Histone variant H2BE enhances chromatin accessibility in neurons to promote synaptic gene expression and long-term memory.

Regulation of histone proteins affects gene expression through multiple mechanisms including exchange with histone variants. However, widely expressed variants of H2B remain elusive. Recent findings link histone variants to neurological disorders, yet few are well studied in the brain. We applied new tools including novel antibodies, biochemical assays, and sequencing approaches to reveal broad expression of the H2B variant H2BE, and defined its role in regulating chromatin structure, neuronal transcription, and mouse behavior. We find that H2BE is enriched at promoters and a single unique amino acid allows it to dramatically enhance chromatin accessibility. Lastly, we show that H2BE is critical for synaptic gene expression and long-term memory. Together, these data reveal a novel mechanism linking histone variants to chromatin regulation, neuronal function, and memory. This work further identifies the first widely expressed H2B variant and uncovers a single histone amino acid with profound effects on genomic structure.

Attitudes on Equal Health Care Access versus Efficient Clinical Decisions across a Not-for-Profit Health Care System.

BACKGROUND: Professional roles within a hospital system may influence attitudes behind clinical decisions. OBJECTIVE: To determine participants' preferences about clinical decisions that either value equal health care access or efficiency. DESIGN: Deidentified survey asking participants to choose between offering a low-cost screening test to a whole population ("equal access") or a more sensitive, expensive test that could be given to only half of the population but resulting in 10% more avoided deaths ("efficient"). Data collection took place from August 18, 2021, to January 24, 2022. Study 1644 was determined to be exempt by Tufts Health Sciences Institutional Review Board (IRB). SETTING: Tufts Medicine Healthcare System. PARTICIPANTS: Approximately 15,000 hospital employees received an e-mail from the Tufts Medicine Senior Vice President of Academic Integration. MEASUREMENTS: Analysis of survey responses with chi-square and 1-sample t tests to determine the proportion who chose each option. Logistic regression models fit to examine relationships between professional role and test choice. RESULTS: A total of 1,346 participants completed the survey (∼9.0% response rate). Overall, approximately equal percentages of respondents chose the "equal access" (48%) and "efficient" option (52%). However, gender, professional role (categorical), and clinical role (dichotomous) were significantly associated with test choice. For example, among those in nonclinical roles, women were more likely than men to choose equal health care access. In multivariable analyses, having clinical roles was significantly associated with 1.73 times the likelihood of choosing equal access (95% confidence interval = 1.33-2.25). LIMITATIONS: Generalizability concerns and survey question wording limit the study results. CONCLUSION: Clinicians were more likely than nonclinicians to choose the equal health care access option, and health care administrators were more likely to choose efficiency. These differing attitudes can affect patient care and health care quality. HIGHLIGHTS: Divergent preferences of valuing equal health care access and efficiency may be in conflict during clinical decision making.In this cross-sectional study that included 1,346 participants, approximately equal percentages of respondents chose the "equal access" (48%) and "efficient" option (52%), a nonsignificant difference. However, gender, professional role (categorical), and clinical role (dichotomous) were significantly associated with test choiceSince clinicians were more likely than nonclinicians to choose the equal health care access option and health care administrators were more likely to choose efficiency, these differing attitudes can affect patient care and health care quality.

Granular cell tumour of the pancreas: a case report and systematic review.

