Efficacy of Trastuzumab Deruxtecan in HER2-Expressing Solid Tumors by Enrollment HER2 IHC Status: Post Hoc Analysis of DESTINY-PanTumor02.

INTRODUCTION: DESTINY-PanTumor02 (NCT04482309) evaluated the efficacy and safety of trastuzumab deruxtecan (T-DXd) in pretreated patients with human epidermal growth factor receptor 2 (HER2)-expressing [immunohistochemistry (IHC) 3+/2+] solid tumors across seven cohorts: endometrial, cervical, ovarian, bladder, biliary tract, pancreatic, and other. Subgroup analyses by HER2 status were previously reported by central HER2 IHC testing, determined at enrollment or confirmed retrospectively. Reflecting the testing methods available in clinical practice, most patients (n = 202; 75.7%) were enrolled based on local HER2 IHC testing. Here, we report outcomes by HER2 IHC status as determined by the local or central test results used for study enrollment. METHODS: This phase 2, open-label study evaluated T-DXd (5.4 mg/kg once every 3 weeks) for HER2-expressing (IHC 3+/2+ by local or central testing) locally advanced or metastatic disease after ≥ 1 systemic treatment or without alternative treatments. The primary endpoint was investigator-assessed confirmed objective response rate (ORR). Secondary endpoints included safety, duration of response (DOR), progression-free survival (PFS), and overall survival. RESULTS: In total, 111 (41.6%) and 151 (56.6%) patients were enrolled with IHC 3+ and IHC 2+ tumors, respectively. In patients with IHC 3+ tumors, investigator-assessed confirmed ORR was 51.4% [95% confidence interval (CI) 41.7, 61.0], and median DOR was 14.2 months (95% CI 10.3, 23.6). In patients with IHC 2+ tumors, investigator-assessed ORR was 26.5% (95% CI 19.6, 34.3), and median DOR was 9.8 months (95% CI 4.5, 12.6). Safety was consistent with the known profile of T-DXd. CONCLUSION: In line with previously reported results, T-DXd demonstrated clinically meaningful benefit in patients with HER2-expressing tumors, with the greatest benefit in patients with IHC 3+ tumors. These data support the antitumor activity of T-DXd in HER2-expressing solid tumors, irrespective of whether patients are identified by local or central HER2 IHC testing.

Voices and experiences of Moroccan-heritage women and men in Spain: Understanding affective reactions to injustice through mixed-methods.

OBJECTIVE: Research has not often delved into the experiences of the Moroccan-heritage community in Western societies. We followed a mixed-methods approach, combining qualitative with quantitative methods, applying an intersectionality perspective to analyze the feelings and perceptions of Moroccan-heritage people about their situation in Spain, interaction with Spaniards, perceived discrimination, and metaperceptions to understand their affective reactions to injustice (Studies 1 and 2), and willingness to mobilize (Study 2). METHOD: In Study 1, we conducted four discussion groups with Moroccan-heritage women (n = 12) and men (n = 13) separately. In Study 2, we analyzed with a quantitative survey (n = 147) participants' identity fusion with Morocco and Spain, perceived metaprejudice and discrimination, metadehumanization, the evaluation of the ingroup situation, affective reactions to their situation, and support of collective actions for their rights. RESULTS: The analysis of Study 1 revealed experiences of discrimination and spontaneous positive but also negative metaperceptions, especially among women, including an alarming metadehumanization. Quantitative analyses in Study 2 confirmed gender differences, with women reporting worse feelings and perceptions, and confirmed that metadehumanization was crucial to predict indignation and anger of Moroccan-heritage people, while perceived discrimination was significant for mobilization. CONCLUSIONS: Although gender differences need additional clarification, these findings advance our theoretical knowledge about the sources of shared grievances among disadvantaged group members and the role of metadehumanization in their affective reactions to injustice. Interventions are urgent to address metadehumanization and canalize its affective consequences to promote social change. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Dose-response relationship of high-intensity training on global cognition in older adults with mild cognitive impairment or dementia: a systematic review with meta-analysis - the ACHIEVE-Study.

