Development of Ribityllumazine Analogue as Mucosal-Associated Invariant T Cell Ligands.

Mucosal-associated invariant T (MAIT) cells are a subset of innate-like T cells abundant in human tissues that play a significant role in defense against bacterial and viral infections and in tissue repair. MAIT cells are activated by recognizing microbial-derived small-molecule ligands presented by the MHC class I related-1 protein. Although several MAIT cell modulators have been identified in the past decade, potent and chemically stable ligands remain limited. Herein, we carried out a structure-activity relationship study of ribityllumazine derivatives and found a chemically stable MAIT cell ligand with a pteridine core and a 2-oxopropyl group as the Lys-reactive group. The ligand showed high potency in a cocultivation assay using model cell lines of antigen-presenting cells and MAIT cells. The X-ray crystallographic analysis revealed the binding mode of the ligand to MR1 and the T cell receptor, indicating that it forms a covalent bond with MR1 via Schiff base formation. Furthermore, we found that the ligand stimulated proliferation of human MAIT cells in human peripheral blood mononuclear cells and showed an adjuvant effect in mice. Our developed ligand is one of the most potent among chemically stable MAIT cell ligands, contributing to accelerating therapeutic applications of MAIT cells.

3D layered co-culture model enhances Trastuzumab Deruxtecan sensitivity and reveals the combined effect with G007-LK in HER2-positive non-small cell lung cancer.

Human epidermal growth factor receptor 2 (HER2) aberrations are observed in various cancers. In non-small cell lung cancer, genetic alterations activating HER2, mostly exon 20 insertion mutations, occur in approximately 2-4% of cases. Trastuzumab deruxtecan (T-DXd), a HER2-targeted antibody-drug conjugate has been approved as the first HER2-targeted drug for HER2-mutant lung cancer. However, some cases are not responsive to T-DXd and the primary resistant mechanism remains unclear. In this study, we assessed sensitivity to T-DXd in JFCR-007, a patient-derived HER2-mutant lung cancer cell line. Although JFCR-007 was sensitive to HER2 tyrosine kinase inhibitors, it showed resistance to T-DXd in attachment or spheroid conditions. Accordingly, we established a three-dimensional (3D) layered co-culture model of JFCR-007, where it exhibited a lumen-like structure and became sensitive to T-DXd. In addition, an in-house inhibitor library screening revealed that G007-LK, a tankyrase inhibitor, was effective when combined with T-DXd. G007-LK increased the cytotoxicity of topoisomerase-I inhibitor, DXd, a payload of T-DXd and SN-38. This combined effect was also observed in H2170, an HER2-amplified lung cancer cell line. These results suggest that the proposed 3D co-culture system may help in evaluating the efficacy of T-DXd and may recapitulate the tumor microenvironment.

Antenatal steroids elicited neurodegenerative-associated transcriptional changes in the hippocampus of preterm fetal sheep independent of lung maturation.

BACKGROUND: Antenatal steroid therapy for fetal lung maturation is routinely administered to women at risk of preterm delivery. There is strong evidence to demonstrate benefit from antenatal steroids in terms of survival and respiratory disease, notably in infants delivered at or below 32 weeks' gestation. However, dosing remains unoptimized and lung benefits are highly variable. Current treatment regimens generate high-concentration, pulsatile fetal steroid exposures now associated with increased risk of childhood neurodevelopmental diseases. We hypothesized that damage-associated changes in the fetal hippocampal transcriptome would be independent of preterm lung function. METHODS: Date-mated ewes carrying a single fetus at 122 ± 2dGA (term = 150dGA) were randomized into 4 groups: (i) Saline Control Group, 4×2ml maternal saline intramuscular(IM) injections at 12hr intervals (n = 11); or (ii) Dex High Group, 2×12mg maternal IM dexamethasone phosphate injections at 12hr intervals followed by 2×2ml IM saline injections at 12hr intervals (n = 12; representing a clinical regimen used in Singapore); or (iii) Dex Low Group, 4×1.5mg maternal IM dexamethasone phosphate injections 12hr intervals (n = 12); or (iv) Beta-Acetate Group, 1×0.125mg/kg maternal IM betamethasone acetate injection followed by 3×2ml IM sterile normal saline injections 12hr intervals (n = 8). Lambs were surgically delivered 48hr after first maternal injection at 122-125dGA, ventilated for 30min to establish lung function, and euthanised for necropsy and tissue collection. RESULTS: Preterm lambs from the Dex Low and Beta-Acetate Groups had statistically and biologically significant lung function improvements (measured by gas exchange, lung compliance). Compared to the Saline Control Group, hippocampal transcriptomic data identified 879 differentially significant expressed genes (at least 1.5-fold change and FDR < 5%) in the steroid-treated groups. Pulsatile dexamethasone-only exposed groups (Dex High and Dex Low) had three common positively enriched differentially expressed pathways related in part to neurodegeneration ("Prion Disease", "Alzheimer's Disease", "Arachidonic Acid metabolism"). Adverse changes were independent of respiratory function during ventilation. CONCLUSIONS: Our data suggests that exposure to antenatal steroid therapy is an independent cause of damage- associated transcriptomic changes in the brain of preterm, fetal sheep. These data highlight an urgent need for careful reconsideration and balancing of how antenatal steroids are used, both for patient selection and dosing regimens.

