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The Milan Score is an Effective Manometric Tool to Predict Gastroesophageal Reflux in Patients With Laryngopharyngeal Symptoms.
No full textINTRODUCTION: According to Lyon 2.0, laryngopharyngeal symptoms (LPS) should undergo upfront pathophysiologic tests. The novel Milan score integrates esophagogastric junction (EGJ) morphology, ineffective esophageal motility, EGJ-contractile integral (EGJ-CI), and straight leg raise (SLR) response. It has been demonstrated to predict abnormal AET. The aim of this study was to assess the value of the Milan score in predicting GERD in these patients.
METHODS: We prospectively enrolled patients with suspected GERD who underwent HRM and MII pH from 12 referral centers. Patients with isolated LPS (reflux symptom index \u3e 13) were compared with typical GERD symptoms (GERD-HRQL ≥ 10). A Milan score \u3e 137 was considered positive. The effectiveness of the Milan score in the identification of patients with pathologic GERD was assessed.
RESULTS: Of 570 patients (49% females, median age 49 years, BMI 24 kg/m
CONCLUSIONS: Patients with isolated LPS demonstrated a lower likelihood of EGJ disruption, pathologic GERD, and abnormal Milan score. The Milan score performed similarly well in the identification of GERD in both LPS and typical symptoms and could therefore be used as an upfront test in LPS patients
Multiomic Characterization of
No full textPurpose: Regulator of chromosome condensation 1 (RCC1) and RCC2 have been shown to play important roles in the regulation of cell cycle, DNA damage response, and nucleocytoplasmic transport.
Materials and methods: DNA (592-gene or whole exome) and RNA (whole transcriptome) sequencing was performed at Caris Life Sciences (Phoenix, AZ). Samples were stratified by RCC1 expression quartile thresholds (Q1: low, Q4: high) for small cell lung cancer (SCLC; n = 876), non-small cell lung cancer (NSCLC; n = 21,603), gastric cancer (GC; n = 1,908), pancreatic cancer (PC; n = 5,071), and colorectal cancer (CRC; n = 14,892). Statistical significance was determined using chi-square and Wilcoxon rank-sum tests and adjusted for multiple comparisons (*P \u3c .05). Corresponding analyses were run for RCC2.
Results: Median RCC1 mRNA expression was highest in SCLC (14.3 transcript per million [TPM]), followed by GC (9.9), NSCLC (9.9), CRC (9.8), and PC (6.9). Similar to RCC1, the median RCC2 expressions were highest in SCLC (36.2 TPM). Tumor mutational burden-high rates were positively associated with increasing RCC1 expression quartiles (Q1-4) in NSCLC (31%-41%), GC (7%-22%), and CRC (5%-17%) and with increasing RCC2 expression in NSCLC and CRC only. Higher expression with RCC1 and RCC2 was associated with worse overall survival in NSCLC (hazard ratio [HR] for RCC1 and RCC2 were 1.3 and 1.3, respectively), PC (HR for RCC1 and RCC2 were 1.5 and 1.12, respectively), and CRC (HR for RCC1 and RCC2 were 1.3 and 1.03, respectively).
Conclusion: RCC1 and RCC2 expression is a negative prognostic marker in NSCLC, PC, and CRC. Further studies to investigate RCC1 and RCC2 function at the molecular level may provide opportunities for novel targeted drug development
Impact of Depressive Symptom Severity on Stroke Risk in a US Cohort of People with HIV.
No full textBACKGROUND: Depression is a common psychiatric condition and an independent stroke risk factor among people with HIV (PWH). The impacts of depressive symptom severity on stroke are not clear in PWH.
METHODS: We studied adult PWH in clinical care at five CNICS sites with ≥1 assessment for depressive symptoms (PHQ-9) from 2010-2022. We used Cox models to evaluate: (1) associations between time-varying depressive symptom severity and adjudicated incident stroke, serially adjusted for clinical factors; (2) modification of this association by age and sex. Participants were followed from 6 months after first CNICS visit or date the CNICS site began stroke adjudication (baseline) (whichever later) until the first stroke, death, loss to follow-up, last clinic visit, or study end.
