Higher 2-Year Cumulative Incidence of Mental Health Disorders Following Irrigation and Debridement in Primary Lumbar Fusion.

Introduction: Spinal fusion is an operation that is employed to treat spinal diseases. Surgical site infection (SSI) after lumbar fusion (LF) is a postoperative complication. SSI is treated with irrigation and debridement (I&D), which requires readmittance following discharge or prolonged hospital stays, which are deleterious to patients' mental health. The long-term relationship between treating SSI with I&D and patients' mental health is still understudied. Methods: Using the Mariner dataset from the PearlDiver Patient Records Database using Current Procedural Terminology and International Classification of Diseases procedure codes, retrospective cohort analysis was carried out. This study involved 445,480 patients who underwent LF with at least 2-year follow-up and were followed up for 2 years. Of the patients, 2,762 underwent I&D. Using univariate analysis employing Pearson Chi-square and Student t-test, where appropriate (Table 1), patient demographics between cohorts were gathered. 2-year cumulative incidence (CI) between LF and I&D cohorts was calculated using Kaplan-Meier analysis (Fig. 1, 2, 3). Cox proportional hazards were employed to observe significant differences in CI rates (Table 2). Results: For patients who received I&D, 2-year CI depression (HR: 1.72; 95% CI: 1.49-1.99; P<0.001) and stress (HR: 1.35; 95% CI: 1.02-1.79; P=0.035) rates were significantly higher than for those who did not. There was no statistically significant difference in 2-year CI anxiety rates between cohorts (HR: 0.92; 95% CI: 0.58-1.46; P=0.719). Conclusions: In conclusion, 16.8% of patients developed new-onset depression 2 years following I&D, in comparison to 10.3% of those who underwent LF. Patients who underwent I&D following LF were significantly more likely to experience depression and stress. To mitigate negative mental health outcomes, mental health services should be available to patients who underwent surgery.

CS-iCCA, A New Clinically Based Staging System for Intrahepatic Cholangiocarcinoma: Establishment and External Validation.

INTRODUCTION: Intrahepatic cholangiocarcinoma (iCCA) is a primary liver malignancy with poor prognosis. Current prognostic methods are most accurate for patients with surgically resectable disease. However, a significant proportion of patients with iCCA are not surgical candidates. We aimed to develop a generalizable staging system based on clinical variables to determine prognosis of all patients with iCCA. METHODS: The derivation cohort included 436 patients with iCCA seen between 2000 and 2011. For external validation, 249 patients with iCCA seen from 2000 to 2014 were enrolled. Survival analysis was performed to identify prognostic predictors. All-cause mortality was the primary end point. RESULTS: Eastern Cooperative Oncology Group status, tumor number, tumor size, metastasis, albumin, and carbohydrate antigen 19-9 were incorporated into a 4-stage algorithm. Kaplan-Meier estimates for 1-year survival were 87.1% (95% confidence interval [CI] 76.1-99.7), 72.7% (95% CI 63.4-83.4), 48.0% (95% CI 41.2-56.0), and 16% (95% CI 11-23.5), respectively, for stages I, II, III, and IV. Univariate analysis yielded significant differences in risk of death for stages II (hazard ratio [HR] 1.71; 95% CI 1.0-2.8), III (HR 3.32; 95% CI 2.07-5.31), and IV (HR 7.44; 95% CI 4.61-12.01) compared with stage I (reference). Concordance indices showed the new staging system was superior to the TNM staging for predicting mortality in the derivation cohort, P < 0.0001. In the validation cohort, however, the difference between the 2 staging systems was not significant. DISCUSSION: The proposed independently validated staging system uses nonhistopathologic data to successfully stratify patients into 4 stages. This staging system has better prognostic accuracy compared with the TNM staging and can assist physicians and patients in treatment of iCCA.

Higher Cell-Mediated Immune Responses in Patients With Inflammatory Bowel Disease on Anti-TNF Therapy After COVID-19 Vaccination.

