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Key Points The Standard versus Accelerated Initiation of Renal Replacement Therapy in AKI trial found that starting dialysis earlier for AKI resulted in a 74% higher risk of still receiving dialysis at 90 days. Among patients who likely would have started dialysis under usual practice, the risks of dialysis dependence were similar. This suggests much of the risk observed may have been due to starting dialysis (versus never starting) rather than starting slightly earlier. Background The Standard versus Accelerated Initiation of Renal Replacement Therapy in AKI Trial showed that among critically ill patients with AKI, an accelerated KRT initiation strategy resulted in more KRT dependence at 90 days, as compared with a standard strategy. However, it is unclear whether this difference exists among participants who likely would have been treated with KRT in usual practice. Methods Secondary analysis of the Standard versus Accelerated Initiation of Renal Replacement Therapy in AKI randomized controlled trial, analyzing participants who received more than the median number of days of KRT, which served as a proxy for high probability of requiring KRT under usual practice. Two sensitivity analyses redefined the cohort as ( 1 ) those with ≥24 hours of oliguria who received KRT and ( 2 ) those who received any KRT. Using the same statistical approach as the original trial, we calculated unadjusted relative risks with 95% confidence intervals (CIs) for the exposure of randomized KRT initiation strategy (accelerated versus standard) on the outcome of KRT dependence at 90 days among survivors. Results Among the 1184 participants who received ≥6 days of KRT (670 and 514 in the accelerated and standard arms, respectively), baseline characteristics remained balanced between treatment arms. The relative risk of KRT dependence at 90 days was attenuated and nonsignificant: 1.21 (95% CI, 0.84 to 1.78), compared with 1.74 (95% CI, 1.24 to 2.43) in the overall trial. The results were similar in sensitivity analyses. Conclusions Among patients who likely would have been treated with KRT in usual practice, there was no significant difference in 90-day KRT dependence among survivors between those randomized to the accelerated and standard KRT initiation strategies. These results suggest that the harm of long-term KRT dependence may be largely due to KRT initiation (versus never initiation) rather than earlier initiation. Clinical Trial registry name and registration number: NCT02568722.

BACKGROUND: Within the US, there has been an overall increase in cost of malpractice insurance for surgeons and decrease in federal reimbursement for surgical work. This study aimed to analyze state-to-state variability to understand differences in costs relative to reimbursement for surgeons and temporal trends. STUDY DESIGN: This study uses publicly available data to conduct a cross-sectional evaluation of surgeon medical malpractice premium rates and surgical reimbursement between 2013 and 2023. Surgeon reimbursement was represented in terms of the unit reimbursement rate for laparoscopic cholecystectomy (LC). The ratio of surgeon reimbursement to malpractice cost was calculated and considered as the number of LCs required in each state to cover the cost of malpractice insurance. RESULTS: Inflation-adjusted reimbursement for LC decreased in all states with a mean decrease of 24%. Although there was an overall decrease in inflation-adjusted medical malpractice premium cost, some states experienced an increase of up to 22% (Rhode Island), whereas other states experienced a decrease in cost of 62% (Oregon). For the year 2023, there was significant variability in the number of LCs needed to afford malpractice insurance premiums across states, ranging from 21 (Minnesota) to 163 (Illinois). Rhode Island experienced the greatest increase in change from 2013 to 2023 (63%), whereas Oregon experienced the greatest decrease (50%). CONCLUSIONS: This study finds significant variation in Medicare-based surgeon compensation relative to malpractice insurance costs across the US. This discrepancy highlights the challenges faced by surgical practices due to inconsistent insurance cost and decreases in reimbursement rates.