Development of a Cytosolic DNA Sensor Agonist Using GALA Peptide-Conjugated DNA and Long Single-Stranded DNA.

Cytosolic DNA sensors (CDSs) recognize DNA molecules that are abnormally located in the cytosol, thus leading to the activation of the stimulator of interferon genes (STING) and the induction of type 1 interferon. In turn, type 1 interferon evokes defensive reactions against viral infections and activates the immune system; therefore, the use of agonists of CDSs as cancer therapeutics and vaccine adjuvants is expected. Double-stranded DNA molecules with dozens to thousands of bases derived from bacteria and viruses are agonists of CDSs. However, DNA is a water-soluble molecule with a high molecular weight, resulting in poor cellular uptake and endosomal escape. In contrast, long single-stranded DNA (lssDNA) obtained by rolling circle amplification is efficiently taken up and localized to endosomes. Here we constructed a CDS-targeting lssDNA via the facilitation of its intracellular transport from endosomes to the cytosol. An endosome-disrupting GALA peptide was used to deliver the lssDNA to the cytosol. A peptide-oligonucleotide conjugate (POC) was successfully obtained via the conjugation of the GALA peptide with an oligonucleotide complementary to the lssDNA. By hybridization of the POC to the complementary lssDNA (POC/lssDNA), the CDS-STING pathway in dendritic cells was efficiently stimulated. GALA peptide-conjugated DNA seems to be a helpful tool for the delivery of DNA to the cytosol.

Postnatal budesonide improved lung function in preterm lambs exposed to antenatal steroids and chorioamnionitis.

BACKGROUND: A combination of budesonide and surfactant decreases the rates of BPD in infants and lung injury in preterm sheep. Whether this combination will show benefit in the setting of chorioamnionitis and antenatal steroids is not known. METHODS: Ewes at 123 ± 1 day gestational age received intra-amniotic (IA) injections of 10 mg LPS before being randomized to receive either 0.25 mg/kg maternal betamethasone phosphate and acetate or saline by intramuscular (IM) injection at 48 and 24 h prior to delivery at 125 ± 1 day. Lambs (N = 6-9/group) underwent intentionally injurious ventilation for 15 min, then lambs received surfactant mixed with either: (1) saline; or (2) Budesonide 0.25 mg/kg and were ventilated for 4 h. RESULTS: Compared with LPS-exposed animals that received no IM steroid treatment, betamethasone exposed fetuses had improved hemodynamic stability, lung compliance, and ventilation efficiency. The addition of budesonide to surfactant further improved markers of injury and pro-inflammatory cytokine mRNA in both betamethasone IM or no IM lambs exposed to LPS IA. Antenatal betamethasone and IA LPS exposures decreased budesonide levels in the fetal lung and plasma. CONCLUSION: Antenatal betamethasone stabilizes physiologic parameters in LPS treated lambs. Budesonide mixed with surfactant further decreases injury and improves respiratory physiology in betamethasone treated animals. IMPACT: Antenatal betamethasone improved lung and systemic physiology in the setting of intra-amniotic LPS. The addition of budesonide to the surfactant further improved lung function. Budesonide levels in the plasma and lung were lower in lambs exposed to either LPS or LPS and Betamethasone animals, and these findings were not explained by increased esterification in the lungs. The combination of antenatal steroids and budesonide with surfactant had the lowest markers of pro-inflammatory cytokines in the lung of LPS exposed animals.

