Using Targeted Transcriptome and Machine Learning of Pre- and Post-Transplant Bone Marrow Samples to Predict Acute Graft-versus-Host Disease and Overall Survival after Allogeneic Stem Cell Transplantation.

Acute graft-versus-host disease (aGvHD) remains a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). We performed RNA analysis of 1408 candidate genes in bone marrow samples obtained from 167 patients undergoing HSCT. RNA expression data were used in a machine learning algorithm to predict the presence or absence of aGvHD using either random forest or extreme gradient boosting algorithms. Patients were randomly divided into training (2/3 of patients) and validation (1/3 of patients) sets. Using post-HSCT RNA data, the machine learning algorithm selected 92 genes for predicting aGvHD that appear to play a role in PI3/AKT, MAPK, and FOXO signaling, as well as microRNA. The algorithm selected 20 genes for predicting survival included genes involved in MAPK and chemokine signaling. Using pre-HSCT RNA data, the machine learning algorithm selected 400 genes and 700 genes predicting aGvHD and overall survival, but candidate signaling pathways could not be specified in this analysis. These data show that NGS analyses of RNA expression using machine learning algorithms may be useful biomarkers of aGvHD and overall survival for patients undergoing HSCT, allowing for the identification of major signaling pathways associated with HSCT outcomes and helping to dissect the complex steps involved in the development of aGvHD. The analysis of pre-HSCT bone marrow samples may lead to pre-HSCT interventions including choice of remission induction regimens and modifications in patient health before HSCT.

Humoral and cellular immune responses against SARS-CoV-2 post-vaccination in immunocompetent and immunocompromised cancer populations.

Cancer patients are at risk for severe coronavirus disease 2019 (COVID-19) outcomes due to impaired immune responses. However, the immunogenicity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination is inadequately characterized in this population. We hypothesized that cancer vs non-cancer individuals would mount less robust humoral and/or cellular vaccine-induced immune SARS-CoV-2 responses. Receptor binding domain (RBD) and SARS-CoV-2 spike protein antibody levels and T-cell responses were assessed in immunocompetent individuals with no underlying disorders (n = 479) and immunocompromised individuals (n = 115). All 594 individuals were vaccinated and of varying COVID-19 statuses (i.e., not known to have been infected, previously infected, or "Long-COVID"). Among immunocompromised individuals, 59% (n = 68) had an underlying hematologic malignancy; of those, 46% (n = 31) of individuals received cancer treatment <30 days prior to study blood collection. Ninety-eight percentage (n = 469) of immunocompetent and 81% (n = 93) of immunocompromised individuals had elevated RBD antibody titers (>1,000 U/mL), and of these, 60% (n = 281) and 44% (n = 41), respectively, also had elevated T-cell responses. Composite T-cell responses were higher in individuals previously infected with SARS-CoV-2 or those diagnosed with Long-COVID compared to uninfected individuals. T-cell responses varied between immunocompetent vs carcinoma (n = 12) cohorts (P < 0.01) but not in immunocompetent vs hematologic malignancy cohorts. Most SARS-CoV-2 vaccinated individuals mounted robust cellular and/or humoral responses, though higher immunogenicity was observed among the immunocompetent compared to cancer populations. The study suggests B-cell targeted therapies suppress antibody responses, but not T-cell responses, to SARS-CoV-2 vaccination. Thus, vaccination continues to be an effective way to induce humoral and cellular immune responses as a likely key preventive measure against infection and/or subsequent more severe adverse outcomes. IMPORTANCE: The study was prompted by a desire to better assess the immune status of patients among our cancer host cohort, one of the largest in the New York metropolitan region. Hackensack Meridian Health is the largest healthcare system in New Jersey and cared for more than 75,000 coronavirus disease 2019 patients in its hospitals. The John Theurer Cancer Center sees more than 35,000 new cancer patients a year and performs more than 500 hematopoietic stem cell transplants. As a result, the work was undertaken to assess the effectiveness of vaccination in inducing humoral and cellular responses within this demographic.

Incidence of occult appendiceal neoplasm in patients over 40 years with acute appendicitis: A single-institution review.

OBJECTIVE: To investigate the incidence of occult appendiceal neoplasm in patients aged 40 years and over who underwent appendicectomy for appendicitis. METHODS: The clinical coding electronic database was used to identify patients aged 40 years and over who were diagnosed with appendicitis from September 2010 to September 2022. Patients were included if they were managed operatively. DESIGN: Retrospective cohort study. SETTING: Modified Monash category 3 (large rural town). PARTICIPANTS: Patients aged 40 years and over undergoing appendicectomy for appendicitis. MAIN OUTCOME MEASURES: Incidence of appendiceal neoplasm within appendicectomy specimen. RESULTS: A total of 279 patients aged 40 years and over underwent appendicectomy, with a median age of 53 years (range 40-95). Nineteen patients (7%) were found to have a primary neoplastic lesion within the appendix: seven neuroendocrine neoplasms (37%), six sessile serrated lesions (32%), two colonic-type adenocarcinoma (11%), two goblet cell adenocarcinoma (11%) and two appendiceal mucinous neoplasms (11%). Additionally, one patient had a metastatic adenocarcinoma of pancreaticobiliary aetiology. CONCLUSIONS: Occult appendiceal neoplasm was higher than reported in the literature in our cohort. This would support appendicectomy as the treatment of choice for patients aged 40 years and over with acute appendicitis and caution against nonoperative management in this demographic.