BACKGROUND: Some patients with inflammatory bowel disease (IBD) on immunosuppressive therapies may have a blunted response to certain vaccines, including the messenger RNA (mRNA) coronavirus disease 2019 (COVID-19) vaccines. However, few studies have evaluated the cell-mediated immune response (CMIR), which is critical to host defense after COVID-19 infection. The aim of this study was to evaluate the humoral immune response and CMIR after mRNA COVID-19 vaccination in patients with IBD. METHODS: This prospective study (HERCULES [HumoRal and CellULar initial and Sustained immunogenicity in patients with IBD] study) evaluated humoral immune response and CMIR after completion of 2 doses of mRNA COVID-19 vaccines in 158 IBD patients and 20 healthy control (HC) subjects. The primary outcome was the CMIR to mRNA COVID-19 vaccines in patients with IBD. The secondary outcomes were a comparison of (1) the CMIR in patients with IBD and HC subjects, (2) CMIR and humoral immune response in all participants, and (3) correlation between CMIR and humoral immune response. RESULTS: The majority (89%) of patients with IBD developed a CMIR, which was not different vs HC subjects (94%) (P = .6667). There was no significant difference (P = .5488) in CMIR between immunocompetent (median 255 [interquartile range, 146-958] spike T cells per million peripheral blood mononuclear cells) and immunosuppressed patients (median 377 [interquartile range, 123-1440]). There was no correlation between humoral and cell-mediated immunity after vaccination (P = .5215). In univariable analysis, anti-tumor necrosis factor therapy was associated with a higher CMIRs (P = .02) and confirmed in a multivariable model (P = .02). No other variables were associated with CMIR. CONCLUSIONS: Most patients with IBD achieved CMIR to a COVID-19 vaccine. Future studies are needed evaluating sustained CMIR and clinical outcomes.

Antibody and T cell responses to coronavirus disease 2019 vaccines in patients with inflammatory bowel disease do not correlate. Most patients with inflammatory bowel disease mount a T cell response despite being on biologic therapies, those on anti-tumor necrosis factor may have a higher T cell response. Anti-tumor necrosis factor therapy has been associated with a lower antibody response to coronavirus disease 2019 vaccines, but the T cell response is augmented.

Humoral Responses After SARS-CoV-2 mRNA Vaccination and Breakthrough Infection in Cancer Patients.

OBJECTIVE: To evaluate the magnitude of humoral response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) messenger RNA (mRNA) vaccines in patients with cancer receiving active therapies. PATIENTS AND METHODS: Patients 18 years or older in whom SARS-CoV-2 spike antibody (anti-S Ab) levels were measured after 2 doses of SARS-CoV-2 mRNA vaccines were included. Patients with prior coronavirus disease 2019 (COVID-19) infection or receiving other immunosuppressive therapy were excluded. RESULTS: Among 201 patients who met the criteria, 61 were immunocompetent, 91 had a hematologic malignancy, and 49 had a solid malignancy while receiving treatments associated with cytopenia, including chemotherapy or cyclin-dependent kinase 4 and 6 inhibitors. A significantly greater proportion of immunocompetent patients (96.7% [59 of 61]) had anti-S Ab titers of 500 U/mL or greater compared to patients with hematologic (7.7% [7 of 91) and solid (55.1% [27 of 49]) malignancy (P<.001). Despite 2 doses of SARS-CoV-2 mRNA vaccines, 52.7% of patients with hematologic malignancy (48 of 91) and 8.2% of those with solid malignancy (4 of 49) receiving cytopenic therapy had no seroconversion (spike antibody titers <0.8 U/mL). Two patients subsequently had development of breakthrough COVID-19 infection after full vaccination. CONCLUSION: A substantial proportion of patients with hematologic and solid malignancies receiving chemotherapies and CDK4/6i had poor humoral responses after SARS-CoV-2 mRNA vaccination. Our study adds to a growing body of literature suggesting that immunosuppressed patients have a suboptimal humoral response to COVID-19 vaccination. Our study also underscores the importance of assessing antibody response after COVID-19 vaccines in these vulnerable patients.

Comparison of Clinical Features and Outcomes Between Intrahepatic Cholangiocarcinoma and Hepatocellular Carcinoma in the United States.

