Small Subgroups Research Articles

Nest raiding by bonnet macaques (Macaca radiata) and the response of nest guarding birds in a suburban habitat.

In many primate species, nest raiding is a form of opportunistic foraging behavior designed to acquire protein-rich eggs and nestlings. In urban environments, this is a significant cause of nest failure in birds. Here, we describe nest raiding and egg predation in bonnet macaques (Macaca radiata) inhabiting a suburban area of Salem, Tamil Nadu, India. During nest raiding, large-billed crows (Corvus macrorhynchos) and house crows (Corvus splendens), actively defended their nest from the macaques. When several macaque foragers jointly raided the nest, they were successful in obtaining and consuming the eggs. In contrast, when a solitary macaque attempted to raid the nest, it was unsuccessful. Bird size appeared to play an important role in nest defense. Small birds, such as the scaly breasted munia (Lonchura punctulata) and the purple sunbird (Cinnyris asiaticus) were not able to protect their nests from lone bonnet macaques. These observations indicate that in urban landscapes, bonnet macaques are egg predators of many bird species. When macaques coordinate their actions and forage in small subgroups, they were more successful in preying on the eggs of larger-bodied bird species.

Effect of iberdomide on cutaneous manifestations in systemic lupus erythematosus: a randomized phase 2 clinical trial

Iberdomide, a cereblon modulator, promotes degradation of transcription factors Ikaros and Aiolos. Evaluate iberdomide efficacy and safety in cutaneous lupus erythematosus (CLE) in a phase 2 study. Patients were randomized (2:2:1:2) to iberdomide 0.45 (n=81), 0.30 (n=82), or 0.15 mg (n=42) or placebo (n=83) daily while continuing background lupus medications. The mean (SD) baseline Cutaneous Lupus Area and Severity Index Activity (CLASI-A) score was 6.9 (7.0); 28% of patients had a score ≥8; 56% had acute CLE, 29% chronic CLE, and 16% subacute CLE. Mean CLASI-A improvement in patients with baseline score ≥8 was 39.7% for iberdomide 0.45 mg versus 20.1% for placebo at week 4 (P=0.032), with continued improvement through week 24 (66.7% vs 54.2%; P=0.295). Proportions of patients achieving ≥50% CLASI-A reduction from baseline at week 24 were significantly greater for iberdomide 0.45 mg versus placebo for patients with subacute (91.7% vs 52.9%, P=0.035) and chronic (62.1% vs 27.8%; P=0.029) CLE but not for the overall population (55.6% vs 44.6%) or patients with baseline CLASI-A ≥8 (66.7% vs 50.0%). Small patient subgroups of CLE subtypes. Iberdomide showed beneficial effects when added to background lupus medications in patients with subacute and chronic CLE.

Evaluating and Reducing Subgroup Disparity in AI Models: An Analysis of Pediatric COVID-19 Test Outcomes.

Artificial Intelligence (AI) fairness in healthcare settings has attracted significant attention due to the concerns to propagate existing health disparities. Despite ongoing research, the frequency and extent of subgroup fairness have not been sufficiently studied. In this study, we extracted a nationally representative pediatric dataset (ages 0-17, n=9,935) from the US National Health Interview Survey (NHIS) concerning COVID-19 test outcomes. For subgroup disparity assessment, we trained 50 models using five machine learning algorithms. We assessed the models' area under the curve (AUC) on 12 small (<15% of the total n) subgroups defined using social economic factors versus the on the overall population. Our results show that subgroup disparities were prevalent (50.7%) in the models. Subgroup AUCs were generally lower, with a mean difference of 0.01, ranging from -0.29 to +0.41. Notably, the disparities were not always statistically significant, with four out of 12 subgroups having statistically significant disparities across models. Additionally, we explored the efficacy of synthetic data in mitigating identified disparities. The introduction of synthetic data enhanced subgroup disparity in 57.7% of the models. The mean AUC disparities for models with synthetic data decreased on average by 0.03 via resampling and 0.04 via generative adverbial network methods.