BACKGROUND: The prevalence of mild cognitive impairment (MCI) and its subsequent progression to dementia has increased progression to dementia has increased worldwide, making it a topic of interest. of interest, and it has been observed that approximately 23% of cases are avoidable through preventable through vigorous exercise. METHODS: A systematic review with meta-analysis was conducted by searching in the PubMed, Scopus, CINAHL, and Web of Science databases. For inclusion, studies had to incorporate High Intensity Training (HIT) as a primary or significant component of the overall intervention for older adults with MCI. Out of the 611 articles identified, 14 randomized clinical trials met the criteria for inclusion in the review. RESULTS: Fourteen trials were included in the systematic review, and seven were included in the meta-analysis. A total of 1839 participants were included in the studies, with 1014 receiving a high-intensity training-based intervention, and 998 were considered in the meta-analysis. Compared to usual care or sedentary activities, the high-intensity training interventions had a positive effect on cognition, either improving it or delaying the decline (g = 0.710 (95% CI: 0.191 - 1.229; p = 0.007). Additionally, the meta-analysis determined that a frequency of 3 sessions per week (g = 0.964, CI = 0.091 - 1.837, p = 0.030) of approximately 60 minutes (g = 0.756, CI = 0.052 - 1.460, p = 0.035) each was the best dose to obtain better effects on global cognition. CONCLUSION: Low-frequency and short-duration high-intensity training interventions are sufficient to improve or at least delay the decline in global cognition.

Atezolizumab Combined With Platinum and Maintenance Niraparib for Recurrent Ovarian Cancer With a Platinum-Free Interval >6 Months: ENGOT-OV41/GEICO 69-O/ANITA Phase III Trial.

PURPOSE: To evaluate atezolizumab combined with platinum-based chemotherapy (CT) followed by maintenance niraparib for late-relapsing recurrent ovarian cancer. METHODS: The multicenter placebo-controlled double-blind randomized phase III ENGOT-OV41/GEICO 69-O/ANITA trial (ClinicalTrials.gov identifier: NCT03598270) enrolled patients with measurable high-grade serous, endometrioid, or undifferentiated recurrent ovarian cancer who had received one or two previous CT lines (most recent including platinum) and had a treatment-free interval since last platinum (TFIp) of >6 months. Patients were stratified by investigator-selected carboplatin doublet, TFIp, BRCA status, and PD-L1 status in de novo biopsy and randomly assigned 1:1 to receive either atezolizumab or placebo throughout standard therapy comprising six cycles of a carboplatin doublet followed (in patients with response/stable disease) by maintenance niraparib until progression. The primary end point was investigator-assessed progression-free survival (PFS) per RECIST v1.1. RESULTS: Between November 2018 and January 2022, 417 patients were randomly assigned (15% BRCA-mutated, 36% PD-L1-positive, 66% TFIp >12 months, 11% previous poly [ADP-ribose] polymerase inhibitor after frontline CT, and 53% previous bevacizumab). Median follow-up was 28.6 months (95% CI, 26.6 to 30.5 months). Atezolizumab did not significantly improve PFS (hazard ratio, 0.89 [95% CI, 0.71 to 1.10]; P = .28). Median PFS was 11.2 months (95% CI, 10.1 to 12.1 months) with atezolizumab versus 10.1 months (95% CI, 9.2 to 11.2 months) with standard therapy. Subgroup analyses generally showed consistent results, including analyses by PD-L1 status. The objective response rate (ORR) was 45% (95% CI, 39 to 52) with atezolizumab and 43% (95% CI, 36 to 49) with standard therapy. The safety profile was as expected from previous experience of these drugs. CONCLUSION: Combining atezolizumab with CT and maintenance niraparib for late-relapsing recurrent ovarian cancer did not significantly improve PFS or the ORR.

Niraparib first-line maintenance therapy in patients with newly diagnosed advanced ovarian cancer: final overall survival results from the PRIMA/ENGOT-OV26/GOG-3012 trial.