Liver anatomy for totally laparoscopic segment 7 resection from a caudal magnified view-a 3-dimensional computed tomographic analysis.

BACKGROUND: Laparoscopic resection of hepatic segment 7 is considered particularly difficult. We analyzed anatomic variation of this segment in caudally oriented 3-dimensional (3D) magnified computed tomographic (CT) images obtained prior to liver resection. METHODS: Analysis included 105 patients with preoperative 3D CT evaluation preceding liver resection for hepatobiliary malignancies between April 2021 and April 2024. RESULTS: Five ramification patterns were evident from a caudal magnified view. Some patients who had multiple segment 7 (S7) portal pedicles and an S7 pedicle branching ventrally posed difficulty in performing segmentectomy for the exact extent of S7. Distance from the point where a perpendicular line from the right rim of the inferior vena cava (IVC) intersected the right posterior portal pedicle to the point of bifurcation of the S6 and 7 pedicles was 34.6 mm (range, 3.9-78.8; mean ± standard deviation, 35.2 ± 14.8 mm). The median angle between the perpendicular line from the right rim of the IVC and the line from the root of the S7 pedicle to the right rim of the IVC was 77° (10-140); the mean ± standard deviation was 75.3° ± 28.1. Differences among ramification patterns also were evident. The angle between the right posterior portal pedicle and the S7 pedicle was 143° (79-215) or 143.3 ± 26.7, and that between S7 and S6 pedicles was 71°(15-123) or 75.5 ± 21.7°, representing relatively little variation. CONCLUSIONS: Understanding these details of caudal-view anatomy may resolve difficulties and clarify access required for exposing S7 portal pedicles.

Impact of perineal pain and delivery related factors on interference with activities of daily living until 1 month postpartum: A longitudinal prospective study.

BACKGROUND: Interference with activities of daily living can negatively impact maternal practices both physically and psychologically. This study aimed to explore the patterns of interference with activities of daily living and perineal pain among Japanese women until 1 month postpartum. Furthermore, we aimed to describe how both perineal pain and delivery-related factors were associated with interference with activities of daily living. METHODS: This study was part of a larger prospective longitudinal study conducted at five maternity hospitals in Japan. The participants were 293 women who had full-term vaginal deliveries and singleton infants. Participants self-evaluated their perineal pain and interference with activities of daily living using a 100 mm visual analogue scale and 'behaviour that interferes with daily life scale' at day 1, day 5, and 1 month postpartum. We used a linear mixed model to calculate the fixed-effects parameter estimates and their 95% confidence intervals. Interference with activities of daily living, which included difficulty sitting, difficulty moving, and difficulties with excretion and cleanliness, were set as the dependent variables. RESULTS: The final analysis included 184 participants with a mean age of 31.5±4.5 years. Perineal pain and the three sub-scales of interference with activities of daily living reduced from day 1 to 5 postpartum, and further from day 5 to 1 month postpartum (perineal pain, p<0.01, p<0.01; difficulty sitting, p<0.01, p<0.01; difficulty moving, p<0.01, p<0.01; difficulties with excretion and cleanliness, p<0.01, p<0.01). These tendencies did not change, even adjusted for independent variables using a mixed model. In the mixed model for follow-up data, perineal pain was a significantly and positively associated with three sub-scales of interference with activities of daily living, even after adjusted for perineal injury and episiotomy. CONCLUSIONS: Positive relationships were observed between perineal pain and interference with activities of daily living until 1 month postpartum, although both reduced. To promote maternal role attainment through child-rearing since early postpartum, midwives should pay additional attention to mothers' perineal pain as it could negatively affect their daily life and child-rearing.

Jejunal vein tributary analysis and intraoperative clamp testing in avoiding congestion after pancreatoduodenectomy.

