Foetal gluten immunogenic peptides during pregnancy: a new determinant on the coeliac exposome.

BACKGROUND: The increasing incidence of coeliac disease is leading to a growing interest in active search for associated factors, even the intrauterine and early life. The exposome approach to disease encompasses a life course perspective from conception onwards has recently been highlighted. Knowledge of early exposure to gluten immunogenic peptides (GIP) in utero could challenge the chronology of early prenatal tolerance or inflammation, rather than after the infant's solid diet after birth. METHODS: We developed an accurate and specific immunoassay to detect GIP in amniotic fluid (AF) and studied their accumulates, excretion dynamics and foetal exposure resulting from AF swallowing. One hundred twenty-five pregnant women with different gluten diets and gestational ages were recruited. RESULTS: GIP were detectable in AF from at least the 16th gestational week in gluten-consuming women. Although no significant differences in GIP levels were observed during gestation, amniotic GIP late pregnancy was not altered by maternal fasting, suggesting closed-loop entailing foetal swallowing of GIP-containing AF and subsequent excretion via the foetal kidneys. CONCLUSIONS: The study shows evidence, for the first time, of the foetal exposure to gluten immunogenic peptides and establishes a positive correlation with maternal gluten intake. The results obtained point to a novel physiological concept as they describe a plausible closed-loop circuit entailing foetal swallowing of GIP contained in AF and its subsequent excretion through the foetal kidneys. The study adds important new information to understanding the coeliac exposome.

Human adaptation to heat in the context of climate change: A conceptual framework.

Climate change is causing serious damage to natural and social systems, as well as having an impact on human health. Among the direct effects of climate change is the rise in global surface temperatures and the increase in the frequency, duration, intensity and severity of heat waves. In addition, understanding of the adaptation process of the exposed population remains limited, posing a challenge in accurately estimating heat-related morbidity and mortality. In this context, this study seeks to establish a conceptual framework that would make it easier to understand and organise knowledge about human adaptation to heat and the factors that may influence this process. An inductive approach based on grounded theory was used, through the analysis of case studies connecting concepts. The proposed conceptual framework is made up of five components (climate change, vulnerability, health risks of heat, axes of inequality and health outcomes), three heat-adaptation domains (physiological, cultural and political), two levels (individual and social), and the pre-existing before a heat event. The application of this conceptual framework facilitates the assistance of decision-makers in planning and implementing effective adaptation measures. Recognizing the importance of addressing heat adaptation as a health problem that calls for political solutions and social changes. Accordingly, this requires a multidisciplinary approach that would foster the participation and collaboration of multiple actors for the purpose of proposing effective measures to address the health impact of the rise in temperature.

Modulating temperature for Cu2ZnSnS4 (CZTS) synthesis via hot injection method and studying the photocatalytic efficiencies for the degradation of rhodamine 6G and methylene blue pollutants.

Cu2ZnSnS4 (CZTS) was synthesized following hot injection method and the process was optimized by varying temperature conditions. Four samples at different temperatures viz., 200, 250, 300 and 350 °C were prepared and analyzed using different characterization techniques. Based on the correlation between XRD, Raman and XPS, we conclude that the formation of ZnS and SnS2 occurs at 350 °C but at 200 °C there is no breakdown of the complex as per XRD. According to Raman and XPS analysis, as the temperature rises, the bonds between the metals become weaker, which is visibly seen in Raman and XPS due to the minor peaks of copper sulfide. Scanning electron microscopic analysis confirmed nanometric particles which increase in size with temperature. The photocatalytic evaluation showed that CZTS synthesized at 200 °C performed efficiently in the removal of the two colorants, methylene blue and Rhodamine 6G, achieving 92.80% and 90.65%, respectively. The photocatalytic degradation efficiencies decreased at higher temperatures due to bigger sized CZTS particles as confirmed by SEM results. Computational simulations confirm that CZTS has a highly negative energy -25,764 Ry, confirming its structural stability and higher covalent than ionic character.

Applicability of Deep Learning to Dynamically Identify the Different Organs of the Pelvic Floor in the Midsagittal Plane.

