Tumour-associated myeloid cells expressing IL-10R2/IL-22R1 as a potential biomarker for diagnosis and recurrence of pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a poor survival rate, largely due to the lack of early diagnosis. Although myeloid cells are crucial in the tumour microenvironment, whether their specific subset can be a biomarker of PDAC progression is unclear. METHODS: We analysed IL-22 receptor expression in PDAC and peripheral blood. Additionally, we analysed gene expression profiles of IL-10R2+/IL-22R1+ myeloid cells and the presence of these cells using single-cell RNA sequencing and murine orthotropic PDAC models, respectively, followed by examining the immunosuppressive function of IL-10R2+/IL-22R1+ myeloid cells. Finally, the correlation between IL-10R2 expression and PDAC progression was evaluated. RESULTS: IL-10R2+/IL-22R1+ myeloid cells were present in PDAC and peripheral blood. Blood IL-10R2+ myeloid cells displayed a gene expression signature associated with tumour-educated circulating monocytes. IL-10R2+/IL-22R1+ myeloid cells from human myeloid cell culture inhibited T cell proliferation. By mouse models for PDAC, we found a positive correlation between pancreatic tumour growth and increased blood IL-10R2+/IL-22R1+ myeloid cells. IL-10R2+/IL-22R1+ myeloid cells from an early phase of the PDAC model suppressed T cell proliferation and cytotoxicity. IL-10R2+ myeloid cells indicated tumour recurrence 130 days sooner than CA19-9 in post-pancreatectomy patients. CONCLUSIONS: IL-10R2+/IL-22R1+ myeloid cells in the peripheral blood might be an early marker of PDAC prognosis.

Delayed care during pregnancy and postpartum linked to poor maternal mental health: evidence in the United States.

BACKGROUND: Mental health disorders are important prenatal and postpartum health complications. In the rapidly changing healthcare landscape, concerns have been raised about maternal mental well-being in the United States. This study aimed to investigate the relationship between delayed perinatal care and women's mental health during pregnancy and postpartum. METHODS: We conducted a cross-sectional survey from March through April, 2022, of women currently pregnant (n = 590) or one-year postpartum (n = 525). A generalised linear model examined the association of delayed care during pregnancy and postpartum with mental health outcomes, specifically Major Depressive Disorder (MDD) and Generalised Anxiety Disorder (GAD). RESULTS: Individuals who experienced delayed care tended to exhibit higher rates of mental health symptoms compared to those without delays, especially during postpartum (69.4% vs. 30.7% for MDD; 46.6% vs. 24.8% for GAD). The results from multivariable regression analysis were consistent, showing a greater prevalence of MDD (aPR [adjusted Prevalence Ratio] 2.25, 95%CI 1.82-2.79; p < .001) and GAD (aPR 2.00, 95%CI 1.53-2.61; p < .001), respectively, when delays in postpartum care occurred. Reasons for delayed care, such as financial and time issues, lack of transportation, nervousness about seeing a doctor, and rural residency, were associated with increased mental health symptoms. CONCLUSION: The current analysis highlights the significant adverse health impact of delayed care among pregnant and postpartum women. Continued, targeted efforts to reduce practical barriers to accessing prenatal and postpartum care are required to ensure maternal mental health.

Differentiation of Isomeric, Nonseparable Carbohydrates Using Tandem-Trapped Ion Mobility Spectrometry-Mass Spectrometry.

Carbohydrates play important roles in biological processes, but their identification remains a significant analytical problem. While mass spectrometry has increasingly enabled the elucidation of carbohydrates, current approaches are limited in their abilities to differentiate isomeric carbohydrates when these are not separated prior to tandem-mass spectrometry analysis. This analytical challenge takes on increased relevance because of the pervasive presence of isomeric carbohydrates in biological systems. Here, we demonstrate that TIMS2-MS2 workflows enabled by tandem-trapped ion mobility spectrometry-mass spectrometry (tTIMS/MS) provide a general approach to differentiate isomeric, nonseparated carbohydrates. Our analysis shows that (1) cross sections measured by TIMS are sufficiently precise and robust for ion identification; (2) fragment ion cross sections from TIMS2 analysis can be analytically exploited to identify carbohydrate precursors even if the precursor ions are not separated by TIMS; (3) low-abundant fragment ions can be exploited to identify carbohydrate precursors even if the precursor ions are not separated by IMS. (4) MS2 analysis of fragment ions produced by TIMS2 can be used to validate and/or further characterize carbohydrate structures. Taken together, our analysis underlines the opportunities that tandem-ion mobility spectrometry/MS methods offer for the characterization of mixtures of isomeric carbohydrates.