PURPOSE: Although venous drainage of the jejunal loop may be maintained after sacrifice of jejunal vein tributaries during pancreatoduodenectomy, risk of severe jejunal mesenteric congestion following division of these tributaries can be difficult to predict. This study considered how best to predict safety of jejunal vein tributary dissection. METHODS: Preoperative imaging findings and results of intraoperative clamp tests of jejunal vein tributaries during pancreatoduodenectomy were analyzed in 121 patients with hepatobiliary and pancreatic disease to determine whether this information adequately predicted safety of resecting superior mesenteric vein branches. RESULTS: Jejunal vein tributaries caudal to the inferior border of the pancreatic uncinate process tended to be fewer when tributaries cranial to this landmark were more numerous. Tributaries cranial to the border drained a relatively wide expanse of jejunal artery territory in the jejunal mesentery. The territory of jejunal tributaries cranial to the inferior border of the pancreas did not vary according to course of the first jejunal vein branch relative to the superior mesenteric artery. One patient among 30 (3%) who underwent intraoperative clamp tests of tributaries cranial to the border showed severe congestion in relation to a venous tributary coursing ventrally to the superior mesenteric artery. CONCLUSION: Jejunal venous tributaries drained an extensive portion of jejunal arterial territory, but tributaries located cranially to the inferior border of the pancreas could be sacrificed without congestion in nearly all patients. Intraoperative clamp testing of these tributaries can identify patients whose jejunal veins must be preserved to avoid congestion.

Determinants of postpartum depression among women in Kampong Chhnang Province, Cambodia.

OBJECTIVE: This study aimed to identify the prevalence of postpartum depression (PPD) and the factors associated with PPD in Kampong Chhnang Province, Cambodia. STUDY DESIGN: A cross-sectional study. PARTICIPANTS: This study included 440 Cambodian women at 6-8 weeks postpartum who visited health centers between July and September 2021. MATERIALS AND METHODS: Data were collected through face-to-face interviews by midwives and nurses using a structured questionnaire. The Edinburgh Postnatal Depression Scale (EPDS) in the Khmer language was used to screen for PPD, and suspected PPD was defined as a total EPDS score ≥ 10. Logistic regression analyses were performed to identify the factors associated with suspected PPD. FINDINGS: The average age of participants was 28.6 years old. The prevalence of suspected-PPD was 30.2 % (n = 133). Factors associated with suspected PPD were income dissatisfaction (adjusted odds ratio (AOR) = 2.66, 95 % confidence interval (CI) 1.27-5.56, P = 0.010), unintended pregnancy (AOR = 1.99, 95 % CI 1.10-3.61, P = 0.023), and a partner employed as a manual laborer (AOR = 3.85, 95 % CI 1.11-13.33, P = 0.034), farmer (AOR = 3.69, 95 % CI 1.11-12.31, P = 0.034), and factory worker (AOR = 5.43, 95 % CI 1.38-21.41, P = 0.016). In addition, poor relationship with partners (AOR = 2.14, 95 % CI 1.17-3.94, P = 0.014), poor relationship with mother-in-law (AOR = 3.51, 95 % CI 1.70-7.21, P < 0.001), and a history of depression before pregnancy (AOR = 6.34, 95 % CI 1.59-25.34, P = 0.009) were significantly associated with suspected-PPD. KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: This study highlighted the need for mental health services in primary healthcare settings. Mental health training for healthcare workers, particularly primary-level nurses, should be prioritized and strengthened. Further clinical study on EPDS validation should be carried out to justify the appropriate cut-off EPDS score for Cambodian women. The EPDS should be integrated into routine PNC services to identify women with suspected-PPD. Education on PPD should be provided not only to the nurses and midwives, but also to the women and their families to support the mental health of pregnant and postpartum women.

Respiratory benefit in preterm lambs is progressively lost when the concentration of fetal plasma betamethasone is titrated below two nanograms per milliliter.

Antenatal steroid therapy is the standard of care for women at imminent risk of preterm delivery. Current dosing regimens use suprapharmacological doses to achieve extended fetal steroid exposures. We aimed to determine the lowest fetal plasma betamethasone concentration sufficient to achieve functional preterm lung maturation. Ewes with single fetuses underwent surgery to install a fetal jugular catheter. Adopting a stepwise design, ewes were randomized to either a saline-only group (negative control group; n = 9) or one of four betamethasone treatment groups. Each betamethasone group fetus received a fetal intravenous infusion to target a constant plasma betamethasone level of either 1) 2 ng/mL (2 ng/mL positive control group, n = 9); 2) 1 ng/mL, (1 ng/mL group, n = 10); 3) 0.5 ng/mL (0.5 ng/mL group, n = 10); or 4) 0.25 ng/mL (0.25 ng/mL group, n = 10). Fetuses were infused for 48 h, delivered, and ventilated. The positive control group, negative control group, and mid-point 0.5 ng/mL group animals were tested first. An interim analysis informed the final betamethasone group tested. Positive control group animals had large, statistically significant improvements in respiratory function. Based on an interim analysis, the 1.0 ng/mL group was studied in favor of the 0.25 ng/mL group. Treatment efficacy was progressively lost at plasma betamethasone concentrations lower than 2 ng/mL. We demonstrated that the acute respiratory benefit conveyed by antenatal steroid exposure in the fetal sheep is progressively lost when constant fetal plasma betamethasone concentrations are reduced below a targeted value of 2 ng/mL.NEW & NOTEWORTHY Lung maturation benefits in preterm lambs were progressively lost when fetal plasma betamethasone concentrations fell below 2 ng/mL. The effective floor threshold for a robust, lung-maturing exposure likely lies between 1 and 2 ng betamethasone per milliliter of plasma. Hypothalamic pituitary adrenal axis signaling and immunocyte populations remained materially disrupted at subtherapeutic steroid concentrations. These data demonstrate the potential to improve antenatal steroid therapy using reduced dose regimens informed by glucocorticoid pharmacokinetics and pharmacodynamics.