Summary of Background Data: Intraductal papillary mucinous neoplasm (IPMN)-derived pancreatic cancer is typically managed like pancreatic intraepithelial neoplasia (PanIN)-derived pancreatic cancer. However, in IPMN-derived pancreatic cancer, the role of chemotherapy remains controversial, particularly in the neoadjuvant setting (NAT). Objective: To evaluate the role of neoadjuvant chemotherapy in IPMN-derived pancreatic cancer. Methods: Patients with IPMN-derived pancreatic cancer treated with either upfront surgery (US) or NAT were identified from eight international centers (2000-2023). Clinicopathologic data were compared. Date of first treatment was used for Kaplan-Meier and log-rank tests to compare overall (OS) and recurrence free survival (RFS). Multivariable Cox-regression was performed in patients that underwent NAT. Results: In 1,019 patients, 76 (7%) underwent NAT. Patients who received NAT had higher baseline CA19-9 levels (P<0.001). Of these 76 patients, 27 (36%), 20 (26%), and 29 (38%) had resectable, borderline resectable, or locally advanced pancreatic cancer at diagnosis, respectively. Advanced resectability stage was significantly more common in the NAT patients as compared to those who underwent US (P<0.001). OS for US patients was 38.0 months (95%CI: 33.7.1-44.3), which was not statistically different than those that received NAT [27.5 mo (95%CI: 23.1-46.7), P=0.121]. This was also valid for patients with resectable disease [US: 38.1 mo vs. NAT: 35.6 mo, P=0.920)]. Complete or marked pathological treatment response (P=0.046) and serological CA19-9 normalization after NAT (P=0.017) were associated with improved survival. On Cox-regression for OS, N2 disease [HR: 4.15 (95%CI: 1.71-10.10)], elevated CA19-9 [HR: 2.02 (95%CI:1.06-3.85)] and R1 margin [HR: 2.36 (95%CI:1.20-4.61)] was independently associated with OS after NAT, while resectability status was not. Conclusion: After NAT and resection, advanced resectability stage was not associated with worse OS indicating the value of this approach for borderline resectable and locally advanced IPMN-derived pancreatic cancer. The benefit of NAT in resectable disease is unclear and may require an individualized approach. Biological treatment effect can be assessed with CA19-9 and confirmed by pathologic response.

Background: Electronic Health Records (EHRs) encompass valuable data essential for disease prediction. The application of artificial intelligence (AI), particularly deep learning, significantly enhances disease prediction by analyzing extensive EHR datasets to identify hidden patterns, facilitating early detection. Recently, numerous foundation models pretrained on extensive data have demonstrated efficacy in disease prediction using EHRs. However, there remains some unanswered questions on how to best utilize such models, especially with very small fine-tuning cohorts. Methods: We utilized Med-BERT, an EHR-specific foundation model, and reformulated the disease binary prediction task into a token prediction task and a next visit mask token prediction task to align with Med-BERT’s pretraining task format in order to improve the accuracy of pancreatic cancer (PaCa) prediction in both few-shot and fully supervised settings. Results: The reformulation of the task into a token prediction task, referred to as Med-BERT-Sum, demonstrated slightly superior performance in both few-shot scenarios and larger data samples. Furthermore, reformulating the prediction task as a Next Visit Mask Token Prediction task (Med-BERT-Mask) significantly outperformed the conventional Binary Classification (BC) prediction task (Med-BERT-BC) by 3% to 7% in few-shot scenarios with data sizes ranging from 10 to 500 samples. These findings highlight that aligning the downstream task with Med-BERT’s pretraining objectives substantially enhances the model’s predictive capabilities, thereby improving its effectiveness in predicting both rare and common diseases. Conclusions: Reformatting disease prediction tasks to align with the pretraining of foundation models enhances prediction accuracy, leading to earlier detection and timely intervention. This approach improves treatment effectiveness, survival rates, and overall patient outcomes for PaCa and potentially other cancers.