BACKGROUND AND AIMS: Intrahepatic cholangiocarcinoma (iCCA) and hepatocellular carcinoma (HCC) are the most common primary liver cancers (PLCs). Differences in their clinical features and outcomes are open for investigation in a large-scale study. We aim to investigate the differences in clinical features and outcomes between iCCA and HCC. APPROACH AND RESULTS: The Surveillance, Epidemiology, and End Results Program 18 Database (2000-2017) was used to extract demographic and clinical features of HCC and iCCA patients. Logistic regression analysis was performed to identify factors associated with iCCA diagnosis versus HCC. Cox regression analysis was used to assess factors affecting overall survival (OS). There were 13,611 iCCA and 96,151 HCC patients. Half of iCCA (50.7%) and three quarters of HCC (76.3%) patients were male. Diagnosis in recent year, age (<50 or ≥65), female sex, non-Hispanic White race, higher income, rural area, and higher tumor burden were independently associated with iCCA diagnosis versus HCC. Patients with iCCA had worse OS than those with HCC (9 vs. 13 months; P < 0.001). However, OS was comparable between iCCA and HCC in multivariable analysis (adjusted hazard ratio [aHR] = 1.02; 95% CI = 0.99-1.05). In subgroup analyses, iCCA was associated with better OS than HCC in patients with tumor ≥5 cm (aHR = 0.83; 95% CI = 0.80-0.86), lymph node involvement (aHR = 0.76; 95% CI = 0.72-0.81), distant metastasis (aHR = 0.76; 95% CI = 0.73-0.79), poorly/undifferentiated tumors (aHR = 0.88; 95% CI = 0.83-0.94), and those receiving noncurative treatment (aHR = 0.96; 95% CI = 0.93-0.98). CONCLUSIONS: We identified the demographic, socioeconomic, and clinical features associated with iCCA diagnosis over HCC among patients with PLC. Although iCCA patients presented at an advanced stage, OS was similar between iCCA and HCC in multivariable analysis. iCCA was associated with longer OS for subgroups with poor prognostic features.

Pathologic Response of Hepatocellular Carcinoma Treated with Yttrium-90 Glass Microsphere Radiation Segmentectomy Prior to Liver Transplantation: A Validation Study.

PURPOSE: To evaluate the pathologic outcomes of hepatocellular carcinoma (HCC) treated with Yttrium-90 radiation segmentectomy using glass microspheres prior to liver transplantation and explore parameters associated with pathologic necrosis. MATERIALS AND METHODS: A single-institution retrospective analysis of HCC patients who received radiation segmentectomy prior to liver transplantation from November 2016 to May 2020 was performed. Patients were included if the treatment angiosome encompassed the entire tumor and could be correlated with available gross pathology. Archived histology slides were reviewed for percentage of pathologic necrosis. Thirty-three patients with 37 tumors were evaluated. The median tumor size was 2.3 cm (range, 1-6.7 cm). RESULTS: All tumors received a single treatment. The median time from radiation segmentectomy to transplantation was 206 days (range, 58-550 days). Objective response per Modified Response Evaluation Criteria in Solid Tumors (mRECIST) was 92% (complete response, 76%; partial response, 16%). A total of 68% (n = 25) of tumors demonstrated ≥99% pathologic necrosis. Complete pathologic necrosis was present in 53% and 75% of tumors treated with >190 Gy (n = 18) and >500 Gy (n = 8) single-compartment Medical Internal Radiation Dose, respectively. Complete response per mRECIST, posttreatment angiosome T1 hypointensity, dose >190 Gy, microsphere specific activity >297 Bq, and a longer time between treatment and transplant were associated with ≥99% tumor necrosis (P < .05). No posttransplant tumor recurrences occurred within a median follow-up of 604 days (range, 138-1,223 days). CONCLUSIONS: Radiation segmentectomy can serve as an ablative modality for the treatment of HCC prior to liver transplant.

Educational Intervention in Primary Care Residents' Knowledge and Performance of Hepatitis B Vaccination in Patients with Diabetes Mellitus.

OBJECTIVES: Although guidelines recommend hepatitis B virus (HBV) immunization for adults with diabetes mellitus (DM), vaccination rates remain low. Our aim was to evaluate knowledge and practice regarding HBV and to assess the effectiveness of a multifaceted educational program. METHODS: Primary care residents (n = 244) at three academic institutions were surveyed about various aspects of HBV. Residents at one training program were then randomly assigned to an educational intervention (E) (n = 20) and control group (C) (n = 19). The E group received a focused didactic lecture and periodic e-mail reminders with immediate feedback. We compared knowledge scores before and after the intervention. Chart audits were conducted to evaluate the residents' behavior. RESULTS: A total of 103 (42%) residents responded to the survey. The survey indicated that residents lacked the necessary knowledge and risk assessment skills concerning HBV in patients with DM. In the controlled trial of the E intervention, both groups had similar baseline knowledge scores. The E group had a significant increase in the immediate postintervention knowledge scores from a mean of 29% at baseline to 70% (P < 0.001) that was sustained 6 months postintervention (65%; P < 0.001). In the C group, 6-month postintervention scores were not different from baseline (38% vs 29%). No significant differences were observed in documentation skills. CONCLUSIONS: A combined educational program was effective in enhancing knowledge about HBV and vaccination in DM but had limited influence on physicians' practice. Further study incorporating system changes along with educational initiatives is required to improve clinical practice.

GAIP interacting protein C-terminus regulates autophagy and exosome biogenesis of pancreatic cancer through metabolic pathways.