Oncofertility-related psycho-educational therapy for young adult patients with breast cancer and their partners: Randomized controlled trial.

BACKGROUND: A couples' psycho-educational program called Oncofertility! Psycho-Education and Couple Enrichment (O!PEACE) therapy was created and its effect when provided before cancer treatment was examined. METHODS: This multicenter randomized controlled trial with nonmasking, parallel two-group comparison enrolled women aged 20 to 39 years with early-stage breast cancer and their partners. They were randomly assigned to receive O!PEACE (37 couples) or usual care (37 couples). Primary end points were cancer-related posttraumatic stress symptoms, symptoms of depression, and anxiety. Secondary end points were stress-coping strategies, resilience, and marital relationship. RESULTS: Women receiving psycho-educational therapy had significantly reduced Impact of Event Scale-revised version for Japanese scores (p = .011, ηp 2  =  = .089). For patients with Impact of Event Scale-revised version for Japanese scores at baseline ≥18.27, O!PEACE therapy improved these scores when compared with usual care (U = 172.80, p = .027, r = 0.258). A >5-point reduction was present in 59.3% and 30% of women in the O!PEACE therapy and usual-care groups, respectively. For partners, O!PEACE therapy significantly improved stress-coping strategies (95% CI, -0.60 to -0.05; p = .018, ηp 2  =  = .074) and escape-avoidance marital communication (95% CI, -0.33 to -0.08; p = .001, ηp 2  = .136). O!PEACE therapy significantly improved the partners' support (95% CI, 0.10-0.50; p = .001, ηp 2  = .127), the rate of receiving fertility preservation consultations, and knowledge levels. CONCLUSIONS: O!PEACE therapy before cancer treatment can improve posttraumatic stress symptoms, stress-coping behavior, and marital relationships. Larger sample sizes and longer term follow-up are required. PLAIN LANGUAGE SUMMARY: A psycho-educational program, the Oncofertility! Psycho-Education and Couple Enrichment (O!PEACE) therapy program was developed and evaluated for women diagnosed with breast cancer and their partners. A multicenter randomized controlled trial showed that the O!PEACE psycho-educational therapy, with only two precancer treatment sessions, can reduce cancer-related posttraumatic stress symptoms and improve oncofertility knowledge and marital relationships in young adult patients with breast cancer. The therapy could also improve stress-coping strategies in marital communications with their partners. Couples may use O!PEACE psycho-educational therapy to consider fertility preservation and improve their psychosocial aspects.

Behavior of Photosystems II and I Is Modulated Depending on N Partitioning to Rubisco in Mature Leaves Acclimated to Low N Levels and Senescent Leaves in Rice.

In mature leaves acclimated to low N levels and in senescent leaves, photosystems II and I (PSII and PSI, respectively) show typical responses to excess light energy. As CO2 assimilation is not transiently suppressed in these situations, the behavior of PSII and PSI is likely caused by endogenous biochemical changes in photosynthesis. In this study, this subject was studied in rice (Oryza sativa L.). Analysis was performed on mature and senescent leaves of control and N-deficient plants. Total leaf-N, Rubisco and chlorophyll (Chl) levels and their ratios were determined as biochemical parameters of photosynthesis. Total leaf-N, Rubisco and Chl levels decreased in the mature leaves of N-deficient plants and senescent leaves. The percentage of Rubisco-N in the total leaf-N decreased in these leaves, whereas that of Chl-N tended to remain almost constant in mature leaves but increased in senescent leaves. Changes in PSII and PSI parameters were best accounted for by the Rubisco-N percentage, strongly suggesting that the behavior of PSII and PSI is modulated depending on changes in N partitioning to Rubisco in mature leaves acclimated to low N levels and in senescent leaves. It is likely that a decrease in N partitioning to Rubisco leads to a decrease in Rubisco capacity relative to other photosynthetic capacities that inevitably generate excess light energy and that the operation of PSII and PSI is modulated in such situations.

