Novel Hemodynamic, Vascular Lesion and Cytokine/Chemokine Differences Regarding Sex in a PAH Model.

Sex differences are recognized in pulmonary hypertension, however the progression of disease with regards to vascular lesion formation and circulating cytokines/chemokines is unknown. To determine whether vascular lesion formation, changes in hemodynamics and alterations in circulating chemokines/cytokines differ between male and female. We used a progressive model of PAH, SU/Hx and analyzed cohorts of male and female rats at timepoints suggested to indicate worsening disease. Our analysis included echocardiograpy for hemodynamics, morphometry, immunofluoresecence and chemokine/cytokine analysis of plasma at each time point in both sexes. We found that male rats had significantly increased Fulton index compared to females at each time point as well as increased medial artery thickening at 8-weeks PAH. Further, females exhibit fewer obliterative vascular lesions than males at our latest time point. Our data also show increased IL-4, GM-CSF, IL-10, and MIP-1 that are not observed in females, while females have increased RANTES and CXCL-10 not found in males. Males also have increased infiltrating macrophages in vascular lesions as compared to females. We found that development of progressive PAH in hemodynamics, morphology and chemokine/cytokine circulation differ significantly between males and females. These data suggest a macrophage driven pathology in males, while there may be T-cell protection from vascular damage in female PAH.

Expanding access to magnetic resonance education through open-source web tutorials.

This study presents a tool that introduces the fundamental concepts of magnetic resonance (MR) by integrating related science, technology, engineering, arts, and mathematical (STEAM) topics in the form of games to improve the access to MR education.

Repeatability of image quality in very low-field MRI.

BACKGROUND: Very low-field MR has emerged as a promising complementary device to high-field MRI scanners, offering several advantages. One of the key benefits is that very low-field scanners are generally more portable and affordable to purchase and maintain, making them an attractive option for medical facilities looking to reduce costs. Very low-field MRI systems also have lower RF power deposition, making them safer and less likely to cause tissue heating or other safety concerns. They are also simpler to maintain, as they do not require cooling agents such as liquid helium. However, these portable MR scanners are impacted by temperature, lower magnetic field strength, and inhomogeneity, resulting in images with lower signal-to-noise ratio (SNR) and higher geometric distortions. It is essential to investigate and tabulate the variations in these parameters to establish bounds so that subsequent in vivo studies and deployment of these portable systems can be well informed. PURPOSE: The aim of this work is to investigate the repeatability of image quality metrics such as SNR and geometrical distortion at 0.05 T over 10 days and three sessions per day. METHODS: We acquired repeatability data over 10 days with three sessions per day. The measurements included temperature, humidity, transmit frequency, off-resonance maps, and 3D turbo spin echo (TSE) images of an in vitro phantom. This resulted in a protocol with 11 sequences. We also acquired a 3 T data set for reference. The image quality metrics included computing SNR and eccentricity (to assess geometrical distortion) to investigate the repeatability of 0.05 T image quality. The image reconstruction included drift correction, k-space filtering, and off-resonance correction. We computed the experimental parameters' coefficient of variation (CV) and the resulting image quality metrics to assess repeatability. We have explored the impact of electromagnetic interference (EMI) on image quality in very low-field MRI. The investigation involved varying both the distance and amplitude of the EMI-producing coil from the signal generator to analyze their effects on image quality. RESULTS: The range of temperature measured during the study was within 1.5 °C. The off-resonance maps acquired before and after the 3D TSE showed similar hotspots and were changed mainly by a global constant. The SNR measurements were highly repeatable across sessions and over the 10 days, quantified by a CV of 6.7%. The magnetic field inhomogeneity effects quantified by eccentricity showed a CV of 13.7%, but less than 5.1% in two of the three sessions over 10 days. The use of conjugate phase reconstruction mitigated geometrical distortion artifacts. Temperature and humidity did not significantly affect SNR or mean frequency drift within the ranges of these environmental factors investigated. The EMI experiment showed that as the amplitude increased the SNR decreased, and concurrently the root mean square of the background increased with a rise in EMI amplitude or a reduction in distance. CONCLUSIONS: We found that humidity and temperature in the range investigated did not impact SNR or frequency. Based on the CV values computed session-wise and for the overall study, our findings indicate high repeatability for SNR and magnetic field homogeneity.

Utilizing nerve conduction studies to identify very early Guillain-Barré syndrome and distinguish it from mimics in emergency settings.