BACKGROUND: The phase III PRIMA/ENGOT-OV26/GOG-3012 trial met its primary endpoint. Niraparib first-line maintenance significantly prolonged progression-free survival (PFS) among patients with newly diagnosed advanced ovarian cancer that responded to first-line platinum-based chemotherapy, regardless of homologous recombination deficiency (HRD) status. Final overall survival (OS) results are reported. PATIENTS AND METHODS: Patients were randomized 2:1 to niraparib or placebo, stratified by response to first-line treatment, receipt of neoadjuvant chemotherapy, and tumor HRD status. After reaching 60% target maturity, OS was evaluated via a stratified log-rank test using randomization stratification factors and summarized using Kaplan-Meier methodology. OS testing was hierarchical [overall population first, then the homologous recombination-deficient (HRd) population]. Other secondary outcomes and long-term safety were assessed; an updated, ad hoc analysis of investigator-assessed PFS was also conducted (cut-off date, 8 April 2024). RESULTS: The median follow-up was 73.9 months. In the overall population, the OS hazard ratio was 1.01 [95% confidence interval (CI) 0.84-1.23; P = 0.8834] for niraparib (n = 487) versus placebo (n = 246). In the HRd (n = 373) and homologous recombination-proficient (n = 249) populations, the OS hazard ratios were 0.95 (95% CI 0.70-1.29) and 0.93 (95% CI 0.69-1.26), respectively. Subsequent poly(ADP-ribose) polymerase inhibitor therapy was received by 11.7% and 15.8% of niraparib patients and 37.8% and 48.4% of placebo patients in the overall and HRd populations, respectively. The 5-year PFS rate numerically favored niraparib in the overall (niraparib, 22%; placebo, 12%) and HRd populations (niraparib, 35%; placebo, 16%). Myelodysplastic syndromes/acute myeloid leukemia incidence was <2.5% (niraparib, 2.3%; placebo, 1.6%). No new safety signals were observed. CONCLUSIONS: In patients with newly diagnosed advanced ovarian cancer at high risk of recurrence, there was no difference in OS between treatment arms. In the HRd population, patients alive at 5 years were two times as likely to be progression free with niraparib treatment than placebo. Long-term safety remained consistent with the established niraparib safety profile.

Effervescence tablets based on magnetic ionic liquids as simple microdevices for the in situ dispersive liquid-liquid microextraction of urinary biomarkers.

BACKGROUND: Magnetic ionic liquids (MILs) have been explored in dispersive liquid-liquid microextraction (DLLME). Their usage allows to substitute centrifugation and/or filtration steps by a quick magnetic separation. Besides, effervescence-assisted DLLME is one of the most known options to improve the dispersion of the extractant in the sample, while allowing to avoid the consumption of external energy during dispersion. Despite these interesting features, only one study incorporates MILs containing the tetrachloroferrate anion in effervescence tablets. These MILs are highly viscous and liquid at room temperature, thus compromising the stability of the tablets when used as extraction microdevices in effervescence-assisted DLLME, and only allowing their use in the conventional MIL-DLLME mode. RESULTS: A new class of effervescence tablets containing a Ni(II)-based MIL, that is solid at room temperature, is here proposed. This type of tablets permits their use, for first time, in the in situ DLLME mode, occurring through the transformation of a water-soluble MIL into a water-insoluble MIL microdroplet. This way, the tablet formulation included: the MIL, the metathesis reagent lithium bis[(trifluoromethyl)sulfonyl]imide, NaH2PO4 and K2CO3 as effervescence precursors salts, and Na2SO4 as salting-out and desiccating agent. The method is combined with high-performance liquid-chromatography and both fluorescence and ultraviolet detection, for the determination of monohydroxylated polycyclic aromatic hydrocarbons (OH-PAHs) and benzophenones (BPs), as biomarkers in urine. The method simply involved the addition of the effervescence tablet to the sample, thus taken place simultaneously the effervescence process and the metathesis reaction, without requiring any external energy consumption. The method presented limits of detection down to 10 ng L-1 for OH-PAHs and to 0.60 µg L-1 for BPs, inter-day relative standard deviations lower than 17 %, and average relative recoveries of 94 % in urine. The determined OH-PAHs contents in urine were between 0.40 and 16 µg L-1, and between 17.8 and 334 µg L-1 for BPs. SIGNIFICANCE: We have developed the first MIL-based effervescence tablets that are completely solid, thus improving the stability and robustness of these microdevices with respect to previously reported tablets involving MILs, while permitting to perform into the in situ DLLME mode (thus gaining in extraction efficiency). This approach including the MIL-based effervescence tablets constitutes an alternative on-site platform for the analysis of urine, as satisfactory precision, accuracy, and sensitivity are achieved despite not involving any external energy input within the analytical sample preparation setup. This method also constitutes the first application of MIL-based effervescence tablets for bioanalysis.