Impact of right ventricular reserve on exercise capacity and quality of life in patients with left ventricular assist device.

Although measuring right ventricular (RV) function during exercise is more informative than assessing it at rest, the relationship between RV reserve function, exercise capacity, and health-related quality of life (HRQoL) in patients with left ventricular assist devices (LVAD) remains unresolved. We aimed to investigate whether RV reserve assessed by the change in RV stroke work index (RVSWI) during exercise is correlated with exercise capacity and HRQoL in patients with LVAD. We prospectively assessed 24 consecutive patients with LVAD who underwent invasive right heart catheterization in the supine position. Exercise capacity and HRQoL were assessed using the 6-min walk distance (6 MWD) and peak oxygen consumption (V̇o2) in cardiopulmonary exercise testing, and the EuroQol visual analog scale (EQ-VAS), respectively. The patients were divided into two groups according to the median ΔRVSWI (change from rest to peak exercise). Patients with lower ΔRVSWI had significantly lower changes in cardiac index and absolute value of RV dP/dt than those with higher ΔRVSWI. The ΔRVSWI was positively correlated with 6 MWD (r = 0.59, P = 0.003) and peak V̇o2 (r = 0.56, P = 0.006). In addition, ΔRVSWI was positively correlated with the EQ-VAS (r = 0.44, P = 0.030). In contrast, there was no significant correlation between RVSWI at rest and 6 MWD (r = -0.34, P = 0.88), peak V̇o2 (r = 0.074, P = 0.74), or EQ-VAS (r = 0.127, P = 0.56). Our findings suggest that the assessment of RV reserve function is useful for risk stratification in patients with LVAD.NEW & NOTEWORTHY The change in right ventricular stroke work index (RVSWI) during exercise, not RVSWI at rest, was associated with exercise capacity and HRQoL. Our findings suggest that the assessment of change in RVSWI during exercise as a surrogate of RV reserve function may aid in risk stratification of patients with LVAD.

System truncation accelerates binding affinity calculations with the fragment molecular orbital method: A benchmark study.

The fragment molecular orbital (FMO) method is a fast quantum-mechanical method that divides systems into pieces of fragments and performs ab initio calculations. The system truncation enables further speed improvement. In this article, we systematically study the effects of system truncations on binding affinity calculations obtained with FMO in combination with either the polarizable continuum model (FMO/PCM) or in combination with the Møller-Plesset method (FMO-MP2). We have used five protein complexes with ligands of several charged states. The calculated binding energies of the size variants of the truncated system, including only a restricted number of atoms around the ligand, are compared to the energy obtained from a full system. The result shows that the systems could be truncated to a radius of 8 Å from neutral ligands within an error of 0.7 kcal/mol, and 12 Å from charged ligands within an error of 1.1 kcal/mol for calculating the binding energy in solution.

Liver stiffness assessed by magnetic resonance elastography predicts clinical outcomes in patients with heart failure and without chronic liver disease.

OBJECTIVES: Evaluation of liver stiffness (LS) by magnetic resonance elastography (MRE) is useful for estimating right atrial pressure (RAP) in patients with heart failure (HF). However, its prognostic implications are unclear. We sought to investigate whether LS measured by MRE (LS-MRE) could predict clinical outcomes in patients with HF. METHODS: We prospectively examined 207 consecutive HF patients between April 2018 and May 2021 after excluding those with organic liver disease. All patients underwent 3.0-T MRE. The primary outcome of interest was the composite of all-cause death and hospitalisation for HF. RESULTS: During a median follow-up period of 720 (interquartile range [IQR] 434-1013) days, the primary outcome occurred in 44 patients (21%), including 15 (7%) all-cause deaths and 29 (14%) hospitalisations for HF. The patients were divided into two groups according to median LS-MRE of 2.54 (IQR 2.34-2.82) kPa. Patients with higher LS-MRE showed a higher incidence of the primary outcome compared to those with lower LS-MRE (p < 0.001). Multivariable Cox regression analyses revealed that LS-MRE value was independently associated with the risk of adverse events (hazard ratio 2.49, 95% confidence interval 1.46-4.24). In multivariable linear regression, RAP showed a stronger correlation with LS-MRE (ß coefficient = 0.31, p < 0.001) compared to markers related to liver fibrosis. CONCLUSIONS: In patients without chronic liver disease and presenting with HF, elevated LS-MRE was independently associated with worse clinical outcomes. Elevated LS-MRE may be useful for risk stratification in patients with HF and without chronic liver disease. KEY POINTS: • Magnetic resonance elastography (MRE) is an emerging non-invasive imaging technique for evaluating liver stiffness (LS) which can estimate right atrial pressure. • Elevated LS-MRE, which mainly reflects liver congestion, was independently associated with worse clinical outcomes in patients with heart failure. • The assessment of LS-MRE would be useful for stratifying the risk of adverse events in heart failure patients without chronic liver disease.