INTRODUCTION AND HYPOTHESIS: The objective was to create and validate the usefulness of a convolutional neural network (CNN) for identifying different organs of the pelvic floor in the midsagittal plane via dynamic ultrasound. METHODS: This observational and prospective study included 110 patients. Transperineal ultrasound scans were performed by an expert sonographer of the pelvic floor. A video of each patient was made that captured the midsagittal plane of the pelvic floor at rest and the change in the pelvic structures during the Valsalva maneuver. After saving the captured videos, we manually labeled the different organs in each video. Three different architectures were tested-UNet, FPN, and LinkNet-to determine which CNN model best recognized anatomical structures. The best model was trained with the 86 cases for the number of epochs determined by the stop criterion via cross-validation. The Dice Similarity Index (DSI) was used for CNN validation. RESULTS: Eighty-six patients were included to train the CNN and 24 to test the CNN. After applying the trained CNN to the 24 test videos, we did not observe any failed segmentation. In fact, we obtained a DSI of 0.79 (95% CI: 0.73 - 0.82) as the median of the 24 test videos. When we studied the organs independently, we observed differences in the DSI of each organ. The poorest DSIs were obtained in the bladder (0.71 [95% CI: 0.70 - 0.73]) and uterus (0.70 [95% CI: 0.68 - 0.74]), whereas the highest DSIs were obtained in the anus (0.81 [95% CI: 0.80 - 0.86]) and levator ani muscle (0.83 [95% CI: 0.82 - 0.83]). CONCLUSIONS: Our results show that it is possible to apply deep learning using a trained CNN to identify different pelvic floor organs in the midsagittal plane via dynamic ultrasound.

The Application of Shear Wave Elastography to Determine the Elasticity of the Levator Ani Muscle and Vaginal Tissue in Patients With Pelvic Organ Prolapse.

OBJECTIVES: The changes of the extracellular matrix of the connective tissue have significantly contributed to the incidence of pelvic organ prolapse (POP). It seems reasonable that sonoelastography could be a useful tool to evaluate the elasticity of pelvic floor tissue in patients with POP and compare it to those without POP. The main aim of this pilot study was to determine if there are differences in the elasticity of the levator ani muscle (LAM) and vaginal tissue between patients with and without POP. METHODS: Prospective observation study, including 60 patients (30 with POP and 30 without POP). Sonoelastography was performed to evaluate the elasticity (in kilopascals, kPa) of the following regions of interest: vagina at the level of middle third of the urethra; vagina at the level of the bladder trigone; vagina in the anterior and posterior fornix; vagina at the level of middle third of the anorectal canal; posterior third of the LAM. RESULTS: A total of 60 patients completed the study (30 with POP, 30 without POP). In the POP group, 18/30 (60%) had an anterior vaginal wall prolapse, 3/30 (10%) a uterine prolapse, 15/30 (50%) a rectocele, and 6/30 (20%) a enterocele. Patients with POP had higher elasticity in all anatomical study areas, with statistically significant differences in the anterior fornix (13.6 vs 11.2 kPa; P: .012). A multiple regression (controlling age, menopausal stage, and parity) allowed to detect statistically significant differences in the elasticity of the middle third of the urethra (P: .03) and the middle third of the anorectal canal (P: .019). CONCLUSION: It is possible to evaluate the elasticity of the LAM and vaginal tissue using sonoelastography, detecting a higher elasticity in patients with POP than in those without POP.

Is the Presence of Levator Ani Muscle Avulsion Relevant for the Diagnosis of Uterine Prolapse?

OBJECTIVE: To determine if the addition of the assessment of levator ani muscle (LAM) avulsion to the measurement of the difference in the pubis-uterine fundus distance between rest and with the Valsalva maneuver could increase the diagnostic capacity of ultrasound for uterine prolapse (UP). METHODS: This multicenter, observational and prospective study included 145 patients. Ultrasound assessment was performed, establishing the diagnosis of UP as a difference between the pubic-uterine fundus distance at rest and during the Valsalva maneuver ≥15 mm (standard technique), while LAM avulsion was defined as an abnormal LAM insertion in three central slices using multislice ultrasound. A binary multivariate logistic regression model was made using nonautomated methods to predict surgical UP (general population, premenopausal, and postmenopausal patients), including the difference between the pubis-uterine fundus distance at rest and with the Valsalva maneuver as well as LAM avulsion. RESULTS: A total of 143 patients completed the study. The addition of LAM avulsion criteria to the standard dynamic distance-based protocol for the diagnosis of UP resulted in a higher sensitivity for the general population (79.7 vs 68.1%) as well as for premenopausal (89.3 vs 79.9%) and postmenopausal patients (76 vs 66.1%). In contrast, the standard technique showed a higher specificity than the model based on the standard technique associated with LAM avulsion for the general population (89.2 vs 74.3%) and premenopausal women (91.7 vs 63.2%). For postmenopausal patients, the model based on the standard technique associated with LAM avulsion had a higher sensitivity (76 vs 66.1%) and specificity (91.7 vs 86.8%) than the ultrasound diagnosis of UP. CONCLUSION: The implementation of the assessment of LAM avulsion in the ultrasound diagnosis of UP is useful in postmenopausal patients, increasing sensitivity and specificity relative to the ultrasound assessment based only on the difference between the pubis-uterine fundus distance at rest and with the Valsalva maneuver.

