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Background: Mesenchymal stromal cells are a safe and promising option to treat knee osteoarthritis as previously demonstrated in different clinical trials. However, their efficacy, optimal dose and addition of adjuvants must be determined. Here, we evaluated the clinical effects of a dose of 100 × 106 bone marrow mesenchymal stromal cells (BM-MSCs) in combination with Platelet Rich Plasma (PRGF®) as adjuvant in a randomized clinical trial.Methods: A phase II, multicenter, randomized clinical trial with active control was conducted. Sixty patients diagnosed with knee OA were randomly assigned to 3 weekly doses of PRGF® or intraarticular administration of 100 × 106 cultured autologous BM-MSCs plus PRGF®. Patients were followed up for 12 months, and pain and function were assessed using VAS and WOMAC and by measuring the knee range of motion range. X-ray and magnetic resonance imaging analyses were performed to analyze joint damage.Results: No adverse effects were reported after BM-MSC administration or during follow-up. According to VAS, the mean value (SD) for PRGF® and BM-MSC with PRGF® went from 5 (1.8) to 4.5 (2.2) (p = 0.389) and from 5.3 (1.9) to 3.5 (2.5) (p = 0.01), respectively at 12 months. In WOMAC, the mean (SD) baseline and 12-month overall WOMAC scores in patients treated with PRGF® was 31.9 (16.2) and 22.3 (15.8) respectively (p = 0.002) while that for patients treated with BM-MSC plus PRGF® was 33.4 (18.7) and 23.0 (16.6) (p = 0.053). Although statistical significances between groups have been not detected, only patients being treated with BM-MSC plus PRGF® could be considered as a OA treatment responders following OARSI criteria. X-ray and MRI (WORMS protocol) revealed no changes in knee joint space width or joint damage.Conclusions: Treatment with BM-MSC associated with PRGF® was shown to be a viable therapeutic option for osteoarthritis of the knee, with clinical improvement at the end of follow-up. Further phase III clinical trials would be necessary to confirm the efficacy. Trial registration Clinical Trials.gov identifier NCT02365142. Nº EudraCT: 2011-006036-23. [ABSTRACT FROM AUTHOR]

The clinical spectrum of 69 episodes of metapneumovirus pediatric infection (55 episodes caused by genotype A and 14 episodes caused by genotype B) was analyzed. Diagnosis of pneumonia was more common and the illness severity index (determined on the basis of need for hospitalization, oxygen saturation <90%, and intensive care unit stay) was higher for patients with metapneumovirus genotype A infection. [ABSTRACT FROM AUTHOR]

Background: Information on the clinical, epidemiological and molecular characterization of human metapneumovirus in critically ill adult patients with severe community-acquired pneumonia (CAP) and the role of biomarkers identifying bacterial coinfection is scarce. Methods: This is a retrospective epidemiological study of adult patients with hMPV severe CAP admitted to ICU during a ten-year period with admission PSI score ≥ 3. Results: The 92.8% of the 28 patients with severe CAP due to human metapneumovirus were detected during the first half of the year. Median age was 62 years and 60.7% were male. The genotyping of isolated human metapneumovirus showed group B predominance (60.7%). All patients had acute respiratory failure. Median APACHE II and SOFA score were 13 and 6.55, respectively. The 25% were coinfected with Streptococcus pneumoniae. 60.7% of the patients had shock at admission and 50% underwent mechanical ventilation. Seven patients developed ARDS, three of them younger than 60 years and without comorbidities. Mortality in ICU was 14.3%. Among survivors, ICU and hospital stay were 6.5 and 14 days, respectively. Plasma levels of procalcitonin were higher in patients with bacterial coinfection (18.2 vs 0.54; p < 0.05). The levels of C-reactive protein, however, were similar. Conclusion: Human metapneumovirus was associated with severe CAP requiring ICU admission among elderly patients or patients with comorbidities, but also in healthy young subjects. These patients often underwent mechanical ventilation with elevated health resource consumption. While one out of four patients showed pneumococcal coinfection, plasma procalcitonin helped to implement antimicrobial stewardship. [ABSTRACT FROM AUTHOR]

Gordonia species differentiation is a tedious task. Herein, Gordonia identification was performed according to the standard Bruker score system and a recently proposed score for Gram positive rods identification (≥ 1.5 genus level and ≥ 1.7 species level). New scores significantly improved the identification at genus and species level. [ABSTRACT FROM AUTHOR]

Background: Established animal trauma models are limited in recapitulating the pathophysiology of human traumatic injury. Herein, we characterize the physiologic insult and inflammatory response in two clinically relevant non-human primate (NHP) trauma models. Methods: Mauritian Cynomolgus Macaques underwent either a laparoscopic closed abdomen liver injury (laparoscopic 60% left-lobe hepatectomy) in an established uncontrolled severe hemorrhage model (THM), or a polytrauma hemorrhage model (PHM) involving combined liver and bowel injury, uncontrolled severe hemorrhage as well as an open full-thickness cutaneous flank wound. Fixed volume resuscitation strategies were employed in the THM and goal directed resuscitation was used in the PHM. Complete peripheral blood and critical clinical chemistry parameters, serum biomarkers of systemic inflammation, tissue perfusion parameters, as well as survival, were compared between the models throughout the 2-week study period. Results: NHPs in both the THM (n = 7) and the PHM (n = 21) demonstrated tissue hypoperfusion (peak lactate 6.3 ± 0.71 mmol/L) with end organ injury (peak creatinine 3.08 ± 0.69 mg/dL) from a similar liver injury (60% left hemi-hepatectomy), though the PHM NHPs had a significantly higher blood loss (68.1% ± 12.7% vs. 34.3% ± 2.3%, p = 0.02), lower platelet counts (59 ± 25 vs. 205 ± 46 K/uL, p = 0.03) and a trend towards higher mortality (90.5% vs. 33.3%, p = 0.09). The inflammatory response was robust in both models with peak cytokine (IL-6 > 6000-fold above baseline) and peak leukocyte values (WBC 27 K/uL) typically occurring around t = 240 min from the time of hepatic injury. A more robust systemic inflammatory response was appreciated in the PHM resulting in marked elevations in peak serum IL-6 (7887 ± 2521 pg/mL vs.1076 ± 4833 pg/mL, p = 0.02), IL-1ra (34,499 ± 5987 pg/mL vs. 2511 ± 1228 pg/mL, p < 0.00), and IL-10 (13,411 pg/mL ± 5598 pg/mL vs. 617 pg/mL ± 252 pg/mL, p = 0.03). Conclusion: This comparative analysis provides a unique longitudinal perspective on the post-injury inflammatory response in two clinically relevant models, and demonstrates that the addition of septic stimuli to solid organ injury increases both the hemorrhagic insult and inflammatory response. [ABSTRACT FROM AUTHOR]

