Combined optimization of spot positions and weights for better FLASH proton therapy.

Objective.In Intensity Modulated Proton Therapy (IMPT), the weights of individual pencil-beams or spots are optimized to fulfil dosimetric constraints. Theses spots are usually located on a regular lattice and their positions are fixed during optimization. In many cases, the range of spot weights may however be limited, leading sometimes to sub-optimal plan quality. An emblematic use case is the delivery of a plan at ultra-high dose rate (FLASH-RT), for which the spot weights are typically constrained to high values.Approach. To improve further the quality of IMPT FLASH plans, we propose here a novel algorithm to optimize both the spot weights and positions directly based on the objectives defined by the treatment planner.Main results. For all cases considered, optimizing the spot positions lead to an enhanced dosimetric score, while maintaining a high dose rate.Significance. Overall, this approach resulted in a substantial plan quality improvement compared to optimizing only the spot weights, and in a similar execution time.

Phage-specific immunity impairs efficacy of bacteriophage targeting Vancomycin Resistant Enterococcus in a murine model.

Bacteriophage therapy is a promising approach to address antimicrobial infections though questions remain regarding the impact of the immune response on clinical effectiveness. Here, we develop a mouse model to assess phage treatment using a cocktail of five phages from the Myoviridae and Siphoviridae families that target Vancomycin-Resistant Enterococcus gut colonization. Phage treatment significantly reduces fecal bacterial loads of Vancomycin-Resistant Enterococcus. We also characterize immune responses elicited following administration of the phage cocktail. While minimal innate responses are observed after phage administration, two rounds of treatment induces phage-specific neutralizing antibodies and accelerate phage clearance from tissues. Interestingly, the myophages in our cocktail induce a more robust neutralizing antibody response than the siphophages. This anti-phage immunity reduces the effectiveness of the phage cocktail in our murine model. Collectively, this study shows phage-specific immune responses may be an important consideration in the development of phage cocktails for therapeutic use.

How effective are mobile apps in managing people with type 2 diabetes mellitus? A systematic literature review protocol.

INTRODUCTION: The rise of new technologies in the field of health is yielding promising results. In certain chronic conditions such as type 2 diabetes mellitus, which ranks among the top five causes of global mortality, it could be useful in supporting patient management. MATERIALS AND METHODS: A systematic review will be conducted on scientific publications from the last 5 years (January 2019 to October 2023) to describe the effect of mobile app usage on glycated hemoglobin for the management of adult patients with type 2 diabetes mellitus who participated in randomized controlled clinical trials. The search will be carried out in the databases of MEDLINE (Ovid), Embase (Ovid), CINAHL (EBSCOhost), CENTRAL, WoS, Scopus, Epistemonikos, and LILACS. The search strategy will be constructed using both controlled and natural language. Additionally, the Cochrane filter will be applied to identify randomized controlled trials. The review will include scientific articles reporting studies that present results from randomized controlled trials, with texts in Spanish, English, or French, utilizing mobile applications for the management of adult individuals (over 18 years) with type 2 diabetes mellitus, and whose outcomes report the effects on glycated hemoglobin. The Cochrane Risk of Bias Tool will be used to assess the quality of the studies, and the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology will be implemented to evaluate the certainty of the evidence. RESULTS: The analysis will be conducted by observing the value of the glycated hemoglobin levels of the participants. Given that this data is a quantitative and continuous value, it facilitates the identification of the effects of the mobile applications used for the management of type 2 diabetes mellitus (T2DM) in adults. Furthermore, if sufficient data are available, a meta-analysis will be conducted using IBM-SPSS. The effect of the intervention will be estimated by the mean difference. All point estimates will be accompanied by 95% confidence intervals. A random effects model will be used. The heterogeneity of the results will be assessed using Cochrane's Q and I2 statistics. DISCUSSION: Considering that the quality of content and functionality of certain applications in the healthcare field is highly variable, it is necessary to evaluate the scientific evidence reported on the effect of the use of this type of technology in people with T2DM.

Predicting the Length of Mechanical Ventilation in Acute Respiratory Disease Syndrome Using Machine Learning: The PIONEER Study.

