Category: Statistics

Front Immunol. 2024 Jun 24;15:1405348. doi: 10.3389/fimmu.2024.1405348. eCollection 2024.

ABSTRACT

BACKGROUND: Antiretroviral therapy (ART) for HIV-1 treatment has improved lifespan but requires lifelong adherence for people living with HIV (PLWH), highlighting the need for a cure. Evaluation of potential cure strategies requires analytic treatment interruption (ATI) with close monitoring of viral rebound. Predictive biomarkers for HIV-1 rebound and/or duration of control during ATI will facilitate these HIV cure trials while minimizing risks. Available evidence suggests that host immune, glycomic, lipid, and metabolic markers of inflammation may be associated with HIV-1 persistence in PLWH who are treated during chronic HIV-1 infection.

METHODS: We conducted post-hoc analysis of HIV controllers who could maintain low levels of plasma HIV-1 without ART in a phase 1b vesatolimod trial. Baseline and pre-ATI levels of immune, glycomic, lipidomic, and metabolomic markers were tested for association with ATI outcomes (time of HIV-1 rebound to 200 copies/mL and 1,000 copies/mL, duration of HIV-1 RNA ≤400 copies/mL and change in intact proviral HIV-1 DNA during ATI) using Spearman’s correlation and Cox proportional hazards model.

RESULTS: Higher levels of CD69+CD8+ T-cells were consistently associated with shorter time to HIV-1 rebound at baseline and pre-ATI. With few exceptions, baseline fucosylated, non-galactosylated, non-sialylated, bisecting IgG N-glycans were associated with shorter time to HIV rebound and duration of control as with previous studies. Baseline plasma MPA and HPA binding glycans and non-galactosylated/non-sialylated glycans were associated with longer time to HIV rebound, while baseline multiply-galactosylated glycans and sialylated glycans, GNA-binding glycans, NPA-binding glycans, WGA-binding glycans, and bisecting GlcNAc glycans were associated with shorter time to HIV rebound and duration of control. Fourteen bioactive lipids had significant baseline associations with longer time to rebound and duration of control, and larger intact proviral HIV-1 DNA changes; additionally, three baseline bioactive lipids were associated with shorter time to first rebound and duration of control.

CONCLUSION: Consistent with studies in HIV non-controllers, proinflammatory glycans, lipids, and metabolites were generally associated with shorter duration of HIV-1 control. Notable differences were observed between HIV controllers vs. non-controllers in some specific markers. For the first time, exploratory biomarkers of ATI viral outcomes in HIV-controllers were investigated but require further validation.

PMID:38979421 | PMC:PMC11229794 | DOI:10.3389/fimmu.2024.1405348

Front Immunol. 2024 Jun 24;15:1394123. doi: 10.3389/fimmu.2024.1394123. eCollection 2024.

ABSTRACT

OBJECTIVE: To evaluate the cardiovascular safety of anticancer drug immune checkpoint inhibitors (ICIs) used in patients with malignant tumors.

METHODS: Four clinical research databases that have been completed since their establishment were searched, and the odds ratios and 95% confidence intervals of each indicator were statistically calculated.

RESULTS: 62 randomized controlled trial and controlled trials were included. In single drug treatment ICIs group, the overall risk of cardio cerebral Vascular disease at all levels was higher than that in the placebo/chemotherapy group. Especially in all grades of Myocarditis and above grade 3 compared with normal controls, except for pericardial lesions, other indicators have no obvious side effects.

CONCLUSION: Single drug use of an anti-tumor ICIs may increase cardiovascular side effects risk in cancer patients, so we need to strengthen monitoring, identification and management, and timely intervention to manage ICI induced adverse events.

PMID:38979409 | PMC:PMC11228135 | DOI:10.3389/fimmu.2024.1394123

BMJ Neurol Open. 2024 Jul 5;6(2):e000724. doi: 10.1136/bmjno-2024-000724. eCollection 2024.

ABSTRACT

OBJECTIVE: Interventional stroke therapy made thrombi available for histological analysis. Unfortunately, simple composition aspects such as erythrocyte versus fibrin/platelet rich did not allow a feasible allocation to thrombi’s cardiac or carotid origin. Since the mentioned criteria represent characteristics of thrombus age, we used established histological criteria for determining thrombus age in patients who had an atherosclerotic (TOAST (Trial of Org 10172 in Acute stroke Treatment) 1) stroke versus patients who had a cardioembolic (TOAST 2) stroke.