The purpose of this study is to explore current perceptions within the military surgery community to stratify key obstacles to pursuing a career in academic surgery and identify opportunities for mitigation. After receiving institutional review board approval, an anonymous electronic survey was distributed to military surgeons across all branches. Survey response data were collected and analyzed using chi-square test. The response rate was approximately 22%. Of those who responded to the survey, most are interested in an academic career (61.5%); however, 64% believe this to be much more difficult as a military surgeon than as a civilian surgeon. The top three perceived obstacles include administrative obstacles (76.4%), operational commitments (65.8%), and lack of funding for academic pursuits (62.7%). Most respondents indicated that they have never received formal education regarding how to apply for research funding (84.5%) and most do not have a research mentor (60.9%). Additionally, 42.9% state that obstacles to an academic career in surgery impact their decision to leave the military. Younger surgeons were more likely to leave the military upon completion of their service commitment (67.9% versus 46.4% aged 20-39 y, P = 0.02). We characterized the perceived challenges to academic surgery within the military. These barriers between academic surgery and military service risk medical force attrition, particularly in future generations of surgeons. Dedicated faculty billets (positions) with limited operational demands as well as associated mentorship and research funding may enhance the retention and productivity of military surgeons. [ABSTRACT FROM AUTHOR]

There continues to be a growing demand for military-civilian partnerships (MCPs) in research collaborations developing medical trauma care in domestic and international affairs. The objective of this comprehensive review is to investigate the difference in the quantity of MCP trauma and critical care publications before and after the COVID-19 pandemic. A systematic literature review was performed for the calendar years 2018 and 2021 utilizing MEDLINE, Cochrane, and EMBASE databases. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we performed a three-tiered review of 603 English language articles to identify trauma-related military and/or civilian partners and describe the changes in geographical relationships. A total of 96 (2018) and 119 (2021) articles met screening criteria for trauma and critical care studies and were used for final data extraction. Ultimately, 59 (2018) and 71 (2021) papers met the inclusion criteria of identifying trauma/critical care MCPs and identified both military and civilian partners. There was also an increase from 10 (2018) to 17 (2021) publications that mentioned advocacy for MCP. Using the author affiliations, four regional MCP types were recorded: of 2018 articles, locoregional (3.4%), US-national (47.5%), single international country (42.4%), and between multiple countries (6.8%); of 2021 articles, locoregional (15.5%), US-national (38%), single international country (29.6%), and between multiple countries (16.9%). There has been an increase in the number of locoregional and multinational MCPs and an overall increase in the number of collaborative trauma publications and MCP advocacy papers. A national geographical heat map was developed to illustrate the changes from 2018 to 2021. There has been an increase in the number of recorded trauma and critical care MCP publications post-pandemic. The growth in the number of manuscripts in more regions post-pandemic suggests an increase in the recognition of collaborations that contribute not only to conflict readiness but also advancements in trauma and surgical care. [ABSTRACT FROM AUTHOR]

2020 was a significant year because of the occurrence of two simultaneous public health crises: the coronavirus pandemic and the public health crisis of racism brought into the spotlight by the murder of George Floyd. The coronavirus pandemic has affected all aspects of health care, particularly the delivery of surgical care, surgical education, and academic productivity. The concomitant public health crisis of racism and health inequality during the viral pandemic highlighted opportunities for action to address gaps in surgical care and the delivery of public health services. At the 2021 Academic Surgical Congress Hot Topics session on flexibility and leadership, we also explored how our military surgeon colleagues can provide guidance in leadership during times of crisis. The following is a summary of the issues discussed during the session and reflections on the important lessons learned in academic surgery over the past year. [ABSTRACT FROM AUTHOR]

This article, published in the American Journal of Gastroenterology, discusses a rare disorder called idiopathic myointimal hyperplasia of the mesenteric veins, which can lead to ischemic proctitis. The case study presented involves a 47-year-old man who experienced symptoms such as rectal and abdominal pain and hematochezia. After various diagnostic tests, including colonoscopy and biopsies, the patient underwent surgical resection as the definitive management for the condition. The article provides detailed information about the patient's symptoms, diagnostic process, treatment, and outcome. [Extracted from the article]

Two consecutive cases of Haemophilus influenzae type a sequence type 23 invasive infection in 2 children attending the same daycare in 2019 triggered epidemiologic surveillance of H. influenzae infections in northern Spain. Despite the invasiveness potential of this virus strain, we detected no additional cases for 2013-2020. [ABSTRACT FROM AUTHOR]