INTRODUCTION/AIMS: Accurately diagnosing Guillain-Barré syndrome (GBS) in its early stages and distinguishing it from mimics poses challenges. This study aimed to evaluate the utility of an existing electrodiagnostic criterion in very early GBS (VEGBS) for discerning mimics. Additionally, we explored specific electrophysiological abnormalities in VEGBS to design a new diagnostic criterion for more accurate VEGBS diagnosis. METHODS: We retrospectively identified all patients with flaccid quadriparesis initially suspected of GBS who underwent nerve conduction studies (NCS) ≤4 days from symptom onset. We then retrieved their NCS data and applied an existing electrodiagnostic criterion for sensitivity and specificity analyses based on the final discharge diagnosis. Furthermore, we designed a new criterion based on the observed electrophysiological abnormalities that have maximum specificity and at least 50% sensitivity. RESULTS: Among 70 patients suspected of VEGBS, 44 (63%) received a final diagnosis of GBS, while in 26 (37%), the GBS diagnosis was later refuted. Umapathi's definite criterion exhibited a sensitivity of 61.36% and a specificity of 92.31%. The probable and possible groups showed very high sensitivity (90.91% and 100%, respectively); however, specificity was low (57.69% and 30.77%, respectively) in the very early stage. Our proposed criterion demonstrated a sensitivity of 88.64% (CI: 75.44%-96.21%) and a specificity of 96.15% (CI: 80.36%-99.90%). DISCUSSION: The criterion based on presumed electrophysiological correlates of specific early GBS pathophysiology proved more effective than the existing electrodiagnostic criterion in differentiating VEGBS from mimics.

Incidence and determinants of perinatal mortality in five urban hospitals in Dar es Salaam, Tanzania: a cohort study with an embedded case-control analysis.

INTRODUCTION: Tanzania has one of the highest burdens of perinatal mortality, with a higher risk among urban versus rural women. To understand the characteristics of perinatal mortality in urban health facilities, study objectives were: I. To assess the incidence of perinatal deaths in public health facilities in Dar es Salaam and classify these into a) pre-facility stillbirths (absence of fetal heart tones on admission to the study health facilities) and b) intra-facility perinatal deaths before discharge; and II. To identify determinants of perinatal deaths by comparing each of the two groups of perinatal deaths with healthy newborns. METHODS: This was a retrospective cohort study among women who gave birth in five urban, public health facilities in Dar es Salaam. I. Incidence of perinatal death in the year 2020 was calculated based on routinely collected health facility records and the Perinatal Problem Identification Database. II. An embedded case-control study was conducted within a sub-population of singletons with birthweight ≥ 2000 g (excluding newborns with congenital malformations); pre-facility stillbirths and intra-facility perinatal deaths were compared with 'healthy newborns' (Apgar score ≥ 8 at one and ≥ 9 at five minutes and discharged home alive). Descriptive and logistic regression analyses were performed to explore the determinants of deaths. RESULTS: A total of 37,787 births were recorded in 2020. The pre-discharge perinatal death rate was 38.3 per 1,000 total births: a stillbirth rate of 27.7 per 1,000 total births and an intra-facility neonatal death rate of 10.9 per 1,000 live births. Pre-facility stillbirths accounted for 88.4% of the stillbirths. The case-control study included 2,224 women (452 pre-facility stillbirths; 287 intra-facility perinatal deaths and 1,485 controls), 99% of whom attended antenatal clinic (75% with more than three visits). Pre-facility stillbirths were associated with low birth weight (cOR 4.40; (95% CI: 3.13-6.18) and with maternal hypertension (cOR 4.72; 95% CI: 3.30-6.76). Intra-facility perinatal deaths were associated with breech presentation (aOR 40.3; 95% CI: 8.75-185.61), complications in the second stage (aOR 20.04; 95% CI: 12.02-33.41), low birth weight (aOR 5.57; 95% CI: 2.62-11.84), cervical dilation crossing the partograph's action line (aOR 4.16; 95% CI:2.29-7.56), and hypertension during intrapartum care (aOR 2.9; 95% CI 1.03-8.14), among other factors.  CONCLUSION: The perinatal death rate in the five urban hospitals was linked to gaps in the quality of antenatal and intrapartum care, in the study health facilities and in lower-level referral clinics. Urgent action is required to implement context-specific interventions and conduct implementation research to strengthen the urban referral system across the entire continuum of care from pregnancy onset to postpartum. The role of hypertensive disorders in pregnancy as a crucial determinant of perinatal deaths emphasizes the complexities of maternal-perinatal health within urban settings.