Background: The ability to predict a long duration of mechanical ventilation (MV) by clinicians is very limited. We assessed the value of machine learning (ML) for early prediction of the duration of MV > 14 days in patients with moderate-to-severe acute respiratory distress syndrome (ARDS). Methods: This is a development, testing, and external validation study using data from 1173 patients on MV ≥ 3 days with moderate-to-severe ARDS. We first developed and tested prediction models in 920 ARDS patients using relevant features captured at the time of moderate/severe ARDS diagnosis, at 24 h and 72 h after diagnosis with logistic regression, and Multilayer Perceptron, Support Vector Machine, and Random Forest ML techniques. For external validation, we used an independent cohort of 253 patients on MV ≥ 3 days with moderate/severe ARDS. Results: A total of 441 patients (48%) from the derivation cohort (n = 920) and 100 patients (40%) from the validation cohort (n = 253) were mechanically ventilated for >14 days [median 14 days (IQR 8-25) vs. 13 days (IQR 7-21), respectively]. The best early prediction model was obtained with data collected at 72 h after moderate/severe ARDS diagnosis. Multilayer Perceptron risk modeling identified major prognostic factors for the duration of MV > 14 days, including PaO2/FiO2, PaCO2, pH, and positive end-expiratory pressure. Predictions of the duration of MV > 14 days showed modest discrimination [AUC 0.71 (95%CI 0.65-0.76)]. Conclusions: Prolonged MV duration in moderate/severe ARDS patients remains difficult to predict early even with ML techniques such as Multilayer Perceptron and using data at 72 h of diagnosis. More research is needed to identify markers for predicting the length of MV. This study was registered on 14 August 2023 at ClinicalTrials.gov (NCT NCT05993377).

Deficiencies in cluster-2 ALA lipid flippases result in salicylic acid-dependent growth reductions.

P4 ATPases (i.e., lipid flippases) are eukaryotic enzymes that transport lipids across membrane bilayers. In plants, P4 ATPases are named Aminophospholipid ATPases (ALAs) and are organized into five phylogenetic clusters. Here we generated an Arabidopsis mutant lacking all five cluster-2 ALAs (ala8/9/10/11/12), which is the most highly expressed ALA subgroup in vegetative tissues. Plants harboring the quintuple knockout (KO) show rosettes that are 2.2-fold smaller and display chlorotic lesions. A similar but less severe phenotype was observed in an ala10/11 double KO. The growth and lesion phenotypes of ala8/9/10/11/12 mutants were reversed by expressing a NahG transgene, which encodes an enzyme that degrades salicylic acid (SA). A role for SA in promoting the lesion phenotype was further supported by quantitative PCR assays showing increased mRNA abundance for an SA-biosynthesis gene ISOCHORISMATE SYNTHASE 1 (ICS1) and two SA-responsive genes PATHOGENESIS-RELATED GENE 1 (PR1) and PR2. Lesion phenotypes were also reversed by growing plants in liquid media containing either low calcium (~0.1 mM) or high nitrogen concentrations (~24 mM), which are conditions known to suppress SA-dependent autoimmunity. Yeast-based fluorescent lipid uptake assays revealed that ALA10 and ALA11 display overlapping substrate specificities, including the transport of LysoPC signaling lipids. Together, these results establish that the biochemical functions of ALA8-12 are at least partially overlapping, and that deficiencies in cluster-2 ALAs result in an SA-dependent autoimmunity phenotype that has not been observed for flippase mutants with deficiencies in other ALA clusters.

Significance of an Interprofessional Healthy Aging Program for Community-Dwelling Older Adults: A Narrative Study.

Participation is widely recognized as an important health determinant for older adults. Exploring interventions to promote active participation of community-dwelling older adults is an important step in translating current knowledge into practice. Few studies have examined community-level interventions to support older adults' participation. The study purpose was to examine the significance of the lived experiences of community-dwelling older adults who participated in an interprofessional healthy aging promotion program. The specific aims were to uncover the narrative significance of the lived experiences and how they evolved and intertwined with the life histories of the older adults 2 years after the intervention ended. A narrative inquiry design was used. Four key informants participated in two semi-structured interviews and a member-checking process. The data were analyzed from a three-dimensional inquiry space of time and continuity, place and context, and social interactions. The findings affirmed three core threads that wove the participants' lived experiences within the program together with their life histories after the intervention. These were enjoyment, learning, and sharing. Four themes revealed the essential elements of the lived experience, and three others exposed participants' growth and life enrichment, all being fundamental to participation. The 3-year community-level intervention was valued and a novel opportunity for facilitating participation and successful aging. It allowed the participants to acquire an evolved vision of self, have meaningful interactions, develop the means to engage in future community activities, implement new self-care strategies, and establish memories and friendships significant for life participation.