Background: Pertussis has re-emerged in many countries despite the wide use of vaccines for over 60 years. During 2023, we observed an increase in the incidence of pertussis in Gipuzkoa, north of Spain (with a population of 657,140 inhabitants), mainly affecting children between 11 and 15 years of age., Methods: This study included all confirmed cases diagnosed by PCR in nasopharyngeal swab samples. The genome of seven isolates collected in 2023 was sequenced., Results: Between 2018 and 2023, 884 cases of whooping cough were diagnosed. Pertussis incidence (in cases per 100,000 inhabitants) decreased from 36.7 in 2018 to no cases in 2021, increasing again to 56.8 in 2023. In 2023, the age group of 11-15 years old had the highest incidence rate of 409.3. Only 2 of the 56 children < 6 years old required hospitalization, and there were no deaths. The seven isolates collected in 2023 showed the same BPagST-4 ( ptxA1/ptxP3/prn2/fim2-1/fim3 -1 allelic combination), with all of them expressing the pertactin antigen., Conclusions: Immunity waning after the last dose of vaccination at 6 years old, together with the lack of circulation of Bordetella pertussis during the COVID-19 pandemic, were probably the main reasons for the high increase in the incidence of pertussis in Gipuzkoa in 2023.

Background: The declining operative volume at Military Treatment Facilities (MTFs) has resulted in Program Directors finding alternate civilian sites for resident rotations. The continued shift away from MTFs for surgical training is likely to have unintended negative consequences., Methods: An anonymous survey was generated and sent to the program directors of military general surgery training programs for distribution to their residents., Results: A total of 42 residents responded (response rate 21%) with adequate representation from all PGY years. Ninety-five percent of residents believed that their programs provided the training needed to be a competent general surgeon. However, when asked about career choices, only 30.9% reported being likely/extremely likely to remain in the military beyond their initial service obligation, while 54.7% reported that it was unlikely/extremely unlikely and 19% reported uncertainty. Eighty-eight percent reported that decreasing MTF surgical volume directly influenced their decision to stay in the military, and half of respondents regretted joining the military. When asked to assess their confidence in the military to provide opportunities for skill sustainment as a staff surgeon, 90.4% were not confident or were neutral., Conclusion: Although military surgical residents have a generally positive perception of their surgical training, they also lack confidence in their future military surgical careers. Our findings suggest that declining MTF surgical volume will likely negatively impact long-term retention of military surgeons and may negatively impact force generation for Operational Commander., Level of Evidence: Prognostic and Epidemiological, Level IV., (Copyright © 2024 Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.)

Objective: To characterize the current state of mental health within the surgical workforce in the United States., Background: Mental illness and suicide is a growing concern in the medical community; however, the current state is largely unknown., Methods: Cross-sectional survey of the academic surgery community assessing mental health, medical error, and suicidal ideation. The odds of suicidal ideation adjusting for sex, prior mental health diagnosis, and validated scales screening for depression, anxiety, post-traumatic stress disorder (PTSD), and alcohol use disorder were assessed., Results: Of 622 participating medical students, trainees, and surgeons (estimated response rate=11.4%-14.0%), 26.1% (141/539) reported a previous mental health diagnosis. In all, 15.9% (83/523) of respondents screened positive for current depression, 18.4% (98/533) for anxiety, 11.0% (56/510) for alcohol use disorder, and 17.3% (36/208) for PTSD. Medical error was associated with depression (30.7% vs. 13.3%, P <0.001), anxiety (31.6% vs. 16.2%, P =0.001), PTSD (12.8% vs. 5.6%, P =0.018), and hazardous alcohol consumption (18.7% vs. 9.7%, P =0.022). Overall, 13.2% (73/551) of respondents reported suicidal ideation in the past year and 9.6% (51/533) in the past 2 weeks. On adjusted analysis, a previous history of a mental health disorder (aOR: 1.97, 95% CI: 1.04-3.65, P =0.033) and screening positive for depression (aOR: 4.30, 95% CI: 2.21-8.29, P <0.001) or PTSD (aOR: 3.93, 95% CI: 1.61-9.44, P =0.002) were associated with increased odds of suicidal ideation over the past 12 months., Conclusions: Nearly 1 in 7 respondents reported suicidal ideation in the past year. Mental illness and suicidal ideation are significant problems among the surgical workforce in the United States., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: To explore the association of clinicopathologic and molecular factors with the occurrence of positive margins after first surgery in breast cancer., Methods: The clinical and RNA-Seq data for 951 (75 positive and 876 negative margins) primary breast cancer patients from The Cancer Genome Atlas (TCGA) were used. The role of each clinicopathologic factor for margin prediction and also their impact on survival were evaluated using logistic regression, Fisher's exact test, and Cox proportional hazards regression models. In addition, differential expression analysis on a matched dataset (71 positive and 71 negative margins) was performed using Deseq2 and LASSO regression., Results: Association studies showed that higher stage, larger tumor size (T), positive lymph nodes (N), and presence of distant metastasis (M) significantly contributed (p ≤ 0.05) to positive surgical margins. In case of surgery, lumpectomy was significantly associated with positive margin compared to mastectomy. Moreover, PAM50 Luminal A subtype had higher chance of positive margin resection compared to Basal-like subtype. Survival models demonstrated that positive margin status along with higher stage, higher TNM, and negative hormone receptor status was significant for disease progression. We also found that margin status might be a surrogate of tumor stage. In addition, 29 genes that could be potential positive margin predictors and 8 pathways were identified from molecular data analysis., Conclusion: The occurrence of positive margins after surgery was associated with various clinical factors, similar to the findings reported in earlier studies. In addition, we found that the PAM50 intrinsic subtype Luminal A has more chance of obtaining positive margins compared to Basal type. As the first effort to pursue molecular understanding of the margin status, a gene panel of 29 genes including 17 protein-coding genes was also identified for potential prediction of the margin status which needs to be validated using a larger sample set., (© 2023. The Author(s).)

