Don't Let the Sun Rise on Small Bowel Obstruction Without Surgical Consultation-Redefining Nonoperative Management Pathways.

Introduction: Small bowel obstruction (SBO) is a common cause of hospital admission leading to resource utilization. The majority of these patients require non-operative management (NOM) which can lead to increased length of stay (LOS), readmissions, resource utilization, and throughput delays. Early surgical consultation (SC) for SBO may improve efficiency and outcomes. Methods: We implemented an institution-wide intervention (INT) to encourage early SC (<1 day of diagnosis) for SBO patients in July 2022. A retrospective analysis was performed on all patients with SBO requiring NOM from January 2021 to June 2023, categorized into pre- and post-INT groups. The primary outcome was the number of SC's and secondary outcomes were early SC (<1 day of diagnosis), utilization of SBFT, LOS, 30-day readmission, and costs of admission. Results: A total of 670 patients were included, 438 in the pre-INT and 232 in the post-INT group. Overall, SBFT utilization was significantly higher in cases with SC (17.2% vs 41.4%, P < .001). Post-INT patients were more likely to receive SC (94.0% vs 83.3%, P < .001) and increased SBFT utilization (47.0% vs 33.6%, P = .001). Additionally, early SC improved significantly in the post-INT group (74.3% vs 65.7%, P = .03). There was no difference in LOS between groups (4.0 vs 3.8 days, P = .48). There was a trend toward decreased readmission rates in the INT group at 30 days (7.3% vs 11.0%, P = .13) and reduced direct costs in the INT group (US$/admission = 8467 vs 8708, P = .1). Conclusion: Hospital-wide interventions to increase early surgical involvement proved effective by improving early SC, increased SBFT utilization, and showed a trend towards decreased readmission rates and direct costs.

Incorporating Robotic Cholecystectomy in an Acute Care Surgery Practice Model is Feasible.

INTRODUCTION: The role of robotic surgery in the nonelective setting remains poorly defined. Accessibility, patient acuity, and high turn-over may limit its applicability and utilization. The goal is to characterize the role of robotic cholecystectomy (CCY) in a busy acute care surgery (ACS) practice at a quaternary medical center, and compare surgical outcomes and resource utilization between robotic and laparoscopic CCY. METHODS: Adult patients who underwent robotic (Da Vinci Xi) or laparoscopic CCY between 01/2021-12/2022 by an ACS attending within 1 week of admission were included. Primary outcomes included time from admission to surgery, off hour (weekend and 6p-6a) cases, operation time, and hospital costs, to reflect "feasibility" of robotic compared to laparoscopic CCY. Secondary outcomes encompassed surgery-related outcomes and complications. RESULTS: The proportion of robotic CCY increased from 5% to 32% within 2 years. In total 361 laparoscopic and 89 robotic CCY were performed. Demographics and gallbladder disease severity were similar. Feasibility measures-operation time, case start time, time from admission to surgery, proportion of off-hour cases, and cost-were comparable between robotic and laparoscopic CCY. There were no differences in surgical complications, common bile duct injury, readmission, or mortality. Conversion to open surgery occurred more often in laparoscopic cases (5% vs 0%, P = .02, OR = 1.05). DISCUSSION: Robotic CCY is associated with fewer open conversions and otherwise similar outcomes compared to laparoscopic CCY in the non-elective setting. Incorporation of robotic CCY in a busy ACS practice model is feasible with available resources.

TGF-ß specifies TFH versus TH17 cell fates in murine CD4+ T cells through c-Maf.

T follicular helper (TFH) cells are essential for effective antibody responses, but deciphering the intrinsic wiring of mouse TFH cells has long been hampered by the lack of a reliable protocol for their generation in vitro. We report that transforming growth factor-ß (TGF-ß) induces robust expression of TFH hallmark molecules CXCR5 and Bcl6 in activated mouse CD4+ T cells in vitro. TGF-ß-induced mouse CXCR5+ TFH cells are phenotypically, transcriptionally, and functionally similar to in vivo-generated TFH cells and provide critical help to B cells. The study further reveals that TGF-ß-induced CXCR5 expression is independent of Bcl6 but requires the transcription factor c-Maf. Classical TGF-ß-containing T helper 17 (TH17)-inducing conditions also yield separate CXCR5+ and IL-17A-producing cells, highlighting shared and distinct cell fate trajectories of TFH and TH17 cells. We demonstrate that excess IL-2 in high-density T cell cultures interferes with the TGF-ß-induced TFH cell program, that TFH and TH17 cells share a common developmental stage, and that c-Maf acts as a switch factor for TFH versus TH17 cell fates in TGF-ß-rich environments in vitro and in vivo.