Association of Health Insurance with Contraceptive Use and Interpersonal Quality of Contraceptive Care in the Southeast United States.

OBJECTIVES: Health insurance remains an important dimension of contraceptive access. This study investigated the role of insurance in contraceptive use, access, and quality in South Carolina and Alabama. METHODS: The study used a cross-sectional statewide representative survey that assessed reproductive health experiences and contraceptive use among reproductive-age women in South Carolina and Alabama. The primary outcomes were current contraceptive method use, barriers to access (inability to afford wanted method, delay/trouble obtaining wanted method), receipt of any contraceptive care in the past 12 months, and perceived quality of care. The independent variable was insurance type. Generalized linear models were applied to estimate prevalence ratios for each outcome's association with insurance type while adjusting for potentially confounding variables. RESULTS: Nearly 1 in 5 women (17.6%) was uninsured, and 1 in 4 women (25.3%) reported not using a contraceptive method at the time of the survey. Compared with women with private insurance, women with no insurance had a lower likelihood of current method use (adjusted prevalence ratio 0.75; 95% confidence interval 0.60-0.92) and receipt of contraceptive care in the past 12 months (adjusted prevalence ratio 0.61; 95% confidence interval 0.45-0.82). These women also were more likely to experience cost barriers to access care. The insurance type was not significantly associated with the interpersonal quality of contraceptive care. CONCLUSIONS: Findings highlight the need for expanding Medicaid in states that did not do so under the Patient Protection and Affordable Care Act, interventions to increase the number of providers who accept Medicaid patients, and protections to Title X funding as key elements for enhancing contraceptive access and population health outcomes.

Delayed or Forgone Care and Virtual Care in a Public Health Crisis Using Nationally Representative Population Data.

Aim: To investigate factors influencing delayed or forgone care due to the coronavirus pandemic and examine patterns in overall virtual care use and virtual care related to the coronavirus pandemic. Methods: The cross-sectional study used the 2020 National Center for Health Statistics, National Health Interview Survey. Individuals (17,586) who responded to delayed or forgone care questions were included. A generalized linear model estimated prevalence ratios (PRs) for delayed care, forgone care, and virtual care. Results: Approximately 26.5% of participants reported either having delayed (23.6%) or forgone care (15.7%). Females showed 1.29 (95% confidence interval [CI] 1.20-1.38; p ≤ 0.000) and 1.29 (95% CI 1.17-1.48; p ≤ 0.000) times greater risk of delayed and forgone care than males, respectively. Being insured and having chronic conditions were associated with more delayed and forgone care. About 32.5% of adults reported 1 year of virtual care, and of these, 83.6% were related to the coronavirus pandemic. Patterns of virtual care use of 1 year and the one related to the coronavirus pandemic varied. In the coronavirus pandemic-related virtual care, adults of 85 years old or above had a lower likelihood (PR 0.87, 95% CI 0.77-1.00; p = 0.043) of receiving virtual care. Low education attainment and nonmetro areas showed less virtual care usage. Conclusions: The coronavirus pandemic greatly affected health care. While virtual care significantly increased, historically underserved populations, such as older adults, rural residents, and those with low education attainment, experienced disparities in virtual care use. The findings provide important implications for sustained health care in a rapidly changing public health landscape.

Reasons for Not Pursuing Virtual Prenatal Care in 2020 Through 2021 and Policy Implications.