An optimal trauma-informed pathway for PTSD, complex PTSD and other mental health and psychosocial impacts of trauma in prisons: an expert consensus statement

ABSTRACT People in prisons have high levels of trauma exposure throughout their lives. Presentations are often complex, with a high prevalence of PTSD and CPTSD and other mental health comorbidities. Prisons themselves can be stressful and traumatising environments. There are challenges in the delivery of effective treatments for PTSD and CPTSD. There is a need for the development of effective clinical pathways for these conditions that are embedded within trauma-informed organisational approaches. Responding to this need, this report is the result of a multidisciplinary expert consensus meeting and review of the research literature on PTSD, CPTSD, associated comorbidities and optimal approaches to trauma-informed practice. The group consisted of 24 expert representatives from psychology, psychiatry, healthcare, academia, social care and Welsh Government. The meeting commenced with presentations on various aspects of the clinical pathway for PTSD and complex PTSD in prisons, and of applications of trauma-informed practice within prisons. Small sub-groups then provided practical recommendations and solutions relevant to their assigned topic. Findings were presented to all meeting attendees for another round of discussion and debate, until consensus was reached. The resulting recommendations provide guidance to improve identification, treatment and support for people living in prison who have experienced trauma.

The sample locator: A federated search tool for biosamples and associated data in Europe using HL7 FHIR

BackgroundThis study outlines the development of a highly interoperable federated IT infrastructure for academic biobanks located at the major university hospital sites across Germany. High-quality biosamples linked to clinical data, stored in biobanks are essential for biomedical research. We aimed to facilitate the findability of these biosamples and their associated data. Networks of biobanks provide access to even larger pools of samples and data even from rare diseases and small disease subgroups. The German Biobank Alliance (GBA) established in 2017 under the umbrella of the German Biobank Node (GBN), has taken on the mission of a federated data discovery service to make biosamples and associated data available to researchers across Germany and Europe. MethodsIn this context, we identified the requirements of researchers seeking human biosamples from biobanks and the needs of biobanks for data sovereignty over their samples and data in conjunction with the sample donor's consent. Based on this, we developed a highly interoperable federated IT infrastructure using standards such as Fast Healthcare Interoperability Resources (HL7 FHIR) and Clinical Quality Language (CQL). ResultsThe infrastructure comprises two major components enabling federated real-time access to biosample metadata, allowing privacy-compliant queries and subsequent project requests. It has been in use since 2019, connecting 16 German academic biobanks, with additional European biobanks joining. In production since 2019 it has run 4941 queries over the span of one year on more than 900,000 biosamples collected from more than 170,000 donors. ConclusionThis infrastructure enhances the visibility and accessibility of biosamples for research, addressing the growing demand for human biosamples and associated data in research. It also underscores the need for improvements in processes beyond IT infrastructure, aiming to advance biomedical research and similar infrastructure development in other fields.

O-247 Validation of an AI (Artificial intelligence) model assessing oocyte quality in a single donor program with frozen-thawed oocytes for blastocyst prediction

Abstract Study question Can an AI model predict blastocyst development in a specific subset population of frozen-thawed oocytes in a single donor program? Summary answer An AI oocyte quality score is predictive of blastocyst formation of frozen-thawed oocytes using post-ICSI images. What is known already The ability to score oocytes based on quality is of paramount importance. A methodology to categorize oocyte quality continues to elude IVF professionals. CHLOE OQ™ is an AI oocyte-quality (OQ) score designed to analyse a single oocyte Timelapse image and provide an OQ score. Responsible use of AI needs the validation of models across different clinical scenarios. The increasing use of frozen-thawed oocytes in IVF has necessitated to objectively score the developmental potential of this oocytes. The objective of this study was to determine if the morphological characteristics of frozen-thawed oocyte images are predictive of blastocyst formation. Study design, size, duration Retrospective cohort study using time-lapse videos of 1318 post-ICSI frozen-thawed donated oocytes between January 2021 and August 2023, with known blastulation outcomes from a single private clinic. Participants/materials, setting, methods Oocytes were evaluated using OQ Score and placed into categories according to their OQ score. Group A: &amp;gt;0.6, Group B: 0.3-0.59, Group C: 0.001-0.29 and Group D: 0. The correlation between OQ score, embryo quality (EQ) score and blastocyst development was measured with binary logistic regression (AUC) and a 2-sample t-test. Chi-square was performed to determine if there were significant differences in blastocyst development rates across these distinct oocyte quality groups. Main results and the role of chance Oocytes that underwent blastulation exhibited a significantly higher OQ Score (7.0 ± 2.3) compared to those that did not blastulate (5.3 ± 3.0, p &amp;lt; 0.001). The predictive capacity for blastocyst formation was observed for OQ score (AUC= 0.67) and EQ Score (AUC= 0.93), with a baseline blastulation of 66% (n = 1318, p &amp;lt; 0.001). Of interest, as early as Day 3 a Blastocyst prediction score was highly predictive of blastulation (AUC= 0.92, p &amp;lt; 0.001). When assessing a subset of transferred oocytes, OQ Score had a higher predictive ability (AUC=0.71, n = 163, p &amp;lt; 0.001).Oocyte quality scores within OQ score groups showed a direct association with blastocyst formation rate: [Group A 74% (656/878), Group B 56% (130/231), Group C 43% (70/164), Group D 13% (3/23), p &amp;lt; 0.05]. The highest-scoring group demonstrated a five-fold increase in blastulation rate compared to the lowest-scoring group (p &amp;lt; 0.001). Furthermore, the highest-scoring group resulted in the highest proportion of good-quality embryos compared to the lowest-scoring group [78% (456/582) vs 0.19% (1/582), p &amp;lt; 0.001]. Limitations, reasons for caution Retrospective assessment of a single clinic. Results reflect the use of frozen-thawed donated oocytes. Therefore, the proportion of data within the four oocyte quality groups is not equally distributed and is biased towards high quality oocytes. This may impact the predictive ability within the smaller subgroups. Wider implications of the findings Developing an objective methodology to categorize oocyte quality post-retrieval is crucial. It is important to validate AI models in different clinical scenarios, for example in oocyte donor programs using frozen-thawed oocytes. AI is a tool that can be used to predict blastocyst development rates within a frozen donor oocyte program. Trial registration number not applicable