Single capture bright field and off-axis digital holographic microscopy.

We report on a single capture approach for simultaneous incoherent bright field (BF) and laser-based quantitative phase imaging (QPI). Common-path digital holographic microscopy (DHM) is implemented in parallel with BF imaging within the optical path of a commercial optical microscope to achieve spatially multiplexed recording of white light images and digital off-axis holograms, which are subsequently numerically demultiplexed. The performance of the proposed multimodal concept is firstly determined by investigations on microspheres. Then, the application for label-free dual-mode QPI and BF imaging of living pancreatic tumor cells is demonstrated.

Single capture bright field and off-axis digital holographic microscopy: publisher's note.

This publisher's note contains corrections to Opt. Lett.48, 876 (2023)10.1364/OL.478674.

Transfusion-associated adverse events incidence and severity after the implementation of an active hemovigilance program with 24 h follow-up. A prospective cohort study.

BACKGROUND: Hemovigilance (HV) is usually based on voluntary reports (passive HV). Our aim is to ascertain credible incidence, severity, and mortality of transfusion-associated adverse events (TAAEs) using an active HV program. STUDY DESIGN AND METHODS: Prospective cohort study to estimate transfusion risk after 46,488 transfusions in 5830 patients, using an active HV program with follow-up within the first 24 h after transfusion. We compared these results to those with the previously established passive HV program during the same 30 months of the study. We explored factors associated with the occurrence of TAAEs using generalized estimating equations models. RESULTS: With the active HV program TAAEs incidence was 57.3 (95% CI, 50.5-64.2) and mortality 1.1 (95% CI, 0.13-2.01) per 10,000 transfusions. Incidence with the new surveillance model was 14.0 times higher than with the passive. Most events occurred when transfusions had already finished (60.2%); especially pulmonary events (80.4%). Three out of five deaths and 50.3% of severe TAAEs were pulmonary. In the multivariate analysis surgical patients had half TAAEs risk when compared to medical patients (OR, 0.53; 95% CI, 0.34-0.78) and women had nearly twice the risk of a pulmonary event compared to men (OR, 1.84; 95% CI, 1.03-3.32). Patient's age, blood component type, or blood component shelf-life were unrelated to TAAEs risk. DISCUSSION: Active hemovigilance programs provide additional data which may lead to better recognition and understanding of TAAEs and their frequency and severity.

Identification of Surgical Uterine Prolapse in Premenopausal Patients With Clinical or Ultrasound Criteria? A Multicenter Comparative Study.

OBJECTIVES: It is unknown whether diagnosing uterine prolapse (UP) via ultrasound or surgical criteria is superior. Our objective is to determine whether the diagnostic capacity of ultrasound with surgical criteria differs from that of surgical criteria only. METHODS: This was a multicenter prospective observational study with 54 premenopausal patients with surgical criteria for a dysfunctional pelvic floor pathology who were consecutively recruited for 1 year. Clinical UP with surgical criteria was defined when UP stage II-IV was identified (during pelvic floor consultation), and UP diagnosed by ultrasound with surgical criteria was established when a difference ≥15 mm was found between rest and Valsalva applied to the pubis-uterine fundus. The sensitivity, specificity and positive and negative predictive values were determined to evaluate clinical and ultrasound methodologies as diagnostic tests. RESULTS: UP diagnosed by ultrasound with surgical criteria presented better sensitivity (78.57 vs 35.71%), specificity (92.11 vs 81.58%), positive predictive value (61.83 vs 23.99%), and negative predictive value (96.35 vs 11.37%) than UP diagnosed by surgical criteria only. CONCLUSION: Ultrasound with surgical criteria is superior to surgical criteria alone when diagnosing UP.