PURPOSE: Granular cell tumours (GCTs) of the pancreas are mostly benign and exceptionally rare, with no unique identifying radiological features. Following a case discussion of a patient with GCT, a comprehensive review of available literature was conducted to identify the common diagnostic features associated with GCT. METHODS: Following a case report identified in our institution, a systematic review was conducted by two authors in accordance with Preferred Reporting Items for Systematic review and Meta-Analysis protocols (PRISMA) guidelines. Databases MEDLINE, EMBASE, Scopus, World of Science, and grey literature were searched on August 2021. Inclusion criteria were histopathology diagnosed granular cell tumour of the pancreas. RESULTS: A 37-year-old male presented with 1 month of abdominal pain and an MRI demonstrating a dilated main pancreatic duct, distal parenchymal atrophy, but no focal lesion. Repeat MRI at 6 months re-demonstrated similar findings and subsequent endoscopic ultrasound was suspicious for main duct IPMN. Following multidisciplinary team discussion, a spleen-preserving distal pancreatectomy was performed. Histopathology demonstrated granular cell tumour with cells diffusely positive for S100 and no malignant transformation. 11 case reports were identified in the literature with diagnosis confirmed on tissue histopathology based on positive immunohistochemical staining for S-100 protein. Eight patients presented with gastrointestinal symptoms with abdominal pain the main presenting complaint (50%). 10 patients underwent CT with portal venous contrast and all underwent endoscopic examination. Imaging findings were similar in five studies for EUS which demonstrated a hypoechoic lesion with homogenous appearance. On non-contrast CT GCT was iso-enhancing, and with portal venous contrast demonstrated hypo-enhancement that gradually enhanced on late phases. Pre-operative diagnosis of pancreatic carcinoma was described in six cases based on imaging and biopsy, resulting in progression to surgical resection. Nine patients were managed surgically and no complications identified on follow-up (6-52 months). CONCLUSION: The currently proposed management pathway includes EUS with biopsy and CT, and surgical resection recommended due to malignancy risk. Improved sample collection with EUS-FNA and microscopic assessment utilising S-100 immunohistochemistry may improve pre-operative diagnosis. Limitations include rare numbers in reported literature and short follow-up not allowing an assessment of GCT's natural history and malignancy risk. Additional cases would expand the current dataset of GCTs of the pancreas, so that surgical resection may be avoided in the future.

Impact of COVID-19 on Adolescent HIV Prevention and Treatment Services in the AHISA Network.

We investigated perceived impacts of COVID-19 on the delivery of adolescent HIV treatment and prevention services in sub-Saharan Africa (SSA) by administering a survey to members of the Adolescent HIV Prevention and Treatment Implementation Science Alliance (AHISA) from February to April 2021. We organized COVID-19 impacts, as perceived by AHISA teams, under three themes: service interruptions, service adjustments, and perceived individual-level health impacts. AHISA teams commonly reported interruptions to prevention programs, diagnostic testing, and access to antiretroviral therapy (ART). Common service adjustments included decentralization of ART refills, expanded multi-month ART distribution, and digital technology use. Perceived individual-level impacts included social isolation, loss to follow-up, food insecurity, poverty, and increases in adolescent pregnancies and sexually transmitted infections. The need for collaboration among stakeholders were commonly cited as lessons learned by AHISA teams. Survey findings highlight the need for implementation science research to evaluate the effects of pandemic-related HIV service adaptations in SSA.

Impact of COVID-19 on Adolescent HIV Prevention and Treatment Research in the AHISA Network.

Members of the Adolescent HIV Prevention and Treatment Implementation Science Alliance (AHISA) network conduct research aiming to close gaps between what is known to be impactful across the HIV prevention and treatment cascade, and services delivered to optimize outcomes for adolescents/young adults (AYA) in high HIV-prevalence settings. The COVID-19 pandemic introduced new challenges which threaten to exacerbate care and access disparities. We report results of a survey among AHISA teams with active AYA HIV research programs in African countries to determine how the pandemic has impacted their efforts. Results highlighted the detrimental impact of the pandemic on research efforts and the expanded need for implementation research to help provide evidence-based, context-specific pandemic recovery support. Key lessons learned included the viability of remote service delivery strategies and other innovations, the need for adaptive systems that respond to evolving contextual needs, and the need for organized documentation plans, within empathic and flexible environments.

Frail patients having vascular surgery during the early COVID-19 pandemic experienced high rates of adverse perioperative events and amputation.