Diversity, dissent, and fragmentation in the #MeToo movement: the role of collective and individual dimensions.

In this research, we examine how intragroup fragmentation, which is the division of a group into smaller subgroups, interacts with different forms of action against gender inequality. We focused on two types of action: actions that promote social change and actions that encourage retribution. We investigated these processes within the #MeToo social movement using data collected in Australia (N = 363) and Romania (N = 135). In both samples, we measured antecedents of 'group consciousness' (previous experience with discrimination, empathic concern, and perspective taking) and its indicators (social identification, perceived group efficacy beliefs, and group emotions such as anger and contempt). As indicators of intragroup fragmentation, we measured endorsement of different categories of group behaviors such as pro-social change action versus pro-retribution action. To assess the predictive power of motivations for joining the movement (antecedents of group consciousness) and of group consciousness for either pro-social or retributive actions, we tested several structural equation models (SEMs). Our results indicate that the motivations for joining such social movements were more complex than anticipated, with perspective-taking emerging as a significant differentiator. Our analyses further show that different dimensions of group consciousness could predict support for either pro-social or retributive actions. These findings highlight the complexity of the intragroup processes in newly emerging, modern social movements such as #MeToo. Our findings have implications for the study of membership dynamics in social movements and suggest that strategies to mobilise support should be tailored to these complexities. Overall, this research contributes to the current understanding of intragroup dynamics in contemporary social movements, thereby providing insights that could inform both grassroots mobilisation strategies and policy interventions aiming to increase gender equality.

Adjuvant mFOLFIRINOX (mFFX) for resected pancreatic cancer (PC): Long term clinical and genomic outcomes.

4170 Background: Adjuvant chemotherapy with mFFX is the standard for pts with ECOG 0-1 (1) after pancreatectomy for resectable PC. Herein, we report long-term survival data on an expanded cohort and present comprehensive genomic analyses. Methods: Pts with resected PC who received &gt;1 dose of adjuvant mFFX identified from institutional databases. Primary endpoints: Recurrence Free Survival (mRFS) and Overall Survival (mOS) calculated from start of treatment until recurrence or death. Key secondary endpoints: clinical factors, genomic descriptors ( KRAS status, whole genome doubling (WGD), and homologous recombination deficiency (HRD)) associated with outcome. Kaplan-Meier method used to estimate RFS and OS. Univariate Cox proportional hazards model correlated clinico-genomic characteristics with RFS and OS. Results: N=147 identified between 01/2015-01/2022. Median age: 67 years; N= 22 (15%) &gt; 75 years. Several prognostically unfavorable groups; N=52 (36%) stage III disease/ N2 nodal status; N=115 (78%) lymphovascular invasion (LVI); N=133 (90%) perineural invasion (PNI). Median time from surgery to start mFFX: 1.78m (IQR; 1.45, 2.12). Median CA 19-9 at start mFFX: 21 (range 0-1,124). N=124 (84%) pts completed 12 doses mFFX (+/- 12 doses oxaliplatin). N=98 pts (67%) stopped oxaliplatin early for neuropathy. With the median follow up 35.1m (range 5.1, 73.0), mRFS 27m (95% CI 20, 39) and OS not reached (NR). For &gt;75 cohort, mRFS 12m (95% CI 9.6, NR) and mOS 30m (95% CI 19, NR). mFFX started &lt;8 weeks from resection associated with improved RFS (HR 0.62; 95% CI 0.41, 0.96; p= 0.033) and OS (HR 0.53; 95% CI 0.3, 0.94; p= 0.030). T3 tumors associated with worse RFS (HR 2.82, 95% CI 1.28, 6.20; p=0.010) and OS (HR 5.10, 95% CI 1.45, 18; p=0.011). Genomic variables summarized (Table). KRASmutation (+), WGD (+), and higher KRAS CNV trended to shorter RFS and OS; statistical significance limited by small subgroups. HRD status did not confer differences in OS. Conclusions: Adjuvant mFFX is an effective therapy and results in long-term OS outcome in resected PC in a non-trial setting, including for pts &gt;75 years. Early initiation of adjuvant mFFX may optimize outcome. Trends observed for improved outcome in select genomic subsets, which require large-scale validation. 1. Conroy, JAMA Onc, 2022. [Table: see text]