Is It Possible to Diagnose Surgical Uterine Prolapse With Transperineal Ultrasound? Multicenter Validation of Diagnostic Software.

OBJECTIVES: To validate an ultrasound software that uses transperineal ultrasound to diagnose uterine prolapse (UP). METHODS: Multicenter, observational and prospective study with 155 patients that had indications for surgical intervention for dysfunctional pelvic floor pathology. Each patient underwent an examination with Pozzi tenaculum forceps was performed in the operating room with the patient anesthetized, followed by surgical correction of stages II-IV UP. Transperineal ultrasound was used to assess the difference in the pubis-uterine fundus measurement. With a multivariate logistic regression binary model (with the measurement ultrasound at rest, the Valsalva maneuver and age) using nonautomated methods to predict UP. With the purpose of evaluating the model, a table with coordinates of the receiver operating characteristic (ROC) curve, after which sensitivity and specificity were assessed. RESULTS: A total of 153 patients were included (73 with a diagnosis of surgical UP). It was obtained from the AUC (0.89) of the probabilities predicted by the model (95% confidence interval, 0.84-0.95; P < .0005). Based on the ROC curve for the model, obtaining a sensitivity of 91.8% and a specificity of 72.7%, values that were superior to those for the clinical exam for surgical UP (sensitivity: 80.8%; specificity: 71.3%). CONCLUSIONS: We validated software that uses transperineal ultrasound of the pelvic floor and patient age to generate a more reliable diagnosis of surgical UP than that obtained from clinical examinations.

Magnetic resonance imaging of fetal abdominal pathology: a complementary tool to prenatal ultrasound.

Fetal magnetic resonance imaging (MRI) is increasingly being used worldwide as a complementary tool to prenatal ultrasound (US) for multiple fetal pathologies. The aim of this article is to describe and illustrate how MRI can help US to evaluate fetal abdominal anomalies, based on cases performed in a tertiary public university hospital. Prenatal US, fetal MRI and postnatal imaging of these cases will be shown side-by-side to describe and illustrate the added value of fetal MRI in the different organs/systems and its impact on clinical management.

Prenatal ultrasound, magnetic resonance imaging and therapeutic options for fetal thoracic anomalies: a pictorial essay.

Congenital thoracic anomalies are uncommon malformations that require a precise diagnosis to guide parental counseling and possible prenatal treatment. Prenatal ultrasound (US) is the gold standard imaging modality to first detect and characterize these abnormalities and the best modality for follow-up. Fetal magnetic resonance imaging (MRI) is a complementary tool that provides multiplanar assessment and tissue characterization and can help estimate prognosis. Prenatal treatment is increasingly being used in fetuses with signs of distress and to potentially decrease morbidity and mortality. In this essay, the authors illustrate side-by-side US, MRI and therapeutic options for congenital thoracic anomalies in cases that presented to a tertiary pediatric hospital during the 7-year period 2014-2021. Entities included are congenital diaphragmatic hernia, congenital pulmonary airway malformation, bronchopulmonary sequestration, hybrid lesions, foregut duplications cysts and congenital lobar overinflation. Treatment options include maternal steroids, thoraco-amniotic shunt and fetal endotracheal occlusion. Recognition of typical findings in congenital thoracic anomalies is helpful to establish diagnosis, predict prognosis and plan perinatal treatment.

Multi-Illumination Single-Holographic-Exposure Lensless Fresnel (MISHELF) Microscopy: Principles and Biomedical Applications.

Lensless holographic microscopy (LHM) comes out as a promising label-free technique since it supplies high-quality imaging and adaptive magnification in a lens-free, compact and cost-effective way. Compact sizes and reduced prices of LHMs make them a perfect instrument for point-of-care diagnosis and increase their usability in limited-resource laboratories, remote areas, and poor countries. LHM can provide excellent intensity and phase imaging when the twin image is removed. In that sense, multi-illumination single-holographic-exposure lensless Fresnel (MISHELF) microscopy appears as a single-shot and phase-retrieved imaging technique employing multiple illumination/detection channels and a fast-iterative phase-retrieval algorithm. In this contribution, we review MISHELF microscopy through the description of the principles, the analysis of the performance, the presentation of the microscope prototypes and the inclusion of the main biomedical applications reported so far.