BACKGROUND: Frailty predicts adverse perioperative outcomes and increased mortality in patients having vascular surgery. Frailty assessment is a potential tool to inform resource allocation, and shared decision-making about vascular surgery in the resource constrained COVID-19 pandemic environment. This cohort study describes the prevalence of frailty in patients having vascular surgery and the association between frailty, mortality and perioperative outcomes. METHODS: The COVID-19 Vascular Service in Australia (COVER-AU) prospective cohort study evaluates 30-day and six-month outcomes for consecutive patients having vascular surgery in 11 Australian vascular units, March-July 2020. The primary outcome was mortality, with secondary outcomes procedure-related outcomes and hospital utilization. Frailty was assessed using the nine-point visual Clinical Frailty Score, scores of 5 or more considered frail. RESULTS: Of the 917 patients enrolled, 203 were frail (22.1%). The 30 day and 6 month mortality was 2.0% (n = 20) and 5.9% (n = 35) respectively with no significant difference between frail and non-frail patients (OR 1.68, 95%CI 0.79-3.54). However, frail patients stayed longer in hospital, had more perioperative complications, and were more likely to be readmitted or have a reoperation when compared to non-frail patients. At 6 months, frail patients had twice the odds of major amputation compared to non-frail patients, after adjustment (OR 2.01; 95% CI 1.17-3.78), driven by a high rate of amputation during the period of reduced surgical activity. CONCLUSION: Our findings highlight that older, frail patients, experience potentially preventable adverse outcomes and there is a need for targeted interventions to optimize care, especially in times of healthcare stress.

Corrigendum: Serum Biomarker Panel for Diagnosis and Prognosis of Pancreatic Ductal Adenocarcinomas.

[This corrects the article DOI: 10.3389/fonc.2021.708963.].

Serum Biomarker Panel for Diagnosis and Prognosis of Pancreatic Ductal Adenocarcinomas.

BACKGROUND: Patients with pancreatic ductal adenocarcinoma (PDAC) have late diagnosis which results in poor prognosis. Currently, surgical resection is the only option for curative intent. Identifying high-risk features for patients with aggressive PDAC is essential for accurate diagnosis, prognostication, and personalised care due to the disease burden and risk of recurrence despite surgical resection. A panel of three biomarkers identified in tumour tissue (S100A4, Ca125 and Mesothelin) have shown an association with poor prognosis and overall survival. The diagnostic and prognostic value of the serum concentration of this particular biomarker panel for patients with PDAC has not been previously studied. METHODS: Retrospectively collected blood samples of PDAC patients (n =120) and healthy controls (n =80) were evaluated for the serum concentration of select biomarkers - S100A4, S100A2, Ca-125, Ca 19-9 and mesothelin. Statistical analyses were performed for diagnostic and prognostic correlation. RESULTS: A panel of four biomarkers (S100A2, S100A4, Ca-125 and Ca 19-9) achieved high diagnostic potential (AUROC 0.913). Three biomarkers (S100A4, Ca-125 and Ca 19-9) correlated with poor overall survival in a univariable model (p < 0.05). PDAC patients with abnormal levels of 2 or more biomarkers in their serum demonstrated significantly lower survival compared to patients with abnormal levels of one or less biomarker (p < 0.05). CONCLUSION AND IMPACT: The identified biomarker panels have shown the potential to diagnose PDAC patients and stratify patients based on their prognostic outcomes. If independently validated, this may lead to the development of a diagnostic and prognosticating blood test for PDAC.

Neoadjuvant therapy for pancreatic cancer changes the composition of the pancreatic parenchyma.