Frailty is related to serum inflammageing markers: results from the VITAL study.

Frailty describes an age-associated state in individuals with an increased vulnerability and less resilience against adverse outcomes. To score frailty, studies have employed the questionnaires, such as the SF-36 and EQ-5D-3L, or the Frailty Index, a composite score based on deficit accumulation. Furthermore, ageing of the immune system is often accompanied by a state of low-grade inflammation (inflammageing). Here, we aimed to associate 29 circulating markers of inflammageing with frailty measures in a prospective cohort study to understand the mechanisms underlying ageing.Frailty measures and inflammageing markers were assessed in 317 participants aged 25-90. We determined four different measures of frailty: the Frailty Index based on 31 deficits, the EQ-5D-3L and two physical domains of the SF-36. Serum/plasma levels of inflammageing markers and CMV/EBV seropositivity were measured using different techniques: Quanterix, Luminex or ELISA.All four measures of frailty strongly correlated with age and BMI. Nineteen biomarkers correlated with age, some in a linear fashion (IL-6, YKL-40), some only in the oldest age brackets (CRP), and some increased at younger ages and then plateaued (CCL2, sIL-6R). After correcting for age, biomarkers, such as IL-6, CRP, IL-1RA, YKL-40 and elastase, were associated with frailty. When corrected for BMI, the number of associations reduced further.In conclusion, inflammageing markers, particularly markers reflecting innate immune activation, are related to frailty. These findings indicate that health decline and the accumulation of deficits with age is accompanied with a low-grade inflammation which can be detected by specific inflammatory markers.

Structural basis of antibacterial photodynamic action of curcumin against S. aureus.

Antimicrobial photodynamic therapy (aPDT) is an alternative tool to commercial antibiotics for the inactivation of pathogenic bacteria (e.g., S. aureus). However, there is still a lack of understanding of the molecular modeling of the photosensitizers and their mechanism of action through oxidative pathways. Herein, a combined experimental and computational evaluation of curcumin as a photosensitizer against S. aureus was performed. The radical forms of keto-enol tautomers and the energies of curcumin's frontier molecular orbitals were evaluated by density functional theory (DFT) to point out the photodynamic action as well as the photobleaching process. Furthermore, the electronic transitions of curcumin keto-enol tautomers were undertaken to predict the transitions as a photosensitizer during the antibacterial photodynamic process. Moreover, molecular docking was used to evaluate the binding affinity with the S. aureus tyrosyl-tRNA synthetase as the proposed a target for curcumin. In this regard, the molecular orbital energies show that the curcumin enol form has a character of 4.5% more basic than the keto form - the enol form is a more promising electron donor than its tautomer. Curcumin is a strong electrophile, with the enol form being 4.6% more electrophilic than its keto form. In addition, the regions susceptible to nucleophilic attack and photobleaching were evaluated by the Fukui function. Regarding the docking analysis, the model suggested that four hydrogen bonds contribute to the binding energy of curcumin's interaction with the ligand binding site of S. aureus tyrosyl-tRNA synthetase. Finally, residues Tyr36, Asp40, and Asp177 contact curcumin and may contribute to orienting the curcumin in the active area. Moreover, curcumin presented a photoinactivation of 4.5 log unit corroborating the necessity of the combined action of curcumin, light, and O2 to promote the photooxidation damage of S. aureus. These computational and experimental data suggest insights regarding the mechanism of action of curcumin as a photosensitizer to inactivate S. aureus bacteria.

Natural versus synthetic curcuminoids as photosensitizers: Photobleaching and antimicrobial photodynamic therapy evaluation.

Antimicrobial photodynamic therapy (aPDT) has been studied as an alternative to combat bacterial resistance to the commonly used antibiotics. aPDT requires the use of a photosensitizer and curcumin is one of the more promising, though the usage of natural curcumin can be inconsistent in certain biomedical uses due to differences in soil condition and turmeric age, besides a large quantity of the plant is necessary to obtain useful amounts of the actual molecule. As such, a synthetic analogue is preferred as it is pure, and its components are better characterized. The present work studied photophysical differences in both natural and synthetic curcumin using photobleaching experiments and searched for whether differences existed in aPDT studies against Staphylococcus aureus. The results showed a faster O2 consumption and a singlet oxygen's generation rate lower by the synthetic curcumin, in comparison with the natural derivative. However, no statistical difference was observed when inactivating S. aureus and these results were following a concentration-based pattern. Thus, the use of synthetic curcumin is indicated, as it can be obtained in controlled amounts and with less environmental impact. Although there are small changes in a photophysical context comparing natural versus synthetic curcumins, we did not observe statistical differences in the photoinactivation of S.aureus bacteria, and reproducibility in biomedical contexts is better achieved with the synthetic analogue.