Platelet-Derived Extracellular Vesicles as Lipid Carriers in Severe Allergic Inflammation.

The resolution of inflammation is a complex process that is critical for removing inflammatory cells and restoring tissue function. The dysregulation of these mechanisms leads to chronic inflammatory disorders. Platelets, essential cells for preserving homeostasis, are thought to play a role in inflammation as they are a source of immunomodulatory factors. Our aim was to identify key metabolites carried by platelet-derived extracellular vesicles (PL-EVs) in a model of allergic inflammation. PL-EVs were isolated by serial ultracentrifugation using platelet-rich plasma samples obtained from platelet apheresis from severely (n = 6) and mildly (n = 6) allergic patients and non-allergic individuals used as controls (n = 8). PL-EVs were analysed by a multiplatform approach using liquid and gas chromatography coupled to mass spectrometry (LC-MS and GC-MS, respectively). PL-EVs obtained from severely and mildly allergic patients and control individuals presented comparable particle concentrations and sizes with similar protein concentrations. Strikingly, PL-EVs differed in their lipid and metabolic content according to the severity of inflammation. L-carnitine, ceramide (Cer (d18:0/24:0)), and several triglycerides, all of which seem to be involved in apoptosis and regulatory T functions, were higher in PL-EVs from patients with mild allergic inflammation than in those with severe inflammation. In contrast, PL-EVs obtained from patients with severe allergic inflammation showed an alteration in the arachidonic acid pathway. This study demonstrates that PL-EVs carry specific lipids and metabolites according to the degree of inflammation in allergic patients and propose novel perspectives for characterising the progression of allergic inflammation.

A method based on plateletpheresis to obtain functional platelet, CD3+ and CD14+ matched populations for research immunological studies.

BACKGROUND: In previous studies with peripheral blood cells, platelet factors were found to be associated with severe allergic phenotypes. A reliable method yielding highly concentrated and pure platelet samples is usually not available for immunological studies. Plateletpheresis is widely used in the clinics for donation purposes. In this study, we designed a protocol based on plateletpheresis to obtain Platelet-Rich Plasma (PRP), Platelet-Poor Plasma (PPP) as well as CD3+ and CD14+ cells matched samples from a waste plateletpheresis product for immunological studies. METHODS: Twenty-seven subjects were voluntarily subjected to plateletpheresis. PRP, PPP and blood cell concentrate contained in a leukocyte reduction system chamber (LRSC) were obtained in this process. CD3+ and CD14+ cells were isolated from the LRSC by density-gradient centrifugation and positive magnetic bead isolation. RNA was isolated from PRP, CD3+ and CD14+ cell samples and used for transcriptomic studies by Affymetrix. PRP and PPP samples were used for platelet protein quantification by multiplex assays. RESULTS: A reliable high yield method to obtain matched samples of PRP, PPP, CD3+ and CD14+ from a single donor for RNA and protein analyses has been designed. The RNA quality indicators (RQI) routinely used for other cell types were not suitable for platelet RNA characterization. Despite this, the platelet RNA was valid for transcriptomic studies by Affymetrix, as platelet transcripts obtained in our previous studies were confirmed in PRP samples. Platelet samples were enriched in platelet factors as determined in protein multiplex analysis. CONCLUSIONS: We have developed a method that yields not only high content and pure platelet samples from a single donor but also CD3+ and CD14+ matched samples that can be used for RNA and protein analyses in immunological studies.

Shadowfocimetry: adapting the holographic principle to a manual focimeter for visualization/marking of permanent engravings in progressive addition lenses.

Focimeters, especially manual versions, are the most used ophthalmic devices for dioptric power measurement in optometric clinical care. In the particular case of progressive addition lenses (PALs), they are used to determine far/near vision correction powers, but the user/clinician needs to know at which part of the PAL the measurement must be taken. For this reason, PALs have permanent engravings acting as reference marks to define the far/near vision areas for every PAL design. However, for several reasons these engravings are often difficult to localize and identify, making an accurate dioptric power determination difficult. In this Letter, we present an adaptation of the Gabor holographic principle to a manual focimeter and describe the methodology for the correct localization, visualization, and marking process of the reference engravings in PALs. Experimental results considering different types of PALs are included and the main limitations of the technique are also discussed.