GAIP interacting protein C terminus (GIPC) is known to play an important role in a variety of physiological and disease states. In the present study, we have identified a novel role for GIPC as a master regulator of autophagy and the exocytotic pathways in cancer. We show that depletion of GIPC-induced autophagy in pancreatic cancer cells, as evident from the upregulation of the autophagy marker LC3II. We further report that GIPC regulates cellular trafficking pathways by modulating the secretion, biogenesis, and molecular composition of exosomes. We also identified the involvement of GIPC on metabolic stress pathways regulating autophagy and microvesicular shedding, and observed that GIPC status determines the loading of cellular cargo in the exosome. Furthermore, we have shown the overexpression of the drug resistance gene ABCG2 in exosomes from GIPC-depleted pancreatic cancer cells. We also demonstrated that depletion of GIPC from cancer cells sensitized them to gemcitabine treatment, an avenue that can be explored as a potential therapeutic strategy to overcome drug resistance in cancer.

Reduced C9orf72 gene expression in c9FTD/ALS is caused by histone trimethylation, an epigenetic event detectable in blood.

Individuals carrying (GGGGCC) expanded repeats in the C9orf72 gene represent a significant portion of patients suffering from amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Elucidating how these expanded repeats cause "c9FTD/ALS" has since become an important goal of the field. Toward this end, we sought to investigate whether epigenetic changes are responsible for the decrease in C9orf72 expression levels observed in c9FTD/ALS patients. We obtained brain tissue from ten c9FTD/ALS individuals, nine FTD/ALS cases without a C9orf72 repeat expansion, and nine disease control participants, and generated fibroblastoid cell lines from seven C9orf72 expanded repeat carriers and seven participants carrying normal alleles. Chromatin immunoprecipitation using antibodies for histone H3 and H4 trimethylated at lysines 9 (H3K9), 27 (H3K27), 79 (H3K79), and 20 (H4K20) revealed that these trimethylated residues bind strongly to C9orf72 expanded repeats in brain tissue, but not to non-pathogenic repeats. Our finding that C9orf72 mRNA levels are reduced in the frontal cortices and cerebella of c9FTD/ALS patients is consistent with trimethylation of these histone residues, an event known to repress gene expression. Moreover, treating repeat carrier-derived fibroblasts with 5-aza-2-deoxycytidine, a DNA and histone demethylating agent, not only decreased C9orf72 binding to trimethylated histone residues, but also increased C9orf72 mRNA expression. Our results provide compelling evidence that trimethylation of lysine residues within histones H3 and H4 is a novel mechanism involved in reducing C9orf72 mRNA expression in expanded repeat carriers. Of importance, we show that mutant C9orf72 binding to trimethylated H3K9 and H3K27 is detectable in blood of c9FTD/ALS patients. Confirming these exciting results using blood from a larger cohort of patients may establish this novel epigenetic event as a biomarker for c9FTD/ALS.

TIMP-1 attenuates blood-brain barrier permeability in mice with acute liver failure.

Blood-brain barrier (BBB) dysfunction in acute liver failure (ALF) results in increased BBB permeability that often precludes the patients from obtaining a life-saving liver transplantation. It remains controversial whether matrix metalloproteinase-9 (MMP-9) from the injured liver contributes to the deregulation of BBB function in ALF. We selectively upregulated a physiologic inhibitor of MMP-9 (TIMP-1) with a single intracerebroventricular injection of TIMP-1 cDNA plasmids at 48 and 72 hours, or with pegylated-TIMP-1 protein. Acute liver failure was induced with tumor necrosis factor-α and D-(+)-galactosamine in mice. Permeability of BBB was assessed with sodium fluorescein (NaF) extravasation. We found a significant increase in TIMP-1 within the central nervous system (CNS) after the administration of TIMP-1 cDNA plasmids and that increased TIMP-1 within the CNS resulted in an attenuation of BBB permeability, a reduction in activation of epidermal growth factor receptor and p38 mitogen-activated protein kinase signals, and a restoration of the tight junction protein occludin in mice with experimental ALF. Pegylated TIMP-1 provided similar protection against BBB permeability in mice with ALF. Our results provided a proof of principle that MMP-9 contributes to the BBB dysfunction in ALF and suggests a potential therapeutic role of TIMP-1 in ALF.

Efficacy and safety of telithromycin 800 mg once daily for 7 days in community-acquired pneumonia: an open-label, multicenter study.