Development of Enzymatic Depletion Methods for Preparation of Small Extracellular Vesicles with Long Blood-Circulation Half-Life.

PURPOSE: Phosphatidylserine (PS)-deficient small extracellular vesicle (sEV) subpopulations (PS(-) sEVs) circulate in blood for long periods; hence, they are expected to have therapeutic applications. However, limited production of PS(-) sEVs makes their application difficult. In this study, a method for the preparation of such populations using an enzymatic reaction was developed. METHODS: Bulk sEVs collected from a cell culture supernatant via ultracentrifugation were subjected to an enzymatic reaction using phosphatidylserine decarboxylase (PSD). The yield of PS(-) sEVs was estimated using magnetic beads that bind to PS(+) sEVs. Then, the physical properties and pharmacokinetics (PK) of the sEVs were evaluated. RESULTS: Enzymatic depletion of PS exposed on sEV surfaces using PSD increased the yield of PS(-) sEVs. PSD treatment hardly changed the physicochemical properties of PS(-) sEVs. Moreover, the serum concentration profile and PK parameters of the PS(-) sEVs derived from PSD-treated bulk sEVs indicated a long blood-circulation half-life. CONCLUSIONS: Treatment of sEVs with PSD successfully reduced surface PS levels and increased the amount of the PS(-) sEV subpopulation among bulk sEVs. This protocol of efficient preparation of PS(-) sEVs based on PSD treatment, as well as information on the basic PK, can be foundational for the therapeutic application of sEVs.

Differences in blood flow dynamics between balloon- and self-expandable valves in patients with aortic stenosis undergoing transcatheter aortic valve replacement.

BACKGROUND: The differences in pre- and early post-procedural blood flow dynamics between the two major types of bioprosthetic valves, the balloon-expandable valve (BEV) and self-expandable valve (SEV), in patients with aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR), have not been investigated. We aimed to investigate the differences in blood flow dynamics between the BEV and SEV using four-dimensional flow cardiovascular magnetic resonance (4D flow CMR). METHODS: We prospectively examined 98 consecutive patients with severe AS who underwent TAVR between May 2018 and November 2021 (58 BEV and 40 SEV) after excluding those without CMR because of a contraindication, inadequate imaging from the analyses, or patients' refusal. CMR was performed in all participants before (median interval, 22 [interquartile range (IQR) 4-39] days) and after (median interval, 6 [IQR 3-6] days) TAVR. We compared the changes in blood flow patterns, wall shear stress (WSS), and energy loss (EL) in the ascending aorta (AAo) between the BEV and SEV using 4D flow CMR. RESULTS: The absolute reductions in helical flow and flow eccentricity were significantly higher in the SEV group compared in the BEV group after TAVR (BEV: - 0.22 ± 0.86 vs. SEV: - 0.85 ± 0.80, P < 0.001 and BEV: - 0.11 ± 0.79 vs. SEV: - 0.50 ± 0.88, P = 0.037, respectively); there were no significant differences in vortical flow between the groups. The absolute reduction of average WSS was significantly higher in the SEV group compared to the BEV group after TAVR (BEV: - 0.6 [- 2.1 to 0.5] Pa vs. SEV: - 1.8 [- 3.5 to - 0.8] Pa, P = 0.006). The systolic EL in the AAo significantly decreased after TAVR in both the groups, while the absolute reduction was comparable between the groups. CONCLUSIONS: Helical flow, flow eccentricity, and average WSS in the AAo were significantly decreased after SEV implantation compared to BEV implantation, providing functional insights for valve selection in patients with AS undergoing TAVR. Our findings offer valuable insights into blood flow dynamics, aiding in the selection of valves for patients with AS undergoing TAVR. Further larger-scale studies are warranted to confirm the prognostic significance of hemodynamic changes in these patients.

