dose constraints were respected in all cases. However, the other formalisms estimated a higher mean dose to OARs and revealed 1 case where the constraint for the brain stem was exceeded. The addition of the external beam radiation therapy and TARGIT IORT doses resulted in 10 cases of OARs exceeding the dose constraints. The more accurate MC calculation of dose-to-tissue led to the highest dosimetric differences, with 3, 3, 2, and 2 cases (out of 8) exceeding the dose constraint to the brain stem, optic chiasm, optic nerves, and lenses, respectively. Moreover, the mean cumulative dose to brain stem exceeded its constraint of 66 Gy with the MC dose-to-tissue method, which was not evident with the current INTRAGO clinical practice. CONCLUSIONS: The current clinical approach of calculating the IORT dose with the TARGIT method may considerably underestimate doses to nearby OARs. In practice, OAR dose constraints may have been exceeded, as revealed by more accurate methods.

Transformer Performance for Chemical Reactions: Analysis of Different Predictive and Evaluation Scenarios.

The prediction of chemical reaction pathways has been accelerated by the development of novel machine learning architectures based on the deep learning paradigm. In this context, deep neural networks initially designed for language translation have been used to accurately predict a wide range of chemical reactions. Among models suited for the task of language translation, the recently introduced molecular transformer reached impressive performance in terms of forward-synthesis and retrosynthesis predictions. In this study, we first present an analysis of the performance of transformer models for product, reactant, and reagent prediction tasks under different scenarios of data availability and data augmentation. We find that the impact of data augmentation depends on the prediction task and on the metric used to evaluate the model performance. Second, we probe the contribution of different combinations of input formats, tokenization schemes, and embedding strategies to model performance. We find that less stable input settings generally lead to better performance. Lastly, we validate the superiority of round-trip accuracy over simpler evaluation metrics, such as top-k accuracy, using a committee of human experts and show a strong agreement for predictions that pass the round-trip test. This demonstrates the usefulness of more elaborate metrics in complex predictive scenarios and highlights the limitations of direct comparisons to a predefined database, which may include a limited number of chemical reaction pathways.

Deep learning-based risk prediction for interventional clinical trials based on protocol design: A retrospective study.

Success rate of clinical trials (CTs) is low, with the protocol design itself being considered a major risk factor. We aimed to investigate the use of deep learning methods to predict the risk of CTs based on their protocols. Considering protocol changes and their final status, a retrospective risk assignment method was proposed to label CTs according to low, medium, and high risk levels. Then, transformer and graph neural networks were designed and combined in an ensemble model to learn to infer the ternary risk categories. The ensemble model achieved robust performance (area under the receiving operator characteristic curve [AUROC] of 0.8453 [95% confidence interval: 0.8409-0.8495]), similar to the individual architectures but significantly outperforming a baseline based on bag-of-words features (0.7548 [0.7493-0.7603] AUROC). We demonstrate the potential of deep learning in predicting the risk of CTs from their protocols, paving the way for customized risk mitigation strategies during protocol design.

Uptake of Per- and Polyfluoroalkyl Substances by Fish, Mussel, and Passive Samplers in Mobile-Laboratory Exposures Using Groundwater from a Contamination Plume at a Historical Fire Training Area, Cape Cod, Massachusetts.

Aqueous film-forming foams historically were used during fire training activities on Joint Base Cape Cod, Massachusetts, and created an extensive per- and polyfluoroalkyl substances (PFAS) groundwater contamination plume. The potential for PFAS bioconcentration from exposure to the contaminated groundwater, which discharges to surface water bodies, was assessed with mobile-laboratory experiments using groundwater from the contamination plume and a nearby reference location. The on-site continuous-flow 21-day exposures used male and female fathead minnows, freshwater mussels, polar organic chemical integrative samplers (POCIS), and polyethylene tube samplers (PETS) to evaluate biotic and abiotic uptake. The composition of the PFAS-contaminated groundwater was complex and 9 PFAS were detected in the reference groundwater and 17 PFAS were detected in the contaminated groundwater. The summed PFAS concentrations ranged from 120 to 140 ng L-1 in reference groundwater and 6100 to 15,000 ng L-1 in contaminated groundwater. Biotic concentration factors (CFb) for individual PFAS were species, sex, source, and compound-specific and ranged from 2.9 to 1000 L kg-1 in whole-body male fish exposed to contaminated groundwater for 21 days. The fish and mussel CFb generally increased with increasing fluorocarbon chain length and were greater for sulfonates than for carboxylates. The exception was perfluorohexane sulfonate, which deviated from the linear trend and had a 10-fold difference in CFb between sites, possibly because of biotransformation of precursors such as perfluorohexane sulfonamide. Uptake for most PFAS in male fish was linear over time, whereas female fish had bilinear uptake indicated by an initial increase in tissue concentrations followed by a decrease. Uptake of PFAS was less for mussels (maximum CFb = 200) than for fish, and mussel uptake of most PFAS also was bilinear. Although abiotic concentration factors were greater than CFb, and values for POCIS were greater than for PETS, passive samplers were useful for assessing PFAS that potentially bioconcentrate in fish but are present at concentrations below method quantitation limits in water. Passive samplers also accumulate short-chain PFAS that are not bioconcentrated.