Interobserver variability of ultrasound measurements for the differential diagnosis of uterine prolapse and cervical elongation without uterine prolapse.

OBJECTIVES: Our study aims to determine the interobserver variability of different ultrasound measurements (pubis-cervix distance, pubis-uterine fundus distance, and pubis-Douglascul-de-sac distance) previously analyzed for the ultrasound differential diagnosis of uterine prolapse (UP) and cervical elongation CE without UP. MATERIALS AND METHODS: We conducted a prospective observational study with 40 patients scheduled to undergo surgical correction of UP and CE without UP. All patients underwent pelvic floor ultrasound examination by an examiner (E1) who acquired ultrasound images. Using these images, E1 measured the distances for the ultrasound differential diagnosis of UP and CE without UP, and these distances were compared with those measured by the other examiner (E2). Values were analyzed by calculating ICCs with 95% CIs. RESULTS: For UP, excellent reliability was obtained for all measurements except the pubis-Douglascul-de-sac measurement at rest, which was moderate (ICC 0.596; p = 0.028) and for the difference between the pubis-Douglascul-de-sac measurement at rest and during the Valsalva maneuver, which was good (ICC 0.691; p < 0.0005). For CE without UP, interobserver reliability was excellent for all measurements analyzed except the pubis-cervix measurement during the Valsalva maneuver, which was moderate (ICC 0.535; p = 0.052) and for the pubis-Douglascul-de-sac measurement at rest, which was good (ICC 0.768; p < 0.0005). CONCLUSIONS: There is excellent interobserver reliability in measurements of the difference in the distance from the pubic symphysis to the uterine fundus at rest and during the Valsalva maneuver for both UP and CE without UP, which are used for the ultrasound differential diagnosis of UP and CE without UP.

Design, Calibration, and Application of a Robust, Cost-Effective, and High-Resolution Lensless Holographic Microscope.

Lensless holographic microscope (LHM) is an emerging very promising technology that provides high-quality imaging and analysis of biological samples without utilizing any lens for imaging. Due to its small size and reduced price, LHM can be a very useful tool for the point-of-care diagnosis of diseases, sperm assessment, or microfluidics, among others, not only employed in advanced laboratories but also in poor and/or remote areas. Recently, several LHMs have been reported in the literature. However, complete characterization of their optical parameters remains not much presented yet. Hence, we present a complete analysis of the performance of a compact, reduced cost, and high-resolution LHM. In particular, optical parameters such as lateral and axial resolutions, lateral magnification, and field of view are discussed into detail, comparing the experimental results with the expected theoretical values for different layout configurations. We use high-resolution amplitude and phase test targets and several microbeads to characterize the proposed microscope. This characterization is used to define a balanced and matched setup showing a good compromise between the involved parameters. Finally, such a microscope is utilized for visualization of static, as well as dynamic biosamples.

Molecular profiling of advanced solid tumours. The impact of experimental molecular-matched therapies on cancer patient outcomes in early-phase trials: the MAST study.

INTRODUCTION: Molecular-matched therapies have revolutionized cancer treatment. We evaluated the improvement in clinical outcomes of applying an in-house customized Next Generation Sequencing panel in a single institution. METHODS: Patients with advanced solid tumors were molecularly selected to receive a molecular-matched treatment into early phase clinical trials versus best investigators choice, according to the evaluation of a multidisciplinary molecular tumor board. The primary endpoint was progression-free survival (PFS) assessed by the ratio of patients presenting 1.3-fold longer PFS on matched therapy (PFS2) than with prior therapy (PFS1). RESULTS: Of a total of 231 molecularly screened patients, 87 were eligible for analysis. Patients who received matched therapy had a higher median PFS2 (6.47 months; 95% CI, 2.24-14.43) compared to those who received standard therapy (2.76 months; 95% CI, 2.14-3.91, Log-rank p = 0.022). The proportion of patients with a PFS2/PFS1 ratio over 1.3 was significantly higher in the experimental arm (0.33 vs 0.08; p = 0.008). DISCUSSION: We demonstrate the pivotal role of the institutional molecular tumor board in evaluating the results of a customized NGS panel. This process optimizes the selection of available therapies, improving disease control. Prospective randomized trials are needed to confirm this approach and open the door to expanded drug access.