METHODS: We assessed prospectively data from stroke patients presenting with occlusion of the middle cerebral artery eligible for catheter-based intervention. Besides patient characteristics and stroke workup, extracted thrombi were classified into different age categories according to their cellular to fibrotic transition. Thrombi were collected in an erythrocyte lysing solution to reduce acute clotting effects. Statistics were done with a non-parametric Kolmogorov-Smirnov test.

RESULTS: 170 patients were included, of which 50 (38 men; 73±12 years) had a TOAST 1 and 99 (59 women; 75±10 years) had a TOAST 2 categorised stroke. Age, National Institutes of Health Stroke Score (13±7 vs 15±7), Alberta Stroke Program Early CT Score (9±3 vs 9±2), Thrombolysis in Cerebral Infarction Score (2.9±0.2 vs 2.9±0.3), modified Rankin Score on discharge (3.2±2 vs 3.2±2), number of vascular risk factors (0.9±1.4 vs 1.0±1.1) or time span between symptom onset to reperfusion (266±115 vs 260±128 min) remained non-significant. Also, thrombus age did not differ between the groups. The mean age of thrombi was 5-8 days. However, the male-female ratio differed significantly (p<0.0005) between groups, with more men in TOAST 1 group and more women in TOAST 2 group.

CONCLUSION: Age aspects of thrombi seem not feasible to allow reliable source allocation. However, the young age of thrombi points to a rapid detachment. The difference in sex relation is in line with previous reports.

PMID:38979394 | PMC:PMC11227751 | DOI:10.1136/bmjno-2024-000724

bioRxiv [Preprint]. 2024 Jun 24:2024.03.05.583616. doi: 10.1101/2024.03.05.583616.

ABSTRACT

A simple lateral dynamic walker, with swing leg dynamics and three adjustable input parameters, is used to study how motor regulation affects frontal plane stepping. Motivated by experimental observations and phenomenological models, we imposed task-level multiobjective regulation targeting the walker’s optimal lateral foot placement at each step. The regulator prioritizes achieving step width and lateral body position goals to varying degrees by choosing a mixture parameter. Our model thus integrates a lateral mechanical template , which captures fundamental mechanics of frontal-plane walking, with a lateral motor regulation template , an empirically verified model of how humans manipulate lateral foot placements in a goal-directed manner. The model captures experimentally observed stepping fluctuation statistics and demonstrates how linear empirical models of stepping dynamics can emerge from first-principles nonlinear mechanics. We find that task-level regulation gives rise to a goal equivalent manifold in the system’s extended state space of mechanical states and inputs, a subset of which contains a continuum of period-1 gaits forming a semistable set: perturbations off of any of its gaits result in transients that return to the set, though typically to different gaits.

PMID:38979349 | PMC:PMC11230222 | DOI:10.1101/2024.03.05.583616

bioRxiv [Preprint]. 2024 Jun 30:2024.06.26.600724. doi: 10.1101/2024.06.26.600724.

ABSTRACT

OBJECTIVES: To provide a level-adjusted correction to the current standard relating anatomical cochlear place to characteristic frequency in humans, and to re-evaluate anatomical frequency mismatch in cochlear implant (CI) recipients considering this correction. It is hypothesized that a level-adjusted place-frequency function may represent a more accurate tonotopic benchmark for CIs in comparison to the current standard.

DESIGN: The present analytical study compiled data from fifteen previous animal studies that reported iso-intensity responses from cochlear structures at different stimulation levels. Extracted outcome measures were characteristic frequencies and centroid-based best frequencies at 70 dB SPL input from 47 specimens spanning a broad range of cochlear locations. A simple relationship was used to transform these measures to human estimates of characteristic and best frequencies, and non-linear regression was applied to these estimates to determine how the standard human place-frequency function should be adjusted to reflect best frequency rather than characteristic frequency. The proposed level-adjusted correction was then compared to average place-frequency positions of commonly used CI devices when programmed with clinical settings.