Targeted siRNA lipid nanoparticles for the treatment of KRAS-mutant tumors.

K-RAS is a highly relevant oncogene that is mutated in approximately 90% of pancreatic cancers and 20-25% of lung adenocarcinomas. The aim of this work was to develop a new anti-KRAS siRNA therapeutic strategy through the engineering of functionalized lipid nanoparticles (LNPs). To do this, first, a potent pan anti-KRAS siRNA sequence was chosen from the literature and different chemical modifications of siRNA were tested for their transfection efficacy (KRAS knockdown) and anti-proliferative effects on various cancer cell lines. Second, a selected siRNA candidate was loaded into tLyp-1 targeted and non-targeted lipid nanoparticles (LNPs). The biodistribution and antitumoral efficacy of selected siRNA-loaded LNP-prototypes were evaluated in vivo using a pancreatic cancer murine model (subcutaneous xenograft CFPAC-1 tumors). Our results show that tLyp-1-tagged targeted LNPs have an enhanced accumulation in the tumor compared to non-targeted LNPs. Moreover, a significant reduction in the pancreatic tumor growth was observed when the anti-KRAS siRNA treatment was combined with a classical chemotherapeutic agent, gemcitabine. In conclusion, our work demonstrates the benefits of using a targeting approach to improve tumor accumulation of siRNA-LNPs and its positive impact on tumor reduction.

Effect of percutaneous electrical stimulation with high-frequency alternating currents at 30 kHz on the sensory-motor system.

Background: Unmodulated high-frequency alternating currents (HFAC) are employed for producing peripheral nerves block. HFAC have been applied in humans with frequencies up to 20 kHz, whether transcutaneously, percutaneously, or via surgically-implanted electrodes. The aim of this study was to assess the effect of percutaneous HFAC, applied with ultrasound-guided needles at 30 kHz, on the sensory-motor nerve conduction of healthy volunteers. Methods: A parallel, double-blind, randomized clinical trial with a placebo control was conducted. Percutaneous HFAC at 30 kHz or sham stimulation was applied via ultrasound-guided needles in 48 healthy volunteers (n = 24 in each group) for 20 min. The assessed outcome variables were pressure pain threshold (PPT), mechanical detection threshold (MDT), maximal finger flexion strength (MFFS), antidromic sensory nerve action potential (SNAP), hand temperature, and subjective sensations by the participants. The measurements were recorded pre-intervention, during the stimulation (at 15 min), immediately post-intervention (at 20 min), and 15 min after the end of treatment. Results: The PPT increased in the active group compared with sham stimulation, both during the intervention [14.7%; 95% confidence interval (CI): 4.4-25.0], immediately post-intervention (16.9%; 95% CI: -7.2-26.5), and 15 min after the end of the stimulation (14.3%; 95% CI: 4.4-24.3) (p < 0.01). The proportion of participants who reported feelings of numbness and heaviness was significantly higher in the active group (46 and 50%, respectively) than in the sham group (8 and 18%, respectively) (p < 0.05). No intergroup differences were observed in the remaining outcome variables. No unexpected adverse effects derived from the electrical stimulation were reported. Conclusion: Percutaneous stimulation with HFAC at 30 kHz applied to the median nerve increased the PPT and subjective perception of numbness and heaviness. Future research should evaluate its potential therapeutic effect in people with pain. Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT04884932, identifier NCT04884932.

Performance Analysis of Software-Defined Networks to Mitigate Private VLAN Attacks.