Importance: Many patients who would benefit from minimally invasive surgery (MIS) have open surgery; robotic-assisted surgery (RAS) addresses some of the limitations of laparoscopic surgery and could increase rates of MIS across different patient populations. Objective: To determine whether the introduction of RAS increases MIS rates and whether increases are seen across different patient populations undergoing common general surgery procedures. Design: A retrospective cohort study was performed to compare rates of MIS in the year before and after the index date for hospitals that did and did not introduce RAS. Generalized estimating equation regression models were used to compare rates in MIS over time. Setting: PINC AI Healthcare Database, an all-payor discharge database of hospitals in the United States. Participants: Hospitals that performed cholecystectomy, inguinal hernia repair, ventral hernia repair, and colorectal resection from 2016 to 2022. Exposure: RAS hospitals performing at least 1 common general surgery procedure using RAS. Main Outcome and Measure: The primary analysis examined rates of MIS, defined as the rate of common general surgeries that were minimally invasive (laparoscopic or RAS) in a hospital. The secondary analysis examined MIS rates for common general surgeries, across age, sex, race, ethnicity, and payor. Results: Of 408 hospitals included in the study, 153 (38%) introduced RAS for common general surgeries. The relative MIS rate for hospitals that introduced RAS compared with hospitals that did not went from 1.08 (95% confidence interval [CI], 1.02–1.14; P < 0.01) before the index date to 1.15 (95% CI, 1.09–1.22; P < 0.01) after the index date (P interaction < 0.01), indicating a larger increase in MIS rates among hospitals introducing RAS. MIS rates increased significantly more in hospitals that introduced RAS across patient age, sex, ethnicity, race, and payor compared with hospitals that did not introduce RAS. Conclusions and Relevance: Hospitals that introduced RAS for common general surgery procedures were associated with an increase in MIS rates across different patient populations compared with hospitals that did not introduce RAS.

ABSTRACTObjectiveTo assess how patient and caregiver factors influence caregiver readiness for hospital discharge in palliative care patients.Study Setting and DesignThis transitional care study uses cross‐sectional data from a randomized controlled trial conducted from 2018 to 2023 testing an intervention for caregivers of hospitalized adult patients with a serious or life‐limiting illness who received a palliative care consult prior to transitioning out of the hospital.Data Sources and Analytical SampleCaregiver readiness was measured with the Family Readiness for Hospital Discharge Scale (n = 231). Caregiver demographic, intra‐ and interpersonal factors were self‐reported. Patient demographic, comorbidity score, and risk score for complicated discharge planning were extracted from electronic health records. Stepwise regression models estimated variance explained (r2) in caregiver readiness for patient hospital discharge.Principal FindingsPatient demographics and complexity were not statistically associated with caregiver readiness for discharge. Caregiver depressive symptoms, poor caregiver‐patient relationship quality, and fewer hours spent caregiving prior to hospitalization explained 29% of the variance in caregiver readiness.ConclusionsReliance on patient data may not be sufficient for explaining caregiver readiness for discharge. Assessing caregiver factors may be a better alternative for identifying caregivers at risk for low discharge readiness and those in need of additional support.Trial Registration: ClinicalTrials.gov on November 13, 2017, (No. NCT03339271)

AbstractBackgroundWe previously identified the novel mechanism of pathological tau transfer via extracellular vesicles (EVs) in Alzheimer’s disease (AD). Targeting EV secretion to mitigate tau transfer is therefore a promising therapeutic approach for AD. P2X purinoreceptor 7 (P2RX7), an ATP‐gated cationic channel, regulates microvesicle shedding or secretion of multivesicular body‐derived exosomes. We aim to investigate the effect of P2rx7 deficiency on disease progression in PS19 tauopathy mouse model in vivo and by proteomic profiling of brain EVs.MethodPS19:P2rx7–/– mice at 9 months of age were tested for the fear conditioning, and pathology assessment of the brain atrophy and tau using immunofluorescence against aggregated tau (Alz50) or phosphorylated tau (AT8) and ELISA. Mice were intracranially injected with viral vectors expressing mEmerald‐CD9 in microglia and P301L tau in neurons to visualize the secretion of microglial EV and extracellular tau in vivo. Brain EV samples were subjected to proteomic profiling by data independent acquisition mass‐spectrometry.ResultPS19:P2rx7–/– mice showed significant improvement in contextual and cued memory compared to age‐matched PS19 mice, which was accompanied by preserved cortical and hippocampal volume, and significant reduction of hippocampal tau pathology and pS396 tau in sarkosyl‐insoluble fraction of brain tissues. The number of GFP+ microglial EVs were significantly reduced in P2rx7–/– compared to WT mice. Gene ontology pathway analysis of EV proteome showed significant enrichment of mitochondrial pathways in PS19 group compared to WT group, which was significantly downregulated in PS19:P2rx7–/– group.ConclusionOur study demonstrated that P2rx7 deficiency ameliorates cognitive dysfunction and tau pathology development in PS19 mice by dampening microglial EV secretion and EV‐mediated mitochondria transfer, further indicating the therapeutic potential of targeting P2RX7, an EV regulatory molecule, to ameliorate AD progression.