Background: Systemic immunotherapy has had limited clinical benefit in pancreatic ductal adenocarcinoma. This is thought to be due to its desmoplastic immunosuppressive tumor microenvironment in addition to high intratumoral pressures that limit drug delivery. Recent preclinical cancer models and early-phase clinical trials have demonstrated the potential of toll-like receptor 9 agonists, including the synthetic CpG oligonucleotide SD-101, to stimulate a wide range of immune cells and eliminate suppressive myeloid cells. We hypothesized that Pressure-Enabled Drug Delivery via Pancreatic Retrograde Venous Infusion of toll-like receptor 9 agonist would improve responsiveness to systemic anti-programmed death receptor-1 checkpoint inhibitor therapy in a murine orthotopic pancreatic ductal adenocarcinoma model., Methods: Murine pancreatic ductal adenocarcinoma (KPC4580P) tumors were implanted into the pancreatic tails of C57BL/6J mice and treated 8 days after implantation. Mice were assigned to one of the following treatment groups: Pancreatic Retrograde Venous Infusion delivery of saline, Pancreatic Retrograde Venous Infusion delivery of toll-like receptor 9 agonist, systemic anti-programmed death receptor-1, systemic toll-like receptor 9 agonist, or the combination of Pancreatic Retrograde Venous Infusion delivery of toll-like receptor 9 agonist and systemic anti-programmed death receptor-1 (Combo). Fluorescently labeled toll-like receptor 9 agonist (radiant efficiency) was used to measure uptake of the drug on day 1. Changes in tumor burden were evaluated by necropsy at 2 different time points, 7 and 10 days after toll-like receptor 9 agonist treatment. Blood and tumors were collected at necropsy 10 days after toll-like receptor 9 agonist treatment for flow cytometric analysis of tumor-infiltrating leukocytes and plasma cytokines., Results: All mice analyzed survived to necropsy. Site of tumor fluorescence measurements revealed 3-fold higher intensity fluorescence in Pancreatic Retrograde Venous Infusion delivery of toll-like receptor 9 agonist compared to systemic toll-like receptor 9 agonist mice. Tumor weights were significantly lower in the Combo group compared to Pancreatic Retrograde Venous Infusion delivery of saline. Flow cytometry of the Combo group demonstrated significantly increased overall T-cell number, specifically CD4+ T-cells, and a trend toward increased CD8+ T-cells. Cytokine analysis showed significantly decreased IL-6 and CXCL1., Conclusion: Pressure-Enabled Drug Delivery of toll-like receptor 9 agonist by Pancreatic Retrograde Venous Infusion with systemic anti-programmed death receptor-1 demonstrated improved pancreatic ductal adenocarcinoma tumor control in a murine pancreatic ductal adenocarcinoma model. These results support study of this combination therapy in pancreatic ductal adenocarcinoma patients and expansion of ongoing Pressure-Enabled Drug Delivery clinical trials., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: To analyze the impact of pneumococcal conjugate vaccines (PCVs) on the incidence of invasive pneumococcal diseases (IPDs) and pneumococcal antibiotic resistance in Gipuzkoa, northern Spain for a 25 years period., Methods: All cases of IPD confirmed by culture between 1998 and 2022 in a population of around 427,416 people were included. Pneumococci were serotyped and antimicrobial susceptibility was assessed by the EUCAST guidelines., Results: Overall, 1,516 S. pneumoniae isolates were collected. Annual IPD incidence rates (per 100,000 people) declined from 19.9 in 1998-2001 to 11.5 in 2017-19 (42.2% reduction), especially in vaccinated children (from 46.7 to 24.9) and non-vaccinated older adult individuals (from 48.0 to 23.6). After PCV13 introduction, the decrease in the incidence of infections caused by PCV13 serotypes was balanced by the increase in the incidence of non-PCV13 serotypes. In the pandemic year of 2020, IPD incidence was the lowest: 2.81. The annual incidence rates of penicillin-resistant isolates also decreased, from 4.91 in 1998-2001 to 1.49 in 2017-19 and 0.70 in 2020. Since 2017, serotypes 14, 19A, and 11A have been the most common penicillin-resistant types. The incidence of erythromycin-resistant strains declined, from 3.65 to 1.73 and 0.70 in the same years., Conclusion: PCV use was associated with declines in the incidence of IPD and the spread of non-vaccine serotypes, that balanced the beneficial effect off PCV13, some of them showing high rates of antibiotic resistance., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Manzanal, Vicente, Alonso, Azkue, Ercibengoa and Marimón.)

Introduction: The Military Health System (MHS) is tasked with the dual mission of providing medical care to beneficiaries while ensuring medical readiness. MHS provides care through a combination of military treatment facilities (MTF) ("direct care"; DC) & off-base civilian facilities ("purchased care"; PC). Given recent concerns regarding low surgical volume at MTFs, we sought to evaluate COVID's impact on elective and non-elective case volume at MTFs with surgical residencies., Methods: Retrospective review of 2017-2021 M2 database was performed on Tricare beneficiaries who underwent bariatric surgery or major colorectal surgery in the DC or PC market at, or, surrounding MTFs with surgical residencies. Procedures were identified using ICD-10 procedure codes and Medicare severity-diagnosis related groups. A detailed analysis was then performed on changes in case volume in the DC and PC markets., Results: 5,698 bariatric and 5,517 major colorectal procedures were performed during the study period. There was an 84% vs 20% quarterly decrease in elective bariatric surgeries completed in the DC and PC markets from Q1 to Q2 2020. Pre to post-COVID (Q1 2017 - Q1 2020 vs Q3 2020 - Q4 2021) there was a decrease in the percentage of bariatric surgeries completed in the DC market (74.1% vs 55.0%, p = 0.001). Meanwhile, major colorectal surgery quarterly case volume remained unchanged in the DC (137 vs 125, p = 0.18) and PC (146 v 137, p = 0.13) markets, pre- and post-COVID., Discussion: Bariatric surgical case volume at MTFs disproportionately decreased during COVID when compared to the PC market and major colorectal cases. Bariatric case volume has rebounded in PC markets surpassing pre-COVID levels while DC case volume remains depressed. Further attention is warranted regarding decreased elective surgical case volume at MTFs., Competing Interests: Declaration of competing interest The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article. Additionally, the views expressed are those of the author(s) and do not reflect the official policy of the Department of the Army, Department of the Navy, the Department of Defense, or the U.S. Government., (Published by Elsevier Inc.)