The defence-in-depth (DiD) methodology is a defensive approach usually performed by network administrators to implement secure networks by layering and segmenting them. Typically, segmentation is implemented in the second layer using the standard virtual local area networks (VLANs) or private virtual local area networks (PVLANs). Although defence in depth is usually manageable in small networks, it is not easily scalable to larger environments. Software-defined networks (SDNs) are emerging technologies that can be very helpful when performing network segmentation in such environments. In this work, a corporate networking scenario using PVLANs is emulated in order to carry out a comparative performance analysis on defensive strategies regarding CPU and memory usage, communications delay, packet loss, and power consumption. To do so, a well-known PVLAN attack is executed using simulated attackers located within the corporate network. Then, two mitigation strategies are analysed and compared using the traditional approach involving access control lists (ACLs) and SDNs. The results show the operation of the two mitigation strategies under different network scenarios and demonstrate the better performance of the SDN approach in oversubscribed network designs.

Aging, Physical Exercise, Telomeres, and Sarcopenia: A Narrative Review.

Human aging is a gradual and adaptive process characterized by a decrease in the homeostatic response, leading to biochemical and molecular changes that are driven by hallmarks of aging, such as oxidative stress (OxS), chronic inflammation, and telomere shortening. One of the diseases associated with the hallmarks of aging, which has a great impact on functionality and quality of life, is sarcopenia. However, the relationship between telomere length, sarcopenia, and age-related mortality has not been extensively studied. Moderate physical exercise has been shown to have a positive effect on sarcopenia, decreasing OxS and inflammation, and inducing protective effects on telomeric DNA. This results in decreased DNA strand breaks, reduced OxS and IA, and activation of repair pathways. Higher levels of physical activity are associated with an apparent increase in telomere length. This review aims to present the current state of the art of knowledge on the effect of physical exercise on telomeric maintenance and activation of repair mechanisms in sarcopenia.

Overcoming Resistance to Osimertinib by T790M Loss and C797S Acquisition Using Gefitinib in a Patient With EGFR-Mutant NSCLC: A Case Report.

Limited strategies are available at disease progression on osimertinib for patients with EGFR-mutant NSCLC. The emergence of the on-target EGFR C797S mutation has been described as one of the most common mechanisms of resistance. In addition, loss of the EGFR T790M mutation has been mainly investigated as a resistance phenomenon to second-line osimertinib exposure. Remarkably, by studying the molecular profile at progression, it has been reported that the presence of the EGFR-sensitizing mutation, concurrently with the T790M, and C797S resulted in resistance to the current available EGFR tyrosine kinase inhibitors. Here, we report the first clinical evidence of gefitinib efficacy at EGFR exon 19 deletion/C797S mutation/T790M loss-mediated resistance to first-line osimertinib. Our findings highlight that dynamic genetic monitoring is a crucial approach in the evolution of EGFR-mutant NSCLC to understand the acquired molecular mechanisms for driving the best treatment strategy.

Effectiveness of Different Electrical Stimulation Modalities for Pain and Masticatory Function in Temporomandibular Disorders: A Systematic Review and Meta-Analysis.

Temporomandibular disorders comprise a set of conditions that include alterations of the temporomandibular joint and masticatory muscles. Although different modalities of electric currents are widely used for treating temporomandibular disorders, previous reviews have suggested these are ineffective. This systematic review and meta-analysis aimed to determine the effectiveness of different electrical stimulation modalities in patients with temporomandibular disorders for reducing musculoskeletal pain, increasing the range of movement, and improving muscle activity. An electronic search was conducted of randomized controlled trials published until March of 2022 that compared the application of an electrical stimulation therapy versus a sham or control group. The main outcome measure was pain intensity. Seven studies were included in the qualitative analysis and in the quantitative analysis (n = 184 subjects). The overall effect of electrical stimulation on pain reduction was statistically superior to sham/control (MD = -1.12 cm; CI 95%: -1.5 to -0.8), showing moderate heterogeneity of results (I2 = 57%, P = .04). The overall effect on range of movement of the joint (MD = 0.97 mm; CI 95%: -0.3 to 2.2) and muscle activity (SMD = -2.9; CI 95%: -8.1 to 2.3) were not significant. Transcutaneous electrical nerve stimulation (TENS) and high-voltage current stimulation reduces pain intensity clinically in people with temporomandibular disorders with a moderate quality of evidence. On the other hand, there is no evidence of the effect of different electrical stimulation modalities on range of movement and muscle activity in people with temporomandibular disorders with a moderate and low quality of evidence respectively. PERSPECTIVE: TENS and high voltage currents are valid options for the control of pain intensity in patients suffering from temporomandibular disorder. Data suggest clinically relevant changes compared to sham. Healthcare professionals should take this into account as it is inexpensive therapy, has no adverse effects and can be self-administered by patients.