Lurbinectedin in small cell lung cancer: real-world experience of a multicentre national early access programme.

BACKGROUND AND AIMS: Lurbinectedin is a novel oncogenic transcription inhibitor active in several cancers, including small cell lung cancer (SCLC). We aimed to describe the first Australian experience of the clinical efficacy and tolerability of lurbinectedin for the treatment of SCLC after progression on platinum-containing therapy. METHODS: Multicentre real-world study of individuals with SCLC initiating lurbinectedin monotherapy (3.2 mg/m2 three-weekly) on an early access programme between May 2020 and December 2021. Key outcomes were clinical utilisation, efficacy and tolerability. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method. Outcome data were collected within the AUstralian Registry and biObank of thoRacic cAncers (AURORA). RESULTS: Data were analysed for 46 individuals across seven sites. Lurbinectedin was given as second- (83%, 38/46) or subsequent- (17%, 8/46) line therapy, mostly with prior chemoimmunotherapy (87%, 40/46). We report dose modifications (17%, 8/46), interruptions/delays (24%, 11/46), high-grade toxicities (28%, 13/46) and hospitalisations (54%, 25/46) during active treatment. The overall response rate was 33% and the disease control rate was 50%. Six-month OS was 44% (95% confidence interval (CI): 29.0-57.1). Twelve-month OS was 15% (95% CI: 6.5-26.8). From lurbinectedin first dose, the median PFS was 2.5 months (95% CI: 1.8-2.9) and OS was 4.5 months (95% CI: 3.5-7.2). From SCLC diagnosis, the median OS was 12.9 months (95% CI: 11.0-17.2). Individuals with a longer chemotherapy-free interval prior to lurbinectedin had longer PFS and OS. CONCLUSION: This real-world national experience of lurbinectedin post-platinum chemotherapy and immunotherapy for individuals with SCLC was similar to that reported in clinical trials.

The Gárdos Channel and Piezo1 Revisited: Comparison between Reticulocytes and Mature Red Blood Cells.

The Gárdos channel (KCNN4) and Piezo1 are the best-known ion channels in the red blood cell (RBC) membrane. Nevertheless, the quantitative electrophysiological behavior of RBCs and its heterogeneity are still not completely understood. Here, we use state-of-the-art biochemical methods to probe for the abundance of the channels in RBCs. Furthermore, we utilize automated patch clamp, based on planar chips, to compare the activity of the two channels in reticulocytes and mature RBCs. In addition to this characterization, we performed membrane potential measurements to demonstrate the effect of channel activity and interplay on the RBC properties. Both the Gárdos channel and Piezo1, albeit their average copy number of activatable channels per cell is in the single-digit range, can be detected through transcriptome analysis of reticulocytes. Proteomics analysis of reticulocytes and mature RBCs could only detect Piezo1 but not the Gárdos channel. Furthermore, they can be reliably measured in the whole-cell configuration of the patch clamp method. While for the Gárdos channel, the activity in terms of ion currents is higher in reticulocytes compared to mature RBCs, for Piezo1, the tendency is the opposite. While the interplay between Piezo1 and Gárdos channel cannot be followed using the patch clamp measurements, it could be proved based on membrane potential measurements in populations of intact RBCs. We discuss the Gárdos channel and Piezo1 abundance, interdependencies and interactions in the context of their proposed physiological and pathophysiological functions, which are the passing of small constrictions, e.g., in the spleen, and their active participation in blood clot formation and thrombosis.

Natural evolution of idiopathic carpal tunnel syndrome with respect to wrist and hand anthropometry: A prospective cohort study.

OBJECTIVE: A greater wrist depth/width ratio and wrist depth/palm length ratio are known risk factors for carpal tunnel syndrome. We hypothesized that these parameters might also predict progression in patients who were not surgically treated. METHODS: Seventy-eight patients with moderately severe idiopathic carpal tunnel syndrome of at least 10 months duration at recruitment, who declined surgical treatment and steroid injection, underwent repeated neurophysiological assessments after 3 years. A > 10% increase in median SNAP latency was taken as evidence of significant deterioration. RESULTS: Patients with a wrist ratio ≥ 0.72 showed a statistically significant deterioration in SNAP latency from 5.46 (SD 2.09) to 7.16 (SD 1.56) ms and in SNAP amplitude from 30.19 (SD 13.8) to 16.62 (SD 14.42) µv. For those with a wrist-to-palm ratio ≥ 0.42, SNAP latency deteriorated from 5.27 (SD 1.21) to 7.1 (SD 1.52) ms, and amplitude from 32.78 (SD 13.76) to 19.45 (SD 16.62) µv. Patients with lower ratios did not show significant changes in any neurophysiological parameter. The relative risk of significant deterioration in SNAP latency in patients with a wrist ratio ≥ 0.72 was 2.04 (95% CI 1.27-3.27). CONCLUSION: In untreated idiopathic carpal tunnel syndrome, patients with larger wrist and wrist-to-palm ratios are more likely to show neurophysiological progression.