Efficient Generation of Murine Chimeric Antigen Receptor (CAR)-T Cells.

Engineered cell therapies utilizing chimeric antigen receptor (CAR)-T cells have achieved remarkable effectiveness in individuals with hematological malignancies and are presently undergoing development for the treatment of diverse solid tumors. So far, the preliminary evaluation of novel CAR-T cell products has predominantly taken place in xenograft tumor models using immunodeficient mice. This approach is chosen to facilitate the successful engraftment of human CAR-T cells in the experimental setting. However, syngeneic mouse models, in which tumors and CAR-T cells are derived from the same mouse strain, allow evaluation of new CAR technologies in the context of a functional immune system and comprehensive tumor microenvironment (TME). The protocol described here aims to streamline the process of mouse CAR-T cell generation by presenting standardized methods for retroviral transduction and ex vivo T cell culture. The methods described in this protocol can be applied to other CAR constructs beyond the ones used in this study to enable routine evaluation of new CAR technologies in immune-competent systems.

Nanobodies as potential tools for microbiological testing of live biotherapeutic products.

Nanobodies are highly specific binding domains derived from naturally occurring single chain camelid antibodies. Live biotherapeutic products (LBPs) are biological products containing preparations of live organisms, such as Lactobacillus, that are intended for use as drugs, i.e. to address a specific disease or condition. Demonstrating potency of multi-strain LBPs can be challenging. The approach investigated here is to use strain-specific nanobody reagents in LBP potency assays. Llamas were immunized with radiation-killed Lactobacillus jensenii or L. crispatus whole cell preparations. A nanobody phage-display library was constructed and panned against bacterial preparations to identify nanobodies specific for each species. Nanobody-encoding DNA sequences were subcloned and the nanobodies were expressed, purified, and characterized. Colony immunoblots and flow cytometry showed that binding by Lj75 and Lj94 nanobodies were limited to a subset of L. jensenii strains while binding by Lc38 and Lc58 nanobodies were limited to L. crispatus strains. Mass spectrometry was used to demonstrate that Lj75 specifically bound a peptidase of L. jensenii, and that Lc58 bound an S-layer protein of L. crispatus. The utility of fluorescent nanobodies in evaluating multi-strain LBP potency assays was assessed by evaluating a L. crispatus and L. jensenii mixture by fluorescence microscopy, flow cytometry, and colony immunoblots. Our results showed that the fluorescent nanobody labelling enabled differentiation and quantitation of the strains in mixture by these methods. Development of these nanobody reagents represents a potential advance in LBP testing, informing the advancement of future LBP potency assays and, thereby, facilitation of clinical investigation of LBPs.

The influence of personality on the quality of vision after multifocal intraocular lens implantation.

OBJECTIVE: To assess the possible correlation between patients' personality traits and subjective perception of quality of vision (QoV), after multifocal intraocular lens (mIOL) implantation. METHODS: patients who had bilateral implantation of a non-diffractive X-WAVE or a trifocal lens were assessed 6 months postoperatively. Patients answered the NEO-Five Factor Inventory (NEO-FFI-20) questionnaire ("Big Five five-factor personality model") to examine their personality. Six months following surgery, patients were asked to fill a QoV questionnaire where they graded the frequency of 10 common visual symptoms. Primary outcomes were to evaluate the correlation between personality scores and the reported frequency of visual disturbances. RESULTS: The study comprised 20 patients submitted to bilateral cataract surgery, 10 with a non-diffractive X-WAVE lens (AcrySof® IQ Vivity) and 10 with a trifocal lens (AcrySof® IQ PanOptix). Mean age was 60.23 (7.06) years. Six months following surgery, patients with lower scores of conscientiousness and extroversion reported a higher frequency of visual disturbances (blurred vision, P = .015 and P = .009, seeing double images P = .018 and P = .006, and having difficulties focusing, P = .027 and P = .022, respectively). In addition, patients with high neuroticism scores had more difficulty focusing (P = .033). CONCLUSIONS: In this study, personality traits such as low conscientiousness and extroversion and high neuroticism significantly influenced QoV perception 6 months after bilateral multifocal lens implantation. Patients' personality questionnaires could be a useful preoperative assessment test to a mIOL.