Splenic marginal zone lymphoma (SMZL) is a B-cell malignancy with a typically indolent course. However, some patients have more aggressive disease and initial treatment can range from observation to chemoimmunotherapy. The reason for this spectrum of disease behavior is incompletely understood but the tumor microenvironment (TME) likely plays a role as recent studies have shown that an optimized antitumor immune response in SMZL patients would allow the immune system to better target malignant B cells and irradicate the disease. Regulatory CD4+T cells (Tregs) are crucial in maintaining TME homeostasis by suppressing effector T cells and malignant B cells and in this study, we therefore explored the key factors influencing the function and development of intratumoral Tregs in SMZL patients. We identified two distinct Treg subsets in the TME of SMZL patients: CD26+Tregs and CD161+Tregs, each with unique phenotypic profiles, functions, and prognostic significance. CD161+Tregs suppress CD8+T cells and malignant B cells more effectively than CD26+Tregs, which only inhibit CD8+T cells. Clinically, patients with inferior outcomes have significantly higher numbers of CD26+Tregs and fewer CD161+Tregs. To delineate differences between these subsets, we performed Cellular Indexing of Transcriptomes and Epitopes Sequencing (CITE-seq) on biopsies from 7 SMZL patients. We found that cytokine-inducible SH2-containing protein (CISH) is the most highly expressed gene in CD26+Tregs compared to CD161+Tregs, aside from FOXP3. CISH has been reported to be a negative regulator of immune effector cell activation in tumor models. Although CISH deficiency leads to a loss of Foxp3 expression and reduced Treg suppressive function, the mechanism by which CISH modulates Treg function, especially immune suppression in hematologic malignancies, remains largely unknown. To further investigate the mechanism of CISH in Treg function in MZL patients, we conducted CITE-seq analysis on a larger cohort of MZL patients (n=12), divided into groups based on outcomes (EFS24 failed, n=4; EFS24 achieved, n=8). The CITE-seq analysis results showed significantly higher CISH expression in Tregs from patients with inferior outcomes (P=1.07E-06). We then explored factors influencing CISH expression and found that TCR engagement and treatment with cytokines (IL-15, IL-2, and IL-7) elevated CISH expression in Tregs. While we previously observed that lymphoma B cells could enhance Foxp3 expression in CD4+CD25-T cells, this study we found that B cells could also enhance CISH and CD26 expression in CD4+CD25-T cells in vitro, indicating that a high frequency of B cells in the environment may lead to increased CISH expression in Treg cells leading to an unfavorable outcome in patients. We further investigated the role of CISH in the function of Treg cells. Following CISH knockdown in Treg cells, we observed decreased CD26 expression and reduced suppressive function on CD8+ T cell proliferation. Using CRISPR-Cas9, we knocked out CISH in the Karpas 299 cell line, a human T cell lymphoma line that constitutively expresses CD25, Foxp3, and CISH. CISH-KO Karpas 299 cells showed significantly less apoptosis and Foxp3 expression compared to CISH-WT cells. Bulk RNA-seq analysis of CISH-KO and CISH-WT Karpas 299 cells revealed that CISH-KO cells showed enhanced DNA replication and cell cycle pathway activity. Taken together, our results suggest that high expression of CISH in Tregs may predict an unfavorable outcome in SMZL patients. Malignant B-cells in the TME of SMZL patients may promote expression of CD26 and CISH in Tregs, thereby modulating Treg function. Targeting CISH could decrease the immunosuppressive activity of Tregs in the TME, potentially optimizing antitumor immunity in SMZL patients.