Expanding Horizons in Cardiac Transplant: Efficacy and Outcomes of Circulatory and Brain Death Donor Hearts in a Newly Implemented Cardiac Transplant Program with Limited Donor Accessibility and a Literature Review.

(1) Background: Cardiac donation after circulatory death (DCD) is an emerging paradigm in organ transplantation. However, this technique is recent and has only been implemented by highly experienced centers. This study compares the characteristics and outcomes of thoraco-abdominal normothermic regional perfusion (TANRP) and static cold-storage DCD and traditional donation after brain death (DBD) cardiac transplants (CT) in a newly stablished transplant program with restricted donor availability. (2) Method: We performed a retrospective, single-center study of all adult patients who underwent a CT between November 2019 and December 2023, with a follow-up conducted until August 2024. Data were retrieved from medical records. A review of the current literature on DCD CT was conducted to provide a broader context for our findings. The primary outcome was survival at 6 months after transplantation. (3) Results: During the study period, 76 adults (median age 56 years [IQR: 50-63 years]) underwent CT, and 12 (16%) were DCD donors. DCD donors had a similar age (46 vs. 47 years, p = 0.727), were mostly male (92%), and one patient had left ventricular dysfunction during the intraoperative DCD process. There were no significant differences in recipients' characteristics. Survival was similar in the DCD group compared to DBD at 6 months (100 vs. 94%) and 12 months post-CT survival (92% vs. 94%), p = 0.82. There was no primary graft dysfunction in the DCD group (9% in DBD, p = 0.581). The median total hospital stay was longer in the DCD group (46 vs. 21 days, p = 0.021). An increase of 150% in transplantation activity due to DCD was estimated. (4) Conclusions: In a new CT program that utilized older donors and included recipients with similar illnesses and comorbidities, comparable outcomes between DCD and DBD hearts were observed. DCD was rapidly incorporated into the transplant activity, demonstrating an expedited learning curve and significantly increasing the availability of donor hearts.

Physician-reported patient involvement and treatment decisions in first-line ovarian cancer in the USA and Europe.

OBJECTIVES: Real-world data evaluating how approvals of novel treatment regimens for ovarian cancer have impacted the treatment paradigm, including first-line maintenance, are lacking. This analysis aimed to describe treatment patterns for advanced epithelial ovarian cancer in Europe and the USA in the first-line maintenance setting. Patient characteristics, biomarker testing rates, and drivers of treatment choice were also evaluated. METHODS: A retrospective chart review study of electronic medical records in Europe and the USA was conducted for patients diagnosed with epithelial ovarian cancer (June 1, 2017-May 31, 2020), in line with Healthcare Market Research guidelines. Eligible physicians extracted data from electronic medical records by completing standardized patient record forms, including questions on patient involvement in treatment decisions. Patients with advanced (stage III/IV) disease were stratified by country and diagnosis date to provide information on treatment patterns. RESULTS: Patient record forms for 7072 patients with epithelial ovarian cancer were completed by 416 physicians; 5386 patients had stage III/IV ovarian cancer. Over time, the percentage of patients who were tested for BRCA mutations or homologous recombination deficiency increased. Patient preference was documented as a reason for treatment selection in approximately one-sixth of cases in the first-line adjuvant and first-line maintenance settings. The use of first-line maintenance poly(ADP-ribose) polymerase inhibitor monotherapy increased over time, while the use of vascular endothelial growth factor inhibitor monotherapy decreased. CONCLUSIONS: This real-world study showed that treatment patterns for advanced epithelial ovarian cancer varied by country. Rates of physician-reported patient involvement in treatment decisions in the first-line adjuvant and maintenance treatment settings for ovarian cancer were low, highlighting an unmet need for initiatives to improve patient involvement in shared decision-making regarding maintenance therapy selection.