Long-term survival outcomes of patients (pts) with relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) treated with brexucabtagene autoleucel (brexu-cel) in ZUMA-3.

6531 Background: Brexu-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for pts ≥18 y with R/R B-ALL in the US (≥26 y in the EU). In the 3-y follow-up of ZUMA-3, median overall survival (OS) was 25.6 mo (N=78). Survival benefit was seen regardless of age, prior treatment, or subsequent allogeneic stem cell transplant (sub alloSCT) status (Shah et al. ASCO 2023. #7023). Here we report 4-y survival outcomes for ZUMA-3. Methods: Eligible pts (≥18 y) had R/R B-ALL and received brexu-cel (1×106 CAR T cells/kg) after leukapheresis and lymphodepleting chemotherapy. The primary endpoint was overall complete remission (CR)/CR with incomplete hematologic recovery (CRi) rate per independent review with OS as a key secondary endpoint. Descriptive statistics are reported for post hoc exploratory subgroup analyses. Results: As of July 23, 2023, median follow-up time in Phase 1 and 2 pts who received the pivotal dose of brexu-cel (N=78) was 53.6 mo (range 44.7-82.3). Median OS (95% CI) was 25.6 mo (16.2-60.4) in all treated pts and 47.0 mo (23.2-not estimable [NE]) in pts with CR/CRi (n=57). In pts &lt;26 y (n=15), median OS (95% CI) was 23.2 mo (9.0-NE) and was 26.0 mo (15.9-NE) in pts ≥26 y (n=63). Median OS (95% CI) in pts with 1 prior therapy (n=15) was 60.4 mo (7.6-NE) and was 25.4 mo (15.9-47.0) in pts with ≥2 prior therapies (n=63). Medians for OS (95% CI) in pts with (n=38) and without (n=40) prior blinatumomab (blina) were 15.9 (8.3-26.0) and 60.4 mo (18.6-NE), respectively. Median OS (95% CI) was 36.3 mo (10.2-NE) in responders who went on to sub alloSCT (n=14) and 60.4 mo (23.2-NE) in those who did not (n=43). The 48-mo OS rate was 40% (95% CI, 28-52) in all pts but appeared lower in pts with prior blina (24%; Table). No new adverse events or deaths occurred since the prior analysis. Grade ≥3 infection rates since the start of study appeared higher in pts &lt;26 y and in pts with prior blina (Table). Rates of non-relapse mortality (NRM) and relapse-related mortality (95% CI) at 48 mo were 25% (15-37) and 34% (24-45; N=78), respectively. Of note, 6/17 NRM events (35%) occurred in pts with sub alloSCT. Conclusions: After &gt;4 y follow-up, pts in ZUMA-3 continued to experience OS benefit regardless of age, prior therapy, or sub alloSCT status, though pts with prior blina had a numerically lower 48-mo OS rate. Small subgroups and unbalanced pt characteristics limit interpretation of these results. No new safety signals were observed. Further studies are needed to fully assess the impact of age, prior therapies, and sub alloSCT on outcomes after brexu-cel. Clinical trial information: NCT02614066 . [Table: see text]

Navigating High-Risk and Ultrahigh-Risk Multiple Myeloma: Challenges and Emerging Strategies.