RESULTS: The present study showed that the best frequency at 70 dB SPL (BF70) tends to shift away from characteristic frequency (CF). The amount of shift was statistically significant (signed-rank test z = 5.143, p < 0.001), but the amount and direction of shift depended on cochlear location. At cochlear locations up to 600° from the base, BF70 shifted downwards in frequency relative to CF by about 4 semitones on average. Beyond 600° from the base, BF70 shifted upwards in frequency relative to CF by about 6 semitones on average. In terms of spread (90% prediction interval), the amount of shift between CF and BF70 varied from relatively no shift to nearly an octave of shift. With the new level-adjusted frequency-place function, the amount of anatomical frequency mismatch for devices programmed with standard of care settings is less extreme than originally thought, and may be nonexistent for all but the most apical electrodes.

CONCLUSIONS: The present study validates the current standard for relating cochlear place to characteristic frequency, and introduces a level-adjusted correction for how best frequency shifts away from characteristic frequency at moderately loud stimulation levels. This correction may represent a more accurate tonotopic reference for CIs. To the extent that it does, its implementation may potentially enhance perceptual accommodation and speech understanding in CI users, thereby improving CI outcomes and contributing to advancements in the programming and clinical management of CIs.

PMID:38979194 | PMC:PMC11230407 | DOI:10.1101/2024.06.26.600724

bioRxiv [Preprint]. 2024 Jun 25:2024.02.20.581048. doi: 10.1101/2024.02.20.581048.

ABSTRACT

BACKGROUND: MHC class I (MHC-I) loss is frequent in non-small cell lung cancer (NSCLC) rendering tumor cells resistant to T cell lysis. NK cells kill MHC-I-deficient tumor cells, and although previous work indicated their presence at NSCLC margins, they were functionally impaired. Within, we evaluated whether NK cell and CD8 T cell infiltration and activation vary with MHC-I expression.

METHODS: We used single-stain immunohistochemistry (IHC) and Kaplan-Meier analysis to test the effect of NK cell and CD8 T cell infiltration on overall and disease-free survival. To delineate immune covariates of MHC-I-disparate lung cancers, we used multiplexed immunofluorescence (mIF) imaging followed by multivariate statistical modeling. To identify differences in infiltration and intercellular communication between IFNγ-activated and non-activated lymphocytes, we developed a computational pipeline to enumerate single cell neighborhoods from mIF images followed by multivariate discriminant analysis.

RESULTS: Spatial quantitation of tumor cell MHC-I expression revealed intra- and inter-tumoral heterogeneity, which was associated with the local lymphocyte landscape. IHC analysis revealed that high CD56 ⁺ cell numbers in patient tumors were positively associated with disease-free survival (DFS) (HR=0.58, p =0.064) and over-all survival (OS) (HR=0.496, p =0.041). The OS association strengthened with high counts of both CD56 ⁺ and CD8 ⁺ cells (HR=0.199, p <1×10 ^-3 ). mIF imaging and multivariate discriminant analysis revealed enrichment of both CD3 ⁺ CD8 ⁺ T cells and CD3 ^– CD56 ⁺ NK cells in MHC-I-bearing tumors (p<0.05). To infer associations of functional cell states and local cell-cell communication, we analyzed spatial single cell neighborhood profiles to delineate the cellular environments of IFNγ ^+/- NK cells and T cells. We discovered that both IFNγ ⁺ NK and CD8 T cells were more frequently associated with other IFNγ ⁺ lymphocytes in comparison to IFNγ ^– NK cells and CD8 T cells (p<1×10 ^-30 ). Moreover, IFNγ ⁺ lymphocytes were most often found clustered near MHC-I ⁺ tumor cells.

CONCLUSIONS: Tumor-infiltrating NK cells and CD8 T cells jointly affected control of NSCLC tumor progression. Co-association of NK and CD8 T cells was most evident in MHC-I-bearing tumors, especially in the presence of IFNγ. Frequent co-localization of IFNγ ⁺ NK cells with other IFNγ ⁺ lymphocytes in near-neighbor analysis suggests NSCLC lymphocyte activation is coordinately regulated.

WHAT IS ALREADY KNOWN ON THIS TOPIC: MHC-I loss occurs frequently in NSCLC and corresponds with waning immunity in the tumor microenvironment (TME). NK cells recognize “missing-self” targets and could be leveraged to target NSCLC tumors with MHC-I loss. While NK cell presence at tumor margins has been documented in NSCLC, they were shown to lose function in this environment.