Aim: To investigate patterns of virtual prenatal visits and examine reasons for not pursuing virtual visits for prenatal care. Methods: A pooled cross-sectional study used Pregnancy Risk Assessment Monitoring System from October 2020 through June 2021, a nationally representative surveillance system targeted at women who recently gave live birth. Individuals (n = 11,829) who reported their prenatal care experiences were included. A modified poison regression estimated prevalence ratios for virtual prenatal visits and reasons for not using virtual services. Results: One-third of participants used virtual prenatal care. Hispanics were more likely to use virtual prenatal care than whites. Compared with college graduates, those with high school graduation (Prevalence Ratios [PR] 0.87, 95% confidence interval [CI] 0.76-0.99; p = 0.033) or some college education (PR 0.86, 95% CI 0.77-0.96; p = 0.009) were less likely to use virtual visits. A preference for in-person was the most common reason for not pursuing virtual visits (77.1%), followed by no available virtual appointments (29.5%), technology barriers (6.1%), and no private space (1.7%). Individuals with less than or with high school graduation had 4.16 times (95% CI 2.32-7.46; p ≤ 0.001) and 2.72 times (95% CI 1.67-4.43; p ≤ 0.001) greater technology barriers, and 10.03 times (95% CI 3.42-29.46; p ≤ 0.001) and 4.29 times (95% CI 1.56-11.80; p = 0.005) greater likelihood of lacking private space, respectively, while they had a lesser in-person preference. Conclusions: In a disrupted health care landscape, barriers to accessing virtual prenatal care may have further exacerbated access to care and effective management of pregnancy among those underserved. The findings provide practical implications for safe and effective prenatal care.

Tandem-trapped ion mobility spectrometry/mass spectrometry coupled with ultraviolet photodissociation.

RATIONALE: Tandem-ion mobility spectrometry/mass spectrometry methods have recently gained traction for the structural characterization of proteins and protein complexes. However, ion activation techniques currently coupled with tandem-ion mobility spectrometry/mass spectrometry methods are limited in their ability to characterize structures of proteins and protein complexes. METHODS: Here, we describe the coupling of the separation capabilities of tandem-trapped ion mobility spectrometry/mass spectrometry (tTIMS/MS) with the dissociation capabilities of ultraviolet photodissociation (UVPD) for protein structure analysis. RESULTS: We establish the feasibility of dissociating intact proteins by UV irradiation at 213 nm between the two TIMS devices in tTIMS/MS and at pressure conditions compatible with ion mobility spectrometry (2-3 mbar). We validate that the fragments produced by UVPD under these conditions result from a radical-based mechanism in accordance with prior literature on UVPD. The data suggest stabilization of fragment ions produced from UVPD by collisional cooling due to the elevated pressures used here ("UVnoD2"), which otherwise do not survive to detection. The data account for a sequence coverage for the protein ubiquitin comparable to recent reports, demonstrating the analytical utility of our instrument in mobility-separating fragment ions produced from UVPD. CONCLUSIONS: The data demonstrate that UVPD carried out at elevated pressures of 2-3 mbar yields extensive fragment ions rich in information about the protein and that their exhaustive analysis requires IMS separation post-UVPD. Therefore, because UVPD and tTIMS/MS each have been shown to be valuable techniques on their own merit in proteomics, our contribution here underscores the potential of combining tTIMS/MS with UVPD for structural proteomics.

Antibacterial Bicyclic Fatty Acids from a Korean Colonial Tunicate Didemnum sp.

Five new bicyclic carboxylic acids were obtained by antibacterial activity-guided isolation from a Korean colonial tunicate Didemnum sp. Their structures were elucidated by the interpretation of NMR, MS and CD spectroscopic data. They all belong to the class of aplidic acids. Three of them were amide derivatives (1-3), and the other two were dicarboxylic derivatives (4 and 5). The absolute configurations were determined by a bisignate pattern of CD spectroscopy, which revealed that the absolute configurations of amides were opposite to those of dicarboxylates at every stereogenic centers. Compound 2 exhibited the most potent antibacterial activity (MIC, 2 µg/mL).

Austalide K from the Fungus Penicillium rudallense Prevents LPS-Induced Bone Loss in Mice by Inhibiting Osteoclast Differentiation and Promoting Osteoblast Differentiation.