Despite significant improvement in the outcomes of patients with newly diagnosed multiple myeloma (NDMM) with novel therapies, there is still an underserved high-risk (HR) population that experiences early disease progression and death. With the median survival crossing 10 years, we defined ultrahigh-risk (uHR)MM as MM leading to death within 24-36 months of diagnosis and HRMM as MM leading to death within 36-60 months. Several features have emerged as markers of uHRMM: the co-occurrence of two or more high-risk cytogenetic abnormalities, extramedullary disease, plasma cell leukemia and a high-risk gene expression profiling signature. The heterogeneous risk definition across trials, the few trials available designed for HR patients, and the small HR subgroups in all-comers trials make it difficult to generate recommendations with high levels of evidence. Nevertheless, regardless of treatment administered, several studies consistently showed that achieving and maintaining measurable residual disease negativity is now considered the main factor able to mitigate the adverse prognosis related to baseline features. For fit patients with HR transplant-eligible (TE) NDMM, quadruplet induction/consolidation treatment with anti-CD38 monoclonal antibodies, immunomodulatory agents, proteasome inhibitors and dexamethasone, and autologous stem-cell transplant and maintenance with, if available, at least a doublet combination could be considered the option of choice. For non-TE NDMM, considering the recent data generated and carefully reviewing those upcoming, quadruplet treatment consisting of anti-CD38 monoclonal antibodies, immunomodulatory agents, proteasome inhibitors, and dexamethasone should also be considered. Future trials integrating BCMA-directed novel generation immunotherapies hold great potential for further advancing the treatment landscape in all NDMM patients with HR disease.

First-line treatment patterns among patients with metastatic pancreatic ductal adenocarcinoma in the real-world setting.

e16320 Background: Treatment options for patients (pts) with metastatic pancreatic ductal adenocarcinoma (mPDAC) have historically been limited. FOLFIRINOX (FFX) and gemcitabine + nab-paclitaxel (GnP) are both recommended first line (1L) treatments that have shown efficacy vs. gemcitabine monotherapy in clinical trials. More recently, small subgroups of pts have benefitted from regimens that include irinotecan liposome injection, targeted therapies, and checkpoint inhibitors (CPIs). To better understand treatment patterns in current practice, we examined the distribution of 1L therapies in a RW cohort of mPDAC pts diagnosed between 2015 and 2022. Methods: This retrospective observational study utilized the Ontada Clinical Data View: Pancreatic Cancer database. Adult pts diagnosed with mPDAC between November 2018 and November 2022 who initiated 1L treatment within 90 days of their diagnosis for metastatic disease were included in the study. Regimens were grouped into the following categories: FFX, GnP, gemcitabine monotherapy, FOLFOX, FOLFIRI, capecitabine/5-FU monotherapy, irinotecan liposome injection-containing regimens, CPI monotherapy, PARP inhibitors and other targeted therapy-containing regimens, no 1L, and other regimens (comprised of combinations of FFX and GnP components as well as other chemotherapeutic agents). Results: Of the 5,358 pts eligible for inclusion in the study, the majority received GnP (33%, 1,785 pts) or FFX (23%, 1,254 pts) in 1L. The next largest segment of pts did not receive 1L therapy (23%, 1,229 pts). Just 6% (345 pts) received gemcitabine monotherapy. The remaining 14% of pts received therapies other than the three primary 1L mPDAC treatments: 4% (207 pts) received FOLFOX, 2% (109 pts) received capecitabine/5-FU monotherapy, 2% (96 pts) received an irinotecan liposome injection-containing regimen, 0.7% (39 pts) received FOLFIRI, 0.5% (28 pts) received CPI monotherapy, and 0.5% (26 pts) received PARP inhibitors or other targeted therapies. 4% (240 pts) received various other chemotherapy combinations (comprised of combinations of FFX and GnP components and a small number of other chemotherapeutic agents, with ≤40 pts per combination). FFX pts were the youngest, with a mean age of 64yrs, compared to 70yrs for gemcitabine + nab-paclitaxel (p &lt; .001). Gemcitabine monotherapy pts were the oldest (mean = 73yrs, p &lt; .001 vs. GnP) and were more likely to have metastatic disease and an ECOG ≥2 (p &lt; .001 vs. GnP). Conclusions: There are limited 1L treatment options for mPDAC. Since the and PRODIGE and MPACT trials, FFX, GnP, or gemcitabine monotherapy have been the primary recommended 1L treatments for most pts with mPDAC. While recent years have seen an increase in the availability of targeted and CPI therapies appropriate for small subgroups of mPDAC pts, in a RW sample, almost all pts received one of the three standard therapies.