Allele-specific CRISPR-Cas9 editing of dominant epidermolysis bullosa simplex in human epidermal stem cells.

Epidermolysis bullosa simplex (EBS) is a rare skin disease inherited mostly in an autosomal dominant manner. Patients display a skin fragility that leads to blisters and erosions caused by minor mechanical trauma. EBS phenotypic and genotypic variants are caused by genetic defects in intracellular proteins whose function is to provide the attachment of basal keratinocytes to the basement membrane zone and most EBS cases display mutations in keratin 5 (KRT5) and keratin 14 (KRT14) genes. Besides palliative treatments, there is still no long-lasting effective cure to correct the mutant gene and abolish the dominant negative effect of the pathogenic protein over its wild-type counterpart. Here, we propose a molecular strategy for EBS01 patient's keratinocytes carrying a monoallelic c.475/495del21 mutation in KRT14 exon 1. Through the CRISPR-Cas9 system, we perform a specific cleavage only on the mutant allele and restore a normal cellular phenotype and a correct intermediate filament network, without affecting the epidermal stem cell, referred to as holoclones, which play a crucial role in epidermal regeneration.

Is dentin analogue material a viable substitute for human dentin in fatigue behavior studies?

This study aimed to compare the fatigue performance of a lithium disilicate ceramic cemented on different substrates (human dentin and glass fiber-reinforced epoxy resin - GFRER), treated with different types of conditioning (CTR - without surface conditioning; HF5 - 5% hydrofluoric acid; HF10 - 10% hydrofluoric acid; H3PO4 - phosphoric acid 37%; SAND - sandblasting with aluminum oxide). The occlusal surface of human molars (DENT group) (n = 15) was ground for dentin exposure and the root portion was cut, then the dentin slice (2.0 mm thick) was conditioned with 37% phosphoric acid and a dual-curing dental adhesive was applied. The GFRER in a round-rod format was cut into discs (Ø = 10 mm, 2.0 mm thick). Lithium disilicate glass ceramic blocks (IPS e.max CAD, Ivoclar, Schaan, Liechtenstein) were shaped into a cylinder format and cut, resulting in 90 discs (Ø = 10 mm, 1.5 mm thick). The substrate materials of each group were etched according to the groups and the ceramic was etched with 5% hydrofluoric acid for 30 s. A silane coupling agent was applied over the cementation surface in ceramic and GFRER surfaces and a dual cement was used for cementation (ceramic/GFRER or dentin). The disc/disc sets were submitted to thermocycling (25,000 cycles + storage for 6 months), and then tested in step-wise accelerated cyclic fatigue test. The failure pattern and topography were analyzed and the roughness and contact angle were measured before and after surface treatment. The DENT group presented the lowest load to failure values and number of cycles to failure in fatigue (637.33 N; 118.333), showing no statistical similarity with any of the other tested groups (p < 0.05). The topographic analysis showed that all proposed surface treatments modified the substrate surface when compared to the CTR group. All of the fractographical inspections demonstrated failure by radial crack. Considering the roughness analysis, the post-etched DENT group showed similar roughness to all groups of GFRER materials with their surface treated, except for SAND, which showed greater roughness and statistically different from the other groups. The DENT group (49.5) showed statistically different post-conditioning contact angle values from the HF10 group (96.5) and similar to the other groups. The glass fiber-reinforced epoxy resin was not able to simulate the results presented by the human dentin substrate when cemented to lithium disilicate regarding fatigue failure load and number of cycles for failure, regardless of the surface treatment. Lithium disilicate cemented on dentin analogue overestimates the load values for fatigue failure.

Transcutaneous Electrical Stimulation of the Abdomen, Ear, and Tibial Nerve Modulates Bladder Contraction in a Rat Detrusor Overactivity Model: A Pilot Study.