WHAT THIS STUDY ADDS: We developed spatial analysis pipelines leveraging the local heterogeneity of the TME at single cell resolution to test whether NK cells and T cells together contribute antitumoral immunity in NSCLC. We discovered that a high density of tumor-infiltrating NK cells corresponded with DFS, and this association was increased in patients with high coincident CD8 T cells, especially those in central tumor. Intriguingly, both cell types were found clustered together in MHC-I-bearing tumors, especially when both expressed IFNγ, suggesting coordinated lymphocyte activities may enhance immune control of NSCLC.

HOW THIS STUDY MIGHT AFFECT RESEARCH PRACTICE OR POLICY: This study provides a rationale for developing novel immunotherapies that simultaneously increase NK and T cell anti-tumoral immunity. Associations linking NK cells with patient survival and increased immune effector activity in NSCLC, even in MHC-I-deficient tumors, further highlights the need to devise and deploy NK cell activating strategies which may be highly efficacious in CD8 T cell refractory NSCLC.

PMID:38979183 | PMC:PMC11230195 | DOI:10.1101/2024.02.20.581048

bioRxiv [Preprint]. 2024 Jun 24:2024.06.19.599719. doi: 10.1101/2024.06.19.599719.

ABSTRACT

PURPOSE: Relaxation correction is crucial for accurately estimating metabolite concentrations measured using in vivo magnetic resonance spectroscopy (MRS). However, the majority of MRS quantification routines assume that relaxation values remain constant across the lifespan, despite prior evidence of T ₂ changes with aging for multiple of the major metabolites. Here, we comprehensively investigate correlations between T ₂ and age in a large, multi-site cohort.

METHODS: We recruited approximately 10 male and 10 female participants from each decade of life: 18-29, 30-39, 40-49, 50-59, and 60+ years old ( n =101 total). We collected PRESS data at 8 TEs (30, 50, 74, 101, 135, 179, 241, and 350 ms) from voxels placed in white-matter-rich centrum semiovale (CSO) and gray-matter-rich posterior cingulate cortex (PCC). We quantified metabolite amplitudes using Osprey and fit exponential decay curves to estimate T ₂ .

RESULTS: Older age was correlated with shorter T ₂ for tNAA, tCr _3.0 , tCr _3.9 , tCho, Glx, and tissue water in CSO and PCC; r _s = -0.21 to -0.65, all p <0.05, FDR-corrected for multiple comparisons. These associations remained statistically significant when controlling for cortical atrophy. T ₂ values did not differ across the adult lifespan for mI. By region, T ₂ values were longer in the CSO for tNAA, tCr _3.0 , tCr _3.9 , Glx, and tissue water and longer in the PCC for tCho and mI.

CONCLUSION: These findings underscore the importance of considering metabolite T ₂ changes with aging in MRS quantification. We suggest that future 3T work utilize the equations presented here to estimate age-specific T ₂ values instead of relying on uniform default values.

PMID:38979133 | PMC:PMC11230243 | DOI:10.1101/2024.06.19.599719

Biologics. 2024 Jul 4;18:181-193. doi: 10.2147/BTT.S461287. eCollection 2024.

ABSTRACT

OBJECTIVE: The purpose of this study was to analyze the mechanism by which STAT5B inhibits ferroptosis in mantle cell lymphoma (MCL) by promoting DCAF13 transcriptional regulation of p53/xCT pathway.

METHODS: The correlations between STAT5B, DCAF13 and ferroptosis in MCL were analyzed using Gene Expression Profiling Interactive Analysis (GEPIA, http://gepia.cancer-pku.cn/index.html). The expression levels and pairwise correlations of STAT5B, DCAF13, p53 and xCT in MCL patients were detected, respectively. STAT5B was silenced to confirm their criticality in MCL ferroptosis. the effects of blocking necrosis, apoptosis and ferroptosis on the anti-MCL effects of STAT5B were examined. Cells with STAT5B overexpression and/or DCAF13 silencing were constructed to confirm the involvement of DCAF13 in the STAT5B-regulated p53/xCT pathway. The regulation of p53 ubiquitination was confirmed by DCAF13 overexpression and MG132. The effects of silencing DCAF13 and MG132 on STAT5B overexpression on MCL was clarified by a tumor-bearing nude mouse model.