Prognostic implications of histologic growth patterns and tumor-infiltrating macrophages in colorectal liver metastases.

PURPOSE: Histopathologic patterns at the invasion fronts of tumors predict metastatic potential and prognosis in several cancers. We examined whether such patterns at the interface between colorectal liver metastases and hepatic parenchyma have similar prognostic value. METHODS: Microscopic growth patterns at edges of metastases including desmoplasia, pushing borders, and replacement of hepatocytes were retrospectively analyzed with respect to surgical outcomes in 142 patients who underwent hepatectomy for colorectal metastases. RESULTS: Patterns included desmoplasia in 58 patients (41%), hepatocyte replacement in 41 (29%), and pushing borders in 43 (30%). Maximum metastasis diameter and serum carcinoembryonic antigen concentration in patients showing desmoplastic tumor growth were lower than those in others (P < 0.05 and P < 0.01). Disease-free survival and overall survival were better in patients showing desmoplastic growth, while a non-desmoplastic tumor growth pattern showed a negative influence. More cluster of differentiation (CD) 68-positive M1 macrophages and fewer CD206-positive M2 macrophages were demonstrated at interfaces of tumors with hepatic parenchyma when desmoplasia was present, although markers for proliferative activity (MIB1 index) and metastatic potential (E-cadherin expression) appeared uninfluenced by desmoplasia. CONCLUSION: Better long-term results were associated with metastatic tumors showing desmoplastic growth patterns at invasion fronts, which may reflect local immune state in a prognostically useful manner.

Failure of peritoneal lavage to prevent operative site infection and peritoneal tumor recurrence in pancreatic surgery.

BACKGROUND: Although intraoperative peritoneal lavage often is performed routinely with the aim of reducing peritoneal contamination, evidence of lavage benefit in elective pancreatic surgery is limited. METHODS: We retrospectively classified patients who had undergone pancreatic surgery to groups given or not given peritoneal lavage, then comparing clinical results. This saline lavage was performed at the end of the operation. The primary endpoint was rate of surgical site infection. Frequency of peritoneal recurrence also was evaluated. RESULTS: Among all 104 patients in the study, incidence of infectious complications in the lavage group (n = 65) was significantly higher than in the non-lavage group (n = 39; 35% vs. 15%, P = 0.041), while incidences of postoperative complications overall and surgical site infection did not differ between lavage (80% and 26%) and non-lavage groups (67% and 10%, P = 0.162 and 0.076, respectively). Among 63 patients undergoing pancratoduodenectomy, frequencies of positive bacterial cultures of drainage fluids on postoperative days 1 and 3 were greater in the non-lavage group (P < 0.001 and P = 0.012), but surgical site infection was significantly more frequent in the lavage group (P = 0.043). Among patients with pancreatic and biliary cancers, lavage did not affect frequency of peritoneal recurrence. CONCLUSION: Intraoperative lavage did not prevent surgical site infection or peritoneal recurrence of pancreatobiliary cancer.

Skin-to-skin contact after birth: Developing a research and practice guideline.

AIM: Skin-to-skin contact immediately after birth is recognised as an evidence-based best practice and an acknowledged contributor to improved short- and long-term health outcomes including decreased infant mortality. However, the implementation and definition of skin-to-skin contact is inconsistent in both practice and research studies. This project utilised the World Health Organization guideline process to clarify best practice and improve the consistency of application. METHODS: The rigorous guideline development process combines a systematic review with acumen and judgement of experts with a wide range of credentials and experience. RESULTS: The developed guideline received a strong recommendation from the Expert Panel. The result concluded that there was a high level of confidence in the evidence and that the practice is not resource intensive. Research gaps were identified and areas for continued work were delineated. CONCLUSION: The World Health Organization guideline development process reached the conclusion immediate, continuous, uninterrupted skin-to-skin contact should be the standard of care for all mothers and all babies (from 1000 g with experienced staff if assistance is needed), after all modes of birth. Delaying non-essential routine care in favour of uninterrupted skin-to-skin contact after birth has been shown to be safe and allows for the progression of newborns through their instinctive behaviours.