Early stage of erythrocyte sedimentation rate test: Fracture of a high-volume-fraction gel.

Erythrocyte sedimentation rate (ESR) is a clinical parameter used as a nonspecific marker for inflammation, and recent studies have shown that it is linked to the collapse of the gel formed by red blood cells (RBCs) at physiological hematocrits (i.e. RBC volume fraction). Previous research has suggested that the observation of a slower initial dynamics is related to the formation of fractures in the gel. Moreover, RBC gels present specific properties due to the anisotropic shape and flexibility of the RBCs. Namely, the onset of the collapse is reached earlier and the settling velocity of the gel increases with increasing attraction between the RBCs, while the gel of spherical particles shows the opposite trend. Here, we report experimental observations of the gel structure during the onset of the collapse. We suggest an equation modeling this initial process as fracturing of the gel. We demonstrate that this equation provides a model for the motion of the interface between blood plasma and the RBC gel, along the whole time span. We also observe that the increase in the attraction between the RBCs modifies the density of fractures in the gel, which explains why the gel displays an earlier onset when the aggregation energy between the RBCs increases. Our work uncovers the detailed physical mechanism underlying the ESR and provides insights into the fracture dynamics of an RBC gel. These results can improve the accuracy of clinical measurements.

Evaluation of the Parkinson's Remote Interactive Monitoring System in a Clinical Setting: Usability Study.

BACKGROUND: The fastest-growing neurological disorder is Parkinson disease (PD), a progressive neurodegenerative disease that affects 10 million people worldwide. PD is typically treated with levodopa, an oral pill taken to increase dopamine levels, and other dopaminergic agonists. As the disease advances, the efficacy of the drug diminishes, necessitating adjustments in treatment dosage according to the patient's symptoms and disease progression. Therefore, remote monitoring systems that can provide more detailed and accurate information on a patient's condition regularly are a valuable tool for clinicians and patients to manage their medication. The Parkinson's Remote Interactive Monitoring System (PRIMS), developed by PragmaClin Research Inc, was designed on the premise that it will be an easy-to-use digital system that can accurately capture motor and nonmotor symptoms of PD remotely. OBJECTIVE: We performed a usability evaluation in a simulated clinical environment to assess the ease of use of the PRIMS and determine whether the product offers suitable functionality for users in a clinical setting. METHODS: Participants were recruited from a user sign-up web-based database owned by PragmaClin Research Inc. A total of 11 participants were included in the study based on the following criteria: (1) being diagnosed with PD and (2) not being diagnosed with dementia or any other comorbidities that would make it difficult to complete the PRIMS assessment safely and independently. Patient users completed a questionnaire that is based on the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale. Interviews and field notes were analyzed for underlying themes and topics. RESULTS: In total, 11 people with PD participated in the study (female individuals: n=5, 45%; male individuals: n=6, 55%; age: mean 66.7, SD 7.77 years). Thematic analysis of the observer's notes revealed 6 central usability issues associated with the PRIMS. These were the following: (1) the automated voice prompts are confusing, (2) the small camera is problematic, (3) the motor test exhibits excessive sensitivity to the participant's orientation and position in relation to the cameras, (4) the system poses mobility challenges, (5) navigating the system is difficult, and (6) the motor test exhibits inconsistencies and technical issues. Thematic analysis of qualitative interview responses revealed four central themes associated with participants' perspectives and opinions on the PRIMS, which were (1) admiration of purpose, (2) excessive system sensitivity, (3) video instructions preferred, and (4) written instructions disliked. The average system usability score was calculated to be 69.2 (SD 4.92), which failed to meet the acceptable system usability score of 70. CONCLUSIONS: Although multiple areas of improvement were identified, most of the participants showed an affinity for the overarching objective of the PRIMS. This feedback is being used to upgrade the current PRIMS so that it aligns more with patients' needs.