Atrial fibrillation recurrence after catheter ablation is associated with RAD51 and p63 proteins

Catheter ablation has been demonstrated to reduce atrial fibrillation (AF) recurrence. The mechanisms of AF recurrence after catheter ablation are unknown, and the present study aimed to identify serum proteins associated with AF recurrence.The present prospective study comprised a cohort of patients with AF, which was divided into two groups after one-year follow-up: group 1 included patients with compensated AF after catheter ablation and group 2 included patients with AF recurrence after catheter ablation. Initial microarray profiling of the serum proteins was performed in small subgroups M1 and M2 recruited from groups 1 and 2, respectively, by an antibody microarray to evaluate potentially relevant proteins. The data of initial proteomic profiling identified candidate proteins in groups 1 and 2, and their levels were then measured by ELISA. The data of profiling suggested an overall increase in the levels of RAD51 and p63 proteins in the M2 subgroup versus that in the M1 subgroup, indicating potential relevance of these two proteins to AF recurrence. The results of ELISA of the levels of RAD51 and p63 in the groups 1 and 2 demonstrated an increase in the levels of RAD51 (11.11 ± 4.36 vs 8.45 ± 4.85 ng/mL; P = 0.009) and p63 (165.73 ± 113.75 vs 100.05 ± 37.56 units of normalized optical density; P = 0.0007) in the group 2 (with AF recurrence or substrate AF) compared with that in the group 1 (compensated AF). Thus, RAD51 and p63 were associated with AF recurrence after catheter ablation and may represent possible etiological factors for subsequent outcomes.

SaLTy: a novel Staphylococcus aureus Lineage Typer.

Staphylococcus aureus asymptomatically colonises 30 % of humans but can also cause a range of diseases, which can be fatal. In 2017 S. aureus was associated with 20 000 deaths in the USA alone. Dividing S. aureus isolates into smaller sub-groups can reveal the emergence of distinct sub-populations with varying potential to cause infections. Despite multiple molecular typing methods categorising such sub-groups, they do not take full advantage of S. aureus genome sequences when describing the fundamental population structure of the species. In this study, we developed Staphylococcus aureus Lineage Typing (SaLTy), which rapidly divides the species into 61 phylogenetically congruent lineages. Alleles of three core genes were identified that uniquely define the 61 lineages and were used for SaLTy typing. SaLTy was validated on 5000 genomes and 99.12 % (4956/5000) of isolates were assigned the correct lineage. We compared SaLTy lineages to previously calculated clonal complexes (CCs) from BIGSdb (n=21 173). SALTy improves on CCs by grouping isolates congruently with phylogenetic structure. SaLTy lineages were further used to describe the carriage of Staphylococcal chromosomal cassette containing mecA (SCCmec) which is carried by methicillin-resistant S. aureus (MRSA). Most lineages had isolates lacking SCCmec and the four largest lineages varied in SCCmec over time. Classifying isolates into SaLTy lineages, which were further SCCmec typed, allowed SaLTy to describe high-level MRSA epidemiology. We provide SaLTy as a simple typing method that defines phylogenetic lineages (https://github.com/LanLab/SaLTy). SaLTy is highly accurate and can quickly analyse large amounts of S. aureus genome data. SaLTy will aid the characterisation of S. aureus populations and ongoing surveillance of sub-groups that threaten human health.

First-line oxaliplatin-based chemotherapy and nivolumab for metastatic microsatellite-stable colorectal cancer—the randomised METIMMOX trial

BackgroundWe evaluated first-line treatment of metastatic microsatellite-stable colorectal cancer with short-course oxaliplatin-based chemotherapy alternating with immune checkpoint blockade.MethodsPatients were randomly assigned to chemotherapy (the FLOX regimen; control group) or alternating two cycles each of FLOX and nivolumab (experimental group). Radiographic response assessment was done every eight weeks with progression-free survival (PFS) as the primary endpoint. Cox proportional-hazards regression models estimated associations between PFS and relevant variables. A post hoc analysis explored C-reactive protein as signal of responsiveness to immune checkpoint blockade.ResultsEighty patients were randomised and 38 in each group received treatment. PFS was comparable—control group: median 9.2 months (95% confidence interval (CI), 6.3–12.7); experimental group: median 9.2 months (95% CI, 4.5–15.0). The adjusted Cox model revealed that experimental-group subjects aged ≥60 had significantly lowered progression risk (p = 0.021) with hazard ratio 0.17 (95% CI, 0.04–0.76). Experimental-group patients with C-reactive protein <5.0 mg/L when starting nivolumab (n = 17) reached median PFS 15.8 months (95% CI, 7.8–23.7). One-sixth of experimental-group cases (all KRAS/BRAF-mutant) achieved complete response.ConclusionsThe investigational regimen did not improve the primary outcome for the intention-to-treat population but might benefit small subgroups of patients with previously untreated, metastatic microsatellite-stable colorectal cancer.Trial registrationClinicalTrials.gov number, NCT03388190 (02/01/2018).