RESULTS: Among 13,817 PWH (mean age 45 years, 19% female, 58% non-white race/ethnicity), 23% screened positive for depression at baseline and 173 had an incident stroke during follow up (mean follow-up 7.6 years). Time-varying depressive symptom severity (per 5-points PHQ-9 score) was associated with higher stroke risk (aHR 1.16, P=0.01) with greater impact in PWH \u3c 50y than ≥50y (Interaction P=0.02) but no significant difference by sex. Adjusting for combinations of sociodemographic, cardiovascular, HIV, and substance use factors only slightly attenuated estimates.
CONCLUSIONS: Depressive symptom severity was an independent risk factor for stroke with higher severity depressive symptoms predicting higher stroke risk and greater impact in PWH \u3c 50 years. Depression may be a modifiable risk factor for stroke and should be studied further to understand, develop, and target interventions to reduce stroke risk, especially in younger PWH
Radiation Induces Pericyte-Myofibroblast Transition.
No full textPURPOSE: Radiation not only kills cancer cells directly through DNA damage but also indirectly by inducing vascular changes. The effects of radiation on tumor vasculature are critical for therapeutic efficacy; however, its impact on pericytes remains largely unknown. In this study, we investigated the effect of radiation on pericytes and sought to elucidate the mechanism by which radiation affects pericytes.
METHODS AND MATERIALS: C3H10T1/2 (10T1/2) mouse embryonic mesenchymal pericyte precursor cells and human pericytes from placenta (hPC-PL) cells were irradiated to study the effects of radiation on pericyte differentiation, maturation, and transition of pericytes into myofibroblasts by flow cytometry, quantitative reverse transcription-polymerase chain reaction (qRT-PCR), and immunofluorescence. Phospho-kinase array, Western blot, and reactive oxygen species (ROS) detection assay were conducted to elucidate the signaling pathways activated by radiation in pericytes. To investigate the pericyte-myofibroblast transition in vivo, MC38 tumor cells were implanted in NG2DsRedBAC (NG2DsRed) transgenic mice whose pericytes express DsRed. Tumors harvested 3, 5, and 7 days after radiation were assessed for myofibroblast markers in DsRed
RESULTS: Radiation promoted pericyte differentiation and increased the expression of adhesion molecules in both 10T1/2 and hPC-PL cells. Permeability and leukocyte adhesion were altered by radiation via an effect on endothelial cells, not pericytes. Radiation increased the expression of myofibroblast markers and induced morphologic changes. Phospho-kinase array indicated radiation activates the Akt signaling pathway, and inhibitors of Akt and ROS suppressed the expression of myofibroblast markers increased by radiation. MC38 tumors implanted in NG2DsRed transgenic mice harvested 3 days after radiation exhibited increased expression of myofibroblast markers in DsRed
CONCLUSIONS: Our data suggest radiation promotes pericyte maturation and transition into myofibroblasts via Akt signaling
Short-term mortality after opioid initiation among opioid-naïve and non-naïve patients with dementia: a retrospective cohort study.
No full textBACKGROUND: In the ongoing opioid epidemic, the mortality risk of opioid initiation in patients with dementia or mild cognitive impairment (MCI) remains understudied despite their vulnerability. This study evaluates mortality risks associated with opioid exposure in patients diagnosed with dementia or MCI by comparing outcomes between the initiation and continuation groups.
METHODS: We conducted a retrospective cohort study using data from a Northern California academic healthcare system (Stanford Health Care Alliance; 2015/01/01-2024/07/31), including 27,757 patients aged 50-100 with dementia or MCI. Of these, 14,105 received opioids after diagnosis and were classified as initiation (opioid-naïve; n=9443) or continuation (non-naïve; n=4662) groups. Cox regression assessed 14-day mortality risk. Aalen\u27s additive model examined time-varying impact up to 180 days. Potential causes of death were extracted from clinical notes using GPT-3.5-Turbo. We also analyzed an independent community healthcare system cohort (Providence Health & Service; n=208,306) from western US states (2015/01/01-2023/05/31) as a replication cohort.
RESULTS: In the primary cohort, 4.1% (572/14,105) of patients died within 14 days of opioid exposure. The initiation group had a significantly higher 14-day mortality risk than the continuation group (adjusted hazard ratio (aHR), 2.00 (1.59-2.52); P\u3c 0.0001). The replication cohort had a 14-day mortality rate of 6.2% (7022/113,343) with a smaller difference between the initiation (n=77,168) and continuation (n=36,175) groups (aHR 1.22 (1.16-1.30); P\u3c 0.0001). In both cohorts, elevated risk stabilized after day 30. In the primary cohort, respiratory conditions (62% vs. 48%, P\u3c 0.1), particularly pneumonia (38% vs. 19%, P\u3c 0.05), were more prevalent among the initiation group who died early.