The role of screening colonoscopy after appendicitis in patients over 40 years of age.

BACKGROUND: There is some evidence of the association between acute appendicitis and colorectal neoplasm in patients over the age of 40 years. Despite this, few centres routinely evaluate the colon endoscopically following an episode of appendicitis in these patients. Our aim was to investigate the incidence of colorectal neoplasm in patients aged 40 years and over who underwent screening colonoscopy following acute appendicitis. METHODS: Retrospective cohort study of patients aged 40 years and over who were diagnosed with acute appendicitis via imaging or histology between January 2015 and May 2022. Findings on subsequent screening colonoscopy were evaluated and classified according to adenomatous and non-adenomatous lesions. RESULTS: A total of 176 patients met inclusion criteria, with a median age of 54 years (range 40-92) and female to male ratio of 1:1.3. One hundred patients (56%) had a colonoscopy following their admission, at a mean duration of 3.5 months post discharge. 15% of patients had an adenomatous polyp detected (10 adenomas, 4 advanced adenomas, and 1 sessile serrated adenoma), and 9% had a non-adenomatous lesion detected (8 hyperplastic polyps and 1 lipoma). CONCLUSION: Adenoma detection rate in patients aged 40 years and over undergoing colonoscopy after acute appendicitis was 15% in our cohort. This high adenoma detection rate supports the view of appendicitis as an indication for screening faecal immunochemical testing or colonoscopy in patients above 40 years.

Outcomes of laparoscopic colorectal cancer surgery in a non-metropolitan Australian hospital: audit of 120 patients with long-term follow-up results.

BACKGROUND: Laparoscopic colorectal cancer surgery has been shown to produce comparable oncological long-term results as well as improved short-term outcomes compared to open surgery in multicentre trials. Limited information is available whether these results are reproduced in non-metropolitan surgery. METHODS: Audit of prospectively collected follow-up data in a rural surgical centre in South Australia. Short- and long-term results of colorectal cancer patients undergoing elective laparoscopic surgery for cure. Outcomes are compared with results of open surgery. RESULTS: Survival and clinical data of 120 patients after laparoscopic resection were analysed and then benchmarked against results of 157 open resections. Conversion rate was 10.8% (N = 13). Mean patient age was 69.9 years. Mean number of lymph nodes analysed was 15.5. Mean follow-up is 53.0 months. Thirty-day mortality was 0.36% (n = 1) and 90-day mortality was 0.72% (n = 2). No differences in complications rates, long term survival or procedures performed were observed. This is a single centre audit of clinical and oncological outcomes and a number of exclusion criteria were applied. Patient gender, cancer stages as well as number of patients undergoing neoadjuvant radio-chemotherapy differ significantly between the study and the benchmarking group. Patients were not randomized and the benchmarking group is in part a historical control. CONCLUSIONS: This audit of clinical outcomes and survival after laparoscopic CRC resection for cure indicates that minimal invasive surgery may be suitable for adequately staffed and equipped rural centres.

Functional mapping of PHF6 complexes in chromatin remodeling, replication dynamics, and DNA repair.

The Plant Homeodomain 6 gene (PHF6) encodes a nucleolar and chromatin-associated leukemia tumor suppressor with proposed roles in transcription regulation. However, specific molecular mechanisms controlled by PHF6 remain rudimentarily understood. Here we show that PHF6 engages multiple nucleosome remodeling protein complexes, including nucleosome remodeling and deacetylase, SWI/SNF and ISWI factors, the replication machinery and DNA repair proteins. Moreover, after DNA damage, PHF6 localizes to sites of DNA injury, and its loss impairs the resolution of DNA breaks, with consequent accumulation of single- and double-strand DNA lesions. Native chromatin immunoprecipitation sequencing analyses show that PHF6 specifically associates with difficult-to-replicate heterochromatin at satellite DNA regions enriched in histone H3 lysine 9 trimethyl marks, and single-molecule locus-specific analyses identify PHF6 as an important regulator of genomic stability at fragile sites. These results extend our understanding of the molecular mechanisms controlling hematopoietic stem cell homeostasis and leukemia transformation by placing PHF6 at the crossroads of chromatin remodeling, replicative fork dynamics, and DNA repair.

Epigenetic reversal of hematopoietic stem cell aging in Phf6-knockout mice.