T follicular helper cells in cancer.

T follicular helper (Tfh) cells provide essential help to B cells for effective antibody-mediated immune responses. Although the crucial function of these CD4+ T cells in infection and vaccination is well established, their involvement in cancer is only beginning to emerge. Increased numbers of Tfh cells in Tfh cell-derived or B cell-associated malignancies are often associated with an unfavorable outcome, whereas in various solid organ tumor types of non-lymphocytic origin, their presence frequently coincides with a better prognosis. We discuss recent advances in understanding how Tfh cell crosstalk with B cells and CD8+ T cells in secondary and tertiary lymphoid structures (TLS) enhances antitumor immunity, but may also exacerbate immune-related adverse events (irAEs) such as autoimmunity during immune checkpoint blockade (ICB) and cancer immunotherapy.

Toxoplasma gondii GRA28 Is Required for Placenta-Specific Induction of the Regulatory Chemokine CCL22 in Human and Mouse.

Toxoplasma gondii is an intracellular protozoan pathogen of humans that can cross the placenta and result in adverse pregnancy outcomes and long-term birth defects. The mechanisms used by T. gondii to cross the placenta are unknown, but complex interactions with the host immune response are likely to play a role in dictating infection outcomes during pregnancy. Prior work showed that T. gondii infection dramatically and specifically increases the secretion of the immunomodulatory chemokine CCL22 in human placental cells during infection. Given the important role of this chemokine during pregnancy, we hypothesized that CCL22 induction was driven by a specific T. gondii-secreted effector. Using a combination of bioinformatics and molecular genetics, we have now identified T. gondii GRA28 as the gene product required for CCL22 induction. GRA28 is secreted into the host cell, where it localizes to the nucleus, and deletion of the GRA28 gene results in reduced CCL22 placental cells as well as a human monocyte cell line. The impact of GRA28 on CCL22 production is also conserved in mouse immune and placental cells both in vitro and in vivo. Moreover, parasites lacking GRA28 are impaired in their ability to disseminate throughout the animal, suggesting a link between CCL22 induction and the ability of the parasite to cause disease. Overall, these data demonstrate a clear function for GRA28 in altering the immunomodulatory landscape during infection of both placental and peripheral immune cells and show a clear impact of this immunomodulation on infection outcome. IMPORTANCE Toxoplasma gondii is a globally ubiquitous pathogen that can cause severe disease in HIV/AIDS patients and can also cross the placenta and infect the developing fetus. We have found that placental and immune cells infected with T. gondii secrete significant amounts of a chemokine (called CCL22) that is critical for immune tolerance during pregnancy. In order to better understand whether this is a response by the host or a process that is driven by the parasite, we have identified a T. gondii gene that is absolutely required to induce CCL22 production in human cells, indicating that CCL22 production is a process driven almost entirely by the parasite rather than the host. Consistent with its role in immune tolerance, we also found that T. gondii parasites lacking this gene are less able to proliferate and disseminate throughout the host. Taken together, these data illustrate a direct relationship between CCL22 levels in the infected host and a key parasite effector and provide an interesting example of how T. gondii can directly modulate host signaling pathways in order to facilitate its growth and dissemination.

Vasopressors in traumatic brain injury: Quantifying their effect on mortality.

BACKGROUND: The benefits of vasopressor (VP) use to improve clinical outcomes in traumatic brain injury (TBI) is unknown. We sought to characterize the use of VP in TBI patients and evaluate its impact on mortality. METHODS: A retrospective review was conducted of all TBI patients admitted to an ICU at a Level I trauma center from January 2014 to August 2016. Patients who had any VP administered (VP+) were compared to those who did not (VP-). RESULTS: Among the 556 patients analyzed, 83 (14.9%) received VP. The overall mortality was 9.2%, significantly higher in the VP + cohort (42.2% vs. 3.4%, p < 0.01). After adjusting for confounding factors, VP + patients had a significantly higher risk for in-hospital mortality (Adjusted Hazard Ratio: 2.77, adjusted p = 0.01). CONCLUSION: Although VP may be temporarily useful in avoiding secondary insult to the brain in TBI patients, their use is not associated with improved survival.