SENECA study: staging endometrial cancer based on molecular classification.

OBJECTIVE: Management of endometrial cancer is advancing, with accurate staging crucial for guiding treatment decisions. Understanding sentinel lymph node (SLN) involvement rates across molecular subgroups is essential. To evaluate SLN involvement in early-stage (International Federation of Gynecology and Obstetrics 2009 I-II) endometrial cancer, considering molecular subtypes and new European Society of Gynaecological Oncology (ESGO) risk classification. METHODS: The SENECA study retrospectively reviewed data from 2139 women with stage I-II endometrial cancer across 66 centers in 16 countries. Patients underwent surgery with SLN assessment following ESGO guidelines between January 2021 and December 2022. Molecular analysis was performed on pre-operative biopsies or hysterectomy specimens. RESULTS: Among the 2139 patients, the molecular subgroups were as follows: 272 (12.7%) p53 abnormal (p53abn, 1191 (55.7%) non-specific molecular profile (NSMP), 581 (27.2%) mismatch repair deficient (MMRd), 95 (4.4%) POLE mutated (POLE-mut). Tracer diffusion was detected in, at least one side, in 97.2% of the cases; with a bilateral diffusion observed in 82.7% of the cases. By ultrastaging (90.7% of the cases) or one-step nucleic acid amplification (198 (9.3%) of the cases), 205 patients were identified with affected sentinel lymph nodes, representing 9.6% of the sample. Of these, 139 (67.8%) had low-volume metastases (including micrometastases, 42.9%; and isolated tumor cells, 24.9%) while 66 (32.2%) had macrometastases. Significant differences in SLN involvement were observed between molecular subtypes, with p53abn and MMRd groups having the highest rates (12.50% and 12.40%, respectively) compared with NSMP (7.80%) and POLE-mut (6.30%), (p=0.004); (p53abn, OR=1.69 (95% CI 1.11 to 2.56), p=0.014; MMRd, OR=1.67 (95% CI 1.21 to 2.31), p=0.002). Differences were also noted among ESGO risk groups (2.84% for low-risk patients, 6.62% for intermediate-risk patients, 21.63% for high-intermediate risk patients, and 22.51% for high-risk patients; p<0.001). CONCLUSIONS: Our study reveals significant differences in SLN involvement among patients with early-stage endometrial cancer based on molecular subtypes. This underscores the importance of considering molecular characteristics for accurate staging and optimal management decisions.

Effects of Dance-Based Aerobic Training on Mental Health and Quality of Life in Older Adults with Mild Cognitive Impairment.

(1) Background: Mild cognitive impairment in older adults is a condition characterized by a decrease in mental abilities that affects their quality of life. The aim of this study is to evaluate the effects of an aerobic training program based on dance on depression, sleep quality, and quality of life in older adults with mild cognitive impairment. (2) Methods: This study employed a randomized controlled trial design with a total of 92 older adults with cognitive impairment, randomly assigned to an experimental group (n = 47) undergoing dance-based aerobic training and a control group (n = 45) who did not receive any intervention. Depression was assessed using the Yesavage Geriatric Depression Scale, sleep quality through the Pittsburgh Sleep Quality Index (PSQI), and quality of life through the SF-36 questionnaire. (3) Results: Statistically significant improvements were observed in depression (t(46) = 4.783, p = 0.000) and in the PSQI domains: subjective sleep quality (t(46) = 3.333, p = 0.002, and Cohen's d = 0.35), sleep duration (t(46) = 5.511, p = 0.000, and Cohen's d = 0.73) and PSQI total score (t(46) = 2.116, p = 0.040, and Cohen's d = 0.20). Regarding quality of life, improvements were observed in all domains of the questionnaire: the general health (t(46) = -9.374, p = 0.000, and Cohen's d = 0.03), physical function (t(46) = -9.374, p = 0.000, and Cohen's d = 0.03), the physical role (t(46) = -5.954, p = 0.000, and Cohen's d = 1.06), the emotional role (t(46) = -6.200, p = 0.000, and Cohen's d = 0.80), social function (t(46) = -5.585, p = 0.000, and Cohen's d = 0.53), physical pain, (t(46) = -9.224, p = 0.000, and Cohen's d = 1.04), vitality (t(46) = 2.289, p = 0.027, and Cohen's d = 1.27), mental health, (t(46) = -7.985, p = 0.000, and Cohen's d = 1.33), the physical summary component, (t(46) = -13.532, p = 0.000, and Cohen's d = 1.81), and in the mental summary component (t(46) = -10.6 81, p = 0.000, and Cohen's d = 0.06); (4) Conclusions: The results of the present study showed that they suggest that a dance-based aerobic training program improves mental health and quality of life in older people with mild cognitive impairment, providing a non-pharmacological approach to improve general well-being in this population.