Aging is characterized by an accumulation of myeloid-biased hematopoietic stem cells (HSCs) with reduced developmental potential. Genotoxic stress and epigenetic alterations have been proposed to mediate age-related HSC loss of regenerative and self-renewal potential. However, the mechanisms underlying these changes remain largely unknown. Genetic inactivation of the plant homeodomain 6 (Phf6) gene, a nucleolar and chromatin-associated factor, antagonizes age-associated HSC decline. Immunophenotyping, single-cell transcriptomic analyses and transplantation assays demonstrated markedly decreased accumulation of immunophenotypically defined HSCs, reduced myeloid bias and increased hematopoietic reconstitution capacity with preservation of lymphoid differentiation potential in Phf6-knockout HSCs from old mice. Moreover, deletion of Phf6 in aged mice rejuvenated immunophenotypic, transcriptional and functional hallmarks of aged HSCs. Long-term HSCs from old Phf6-knockout mice showed epigenetic rewiring and transcriptional programs consistent with decreased genotoxic stress-induced HSC aging. These results identify Phf6 as an important epigenetic regulator of HSC aging.

Impact of a Dedicated Education Unit Experience on Critical Thinking Development in Nursing Students.

AIM: The purpose of this study was to identify the impact of the dedicated education unit (DEU) on nursing students' critical thinking ability. BACKGROUND: The DEU is an innovative approach to clinical education, which uses clinical nurses with expert practice consistently in a competency-based experience. METHOD: Participants (intervention and control groups) completed the Nursing Executive Center's Critical Thinking Diagnostic Assessment tool before and after clinical experience. RESULTS: Participants included 243 students with 179 non-DEU and 64 DEU students. There were significant increases in total pretest and posttest score means (P < .05) for the DEU (intervention) group. A significant change (P < .0001) was seen in critical thinking scores by category for both groups and in the intervention group on pretest and posttest scores, even after controlling for pretest scores (P < .0001). CONCLUSIONS: Results support the efficacy of the DEU model in developing critical thinking. Prior DEU studies have focused on implementation and satisfaction with the model.

Mutational and functional genetics mapping of chemotherapy resistance mechanisms in relapsed acute lymphoblastic leukemia.

Multi-agent combination chemotherapy can be curative in acute lymphoblastic leukemia (ALL). Still, patients with primary refractory disease or with relapsed leukemia have a very poor prognosis. Here we integrate an in-depth dissection of the mutational landscape across diagnostic and relapsed pediatric and adult ALL samples with genome-wide CRISPR screen analysis of gene-drug interactions across seven ALL chemotherapy drugs. By combining these analyses, we uncover diagnostic and relapse-specific mutational mechanisms as well as genetic drivers of chemoresistance. Functionally, our data identifies common and drug-specific pathways modulating chemotherapy response and underscores the effect of drug combinations in restricting the selection of resistance-driving genetic lesions. In addition, by identifying actionable targets for the reversal of chemotherapy resistance, these analyses open novel therapeutic opportunities for the treatment of relapse and refractory disease.

Intraoperative cholangiogram during laparoscopic cholecystectomy: A clinical trial in rural setting.

OBJECTIVE: The routine use of intraoperative cholangiogram (IOC) in laparoscopic cholecystectomy (LC) remains a contentious issue. IOC helps to delineate biliary tree anatomy, prevent bile duct injury and image stones in the common bile duct (CBD). It may prove to be a valuable alternative to ERCP or MRCP, especially in the rural setting with limited resources. DESIGN/SETTING/PARTICIPANTS/INTERVENTIONS/MAIN OUTCOME MEASURES: All patients undergoing laparoscopic cholecystectomy during a 12-month period were audited. For the first 6 months, patients were recruited for routine IOC and for the second 6 months, routine IOC was not performed. Cases were analysed with regard to patient demographics, operative details and clinical outcomes. RESULTS: A total of 75 patients were analysed within the 12-month period. The majority were women aged 41-50. Ultrasound suggested common bile duct stones in 6.7% of cases. IOC was attempted in 50.7% of cases. Of these, 29 (76.3%) were successful. IOC added an average of 28 min to total theatre time. A total of 75% (n = 22) of IOCs showed normal flow of contrast into the intra- and extra-hepatic biliary systems. In 17% (n = 5) of patients, stones within the CBD were suspected, and these were referred for further management. ERCP/MRCP confirmed CBD stones in 60% (n = 3) of these patients. There was poor correlation between pre-operative suspicion and confirmed CBD stones (two patients only with pre-operative suspected CBD stone confirmed on IOC and ERCP). There were no operative complications related to IOC. There were no post-operative complications in cases where no IOC was done. CONCLUSION: The majority of patients treated in our centre were women, middle-aged patients booked for elective laparoscopic cholecystectomy. Although only 6.7% cases were suspicious for CBD stones pre-operatively, a total of 17% of patients with routine IOC suggested CBD stones. IOC was found to be safe, taking only an additional 28 min of total theatre time. Routine rather than selective use of IOC could be considered to improve patient safety and long-term results.

Building for an exit (or not).

A young biotech firm can grow in several ways. The key to success is preparing for them all.

Harmonizing legal and ethical standards for interactions between health care providers and industry.

A complex set of federal and state laws, together with numerous voluntary codes, regulate the provision of gifts, consulting arrangements, and other interactions between industry and health care professionals. The provisions of these laws and codes are reviewed, and a suggested harmonization with respect to the most common types of interactions is proposed.