BACKGROUND: Postoperative pancreatic fistula (POPF) remains a prominent complication following pancreatic cancer resections. The primary aim of this study was to evaluate the histological changes that occur in the pancreas due to neoadjuvant therapy (NAT) by comparing the acinar, collagen and fat scores in resected PDAC specimens of patients who did and did not receive NAT. Secondary aims included (1) the difference in rates of POPF in PDAC patients who received NAT versus upfront resection; and (2) the association between acinar/collagen/fat scores and the development of POPF. METHODS: Consecutive patients who underwent pancreaticoduodenectomy for PDAC, with and without NAT were included for analysis. Acinar, collagen and fat scores were determined from histology slides of the pancreatic resection margin. RESULTS: One hundred and thirty-four patients were included. There was a significant decrease in the median acinar score (48 vs 23, p = 0.003) and increase in the collagen score (28 vs 50, p = 0.011) for patients who received NAT and a significant correlation with the number of cycles of NAT. This study found no statistical difference between NAT and the development of POPF. CONCLUSION: The use of NAT in the treatment of PDAC changes the composition of the pancreas.

Identification of Novel Biomarkers in Pancreatic Tumor Tissue to Predict Response to Neoadjuvant Chemotherapy.

Background: Neoadjuvant chemotherapy (NAC) has been of recent interest as an alternative to upfront surgery followed by adjuvant chemotherapy in patients with pancreatic ductal adenocarcinoma (PDAC). However, a subset of patients does not respond to NAC and may have been better managed by upfront surgery. Hence, there is an unmet need for accurate biomarkers for predicting NAC response in PDAC. We aimed to identify upregulated proteins in tumor tissue from poor- and good-NAC responders. Methods: Tumor and adjacent pancreas tissue samples were obtained following surgical resection from NAC-treated PDAC patients. SWATH-MS proteomic analysis was performed to identify and quantify proteins in tissue samples. Statistical analysis was performed to identify biomarkers for NAC response. Pathway analysis was performed to characterize affected canonical pathways in good- and poor-NAC responders. Results: A total of 3,156 proteins were identified, with 19 being were significantly upregulated in poor-responders compared to good-responders (log2 ratio > 2, p < 0.05). Those with the greatest ability to predict poor-NAC response were GRP78, CADM1, PGES2, and RUXF. Notably, canonical pathways that were significantly upregulated in good-responders included acute phase signaling and macrophage activation, indicating a heightened immune response in these patients. Conclusion: A novel biomarker signature for poor-NAC response in PDAC was identified.

Tissue biomarker panel as a surrogate marker for squamous subtype of pancreatic cancer.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) has been recently classified into four subtypes based on the gene expression levels, with squamous subtype having worst prognostic outcomes. However, gene expression analysis for each individual patient is not clinically feasible due to very high associated cost. We previously reported that levels of three biomarkers (S100A4, Ca-125 and Mesothelin) can be used to classify PDAC patients based on their survival outcomes. This project aimed to determine if this novel biomarker panel can be used as a surrogate to identify squamous PDAC subtype. METHODS: Using the Nanostring gene expression platform, tumor tissue from 24 PDAC patients were analysed for our novel biomarkers and markers associated with four PDAC subtypes. RESULTS: Gene expression of our biomarker panel (S100A4, Ca-125 and Mesothelin) closely clustered together with markers for squamous PDAC subtype. CONCLUSION: These results highlight the potential of our biomarkers to be utilized for identification of squamous PDAC subtype.

Pancreatic resection in patients with synchronous extra-pancreatic malignancy: outcomes and complications.