CONCLUSIONS: Starting opioids in patients with dementia or MCI is associated with elevated short-term mortality risks, with the initiation group having twice the 14-day mortality risk in academic settings and a smaller but significant increase in community healthcare systems. The first 30 days after initiation represent a critical risk window, likely due to a lack of tolerance to opioid adverse effects. These findings underscore the need for cautious initiation, tailored follow-up protocols accounting for healthcare setting characteristics, and close monitoring during the first month in this vulnerable population
A phase I/II trial of WT1-specific TCR gene therapy for patients with acute myeloid leukemia and active disease post-allogeneic hematopoietic cell transplantation: skewing towards NK-like phenotype impairs T cell function and persistence.
No full textRelapsed and/or refractory acute myeloid leukemia (AML) post-allogeneic hematopoietic cell transplantation (HCT) is usually fatal. We previously reported that post-HCT immunotherapy with Epstein-Barr virus (EBV)-specific donor CD8+ T cells engineered to express a Wilms Tumor Antigen 1-specific T-cell receptor (TTCR-C4) appeared to prevent relapse in high-risk patients. In this phase I/II clinical trial (NCT01640301), we evaluated safety (primary endpoint), persistence and efficacy (secondary endpoints) of EBV- or Cytomegalovirus (CMV)-specific TTCR-C4 in fifteen patients with active AML post-HCT. Infusions were well tolerated, with no dose-limiting toxicities or serious adverse events related to the product. However, TTCR-C4 cells did not clearly improve outcomes despite EBV-specific TTCR-C4 cells showing enhanced potential for prolonged persistence compared to CMV-specific TTCR-C4. Investigating the fate of persisting TTCR-C4, we identified a shift towards natural killer-like (NKL) terminal differentiation, distinct from solid tumor-associated canonical exhaustion programs. In one patient, treatment with azacitidine appeared to mitigate this NKL skewing, promoting TTCR-C4 persistence. These findings suggest that AML drives a distinct form of T-cell dysfunction, highlight the need for targeted approaches that preserve T-cell fitness, ultimately improving the efficacy of cellular therapies for AML
Severity of acute SARS-CoV-2 infection and risk of new-onset autoimmune disease: A RECOVER initiative study in nationwide U.S. cohorts.
No full textSARS-CoV-2 infection has been associated with increased autoimmune disease risk. Past studies have not aligned regarding the most prevalent autoimmune diseases after infection, however. Furthermore, the relationship between infection severity and new autoimmune disease risk has not been well examined. We used RECOVER\u27s electronic health record (EHR) networks, N3C, PCORnet, and PEDSnet, to estimate types and frequency of autoimmune diseases arising after SARS-CoV-2 infection and assessed how infection severity related to autoimmune disease risk. We identified patients of any age with SARS-CoV-2 infection between April 1, 2020 and April 1, 2021, and assigned them to a World Health Organization COVID-19 severity category for adults or the PEDSnet acute COVID-19 illness severity classification system for children (30 days after SARS-CoV-2 infection index date and occurring ≥1 day apart. We calculated overall and infection severity-stratified incidence ratesper 1000 person-years for all autoimmune diseases. With least severe COVID-19 severity as reference, survival analyses examined incident autoimmune disease risk. The most common new-onset autoimmune diseases in all networks were thyroid disease, psoriasis/psoriatic arthritis, and inflammatory bowel disease. Among adults, inflammatory arthritis was the most common, and Sjögren\u27s disease also had high incidence. Incident type 1 diabetes and hematological autoimmune diseases were specifically found in children. Across networks, after adjustment, patients with highest COVID-19 severity had highest risk for new autoimmune disease vs. those with least severe disease (N3C: adjusted Hazard Ratio, (aHR) 1.47 (95%CI 1.33-1.66); PCORnet aHR 1.14 (95%CI 1.02-1.26); PEDSnet: aHR 3.14 (95%CI 2.42-4.07)]. Overall, severe acute COVID-19 was most strongly associated with autoimmune disease risk in three EHR networks