Cord Blood Cortisol Level - A Possible Predictor for Respiratory Distress Syndrome in Preterm Neonates.

BACKGROUND: Respiratory Distress Syndrome (RDS) is a leading cause of death in premature infants. There are different clinical/ biochemical markers associated with the RDS. One of the potential biochemical markers is cortisol in cord blood. PURPOSE: This study aims to correlate cortisol levels in preterm neonates with RDS and to establish whether cord blood cortisol is a reliable predictor for RDS. MATERIALS AND METHODS: This prospective analytical study was conducted in a tertiary care hospital over nine months among fifty preterm neonates. Data were collected using proforma, and cord blood was collected at the time of delivery. Cortisol levels were compared and correlated to the development of RDS. RESULTS AND DISCUSSION: The mean ± SD cord blood cortisol level among preterm neonates was 5.97 ± 2.74 (SD) µg/dl. The levels were higher in neonates whose mothers received antenatal steroids and were significantly lower (2.86 ± 1.66 µg/dl) in those who developed RDS. Association between cord blood cortisol level and RDS was found with an odds ratio of 57.4, which was statistically significant. The percentage of babies developing RDS in mothers not covered with antenatal steroids was significantly higher than those covered (p-value is 0.000). The mean cord blood cortisol levels were exceptionally low (1.89 µg/dl) in neonates who expired compared to those who survived (7.02 µg/dl). CONCLUSION: There is an association between cord blood cortisol levels and RDS. Hence, Cord blood cortisol levels may be used to predict RDS and help initiate early treatment, thus preventing mortality and morbidity.

EXPRESS: Increased Metamemory Accuracy with Practice Does Not Require Practice with Metamemory.

Given that learners do not always predict their future memory performance accurately, there is a need to better understand how metamemory accuracy can be improved. Prior research suggests that one way to improve is practice - participants tend to become better at predicting their future memory performance over the course of multi-trial learning experiments. However, it is currently unclear whether such improvements result from participants having practiced making metamemory judgments or whether comparable improvements occur even in their absence. This issue was investigated in three multi-trial, cued recall experiments wherein participants either did or did not receive practice making judgments of learning. Metamemory accuracy increased across study blocks but did so equally for the two groups. These results indicate that increased metamemory accuracy with practice is not due to participants having practiced explicit metamemory monitoring, but instead due to other factors associated with multi-trial learning such as retrieval practice and the availability of prior test performance as a metamemory cue.

The "Personalising Actinic Keratosis Treatment for Immunocompromised Patients" (IM-PAKT) Project: An Expert Panel Opinion.

Actinic keratosis (AK) is an intraepithelial condition characterized by the development of scaly, erythematous lesions after repeated exposure to ultraviolet radiation. Significant immunosuppression is a risk factor for the development of AK and subsequent lesion progression to squamous cell carcinoma. Immunocompromised patients (ICPs), particularly organ transplant recipients, often have more advanced or complex AK presentations and an increased risk of skin carcinomas versus non-ICPs with AK, making lesions more difficult to treat and resulting in worse treatment outcomes. The recent "Personalising Actinic Keratosis Treatment" (PAKT) consensus reported that delivering patient-centric care may play a role in supporting better clinical outcomes and patient satisfaction with treatments for chronic dermatologic conditions such as AK, which require repeated cycles of treatment. Additionally, currently published guidance and recommendations were considered by the PAKT panel to be overly broad for managing ICPs with their unique and complex needs. Therefore, the "Personalising Actinic Keratosis Treatment for Immunocompromised Patients" (IM-PAKT) panel was established to build upon general recommendations from the PAKT consensus. The panel identified current gaps in guidance for AK care in ICPs, offered practical care approaches based on typical ICP scenarios, and highlighted the need to adapt AK management to optimize care and improve treatment outcomes in ICPs. In particular, dermatologists should establish collaborative and transparent relationships with patients' multidisciplinary teams to enhance overall care for patients' comorbidities: given their increased risk of progression to malignancy, earlier assessments/interventions and frequent follow-ups are vital.The panel also developed a novel "triage" tool outlining effective treatment follow-up and disease surveillance plans tailored to patients' risk profiles, guided by current clinical presentation and relevant medical history. Additionally, we present the panel's expert opinion on three fictional ICP scenarios to explain their decision-making process for assessing and managing typical ICPs that they may encounter in clinical practice.

Summary of Research: Overall Survival with Osimertinib in Resected EGFR-Mutated NSCLC.