BACKGROUND: Patients may present with a resectable pancreatic tumour in the context of a concurrent primary extra-pancreatic malignancy. These patients pose a dilemma regarding their suitability for surgery. We evaluated our experience with such patients who underwent pancreatic resection with curative intent and detailed their outcomes and rationale for surgical decision-making. METHODS: A retrospective review of patients with pancreatic concurrent extra-pancreatic primary malignancy who underwent pancreatic resection at our institution over a 12-year period (2005-2016) was performed. Clinical, histopathological and perioperative outcomes were reviewed. RESULTS: Ten patients with a median age of 74 years (40-85 years) were identified. Secondary primary tumours included thyroid (n = 2), gastrointestinal (n = 4), small bowel neuroendocrine (n = 1), renal (n = 1) and haematological malignancies (n = 2). Pancreatic tumours included pancreatic ductal adenocarcinomas (n = 6), solid pseudopapillary neoplasms (n = 2) and ampullary carcinomas (n = 2). After a median follow up of 41.3 months (31.3-164 months), 8 of 10 patients were still alive. Two patients died due to metastatic disease from the secondary malignancy (small bowel neuroendocrine tumour and sigmoid colon adenocarcinoma). The post-operative complication rate was 30% with no perioperative 90-day mortality. CONCLUSION: Selected patients with a pancreatic and concurrent primary extra-pancreatic malignancy may undergo curative pancreatic resection with favourable outcomes.

Preoperative cardiac and respiratory investigations do not predict cardio-respiratory complications after pancreatectomy.

BACKGROUND: The process of undergoing a pancreatic resection places a patient under notable physiologic strain throughout the perioperative journey, with well recognized risks of postoperative cardiopulmonary complications. Preoperative preparations and screening often incorporate a barrage of testing, including electrocardiograms, transthoracic echocardiography, chest X-rays and spirometric evaluations. However, the current literature does not demonstrate whether these common tests provide any predictive correlation with postoperative cardiopulmonary complications. This retrospective study is structured to identify complications in post-pancreatic resection patients and assess for a predictive correlation with preoperative test results. METHODS: A retrospective analysis of all patients having undergone a pancreatic resection at a single tertiary centre, between 2014 and 2016. The inpatient medical records were reviewed for 30-day postoperative complications, including acute myocardial infarction, cardiac dysrhythmia, pulmonary embolism, pneumonia or pleural effusions. The results of routine preoperative diagnostic tests and complication rates were analysed. RESULTS: A total of 244 patients, median age of 66 years (range 18-88 years) were included in the study. Of these, 11 patients experienced a cardiac complication and 16 patients experienced a respiratory complication. Among those who experienced cardiac events, only two patients had abnormalities in their preoperative electrocardiograms. Patients who sustained a cardiac or respiratory event did not have any evidence of abnormality in their preoperative transthoracic echocardiography or respiratory investigations, respectively. CONCLUSION: Despite the recommendation that high-risk procedures such as pancreatic resections warrant thorough, routine, preoperative cardiac and respiratory investigation, a more functional preoperative assessment should be considered to stratify and predict postoperative outcomes.

Pancreatoduodenectomy and the risk of complications from perioperative fluid administration.

BACKGROUND: The dogma of administering sufficient intravenous fluids aggressively to avoid under-resuscitation has recently been challenged. Evidence suggests that excessive perioperative fluid administration may be associated with negative clinical outcomes in gastrointestinal surgery. This study examines the impact of fluid administration on perioperative outcomes in patients undergoing pancreatoduodenectomy (PD). METHODS: A retrospective analysis of 202 patients undergoing PD between January 2004 and August 2015 was performed. A cut-off value of 10 mL/kg/h was applied (low fluid group: <10 mL/kg/h versus high fluid group: ≥10 mL/kg/h). RESULTS: There were 76 patients in the low fluid group and 126 patients in the high fluid group. Both groups had comparable age, American Society of Anesthesiologists score and preoperative morbidity rates. Patients in the high fluid group received significantly more total fluids, crystalloids and colloids intraoperatively (P < 0.0001, P < 0.0001 and P = 0.013, respectively) without a significant difference in estimated blood loss (P = 0.586). The net fluid balance on post-operative day 0 was also significantly higher in the high fluid group (P < 0.0001). The mortality rate was 0% in the cohort. Major morbidity rate was 46.1% and 44.4% in low and high fluid groups, respectively (P = 0.836). Reoperation rate was 5.3% for the low fluid group and 1.6% for the high fluid group (P = 0.136). There were no significant differences between the groups for any of the individual complications. CONCLUSION: This study did not identify a difference in post-operative outcomes between the low and high fluid regime in patients undergoing PD.