Introduction: The pathophysiology of the inflammatory response after major trauma is complex, and the magnitude correlates with severity of tissue injury and outcomes. Study of infection-mediated immune pathways has demonstrated that cellular microRNAs may modulate the inflammatory response. The authors hypothesize that the expression of microRNAs would correlate to complicated recoveries in polytrauma patients (PtPs)., Methods: Polytrauma patients enrolled in the prospective observational Tissue and Data Acquisition Protocol with Injury Severity Score of >15 were selected for this study. Polytrauma patients were divided into complicated recoveries and uncomplicated recovery groups. Polytrauma patients' blood samples were obtained at the time of admission (T0). Established biomarkers of systemic inflammation, including cytokines and chemokines, were measured using multiplexed Luminex-based methods, and novel microRNAs were measured in plasma samples using multiplex RNA hybridization., Results: Polytrauma patients (n = 180) had high Injury Severity Score (26 [20-34]) and complicated recovery rate of 33%. MicroRNAs were lower in PtPs at T0 compared with healthy controls, and bivariate analysis demonstrated that variations of microRNAs correlated with age, race, comorbidities, venous thromboembolism, pulmonary complications, complicated recovery, and mortality. Positive correlations were noted between microRNAs and interleukin 10, vascular endothelial growth factor, Acute Physiology and Chronic Health Evaluation, and Sequential Organ Failure Assessment scores. Multivariable Lasso regression analysis of predictors of complicated recovery based on microRNAs, cytokines, and chemokines revealed that miR-21-3p and monocyte chemoattractant protein-1 were predictive of complicated recovery with an area under the curve of 0.78., Conclusion: Systemic microRNAs were associated with poor outcomes in PtPs, and results are consistent with previously described trends in critically ill patients. These early biomarkers of inflammation might provide predictive utility in early complicated recovery diagnosis and prognosis. Because of their potential to regulate immune responses, microRNAs may provide therapeutic targets for immunomodulation., Level of Evidence: Diagnostic Tests/Criteria; Level II., (Copyright © 2022 Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.)

Background: Listeriosis continues to be one of the most important notifiable foodborne diseases. Nonetheless, in Spain, there are few data on the molecular epidemiology of Listeria monocytogenes infections in recent years., Aim: To describe clinical features and the molecular epidemiology of human listeriosis over an 11-year period (2010-2020) in Gipuzkoa, Northern Spain., Methods: A total of 111 isolates, all but one from invasive disease, were studied. Serotyping (agglutination and multiplex polymerase chain reaction [PCR]) and multilocus sequence typing were performed for all isolates. Antibiotic susceptibility was assessed by the broth microdilution method., Results: The average annual incidence of listeriosis in non-pregnancy-associated cases was 1.55 per 100,000 population, with a 1-month mortality rate of 22.2%. In pregnant women, the average incidence was 0.45 cases per 1,000 pregnancies. Twenty-four sequence types were identified, serotype 4b ST1 (24.3%) being the most frequent followed by 1/2b ST87 (18.9%), which caused two long outbreaks in 2013-2014. A significant association was observed between ST219 and meningitis ( p < 0.001). All isolates were susceptible to ampicillin as well as other antibiotics used in listeriosis treatment., Conclusion: Despite current control measures, listeriosis continues to be an important cause of mortality in the elderly, preterm birth, and miscarriages in pregnant women. Improvements in the control and diagnosis of listeriosis are needed to reduce the impact of this infection on vulnerable populations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Vallejo, Cilla, López-Olaizola, Vicente and Marimón.)

Purpose: There is a great need to reduce the toxicity of chemotherapy used in the management of pancreatic ductal adenocarcinoma (PDAC). Here we explore if regional pressurized delivery of oxaliplatin can minimize peripheral neuropathy in mice., Methods: We used an orthotopic PDAC mouse model and delivered a single dose of oxaliplatin through the portal vein using a pressure-enabled system (pancreatic retrograde venous infusion, PRVI). We analyzed the effects of PRVI on tumor burden and peripheral neuropathy using histopathological and functional assays., Results: Tumor weights in mice treated with 2 mg/kg oxaliplatin using PRVI were significantly lower than in mice treated with the same dose systemically. This resulted in reduced peripheral neuropathy signatures in PRVI mice compared to the 20 mg/kg systemic dose required to achieve similar tumor control., Conclusion: Regional delivery of highly cytotoxic agents using PRVI can reduce the therapeutic dose of these drugs, thereby lowering toxic side effects., (© 2022. The Author(s).)

We report the case of a 17-year-old male who presented with intractable nausea and vomiting. Cross-sectional imaging revealed a large retrogastric abdominal mass. Fine needle aspiration done via endoscopic ultrasound (EUS) was nondiagnostic. Exploratory laparotomy revealed a large inflammatory mass densely adherent to the stomach and retroperitoneum. Incisional biopsy frozen section revealed spindle cells, and subsequent resection of the mass with en-bloc subtotal gastrectomy with Roux-en-y gastrojejunostomy reconstruction was performed. Final pathology demonstrated a lymphatic malformation with reactive myofibroblastic proliferation. Inflammatory abdominal lymphatic malformations are especially rare and not well described in the literature. These masses may present diagnostic challenges until the specimen is sent for pathologic analysis., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Lee et al.)