This is a summary of the original article ?Overall survival with osimertinib in resected EGFR-mutated NSCLC.Ë® Osimertinib blocks the activity of the epidermal growth factor receptor (EGFR) on cancer cells, causing cancer cell death and tumor shrinkage, and is an effective treatment for EGFR-mutated non-small cell lung cancer (NSCLC). The ADAURA study assessed the effects of osimertinib versus placebo in patients with EGFR-mutated (exon 19 deletion or L858R) early stage (IB-IIIA) NSCLC removed by surgery (resected). Previous results from ADAURA demonstrated that patients treated with osimertinib stayed alive and cancer-free (disease-free survival) significantly longer than patients who received placebo. Recent data showed the overall length of time patients were alive after starting treatment (overall survival). In both the primary stage II-IIIA and overall stage IB-IIIA populations, patients in the osimertinib group had a significant 51% reduction in the risk of death compared with the placebo group. The data demonstrated that osimertinib after surgery significantly improved overall survival in patients with resected, EGFR-mutated, stage IB-IIIA NSCLC.

Updated efficacy and safety of entrectinib in NTRK fusion-positive non-small cell lung cancer.

OBJECTIVES: NTRK fusions result in constitutively active oncogenic TRK proteins responsible for âˆ¼ 0.2 % of non-small cell lung cancer (NSCLC) cases. Approximately 40 % of patients with advanced NSCLC develop CNS metastases; therefore, treatments with intracranial (IC) efficacy are needed. In an integrated analysis of three phase I/II studies (ALKA-372-001: EudraCT 2012-000148-88; STARTRK-1: NCT02097810; STARTRK-2: NCT02568267), entrectinib, a potent, CNS-active, TRK inhibitor, demonstrated efficacy in patients with NTRK fusion-positive (fp) NSCLC (objective response rate [ORR]: 64.5 %; 2 August 2021 data cut-off). We present updated data for this cohort. MATERIALS AND METHODS: Eligible patients were ≥ 18 years with locally advanced/metastatic, NTRK-fp NSCLC with ≥ 12 months of follow-up. Tumor responses were assessed by blinded independent central review (BICR) per RECIST v1.1 at Week 4 and every eight weeks thereafter. Co-primary endpoints: ORR; duration of response (DoR). Secondary endpoints included progression-free survival (PFS); overall survival (OS); IC efficacy; safety. Enrolment cut-off: 2 July 2021; data cut-off: 2 August 2022. RESULTS: The efficacy-evaluable population included 51 patients with NTRK-fp NSCLC. Median age was 60.0 years (range 22-88); 20 patients (39.2 %) had investigator-assessed baseline CNS metastases. Median survival follow-up was 26.3 months (95 % CI 21.0-34.1). ORR was 62.7 % (95 % CI 48.1-75.9), with six complete and 26 partial responses. Median DoR and PFS were 27.3 months (95 % CI 19.9-30.9) and 28.0 months (95 % CI 15.7-30.4), respectively. Median OS was 41.5 months. In patients with BICR-assessed baseline CNS metastases, IC-ORR was 64.3 % (n = 9/14; 95 % CI 35.1-87.2), including seven complete responders, and IC-DoR was 55.7 months. In the safety-evaluable population (n = 55), most treatment-related adverse events were grade 1/2; no treatment-related deaths were reported. CONCLUSION: Entrectinib has continued to demonstrate deep and durable systemic and IC responses in patients with NTRK-fp NSCLC.

A Phase II trial of alternating osimertinib and gefitinib therapy in advanced EGFR-T790M positive non-small cell lung cancer: OSCILLATE.

In this phase II, single arm trial (ACTRN12617000720314), we investigate if alternating osimertinib and gefitinib would delay the development of resistance to osimertinib in advanced, non-small cell lung cancer (NSCLC) with the epidermal growth factor receptor (EGFR) T790M mutation (n = 47) by modulating selective pressure on resistant clones. The primary endpoint is progression free-survival (PFS) rate at 12 months, and secondary endpoints include: feasibility of alternating therapy, overall response rate (ORR), overall survival (OS), and safety. The 12-month PFS rate is 38% (95% CI 27.5-55), not meeting the pre-specified primary endpoint. Serial circulating tumor DNA (ctDNA) analysis reveals decrease and clearance of the original activating EGFR and EGFR-T790M mutations which are prognostic of clinical outcomes. In 73% of participants, loss of T790M ctDNA is observed at progression and no participants have evidence of the EGFR C797S resistance mutation following the alternating regimen. These findings highlight the challenges of treatment strategies designed to modulate clonal evolution and the clinical importance of resistance mechanisms beyond suppression of selected genetic mutations in driving therapeutic escape to highly potent targeted therapies.