BACKGROUND: Community-acquired pneumonia (CAP) remains a major cause of morbidity and mortality throughout the world. Telithromycin (a new ketolide) has shown good in vitro activity against the key causative pathogens of CAP, including S pneumoniae resistant to penicillin and/or macrolides. METHODS: The efficacy and safety of telithromycin 800 mg orally once daily for 7 days in the treatment of CAP were assessed in an open-label, multicenter study of 442 adults. RESULTS: Of 149 microbiologically evaluable patients, 57 (9 bacteremic) had Streptococcus pneumoniae. Of the 57 S pneumoniae pathogens isolated in these patients, 9 (2 bacteremic) were penicillin- or erythromycin-resistant; all 57 were susceptible to telithromycin and were eradicated. Other pathogens and their eradication rates were: Haemophilus influenzae (96%), Moraxella catarrhalis (100%), Staphylococcus aureus (80%), and Legionella spp. (100%). The overall bacteriologic eradication rate was 91.9%. Of the 357 clinically evaluable patients, clinical cure was achieved in 332 (93%). In the 430 patients evaluable for safety, the most common drug-related adverse events were diarrhea (8.1%) and nausea (5.8%). CONCLUSION: Telithromycin 800 mg once daily for 7 days is an effective and well-tolerated oral monotherapy and offers a new treatment option for CAP patients, including those with resistant S pneumoniae.

Development of a New Zealand white rabbit model of spinal pseudarthrosis repair and evaluation of the potential role of OP-1 to overcome pseudarthrosis.

STUDY DESIGN: Posterolateral lumbar fusions were performed in nicotine-exposed, New Zealand white rabbits. Animals that developed a pseudarthrosis were then regrafted with no graft, autograft, or osteogenic protein-1 (OP-1). OBJECTIVES: To establish a model of pseudarthrosis repair and to evaluate the ability of OP-1 to induce fusion in this model. SUMMARY OF BACKGROUND DATA: OP-1 has been shown to have a 100% fusion rate in an established rabbit fusion model, even in the presence of nicotine, which is known to inhibit fusion. METHODS: Forty-four New Zealand white rabbits underwent posterolateral lumbar fusion with iliac crest autograft. To maximize the incidence of pseudarthroses, nicotine was administered to all rabbits. At 5 weeks, the spines were explored, and all pseudarthroses were redecorticated and grafted with no graft, autograft, or OP-1. At 10 weeks, the rabbits were killed and fusions masses were assessed with manual palpation, radiography, computed tomography, and/or histology. RESULTS: Nine rabbits (20%) were lost to complications. Thirty-four (94%) had pseudarthroses on exploration at 5 weeks. By manual palpation at 10 weeks, 1 of 10 (10%) pseudarthroses that received no graft fused, 5 of 12 (42%) pseudarthroses that received autograft fused, and 9 of 11 (82%) pseudarthroses that received OP-1 fused. Computed tomography and histology further characterized the fusion masses. CONCLUSIONS: This study establishes a model for treatment of pseudarthroses. OP-1, which has previously been shown to have 100% fusion rate in animal models, outperformed autograft and induced fusion in 82% of rabbits.

Posterolateral lumbar fusions in athymic rats: characterization of a model.

BACKGROUND CONTEXT: The athymic rat has been used to study the role of osteoinductive products in spinal fusions. This small animal model has been advocated to minimize potential inflammatory responses to allogeneic or xenogenic proteins. Despite past experience, this model has not yet been well characterized. PURPOSE: To further define and validate a posterolateral lumbar fusion model in the athymic rat. STUDY DESIGN/SETTING: Comparison of fusions after animal survival surgery. PATIENT SAMPLE: Forty athymic and 20 normothymic rats. OUTCOME MEASURES: Manual palpation, radiography and histology at 3 and 6 weeks. METHODS: Single-level intertransverse fusions were performed at the L4-L5 level of 40 athymic rats. Twenty rats were implanted with autograft (athymic/autograft), and 20 had no graft placed (athymic/no graft). An additional 20 autograft fusions were performed on normothymic rats (normothymic/autograft). Half were sacrificed at 3 weeks; half were sacrificed at 6 weeks. RESULTS: At 3 weeks, 0% of the athymic/no graft rats fused, 20% of the athymic/autograft rats fused and 20% of the normothymic/autograft rats fused by manual palpation. At 6 weeks, 0% of the athymic/no graft rats fused, 30% of the athymic/autograft rats fused and 40% of the normothymic/autograft rats fused by manual palpation. Radiographs were of limited utility in determining fusion, and histology results were roughly concordant with those of manual palpation. CONCLUSIONS: This work further characterizes the athymic rat posterolateral lumbar fusion model. The absence of a thymus does not appear to affect autograft fusion rates, and no spontaneous fusions were seen when no graft was placed.