We investigated whether the difference of antigen tube 2 (TB2) minus antigen tube 1 (TB1) (TB2-TB1) of the QuantiFERON-TB gold plus test, which has been postulated as a surrogate for the CD8 + T-cell response, could be useful in identifying recent tuberculosis (TB) exposure. We looked at the interferon gamma (IFN-γ) responses and differences in TB2 and TB1 tubes for 686 adults with QFT-plus positive test results. These results were compared among groups with high (368 TB contacts), low (229 patients with immune-mediated inflammatory diseases [IMID]), and indeterminate (89 asylum seekers or people from abroad [ASPFA]) risks of recent TB exposure. A TB2-TB1 value >0.6 IU·ml -1 was deemed to indicate a true difference between tubes. In the whole cohort, 13.6%, 10.9%, and 11.2% of cases had a TB2>TB1 result in the contact, IMID, and ASPFA groups, respectively ( P  = 0.591). The adjusted odds ratios (aORs) for an association between a TB2-TB1 result of >0.6 IU·ml -1 and risk of recent exposure versus contacts were 0.71 (95% confidence interval [CI], 0.31 to 1.61) for the IMID group and 0.86 (95% CI, 0.49 to 1.52) for the ASPFA group. In TB contact subgroups, 11.4%, 15.4%, and 17.7% with close, frequent, and sporadic contact had a TB2>TB1 result ( P  = 0.362). The aORs versus the close subgroup were 1.29 (95% CI, 0.63 to 2.62) for the frequent subgroup and 1.55 (95% CI, 0.67 to 3.60) for the sporadic subgroup. A TB2-TB1 difference of >0.6 IU·ml -1 was not associated with increased risk of recent TB exposure, which puts into question the clinical potential as a proxy marker for recently acquired TB infection. IMPORTANCE Contact tuberculosis tracing is essential to identify recently infected people, who therefore merit preventive treatment. However, there are no diagnostic tests that can determine whether the infection is a result of a recent exposure or not. It has been suggested that by using the QuantiFERON-TB gold plus, an interferon gamma (IFN-γ) release assay, a difference in IFN-γ production between the two antigen tubes (TB2 minus TB1) of >0.6 IU·ml -1 could serve as a proxy marker for recent infection. In this large multinational study, infected individuals could not be classified according to the risk of recent exposure based on differences in IFN-γ in TB1 and TB2 tubes that were higher than 0.6 IU·ml -1 . QuantiFERON-TB gold plus is not able to distinguish between recent and remotely acquired tuberculosis infection, and it should not be used for that purpose in contact tuberculosis tracing.

Introduction: Navy Medicine's Role 2 Light Maneuver (R2LM) Emergency Resuscitative Surgical Systems (ERSS) are austere surgical teams manned, trained, and equipped to provide life-saving damage control resuscitation and surgery in any environment on land or sea. Given the restrictions related to the COVID-19 pandemic, the previously established pre-deployment training pipeline for was modified to prepare a new R2LM team augmenting a Role 1 shipboard medical department., Methods: The modified curriculum created in response to COVID-19 related restriction is compared and contrasted to the established pre-deployment R2LM ERSS curriculum. Subject Matter Experts and currently deployed R2LM members critically evaluate the two curricula., Results: Both curricula included the team R2LM platform training and exposure to cadaver based team trauma skills training. The modified curriculum included didactics on shipboard resuscitation, anesthesia and surgery, shipboard COVID-19 management, and prolonged field care in austere maritime environments., Conclusions: We describe Navy Medicines R2LM ERSS capability and compare and contrast the standard R2LM pre-COVID-19 curriculum to the modified curriculum. Central to both curricula, the standard R2LM platform training is important for developing and honing team dynamics, communication skills and fluid leadership; important for the successful function austere surgical teams. Several opportunities for improvement in the pre-deployment training were identified for R2LM teams augmenting shipboard Role 1 medical departments., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2021. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Background: This study investigated the safety and feasibility of intraoperative portal vein blood (PVB) collection at the time of pancreatic ductal adenocarcinoma (PDAC) resection. Relationships of circulating tumor cells (CTCs) in PVB and peripheral blood (PB) with overall survival (OS) and recurrence-free survival were studied., Methods: Patients undergoing PDAC resection were offered enrollment in a prospective liquid biopsy protocol. The patients had PB drawn before incision and PVB drawn before tumor mobilization, then again immediately after resection. Using standard CellSearch protocols, CTCs were identified and compared with OS., Results: Of the 34 patients enrolled in this study, 23 (68%) underwent pancreaticoduodenectomy, 8 (23%) underwent distal pancreatectomy, and 3 (9%) underwent total pancreatectomy. Peripheral blood was available for 22 (65%) and PVB for 31 (91%) of the patients. No bleeding or thrombotic complications occurred with the PVB draws. The CTC counts per 7.5 mL of PVB collected before and after resection were highly correlated (R 2  = 0.89). The study found CTCs in 11 (50%) of 22 PB samples and 22 (71%) of 31 PVB samples. The OS rate at 18 months was 92% for the patients with < 3 CTCs, 71% for the patients with ≥ 3 CTCs per 7.5 mL of PB (p = 0.30), 100% for the patients without PVB CTCs, and 70% for the patients with PVB CTCs (p < 0.01)., Conclusions: Collection of PVB during PDAC resection is safe. In this pilot study, PVB CTC counts but not PB CTC counts were significantly correlated with OS. This opens the door for future studies on selective omission of adjuvant chemotherapy for patients treated preoperatively and tailored surveillance intensity for patients without PVB CTCs at PDAC resection.