Four-year clinical update and treatment switching-adjusted outcomes with first-line nivolumab plus ipilimumab with chemotherapy for metastatic non-small cell lung cancer in the CheckMate 9LA randomized trial.

BACKGROUND: In CheckMate 9LA, nivolumab plus ipilimumab with chemotherapy prolonged overall survival (OS) versus chemotherapy regardless of tumor PD-L1 expression or histology. We report updated efficacy and safety in all randomized patients with a minimum 4-year follow-up and an exploratory treatment-switching adjustment analysis in all treated patients who received chemotherapy and subsequent immunotherapy. METHODS: Adults with stage IV/recurrent non-small cell lung cancer (NSCLC), no sensitizing EGFR/ALK alterations, and ECOG performance status ≤1 were randomized 1:1 to nivolumab 360 mg every 3 weeks plus ipilimumab 1 mg/kg every 6 weeks with chemotherapy (two cycles) or chemotherapy (four cycles, with optional maintenance pemetrexed for the nonsquamous population). Assessments included OS, progression-free survival, and objective response rate. Exploratory analyses included efficacy by tumor PD-L1 expression and histology and in patients who discontinued nivolumab plus ipilimumab with chemotherapy due to treatment-related adverse events (TRAEs), and a treatment-switching adjustment analysis using inverse probability of censoring weighting. RESULTS: With a 47.9-month minimum follow-up for OS, nivolumab plus ipilimumab with chemotherapy continued to prolong OS over chemotherapy in all randomized patients (HR 0.74, 95% CI 0.63 to 0.87; 4-year OS rate: 21% versus 16%), regardless of tumor PD-L1 expression (HR (95% CI): PD-L1<1%, 0.66 (0.50 to 0.86) and ≥1%, 0.74 (0.60 to 0.92)) or histology (squamous, 0.64 (0.48 to 0.84) and non-squamous, 0.80 (0.66 to 0.97)). In patients who discontinued all components of nivolumab plus ipilimumab with chemotherapy due to TRAEs (n=61), the 4-year OS rate was 41%. With treatment-switching adjustment for the 36% of patients receiving subsequent immunotherapy in the chemotherapy arm, the estimated HR of nivolumab plus ipilimumab with chemotherapy versus chemotherapy was 0.66 (95% CI 0.55 to 0.80). No new safety signals were observed. CONCLUSIONS: In this 4-year update, patients treated with nivolumab plus ipilimumab with chemotherapy continued to have long-term, durable efficacy benefit over chemotherapy regardless of tumor PD-L1 expression and/or histology. A greater estimated relative OS benefit was observed after adjustment for subsequent immunotherapy use in the chemotherapy arm. These results further support nivolumab plus ipilimumab with chemotherapy as a first-line treatment for patients with metastatic/recurrent NSCLC, including those with tumor PD-L1<1% or squamous histology, populations with high unmet needs.

Subcutaneous versus Intravenous Amivantamab, both in Combination with Lazertinib, in Refractory EGFR-mutated NSCLC: Primary Results from the Phase 3 PALOMA-3 Study.

PURPOSE: Phase 3 studies of intravenous amivantamab demonstrated efficacy across EGFR-mutated advanced non-small cell lung cancer (NSCLC). A subcutaneous formulation could improve tolerability and reduce administration time while maintaining efficacy. PATIENTS AND METHODS: Patients with EGFR-mutated advanced NSCLC who progressed following osimertinib and platinum-based chemotherapy were randomized 1:1 to receive subcutaneous or intravenous amivantamab, both combined with lazertinib. Co-primary pharmacokinetic noninferiority endpoints were trough concentrations (Ctrough; on cycle-2-day-1 or cycle-4-day-1) and cycle-2 area under the curve (AUCD1-D15). Key secondary endpoints were objective response rate (ORR) and progression-free survival (PFS). Overall survival (OS) was a predefined exploratory endpoint. RESULTS: Overall, 418 patients underwent randomization (subcutaneous group, n=206; intravenous group, n=212). Geometric mean ratios of Ctrough for subcutaneous to intravenous amivantamab were 1.15 (90% CI, 1.04-1.26) at cycle-2-day-1 and 1.42 (90% CI, 1.27-1.61) at cycle-4-day-1; the cycle-2 AUCD1-D15 was 1.03 (90% CI, 0.98-1.09). ORR was 30% in the subcutaneous and 33% in the intravenous group; median PFS was 6.1 and 4.3 months, respectively. OS was significantly longer in the subcutaneous versus intravenous group (hazard ratio for death, 0.62; 95% CI, 0.42-0.92; nominal P=0.02). Fewer patients in the subcutaneous group experienced infusion-related reactions (13% versus 66%) and venous thromboembolism (9% versus 14%) versus the intravenous group. Median administration time for first infusion was reduced to 4.8 minutes (range, 0-18) for subcutaneous amivantamab from 5 hours (range, 0.2-9.9) for intravenous amivantamab. During cycle-1-day-1, 85% and 52% of patients in the subcutaneous and intravenous groups, respectively, considered treatment convenient; end-of-treatment rates were 85% and 35%, respectively. CONCLUSION: Subcutaneous amivantamab-lazertinib demonstrated noninferiority to intravenous amivantamab-lazertinib, offering a consistent safety profile with reduced infusion-related reactions, increased convenience, and prolonged survival.