Multimorbidity analysis with low condition counts: a robust Bayesian approach for small but important subgroups

BackgroundRobustly examining associations between long-term conditions may be important in identifying opportunities for intervention in multimorbidity but is challenging when evidence is limited. We have developed a Bayesian inference framework that is robust to sparse data and used it to quantify morbidity associations in the oldest old, a population with limited available data. MethodsWe conducted a retrospective cross-sectional study of a representative dataset of primary care patients in Scotland as of March 2007. We included 40 long-term conditions and studied their associations in 12,009 individuals aged 90 and older, stratified by sex (3,039 men, 8,970 women). We analysed associations obtained with Relative Risk (RR), a standard measure in the literature, and compared them with our proposed measure, Associations Beyond Chance (ABC). To enable a broad exploration of interactions between long-term conditions, we built networks of association and assessed differences in their analysis when associations are estimated by RR or ABC. FindingsOur Bayesian framework was appropriately more cautious in attributing association when evidence is lacking, particularly in uncommon conditions. This caution in reporting association was also present in reporting differences in associations between sex and affected the aggregated measures of multimorbidity and network representations. InterpretationIncorporating uncertainty into multimorbidity research is crucial to avoid misleading findings when evidence is limited, a problem that particularly affects small but important subgroups. Our proposed framework improves the reliability of estimations of associations and, more in general, of research into disease mechanisms and multimorbidity. FundingNational Institute for Health and Care Research.

Effects of postnatal corticosteroids on lung development in newborn animals. A systematic review.

Postnatal systemic corticosteroids reduce the risk of bronchopulmonary dysplasia but the effect depends on timing, dosing, and type of corticosteroids. Animal studies may provide valuable information on these variable effects. This systematic review summarizes the effects of postnatal systemic corticosteroids on lung development in newborn animals. A systematic search was performed in PubMed and Embase in December 2022. The protocol was published on PROSPERO (CRD42021177701). Of the 202 eligible studies, 51 were included. Only newborn rodent studies met the inclusion criteria. Most studies used dexamethasone (98%). There was huge heterogeneity in study outcome measures and corticosteroid treatment regimens. Reporting of study quality indicators was mediocre and risk of bias was unclear due to poor reporting of study methodology. Meta-analysis showed that postnatal corticosteroids caused a decrease in body weight as well as persistent alveolar simplification. Subgroup analyses revealed that healthy animals were most affected. In newborn rodents, postnatal systemic corticosteroids have a persistent negative effect on body weight and lung development. There was huge heterogeneity in experimental models, mediocre study quality, unclear risk of bias, and very small subgroups for meta-analysis which limited firm conclusions. Postnatal corticosteroids reduce the risk of bronchopulmonary dysplasia but the effect depends on timing, dosing, and type of corticosteroids while the underlying mechanism of this variable effect is unknown. This is the first systematic review and meta-analysis of preclinical newborn animal studies reviewing the effect of postnatal systemic corticosteroids on lung development. In newborn rodent models, postnatal corticosteroids have a persistent negative effect on body weight and lung alveolarization, especially in healthy animals.

Pointwise and correlation bounds on Dedekind sums over small subgroups

Pointwise and correlation bounds on Dedekind sums over small subgroups

Tubulointerstitial nephritis antigen-like 1 from cancer-associated fibroblasts contribute to the progression of diffuse-type gastric cancers through the interaction with integrin β1