Background: We describe the use of pancreatic retrograde venous infusion in an orthotopic murine model of pancreatic ductal adenocarcinoma and hypothesize that pancreatic retrograde venous infusion delivery of gemcitabine will increase concentrations of gemcitabine in the tumor and the subsequent tumor response to treatment., Methods: Murine pancreatic ductal adenocarcinoma (KPC4580P) was transplanted onto the pancreatic tail of C57BL/6J mice. Groups (n = 15) of mice were assigned to sham laparotomy and 100 mg/kg intraperitoneal infusion of gemcitabine (systemic gemcitabine), pancreatic venous isolation with pancreatic retrograde venous infusion of 100 mg/kg gemcitabine, or pancreatic retrograde venous infusion with saline infusion. Tumor pressures were recorded during pancreatic retrograde venous infusion. Mice were killed at 1 hour or 7 days after infusion., Results: Baseline tumor pressures were 45 ± 8 mm Hg, and pancreatic retrograde venous infusion increased tumor pressures by 29 ± 6 mm Hg (P < .01). Pancreatic retrograde venous infusion gemcitabine mice had greater tumor gemcitabine concentrations compared with systemic gemcitabine (127 vs 19 ng/mg; P < .01) and lesser tumor volumes compared with both systemic gem and pancreatic retrograde venous infusion with saline (274 vs 857 vs 629 mm 3 ; P < .01)., Conclusion: Pancreatic retrograde venous infusion increased tumor pressures greater than baseline, improved gemcitabine delivery, and increased the treatment response. These findings suggest that pressurized, regional delivery overcomes the increased pressure barrier in pancreatic ductal adenocarcinoma. Additional preclinical studies with cytotoxic and immunotherapeutic agents and clinical trials using pressure-enabled drug delivery with pancreatic retrograde venous infusion devices are underway., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Portal vein (PV) circulating tumor cells (CTCs) and elevated peripheral blood (PB) levels of biomarkers have been associated with poor outcomes in pancreatic ductal adenocarcinoma (PDAC). Although transforming growth factor-beta (TGFβ) is associated with CTCs in breast cancer, there are limited data evaluating a comprehensive biomarker panel and CTCs in PDAC patients. The authors hypothesized that tumor progression biomarkers would be associated with PV CTCs., Methods: PDAC patients at one institution were enrolled January to August 2018 and underwent preincision PB draws (T0) and on postoperative day 1 (T3), plus intraoperative PV draws before tumor manipulation (T1) and after resection (T2). CTCs were detected using CellSearch. Plasma biomarker levels (pg/mL) were measured with a multiplex bead assay. Patients were divided into two groups: high (≥3 CTCs/7.5 mL blood) versus low (<3). Clinicopathologic variables and biomarkers were compared in the two groups., Results: Fourteen had complete blood draws with PDAC resection, with five demonstrating high CTCs. Fewer patients in the high-CTC group received preoperative radiation (78 versus 20%), whereas more of the high-CTC had pT3 tumors (80 versus 11%) (all P < 0.037). High-CTC patients demonstrated higher TGFβ-2 levels (T0 [906 versus 586], T1 [1337 versus 627], T2 [1149 versus 445]), as well as higher TGFβ-3 (T0 [320 versus 173], T2 [605 versus 120]) (all P < 0.021)., Conclusions: PDAC patients with high CTCs demonstrated a distinct biomarker profile with elevated PB and PV levels of immunosuppressive cytokines (TGFβ-2 and TGFβ-3). These exploratory results prompt further study into interrupting TGFβ signaling., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: Although the incidence of tuberculosis (TB) has declined, TB drug resistance remains a major problem. The TB rate in Gipuzkoa (northern Spain) is higher than the European average. The objective of this study was to determine the antimicrobial susceptibility of 1855 Mycobacterium tuberculosis complex isolates (94.5% of confirmed cases between 2000 and 2015)., Methods: Susceptibility testing was performed using the agar proportion method and a commercial broth system (MGIT 960). In isoniazid- or rifampicin-resistant strains, we studied genetic determinants of drug resistance and genotype (MIRU-VNTR)., Results: The annual mean incidence of TB was 24.5 cases per 100,000 population on average, and tended to decrease. The multidrug-resistant TB rate was 0.5% (9/1855), and no extensively drug-resistant TB strains were detected. Rates of resistance to isoniazid and rifampicin were 3.9% (range, 3.4-4.3%) and 0.6% (range, 0.4-1.4%), respectively. TB resistance was more common among foreign-born individuals and those who had received previous TB treatment. Genotyping of 102 resistant strains showed predominance of the Euro-American lineage, although 4/9 multidrug-resistant strains had Eastern lineages (2 East African-Indian, and 2 East Asian [Beijing])., Conclusions: In Gipuzkoa, with a moderate incidence of TB, resistance was very low, mostly being detected among individuals who were born abroad or who had a history of TB treatment., (Copyright © 2019 Elsevier España, S.L.U. and Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.)

A nosocomial case of Legionella pneumophila pneumonia likely caused by a serogroup 3 strain was detected by a urinary antigen test in Spain in 2018. Although Legionella bacteria could not be isolated from respiratory samples, molecular methods implicated the sink faucet of the patient's room as the probable infection source.

Irreversible electroporation (IRE) is a nonthermal ablation technique that is used clinically in selected patients with locally advanced pancreatic cancer, but most patients develop recurrent distant metastatic disease. We hypothesize that IRE can induce an in situ vaccination effect by releasing tumor neoantigens in an inflammatory context. Using an immunocompetent mouse model, we demonstrated that IRE alone produced complete regression of subcutaneous tumors in approximately 20% to 30% of mice. IRE was not effective in immunodeficient mice. Mice with complete response to IRE demonstrated prophylactic immunity and remained tumor free when rechallenged with secondary tumors on the contralateral flank. CD8 + T cells from IRE-responsive mice were reactive against peptides representing model-inherent alloantigens and conferred protection against tumor challenge when adoptively transferred into immunocompromised, tumor-naïve mice. Combining IRE with intratumoral Toll-like receptor-7 (TLR7) agonist (1V270) and systemic anti-programmed death-1 receptor (PD)-1 checkpoint blockade resulted in improved treatment responses. This combination also resulted in elimination of untreated concomitant distant tumors (abscopal effects), an effect not seen with IRE alone. These results suggest that the systemic antitumor immune response triggered by IRE can be enhanced by stimulating the innate immune system with a TLR7 agonist and the adaptive immune system with anti-PD-1 checkpoint blockade simultaneously. Combinatorial approaches such as this may help overcome the immunosuppressive pancreatic cancer microenvironment., (©2019 American Association for Cancer Research.)