PURPOSE: The global prevalence of overactive bladder (OAB) is estimated at 11.8%. Despite existing treatment options such as sacral neuromodulation, a substantial number of patients remain untreated. One potential alternative is noninvasive transcutaneous electrical stimulation. This form of stimulation does not necessitate the implantation of an electrode, thereby eliminating the need for highly skilled surgeons, expensive implantable devices, or regular hospital visits. We hypothesized that alternative neural pathways can impact bladder contraction. METHODS: In this pilot study, we conducted transcutaneous electrical stimulation of the abdominal wall (T6-L1), the ear (vagus nerve), and the ankle (tibial nerve) of 3 anesthetized female Sprague-Dawley rats. Stimulation was administered within a range of 20 Hz to 20 kHz, and its impact on intravesical pressure was measured. We focused on 3 primary outcomes related to intravesical pressure: (1) the pressure change from the onset of a contraction to its peak, (2) the average duration of contraction, and (3) the number of contractions within a specified timeframe. These measurements were taken while the bladder was filled with either saline or acetic acid (serving as a model for OAB). RESULTS: Transcutaneous stimulation of the abdominal wall, ear, and ankle at a frequency of 20 Hz decreased the number of bladder contractions during infusion with acetic acid. As revealed by a comparison of various stimulation frequencies of the tibial nerve during bladder infusion with acetic acid, the duration of contraction was significantly shorter during stimulation at 1 kHz and 3 kHz relative to stimulation at 20 Hz (P = 0.025 and P = 0.044, respectively). CONCLUSION: The application of transcutaneous electrical stimulation to the abdominal wall, ear, and tibial nerve could provide less invasive and more cost-effective treatment options for OAB relative to percutaneous tibial nerve stimulation and sacral neuromodulation. A follow-up study involving a larger sample size is recommended.

Probiotic-guided CAR-T cells for solid tumor targeting.

A major challenge facing tumor-antigen targeting therapies such as chimeric antigen receptor (CAR)-T cells is the identification of suitable targets that are specifically and uniformly expressed on heterogeneous solid tumors. By contrast, certain species of bacteria selectively colonize immune-privileged tumor cores and can be engineered as antigen-independent platforms for therapeutic delivery. To bridge these approaches, we developed a platform of probiotic-guided CAR-T cells (ProCARs), in which tumor-colonizing probiotics release synthetic targets that label tumor tissue for CAR-mediated lysis in situ. This system demonstrated CAR-T cell activation and antigen-agnostic cell lysis that was safe and effective in multiple xenograft and syngeneic models of human and mouse cancers. We further engineered multifunctional probiotics that co-release chemokines to enhance CAR-T cell recruitment and therapeutic response.

Association study between ceftriaxone and a synthetic amide against strains of Pseudomonas aeruginosa.

Pseudomonas aeruginosa is a non-lactose fermenting Gram-negative bacteria responsible for causing numerous nosocomial infections. The present research aimed to analyze the anti-Pseudomonas aeruginosa potential of 2-Chloro-N-(4-fluoro-3-nitrophenyl)acetamide (A8). The antibacterial potential of A8 was evaluated from the Minimum Inhibitory Concentration (MIC), Minimum Bactericidal Concentration (MBC) and Association using the checkerboard method. MIC and MBC values were 512 µg/mL for all P. aeruginosa strains evaluated, demonstrating predominantly bactericidal activity. Furthermore, when A8 was associated with the drug ceftriaxone, pharmacological additivity and indifference were evidenced. In this sense, the synthetic amide was interesting, since it demonstrates the potential to become a possible candidate for an antimicrobial drug.

Variation of diagnosis and treatment of catheter-associated urinary tract infections: an online survey among caretakers involved.