Introduction MYD88 L265P mutations (MUT) are found in 90% of patients with Waldenstrom macroglobulinemia (WM) and lead to the activation of pro-survival signaling. Limited literature has demonstrated that patients with MYD88 wild-type (WT) WM have poorer responses to conventional therapies and a higher likelihood of histological transformation. Increasingly the role of non-coding genomics in lymphomagenesis has demonstrated importance and currently, the epigenetic landscape of MYD88 WT WM remains underexplored. This study utilized a multi-omics approach to assess DNA methylation in MYD88 WT WM compared to MYD88 MUT patients and controls. Methods Bone marrow samples were prospectively collected from 20 subjects [3 MYD88 WT/CXCR4 WT WM, 12 MYD88 MUT WM and 5 normal controls] and positive selection for CD19+ and/or CD138+ B cells was performed. The analysis focused on the comparison between MYD88 WT WM to normal controls and MYD88-WT to MUT WM. Genome-wide DNA methylation analysis was performed, and CpG methylation ratios were segmented into 200-bp regions. Differentially methylated regions (DMRs) were determined using a Q-value &lt;0.05 and absolute methylation difference ≥10%. Next, RNA-seq data was interrogated and differentially expressed genes (log2fold change&gt;0.5 or &lt;-0.5, false discovery rate&lt;0.05) with corresponding promoter hypo- or hypermethylation were assessed. Ingenuity Pathway Analysis was used to determine potentially epigenetically regulated pathways using a corrected p&lt;0.05. Results Comparing MYD88 WT WM samples to controls, a statistically greater number of hypermethylated DMRs were observed across genomic regions (hyper- vs hypomethylated): promoter (29129 vs 6300), 3'untranslated region (UTR) (2068 vs 1551), 5'UTR (10169 vs 735), intron (30344 vs 24511), exon (2224 vs 6855), CpG island (30372 vs 1240) and CpG shore (14477 vs 5872) (all p&lt;0.001). Next, mRNA analysis demonstrated that 214 genes were differentially up-/downregulated with concordant promoter hypo-/hypermethylation. On the assessment of promoter-methylation-based pathways, multiple pathways involved in cell signaling, proliferation, gene regulation, cytokine and immune signaling and metabolism were found to be deregulated. Most pathways were found to be negatively enriched in MYD88 WT patients compared to controls including several members of interleukin (IL) signaling (IL-2, IL-3, IL,7) and regulators of cell proliferation and signaling including mTOR, PI3K/AKT, and p53. Positive enrichment of the PTEN, FGFR3 and ERK/MAPK pathways were observed. Underlying multiple pathways was promoter hypermethylation with corresponding mRNA downregulation of AKT3 and PIK3CA. Furthermore, promoter hypomethylation with transcript upregulation of PTEN was observed. Next, in comparison of MYD88 WT to MUT samples, a statistically greater number of hypermethylated DMRs were observed across genomic regions (hyper- vs hypomethylated): promoter (24829 vs 2544), 3'UTR (3534 vs 378), 5'UTR (6111 vs 605), intron (52292 vs 5360), exon (21066 vs 2187), CpG island (18334 vs 1551) and CpG shore (16351 vs 1957) (all p&lt;0.001). Assessing mRNA expression, 354 genes were up-/downregulated with concordant promoter hypo-/hypermethylation. Pathway analysis revealed positive enrichment of the mitotic G1 phase to G1/S transition pathway with upregulation of the CDK4, LYN, and PSMA6 transcripts in MYD88 WT compared to MUT samples. Further, negative enrichment of cell signaling regulators including the RHO GTPase family, IL pathways (IL-4, IL-8, IL-13, IL-17) and integrin signaling were found in MYD88 WT compared to MUT samples. Underlying multiple pathways were downregulation with promoter hypermethylation of BCL2, an important regulator of apoptosis. Conclusion Genome-wide methylation analysis of MYD88 WT WM revealed a unique DNA methylation profile, with potential epigenetic alteration of key oncogenic transcripts and pathways. The negative enrichment of cell signaling and cytokine/inflammatory pathways in MYD88 WT samples compared to controls and MYD88 MUT WM suggests an epigenetic mechanism for immune evasion and potentially underlies the reduced response to conventional WM-directed therapies. Overall, this study reveals that MYD88 WT WM is epigenetically distinct from MYD88 MUT WM and regulators such as methylation may underlie the unique clinical and phenotypic properties observed.