Immunoregulatory Forkhead Box Protein p3-Positive Lymphocytes Are Associated with Overall Survival in Patients with Pancreatic Neuroendocrine Tumors.

BACKGROUND: Forkhead box protein p3-positive (FoxP3(+)) regulatory T cells (Tregs) suppress host T-cell-mediated immune responses, limit surveillance against cancers, and have been associated with a poor prognosis. STUDY DESIGN: This study aims to identify the prognostic significance of FoxP3(+) Tregs in pancreatic neuroendocrine tumors (PNETs). Patients diagnosed with PNETs between 1992 and 2014 (n = 101) were included in this retrospective analysis. Clinical data, histopathology, and expression of FoxP3(+) Tregs and Ki-67 by immunohistochemistry were assessed. The association of these factors with survival was tested by log-rank test and in additional multivariable analysis. RESULTS: A total of 101 patients were included in this study. Mean age was 58.0 years (range 18 to 87 years) and median tumor size was 25 mm (range 8 to 160 mm). The degree of infiltration of tumor by FoxP3(+) Tregs was graded as 0 (n = 75), 1 (n = 15), or 2 (n = 11). Median follow-up was 50 months (interquartile range 123 months; Q1 = 20 months and Q3 = 123 months). In univariate analyses, patient age older than 57 years, TNM stage III or IV, tumor size >25 mm, Ki-67 labeling index >20, and a high number of FoxP3(+) tumor-infiltrating lymphocytes were significantly associated with poorer overall survival. In multivariable analyses, FoxP3(+) expression score of 2 (hazard ratio = 6.9; 95% CI 1.4-34.4) was the only statistically significant predictor for overall mortality. CONCLUSIONS: FoxP3(+) Treg expression is an independent prognostic factor in patients with PNETs, associated with statistically significant shorter overall survival. There is a role for additional research into the immune-mediated role of FoxP3(+) Tregs in PNETs.

Somatostatin Receptor SSTR-2a Expression Is a Stronger Predictor for Survival Than Ki-67 in Pancreatic Neuroendocrine Tumors.

Somatostatin receptors (SSTR) are commonly expressed by neuroendocrine tumors. Expression of SSTR-2a and SSTR-5 may impact symptomatic management; however, the impact on survival is unclear. The aim of this study is to correlate SSTR-2a and SSTR-5 expression in pancreatic neuroendocrine tumors (PNETs) with survival. This study is designed to determine the prognostic significance of somatostatin receptors SSTR-2a and SSTR-5 in PNETs. This retrospective cohort study included cases of resected PNETs between 1992 and 2014. Clinical data, histopathology, expression of SSTR and Ki-67 by immunohistochemistry, and long-term survival were analyzed. A total of 99 cases were included in this study. The mean age was 57.8 years (18-87 years) and median tumor size was 25 mm (range 8-160 mm). SSTR-2a and SSTR-5 expression was scored as negative (n = 19, 19.2%; n = 75, 75.8%, respectively) and positive (n = 80, 80.1%; n = 24, 24.2%). The median follow-up was 49 months. SSTR-2a expression was associated with improved overall survival, with cumulative survival rates at 1, 3, and 5 years being 97.5%, 91.5%, and 82.9%, respectively. Univariate analysis demonstrated better survival in SSTR-2a positive patients (log rank P = 0.04). SSTR-5 expression was not associated with survival outcomes (log rank P = 0.94). Multivariate analysis showed that positive SSTR-2a expression is a stronger prognostic indicator for overall survival [Hazard Ratio (HR): 0.2, 95% Confidence interval (CI): 0.1-0.8] compared to high Ki-67 (HR: 0.8, 95% CI: 0.1-5.7). Expression of SSTR-2a is an independent positive prognostic factor for survival in PNETs.