Background: Postoperative complications (POC) are associated with poor oncologic outcomes in gastric cancer. We sought to evaluate the impact of POC on survival in patients with gastric cancer treated with upfront surgery (UpSurg) versus those treated with preoperative therapy (PreT)., Methods: We analyzed data from a prospectively maintained database of patients who had undergone resection of their gastric cancer at our institution. Patients with T1N0 or M1 lesions, recurrent disease, and mortality within 90 days were excluded. Survival was compared between patients with and without POC in the UpSurg and PreT groups. Cox regression analyses were used to examine factors associated with overall survival (OS) and disease-free survival (DFS)., Results: A total of 421 patients underwent resection of gastric cancer: 30% underwent upfront surgery, and 51% had a POC. Among patients who had POCs, 71% were infectious and 53% were Clavien-Dindo grade III or IV. UpSurg patients with a POC had shorter OS (5-year, 47 vs. 85%; p < 0.001) and DFS (5-year, 46 vs. 76%; p < 0.001) than those without a POC. In contrast, there was no difference in OS (5-year, 57 vs. 63%; p = 0.77) and DFS (5-year, 52 vs. 52%; p = 0.52) between PreT patients with and without POC. Multivariable Cox regression model demonstrated that a POC in UpSurg patients had significant impact on DFS (2.6 [95% confidence interval (CI) 1.48-4.74]), whereas it did not in PreT patients (0.9 [95% CI 0.70-1.33])., Conclusions: The use of preoperative therapy negated the impact of POCs on OS and DFS in patients undergoing resection for gastric cancer.

The infections of the central nervous system are associated with high morbidity and mortality. Several agents including bacteria, viruses, fungi and protozoa can invade the CNS. They are different clinical presentations of these infections: meningitis, encephalitis, brain and epidural abscesses and cerebrospinal fluid shunt infections. The clinical course could be acute, subacute or chronic depending on the infecting agent and the location of the infection. The travelling entails a risk of infection by exotic agents of meningo-encephalitis such as robovirus and arbovirus, which require new diagnostic and therapeutic methods. Despite some progress in the treatment of the CNS infections, the mortality is usually high. Rapid diagnosis and emergent interventions are necessary to improve the outcome of those patients, and early and targeted antimicrobial treatment and support measures are of paramount importance for a favourable clinical patient outcome. The antigen detection techniques and particularly those of genetic diagnosis by amplification (PCR and others) have advanced, and improved the diagnostic of those diseases. In this paper the clinical signs and symptoms and diagnostic procedures of CNS infections are presented., (Copyright © 2010 Elsevier España, S.L. All rights reserved.)

Introduction: Adenovirus serotype 4a is a respiratory virus that occasionally causes conjunctivitis. This paper describes an outbreak of follicular conjunctivitis that occurred in a geriatric centre., Material and Methods: Outbreak description and epidemiological research through a survey. For the microbiological study conjunctival swabs were collected using viral and bacterial transport media. Adenovirus was detected by real-time polymerase chain reaction. The serotype was determined by sequencing of a fragment of the hexon and E1 genes., Results: In autumn 2008 an outbreak of follicular conjunctivitis caused by adenovirus serotype 4a was detected. Twenty three percent 23% (69/300) of residents and 5% (9/180) of workers in a geriatric centre in Gipuzkoa were affected. The clinical symptoms were of prolonged duration (11±5 days). The temporal association of the cases suggested transmission from person to person. The sanitary measures established (asepsis and frequent hand washing, cleaning and disinfection of objects and surfaces) were effective, interrupting the transmission of the disease within a short period of time., Conclusion: Rapid detection, identification of the causative agent and implementing appropriate control measures can significantly reduce the impact on both health and economic costs of these outbreaks., (Copyright © 2009 Elsevier España, S.L. All rights reserved.)

Rapid diagnosis of acute viral and bacterial infections of the central nervous system (meningitis and encephalitis) is highly important for the clinical management of the patient and helps to establish early therapy that may solve life-threatening situations, to avoid unnecessary empirical treatments, to reduce hospital stay, and to facilitate appropriate interventions in the context of public health. Molecular techniques, especially real-time polymerase chain reaction, have become the fastest and most sensitive diagnostic procedures for autochthonous viral meningitis and encephalitis, and their role is becoming increasingly important for the diagnosis and control of most frequent acute bacterial meningitides. Automatic and closed systems may encourage the widespread and systematic use of molecular techniques for the diagnosis of these neurological syndromes in most laboratories.

Erythromycin resistance and the characterization of the corresponding determinants of resistance were studied in clinical Streptococcus pneumoniae isolates belonging to the four major multiresistant pneumococcal Spanish clones (ermB and mefA genes for the Spain23F-1, Spain9V-3, serotype 14 variant of the Spain9V-3 and Spain14-5 clones and ermB gene for the Spain6B-2 clone). These isolates were confirmed as major clones by pulsed-field gel electrophoresis (PFGE), BOX-PCR, and multilocus sequence typing (MLST). The spread and prevalence of these erythromycin-resistant variants of the Spanish clones in an area of the north of Spain were dissimilar-low for the Spain9V-3 clone (5.8% among the isolates belonging to this clone, including isolates of the serotype 14 variant) and very frequent for the Spain14-5 clone (91.7%).