Osteoporosis is a chronic disease that has become a serious public health problem due to the associated reduction in quality of life and its increasing financial burden. It is known that inhibiting osteoclast differentiation and promoting osteoblast formation prevents osteoporosis. As there is no drug with this dual activity without clinical side effects, new alternatives are needed. Here, we demonstrate that austalide K, isolated from the marine fungus Penicillium rudallenes, has dual activities in bone remodeling. Austalide K inhibits the receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation and improves bone morphogenetic protein (BMP)-2-mediated osteoblast differentiation in vitro without cytotoxicity. The nuclear factor of activated T cells c1 (NFATc1), tartrate-resistant acid phosphatase (TRAP), dendritic cell-specific transmembrane protein (DC-STAMP), and cathepsin K (CTSK) osteoclast-formation-related genes were reduced and alkaline phosphatase (ALP), runt-related transcription factor 2 (Runx2), osteocalcin (OCN), and osteopontin (OPN) (osteoblast activation-related genes) were simultaneously upregulated by treatment with austalide K. Furthermore, austalide K showed good efficacy in an LPS-induced bone loss in vivo model. Bone volume, trabecular separation, trabecular thickness, and bone mineral density were recovered by austalide K. On the basis of these results, austalide K may lead to new drug treatments for bone diseases such as osteoporosis.

Activation of Hypoxia-Inducible Factor-1α Signaling Pathway Has the Protective Effect of Intervertebral Disc Degeneration.

Intervertebral discs (IVDs) have poor nutrient diffusion, because the nucleus pulposus (NP) lacks direct vascular supply and likely generates adenosine triphosphate by anaerobic glycolysis. Regulation of glycolysis is mediated by hypoxia-inducible factor-1α (HIF-1α), a transcription factor that responds to local oxygen tension. Constitutively active HIF-1α (CA HIF-1α) was created by point mutation and determined the protective role of HIF-1α in IVD degeneration. Under fluoroscopy, rat caudal IVD segments were stabbed by a needle puncture, and pcDNA3- HIF-1α wild-type (WT) or pcDNA3-CA HIF-1α was transfected into NP cell lines. The constitutive activity of CA HIF-1α was analyzed using a luciferase assay after cell lysis. Next, IVD tissue samples were retrieved from five patients with degenerative lumbar spinal stenosis at the time of surgery, and NP cells were cultured. NP cells were transfected with CA HIF-1α, and relevant gene expression was measured. HIF-1α protein levels in the nucleus were significantly higher, and transcriptional activity was 10.3-fold higher in NP cells with CA HIF-1α than in those with HIF-1α WT. Gene transfer of CA HIF-1α into NP cells enhanced the expression of Glut-1, Glut-3, aggrecan, type II collagen, and Sox9. Moreover, CA HIF-1α reduced the apoptosis of NP cells induced by the Fas ligand. The HIF-1α and collagen 2 expression levels were notably increased in the NP cells of the CA HIF-1α transfected segments in histology and immunohistochemistry study. Collectively, these results suggest that activation of HIF-1α signaling pathway may play a protective role against IVD degeneration and could be used as a future therapeutic agent.

A New Thiopeptide Antibiotic, Micrococcin P3, from a Marine-Derived Strain of the Bacterium Bacillus stratosphericus.

A new thiopeptide (micrococcin P3, 1) and a known one (micrococcin P1, 2) were isolated from the culture broth of a marine-derived strain of Bacillus stratosphericus. The structures of both compounds were elucidated using spectroscopic methods, including extensive 1D and 2D NMR analysis, high resolution mass spectrometry (HRMS), and tandem mass spectrometry. Both compounds exhibited potent antibacterial activities against Gram-positive strains with minimum inhibitory concentration (MIC) values of 0.05-0.8 µg/mL and did not show cytotoxicity in the MTT assay up to a concentration of 10 µM. This study adds a new promising member, micrococcin P3, to the family of thiopeptide antibiotics, which shows potential for the development of new antibiotics targeting Gram-positive bacteria.

Benzophenone Compounds, from a Marine-Derived Strain of the Fungus Pestalotiopsis neglecta, Inhibit Proliferation of Pancreatic Cancer Cells by Targeting the MEK/ERK Pathway.