Management of Peri-implant Mucosal Dehiscences: A Scoping Review.

Several treatment-oriented classifications for the management of peri-implant marginal mucosal defects (PMMDs) have been published to date. While each classification provides valuable insights into key diagnostic and therapeutic aspects, there is a marked heterogeneity regarding the recommended clinical guidelines to achieve success in specific scenarios. The purpose of this review was to critically analyze and organize the similarities and differences enclosed in the available classifications linked with treatment recommendations on the management of PMMDs at single implant non-molar sites with the purpose of providing an overview of recommended interdisciplinary treatment options to facilitate clinical decision-making processes.

Associations between Non-Essential Trace Elements in Women's Biofluids and IVF Outcomes in Euploid Single-Embryo Transfer Cycles.

Previous studies have found inconsistent associations between heavy metals and metalloids (cadmium, lead, mercury, and arsenic), and reproductive outcomes. The biofluid concentrations of ten non-essential trace elements (Hg, Pb, As, Ba, Sr, Rb, Cs, Sn, Ni, and Co) were evaluated in 51 Spanish women undergoing ICSI, PGT-A, and SET/FET. Nine out of ten non-essential elements were detectable in follicular fluid, whole blood, and urine collected the day of vaginal oocyte retrieval (VOR) and the day of embryo transfer and then analyzed by ICP-MS or Tricell DMA-80 for mercury. Elevated mercury and strontium concentrations in follicular fluid were associated with poor ovarian response and preimplantation outcomes. Worst preimplantation outcomes were also identified in women with elevated whole-blood strontium or mercury, urinary arsenic, barium, and tin the day of VOR. High concentrations of urinary rubidium on VOR day were linked with enhanced fertilization and blastocyst development. Excessive titanium in whole blood was associated with lower odds of implantation, clinical pregnancy, and achieving a live birth in a given IVF cycle. Excessive urinary arsenic on the day of embryo transfer was associated with lower odds of live birth. Although these preliminary results need to be confirmed in larger populations, distinguishing organic and inorganic element forms, our findings show that some non-essential elements have a detrimental impact on human IVF outcomes.

The differential illusion memory for high-associated abstract concepts (DIM-HA) effect.

A vast body of evidence has shown that concrete concepts are processed faster and more accurately than abstract concepts in a variety of cognitive tasks. This phenomenon is widely known as the concreteness effect, and explanations for its occurrence seem to reflect differences in processing and organization for both types of representations. While there is considerable evidence to support this concreteness effect, the nature of these differences is still controversial. In developing an explanation, we have proposed a relatively different approach from a false memory perspective using the Deese-Roediger-McDermott paradigm. To explore the implications of the association in creating false memories, we explore behavioral and electrophysiologically the false memory effect, where targets were manipulated according to their association strength and their concreteness. Results showed that false recognition rates differed significantly between concrete and abstract critical words when they were associated strongly with their respective lists, which led to a higher proportion of abstract false alarms both in behavioral and electrophysiological experiments. The principal outcome, which was called the DIM-HA effect, was discussed in terms of theories of associative activation and qualitatively different representation.

The effect of years of schooling and age on CERAD-MX performance in Mexican preclinical carriers of the APP V717I mutation: Randomized data simulation.