RESULTS: DCAF13 was overexpressed in MCL and positively correlated with STAT5B, negatively correlated with p53, and positively correlated with xCT. Inhibition of ferroptosis alleviated the inhibitory effects of siSTAT5B on MCL, while inhibition of necrosis and apoptosis had few effects. Silencing of DCAF13 led to the blocking of STAT5B regulation of p53/xCT and ferroptosis. The changes in DCAF13 and the addition of MG132 did not have statistically significant effects on p53 mRNA. Elevation of DCAF13 resulted in downregulation of p53 protein levels, and this inhibition was reversed by MG132. In animal models, the promotion of MCL and the inhibition of ferroptosis by STAT5B. Silencing of DCAF13 blocked STAT5B inhibition of p53 and induction of xCT, GPX4, and GSH.

CONCLUSION: STAT5B suppresses ferroptosis by promoting DCAF13 transcription to regulate p53/xCT pathway to promote MCL progression.

PMID:38979130 | PMC:PMC11229983 | DOI:10.2147/BTT.S461287

Int J Qual Health Care. 2024 Jul 8:mzae064. doi: 10.1093/intqhc/mzae064. Online ahead of print.

ABSTRACT

BACKGROUND: The new building of the Hospital in Lichtenfels (Germany) was put into operation in mid-July 2018. Neither the medical personnel nor medical departments have been changed. We want to evaluate how “safe” or “insecure” the new hospital or department in the beginning might have been. Our objective is to investigate if safety decreases at the beginning in a new hospital, despite modern environments and conditions.

METHODS: Adverse events associated with treatment were included to evaluate the total number of adverse events resulting from medical care and medications. Patients records had to be closed and completed, the length of stay had to be at least 24 hours, the patient had to have been formally admitted to the hospital (Institute for Healthcare Improvement IHI GTT “Global Trigger Tool” recommendation). The identified adverse events were grouped into 27 categories of the Institute for Healthcare Improvement “Global Trigger Tool.” We randomly reviewed 40 patient records per month 6 months before and 6 months after moving to the new hospital.

RESULTS: Statistical analysis showed that there was no significant difference in individual adverse events. The sum of adverse events was statistically higher after moving into a new hospital. Complete number of harms did reach statistical significance (χ2=6.62; df=1; p<.05; Cramer’s V=0.12), indicating that new environments “triggers” significantly more potential errors (50%) in comparison to the old environments (38.33%).

CONCLUSION: According to our results, the new hospital is slightly insecure in the first period (6 months) after its founding.

PMID:38978150 | DOI:10.1093/intqhc/mzae064

BMC Res Notes. 2024 Jul 8;17(1):190. doi: 10.1186/s13104-024-06853-1.

ABSTRACT

OBJECTIVE: Twenty percent of all classical Hodgkin lymphoma (CHL) cases relapse and recur, especially in advanced stages with a high International Prognostic Score (IPS). Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is a regulatory molecule that can inhibit the immune response and is related to tumor aggressiveness. This study aimed to determine the relationship between CTLA-4 expression in advanced-stage CHL and IPS, identifying it as a potential therapy target.

RESULTS: In advanced-stage CHL, the group with a high IPS exhibited significantly higher mean CTLA-4 expression compared to the group with a low IPS (p = 0.003).The group with Hb level < 10.5 g/dl, leukocyte count > 15,000/µL, lymphocyte count < 8%, albumin level < 4 g/dl, and stage 4 exhibited higher CTLA-4 expression than the other group, although only leukocyte count and stage showed statistical significance (p = 0.004 and p = 0.020). Mean CTLA-4 expression was 239.84 ± 76.36 for nodular sclerosis, 293.95 ± 147.94 for mixed cellularity, 271.4 ± 23.56 for lymphocyte depleted, and 225.2 for lymphocyte-rich subtypes. The results suggest that CTLA-4 expression is associated with adverse prognostic factors in the IPS for advanced-stage CHL, supporting the notion that immune checkpoints play a role in cancer progression.

PMID:38978137 | DOI:10.1186/s13104-024-06853-1