Background: The diagnosis of a clinically significant catheter-associated urinary tract infection (CAUTI) in patients performing clean intermittent catheterization (CIC) or with an indwelling catheter (IC) can be challenging. Objective: To get an insight into the variation of the used definition, diagnosis and management of CAUTIs by relevant healthcare workers in the Netherlands. Design: An online clinical scenario-based survey. Methods: The survey was built in Limesurvey and distributed to healthcare workers from randomly selected urology departments, rehabilitation departments/centres and general practice offices between January and May 2022. Questions regarding their field of experience, management strategies, used guidelines and two hypothetical cases with clinical scenarios of a possible CAUTI were included. Results: A total of 172 individuals participated, of which 112 completed the survey. In all, 32 individuals who completed the survey partially were also included. Participants consisted of 68 [44 urologists, 22 rehabilitation doctors (RDs) and 2 general practitioners (GPs)] doctors, 60 nurses (46 from the urology department and 14 from rehabilitation centres/departments) and 16 medical assistants (13 from urology department and 3 from GP offices). The majority consulted patients with an IC or on CIC on a daily/weekly or monthly basis. In all, 35 urologists (79.5%), 9 RDs (40.9%), 21 (45.7%) nurses in the urology department and 6 (42.9%) nurses from a rehabilitation department/centre indicated bladder irrigation as a treatment option for prevention/treatment of CAUTIs, treatment of symptoms or treatment of blockage of the catheter. In the clinical scenarios presented, treatment discrepancies were seen between subspecialties and healthcare workers. Various guidelines were named for the definition of CAUTIs. Conclusion: A considerable variation in diagnoses and management of CAUTIs between the healthcare workers involved was seen. Uniformity in diagnosing and managing CAUTIs, to prevent overtreatment and possible resistance to antibiotics, is advised. Suitable multidisciplinary guidelines are preferred.

Mental health outcomes in frontline healthcare workers in Brazil during the COVID-19 epidemic: Results of an online survey in four regions using respondent-driven sampling (RDS).

BACKGROUND: The COVID-19 pandemic overwhelmed health facilities and presented healthcare workers (HCWs) with a new infectious disease threat. In addition to a sanitary crisis, Brazil still had to face major political, economic, and social challenges. This study aimed to investigate mental health outcomes in frontline HCWs in different regions of the country and at different epidemic times. We also sought to identify the main risk factors associated with these outcomes. METHODS: A cross-sectional online survey using respondent-driven sampling was conducted to recruit physicians (n = 584), nurses (n = 997), and nurse technicians (n = 524) in 4 regions of Brazil (North, Northeast, Southeast, and South) from August 2020 to July 2021. We used standardized instruments to screen for common mental disorders (CMD)(SRQ-20), alcohol misuse (AUDIT-C), depression (PHQ-9), anxiety (GAD-7), and post-traumatic stress disorder (PTSD)(PCL-5). Gile's successive sampling estimator was used to produce weighted estimates. We created a three-cluster data set for each HCW category and developed a hierarchical regression model with three levels: individual characteristics; workplace-related aspects; COVID-19 personal experience. The impact of the epidemic moment on the outcomes was also studied. RESULTS: The prevalence of probable CMD was 26.8-36.9%, alcohol misuse 8.7-13.6%, depression 16.4-21.2%, anxiety 10.8-14.2%, and PTSD 5.9-8.0%. We found a stronger association between mental health outcomes and the following factors: history of psychiatric disorders, female gender, and clinical comorbidities (level 1); work overload and family isolation (level 2); sick leave (level 3). Epidemic variables, such as the number of deaths and trend of deaths by COVID-19, had almost no impact on the outcomes. CONCLUSION: An alarmingly high prevalence of depression and anxiety was found in Brazilian frontline HCWs. Individual factors were the most strongly associated with mental health outcomes. These findings indicate the need to develop programs that provide emotional support, identify professionals at risk and refer them to specialized treatment when necessary.

Predicting ICU Mortality in Acute Respiratory Distress Syndrome Patients Using Machine Learning: The Predicting Outcome and STratifiCation of severity in ARDS (POSTCARDS) Study.