BackgroundTumor cells of diffuse-type gastric cancer (DGC) are discohesive and infiltrate into the stroma as single cells or small subgroups, so the stroma significantly impacts DGC progression. Cancer-associated fibroblasts (CAFs) are major components of the tumor stroma. Here, we identified CAF-specific secreted molecules and investigated the mechanism underlying CAF-induced DGC progression.MethodsWe conducted transcriptome analysis for paired normal fibroblast (NF)-CAF isolated from DGC patient tissues and proteomics for conditioned media (CM) of fibroblasts. The effects of fibroblasts on cancer cells were examined by transwell migration and soft agar assays, western blotting, and in vivo. We confirmed the effect of blocking tubulointerstitial nephritis antigen-like 1 (TINAGL1) in CAFs using siRNA or shRNA. We evaluated the expression of TINAGL1 protein in frozen tissues of DGC and paired normal stomach and mRNA in formalin-fixed, paraffin-embedded (FFPE) tissue using RNA in-situ hybridization (RNA-ISH).ResultsCAFs more highly expressed TINAGL1 than NFs. The co-culture of CAFs increased migration and tumorigenesis of DGC. Moreover, CAFs enhanced the phosphorylation of focal adhesion kinase (FAK) and mesenchymal marker expression in DGC cells. In an animal study, DGC tumors co-injected with CAFs showed aggressive phenotypes, including lymph node metastasis. However, increased phosphorylation of FAK and migration were reduced by blocking TINAGL1 in CAFs. In the tissues of DGC patients, TINAGL1 was higher in cancer than paired normal tissues and detected with collagen type I alpha 1 chain (COL1A1) in the same spot. Furthermore, high TINAGL1 expression was significantly correlated with poor prognosis in several public databases and our patient cohort diagnosed with DGC.ConclusionsThese results indicate that TINAGL1 secreted by CAFs induces phosphorylation of FAK in DGC cells and promotes tumor progression. Thus, targeting TINAGL1 in CAFs can be a novel therapeutic strategy for DGC.

Evaluation of ChatGPT's Real-Life Implementation in Undergraduate Dental Education: Mixed Methods Study.

The recent artificial intelligence tool ChatGPT seems to offer a range of benefits in academic education while also raising concerns. Relevant literature encompasses issues of plagiarism and academic dishonesty, as well as pedagogy and educational affordances; yet, no real-life implementation of ChatGPT in the educational process has been reported to our knowledge so far. This mixed methods study aimed to evaluate the implementation of ChatGPT in the educational process, both quantitatively and qualitatively. In March 2023, a total of 77 second-year dental students of the European University Cyprus were divided into 2 groups and asked to compose a learning assignment on "Radiation Biology and Radiation Protection in the Dental Office," working collaboratively in small subgroups, as part of the educational semester program of the Dentomaxillofacial Radiology module. Careful planning ensured a seamless integration of ChatGPT, addressing potential challenges. One group searched the internet for scientific resources to perform the task and the other group used ChatGPT for this purpose. Both groups developed a PowerPoint (Microsoft Corp) presentation based on their research and presented it in class. The ChatGPT group students additionally registered all interactions with the language model during the prompting process and evaluated the final outcome; they also answered an open-ended evaluation questionnaire, including questions on their learning experience. Finally, all students undertook a knowledge examination on the topic, and the grades between the 2 groups were compared statistically, whereas the free-text comments of the questionnaires were thematically analyzed. Out of the 77 students, 39 were assigned to the ChatGPT group and 38 to the literature research group. Seventy students undertook the multiple choice question knowledge examination, and examination grades ranged from 5 to 10 on the 0-10 grading scale. The Mann-Whitney U test showed that students of the ChatGPT group performed significantly better (P=.045) than students of the literature research group. The evaluation questionnaires revealed the benefits (human-like interface, immediate response, and wide knowledge base), the limitations (need for rephrasing the prompts to get a relevant answer, general content, false citations, and incapability to provide images or videos), and the prospects (in education, clinical practice, continuing education, and research) of ChatGPT. Students using ChatGPT for their learning assignments performed significantly better in the knowledge examination than their fellow students who used the literature research methodology. Students adapted quickly to the technological environment of the language model, recognized its opportunities and limitations, and used it creatively and efficiently. Implications for practice: the study underscores the adaptability of students to technological innovations including ChatGPT and its potential to enhance educational outcomes. Educators should consider integrating ChatGPT into curriculum design; awareness programs are warranted to educate both students and educators about the limitations of ChatGPT, encouraging critical engagement and responsible use.

Cognitive aspect of concept strangeness in English

The paper aims to explore the cognitive aspect of the concept of "Strangeness" in English. It examines this concept through the lens of the image-schema of Relation, as "strangeness" is primarily perceived as a quality associated with being unnatural, unknown, or unrecognizable. Through an analysis of the meanings of the synonymic set of adjectives with the dominant "strange", the study reveals that, in addition to the common semantic component of "different from what is usual or ordinary," these adjectives also share other semes. These semes include "striking or shocking," "eccentric," "inspiring fear," and "remote in space/time," which differentiate them into smaller subgroups. Overall, based on the semantic analysis of the selected adjectives, it can be concluded that English speakers perceive something or someone as strange when they cannot categorize them into known categories or when the objects are distant in time and space. The quality of strangeness typically carries a negative connotation.