INTRODUCTION: We aimed to determine the effect of years of schooling (YoS) and age on the Mexican adaptation of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD-MX) scores in preclinical carriers group (PCG) and non-carriers group (NCG) of the APP V717I mutation. METHODS: We included 39 first-degree Mexican relatives of APP V717I carriers (PCG = 15; NCG = 24). We report eight CERAD-MX tasks: Mini-Mental State Examination (MMSE), Word List Learning (WLL), Delayed Recall (WLD) and Recognition (WLR), Constructional Praxis Copy (CPC) and Recall (CPR), Semantic Verbal Fluency (SVF), and Verbal Boston Naming (VBN), comparing both groups' performance and simulating new samples' random vectors by inverse transform sampling. RESULTS: PCG and NCG performed similarly on CERAD-MX. In both groups, YoS and age influence all z scores. A positive age effect resulted for PCG on CPC and SVF; for the NCG on MMSE, SVF, and VBN. DISCUSSION: All tasks are influenced by YoS. Higher YoS/younger age or YoS/older age interactions affected different tasks, suggesting that YoS confounds outcomes. Highlights: Years of schooling (YoS) and age affect the Mexican adaptation of the Consortium to Establish a Registry for Alzheimer's Disease scores of APP V717I preclinical carriers.Preclinical carriers underperformed non-carriers on Constructional Praxis Recall.Fewer YoS emerges as a confounding variable when detecting cognitive failures.Younger participants in both groups overperformed the older ones in the Memory tasks.Randomized data simulation increases statistical power when analyzing rare diseases.

Nucleocytoplasmic transport senses mechanical forces independently of cell density in cell monolayers.

Cells sense and respond to mechanical forces through mechanotransduction, which regulates processes in health and disease. In single adhesive cells, mechanotransduction involves the transmission of force from the extracellular matrix to the cell nucleus, where it affects nucleocytoplasmic transport (NCT) and the subsequent nuclear localization of transcriptional regulators, such as YAP (also known as YAP1). However, if and how NCT is mechanosensitive in multicellular systems is unclear. Here, we characterize and use a fluorescent sensor of nucleocytoplasmic transport (Sencyt) and demonstrate that NCT responds to mechanical forces but not cell density in cell monolayers. Using monolayers of both epithelial and mesenchymal phenotype, we show that NCT is altered in response both to osmotic shocks and to the inhibition of cell contractility. Furthermore, NCT correlates with the degree of nuclear deformation measured through nuclear solidity, a shape parameter related to nuclear envelope tension. In contrast, YAP is sensitive to cell density, showing that the YAP response to cell-cell contacts is not via a mere mechanical effect of NCT. Our results demonstrate the generality of the mechanical regulation of NCT.

Ocular hypertension after EyeCee One preload lens implantation: a retrospective cohort study.

Objective: In 2022, several cases of ocular hypertension (OHT) related to EyeCee One preloaded IOLs were reported. The aim of this study was to determine the presurgical and surgical variables associated with this response. Methods and analysis: An analysis was conducted on patients who underwent isolated cataract surgery between September 2022 and December 2022 at the Hospital Universitario del Henares. The influence of potential factors was studied using the Kruskal-Wallis test and multiple regression analysis. Results: A total of 353 cataract surgeries were included in the study. No significant differences between the different IOLs were found related to a change in the IOP on the first postoperative day (p = 0.395), but the change in the IOP after 1 month was higher in the EyeCee One group (p = 0.016). Approximately 6.1% of the patients who received EyeCee One had an IOP increase greater than 10 mmHg, compared to only 0.8% of the patients who received other IOLs. The odds ratio (OR) of experiencing an IOP increase greater than 10 mmHg in the EyeCee One group at the 1-month visit was 7.99 (1.52-41.99). The multiple regression analysis showed that receiving the EyeCee One lens was associated with a 2-mmHg increase in IOP. A previous history of glaucoma or OHT was not associated with greater IOP. Two patients in the EyeCee One group developed severe visual loss. Conclusion: Patients who received the EyeCee One IOL experienced significant increases in IOP at the 1-month visit. A small number of patients might suffer visual loss secondary to the rise in IOP.

Niraparib Population Pharmacokinetics and Exposure-Response Relationships in Patients With Newly Diagnosed Advanced Ovarian Cancer.