OBJECTIVES: To assess the value of machine learning approaches in the development of a multivariable model for early prediction of ICU death in patients with acute respiratory distress syndrome (ARDS). DESIGN: A development, testing, and external validation study using clinical data from four prospective, multicenter, observational cohorts. SETTING: A network of multidisciplinary ICUs. PATIENTS: A total of 1,303 patients with moderate-to-severe ARDS managed with lung-protective ventilation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We developed and tested prediction models in 1,000 ARDS patients. We performed logistic regression analysis following variable selection by a genetic algorithm, random forest and extreme gradient boosting machine learning techniques. Potential predictors included demographics, comorbidities, ventilatory and oxygenation descriptors, and extrapulmonary organ failures. Risk modeling identified some major prognostic factors for ICU mortality, including age, cancer, immunosuppression, Pa o2 /F io2 , inspiratory plateau pressure, and number of extrapulmonary organ failures. Together, these characteristics contained most of the prognostic information in the first 24 hours to predict ICU mortality. Performance with machine learning methods was similar to logistic regression (area under the receiver operating characteristic curve [AUC], 0.87; 95% CI, 0.82-0.91). External validation in an independent cohort of 303 ARDS patients confirmed that the performance of the model was similar to a logistic regression model (AUC, 0.91; 95% CI, 0.87-0.94). CONCLUSIONS: Both machine learning and traditional methods lead to promising models to predict ICU death in moderate/severe ARDS patients. More research is needed to identify markers for severity beyond clinical determinants, such as demographics, comorbidities, lung mechanics, oxygenation, and extrapulmonary organ failure to guide patient management.

Sexual dysfunction in multiple sclerosis: The impact of different MSISQ-19 cut-offs on prevalence and associated risk factors.

BACKGROUND: Although multiple sclerosis (MS) Intimacy and Sexuality Questionnaire-19 (MSISQ-19) is a widely applied tool, no unique definition of sexual dysfunction (SD) based on its score exists. OBJECTIVE: To explore the impact of different MSISQ-19 cut-offs on SD prevalence and associated risk factors, providing relevant information for its application in research and clinical settings. METHODS: After defining SD according to two different MSISQ-19 cut-offs in 1155 people with MS (pwMS), we evaluated SD prevalence and association with sociodemographic and clinical features, mood status and disability via logistic regression. RESULTS: Depending on the chosen cut-off, 45% to 54% of pwMS reported SD. SD defined as MSISQ-19 score >30 was predicted by age (OR=1.01, p=0.047), cognition (OR=0.96, p=0.004) and anxiety (OR=1.03, p=0.019). SD defined as a score >3 on any MSISQ-19 item was predicted by motor disability (OR=1.12, p=0.003) and cognition (OR= 0.96, p=0.002). CONCLUSION: Applying different MSISQ-19 cut-offs influences both the estimated prevalence and the identification of risk factors for SD, a finding that should be considered during study planning and data interpretation. Preserved cognition exerts a protective effect towards SD regardless from the specific study setting, representing a key point for the implementation of preventive and therapeutic strategies.

Conceptual DFT, machine learning and molecular docking as tools for predicting LD50 toxicity of organothiophosphates.

CONTEXT: Several descriptors from conceptual density functional theory (cDFT) and the quantum theory of atoms in molecules (QTAIM) were utilized in Random Forest (RF), LASSO, Ridge, Elastic Net (EN), and Support Vector Machines (SVM) methods to predict the toxicity (LD50) of sixty-two organothiophosphate compounds. The A-RF-G1 and A-RF-G2 models were obtained using the RF method, yielding statistically significant parameters with good performance, as indicated by R2 values for the training set (R2Train) and R2 values for the test set (R2Test), around 0.90. METHODS: The molecular structure of all organothiophosphates was optimized via the range-separated hybrid functional ωB97XD with the 6-311 + + G** basis set. Seven hundred and eighty-seven descriptors have been processed using a variety of machine learning algorithms: RF LASSO, Ridge, EN and SVM to generate a predictive model. The properties were obtained with Multiwfn, AIMALL and VMD programs. Docking simulations were performed by using AutoDock 4.2 and LigPlot + programs. All the calculations in this work are carried out in Gaussian 16 program package.

A structured jet explains the extreme GRB 221009A.

Long-duration gamma-ray bursts (GRBs) are powerful cosmic explosions, signaling the death of massive stars. Among them, GRB 221009A is by far the brightest burst ever observed. Because of its enormous energy (Eiso ≈ 1055 erg) and proximity (z ≈ 0.15), GRB 221009A is an exceptionally rare event that pushes the limits of our theories. We present multiwavelength observations covering the first 3 months of its afterglow evolution. The x-ray brightness decays as a power law with slope ≈t-1.66, which is not consistent with standard predictions for jetted emission. We attribute this behavior to a shallow energy profile of the relativistic jet. A similar trend is observed in other energetic GRBs, suggesting that the most extreme explosions may be powered by structured jets launched by a common central engine.