A Machine Learning-Driven Virtual Biopsy System For Kidney Transplant Patients.

In kidney transplantation, day-zero biopsies are used to assess organ quality and discriminate between donor-inherited lesions and those acquired post-transplantation. However, many centers do not perform such biopsies since they are invasive, costly and may delay the transplant procedure. We aim to generate a non-invasive virtual biopsy system using routinely collected donor parameters. Using 14,032 day-zero kidney biopsies from 17 international centers, we develop a virtual biopsy system. 11 basic donor parameters are used to predict four Banff kidney lesions: arteriosclerosis, arteriolar hyalinosis, interstitial fibrosis and tubular atrophy, and the percentage of renal sclerotic glomeruli. Six machine learning models are aggregated into an ensemble model. The virtual biopsy system shows good performance in the internal and external validation sets. We confirm the generalizability of the system in various scenarios. This system could assist physicians in assessing organ quality, optimizing allograft allocation together with discriminating between donor derived and acquired lesions post-transplantation.

Identificación oportuna del sangrado anormal postparto: método gravimétrico para cuantificar sangrado. Proyecto de mejora / Timely detection of abnormal postpartum bleeding: use of the gravimetric method to quantify bleeding. Improvement project

Resumen: Introducción: La hemorragia postparto es una entidad que no se detecta oportunamente con la estimación visual del sangrado. Material y métodos: Se implementó un protocolo estandarizado de cuantificación gravimétrica del sangrado postparto en pacientes sometidas a cesárea. Un estudio prospectivo, comparativo, no aleatorizado determinó el cumplimiento del protocolo, frecuencia proporcional del sangrado postparto anormal, basal y postintervención de mejora; y asociación entre metodologías de evaluación del sangrado y clasificación del sangrado. Pruebas z, Fisher, p < 0.05 significativa. Resultados: El cumplimiento del protocolo estandarizado fue 53% (± 0.18). En el grupo postintervención de mejora, la frecuencia del sangrado anormal postparto se incrementó en 30% con respecto al grupo basal (p < 0.05). Se demostró asociación significativa entre la cuantificación gravimétrica del sangrado postparto, y el sangrado postparto anormal. Conclusión: La implementación del protocolo de cuantificación gravimétrica del sangrado postparto fue posible, permitió mejorar la capacidad de identificación del sangrado postparto anormal en pacientes sometidas a cesárea.

Abstract: Introduction: Postpartum hemorrhage is a complication, that is not timely detected with the visual estimation of bleeding. Material and methods: A standardized protocol for the gravimetric quantification of postpartum bleeding was implemented to improve the ability to identify abnormal bleeding in patients undergoing caesarean section. A prospective, comparative, non-randomized study evaluated the improvement intervention. Compliance with the protocol, classification of postpartum bleeding before and after intervention; and the association between methodologies for assessing bleeding and postpartum bleeding classification were determined. Fisher z tests, p < 0.05 significant. Results: Compliance with the standardized protocol was 53% (± 0.18). In the post-intervention group, the frequency of abnormal postpartum bleeding increased by 30% with respect to the baseline group (p < 0.05). A significant association was demonstrated between gravimetric quantification of postpartum bleeding and abnormal postpartum bleeding. Conclusion: The implementation of the protocol for the gravimetric quantification of postpartum bleeding was possible. It improved the ability to identify abnormal postpartum bleeding in patients undergoing cesarean section.