PURPOSE: Niraparib is a poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitor approved for the maintenance treatment of advanced ovarian cancer (OC). Niraparib was originally approved in recurrent OC at a fixed starting dose (FSD) of 300 mg once daily (QD). This analysis characterized the population pharmacokinetics (PK) of niraparib and evaluated the relationships between exposure, efficacy, and safety to support clinical use of an individualized dosing strategy, in which the starting dose of niraparib was adjusted based on patient characteristics to improve the benefit-risk profile. METHODS: A population PK model was developed by pooling data from four niraparib clinical trials (PN001 [n = 104], QUADRA [n = 455], NOVA [n = 403], and PRIMA [n = 480]) in patients with solid tumors, including OC. Exposure-response analyses were conducted to explore the relationships of niraparib exposure with progression-free survival (PFS) and adverse events in the PRIMA study. A multivariate logistic regression model was also developed to estimate the probability of grade ≥3 thrombocytopenia, using data from patients enrolled in PRIMA and NOVA. The impact of an individualized starting dose (ISD) regimen (200 mg QD in patients with body weight [BW] <77 kg or platelet count [PLT] <150,000/µL, or 300 mg QD in patients with BW ≥77 kg and PLT ≥150,000/µL) on systemic exposure, efficacy, and safety was assessed. FINDINGS: Niraparib disposition was best described by a 3-compartment model with linear elimination. Key covariates included baseline creatinine clearance, BW, albumin, and age, all of which had minor effects on niraparib exposure. Comparable model-predicted exposure up to the time of disease progression/death or censoring in the 300-mg FSD and 200-/300-mg ISD groups was consistent with the lower rate of dose reduction in the ISD groups. No consistent niraparib exposure-response relationship was observed for efficacy in all PRIMA patients (first-line OC), and no statistically significant difference was seen in PFS curves for patients receiving a niraparib dose of 200 mg versus 300 mg. In the multivariate regression model, performed using combined data from PRIMA and NOVA, higher niraparib exposure (area under the concentration-time curve at steady-state [AUCss]), lower BW, and lower PLT were associated with an increased risk of grade ≥3 thrombocytopenia. IMPLICATIONS: Population PK and exposure-response analyses support use of an ISD to improve the safety profile of niraparib, including reducing the rate of grade ≥3 thrombocytopenia, without compromising efficacy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT01847274 (NOVA), NCT00749502 (PN001), NCT02655016 (PRIMA), NCT02354586 (QUADRA), www. CLINICALTRIALS: gov.

Patterns of initial ovarian cancer recurrence on niraparib maintenance monotherapy in patients with no baseline evidence of disease after first-line chemotherapy: An ad hoc subgroup analysis of PRIMA/ENGOT-OV26/GOG-3012.

OBJECTIVES: Patterns of disease recurrence on poly(ADP-ribose) polymerase inhibitor maintenance therapy are unclear and may affect subsequent treatment. This ad hoc subgroup analysis of the phase 3 PRIMA/ENGOT-OV26/GOG-3012 study evaluated patterns of initial recurrence in patients with advanced ovarian cancer (AOC). METHODS: PRIMA included participants at high risk for disease progression. This ad hoc analysis only evaluated participants randomized to niraparib maintenance without evidence of disease at baseline. The number and site(s) of initial recurrent lesions at investigator-assessed progressive disease (PD) were evaluated. RESULTS: Of the 314 niraparib-treated patients analyzed, 190 developed ≥1 new lesion (median number of new lesions, 1.0; interquartile range, 1-2). In total, 93.2% (177/190) of patients developed 1-3 lesions at first disease progression. The most common sites of recurrence were the peritoneum (30.0% [57/190]), lymph nodes (26.3% [50/190]), and liver (20.5% [39/190]). Similar results were observed when patients with PD were stratified by biomarker status, disease stage at diagnosis, and type of debulking surgery. Patients with homologous recombination-proficient tumors, stage III disease, or a history of primary debulking developed a median of 2.0 new lesions at first progression; patients with homologous recombination-deficient tumors, stage IV disease, or a history of interval debulking developed a median of 1.0 new lesion. CONCLUSIONS: Many patients with AOC without lesions at first-line maintenance treatment initiation develop oligometastatic disease at first recurrence. Prospective evaluation is required to determine whether these patients have improved outcomes when local therapies are combined with continuous, systemic, targeted maintenance therapy.