Pancreatic cancer, which has an extremely poor prognosis, is one of the most fatal human cancers. Chemotherapy is the main palliative treatment for advanced cancer patients and also plays an indispensable role in postoperative treatments for surgical patients. Therefore, there is an urgent need to develop more innovative anticancer drugs to fight against this fatal disease. Here, we investigate the potential of benzophenone derivatives, obtained from a marine-derived strain of the fungus Pestalotiopsis neglecta, as antiproliferative lead compounds for the treatment of pancreatic cancer. The compounds, seven new (1-7) and two known (8 and 9) halogenated benzophenone derivatives, were obtained by bioactivity-guided fractionation from the cultures of Pestalotiopsis neglecta. The structures were defined by spectroscopic methods including X-ray crystallographic analysis. Using the commonly used pancreatic cancer cell line PANC-1, 2 and 4 were found to suppress cell proliferation and induce apoptosis in the low micromolar range of 7.6 and 7.2 µM, respectively. Mechanistically, benzophenone derivatives not only inhibit MEK activity in the cytoplasm but also suppress ERK activity in the cytoplasm and nucleus. An in silico study suggests that benzophenone derivatives could potentially inhibit MEK activity by binding to the allosteric pocket in MEK. Benzophenones could serve as new lead compounds for the treatment of pancreatic cancer.

Austalides, Osteoclast Differentiation Inhibitors from a Marine-Derived Strain of the Fungus Penicillium rudallense.

Four new meroterpenoids, austalides V-X (1-3) and a farnesylated phthalide derivative (4), were isolated from the culture of the marine fungus Penicillium rudallense, together with eight known meroterpenoids derivatives (5-12). Their structures, including absolute configurations, were determined by spectroscopic methods. All of the isolated compounds were evaluated for their inhibitory activities on the receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclast differentiation. Compounds 1, 2, 5-7, and 10 exhibited potent osteoclast differentiation inhibitory activity with ED50 values of 1.9-2.8 µM.

Mycousfurans A and B, Antibacterial Usnic Acid Congeners from the Fungus Mycosphaerella sp., Isolated from a Marine Sediment.

Mycousfurans (1 and 2), two new usnic acid congeners, along with (-)-mycousnine (3), (-)-placodiolic acid (4), and (+)-usnic acid (5), were isolated using high-performance liquid chromatography-ultraviolet (HPLC-UV)-guided fractionation of extracts of Mycosphaerella sp. isolated from a marine sediment. The planar structures of 1 and 2 were elucidated using 1D and 2D NMR spectra. The relative configurations of the stereogenic carbons of 1 and 2 were established via analysis of their nuclear Overhauser spectroscopy (NOESY) spectra, and their absolute configurations were determined using a comparison of experimental and calculated electronic circular dichroism (ECD) spectra. Compounds 1 and 2 were found to have antibacterial activity, showing moderate activity against Kocuria rhizophila and Staphylococcus aureus.

Scalalactams A⁻D, Scalarane Sesterterpenes with a γ-Lactam Moiety from a Korean Spongia Sp. Marine Sponge.

Intensive study on the chemical components of a Korean marine sponge, Spongia sp., has led to the isolation of four new scalarane sesterterpenes, scalalactams A⁻D (1⁻4). Their chemical structures were elucidated from the analysis of spectroscopic data including 1D-and 2D-NMR as well as MS data. Scalalactams A⁻D (1⁻4) possess a scalarane carbon skeleton with a rare structural feature of a γ-lactam moiety within the molecules. Scalalactams A and B (1 and 2) have an extended isopropanyl chain at the lactam ring, and scalalactams C and D (3 and 4) possess a phenethyl group at the lactam ring moiety. Scalalactams A⁻D (1⁻4) did not show FXR antagonistic activity nor cytotoxicity up to 100 µM.

What is the tolerated width of periacetabular osteophytes to avoid impingement in cementless THA?: a three-dimensional simulation study.

BACKGROUNDS: Impingement is a risk factor for instability and prosthetic failure following total hip arthroplasty (THA). If the periacetabular osteophytes are not removed at surgery, impingement could occur between the osteophytes and the femoral stem following THA. However, excessive removal of the osteophytes could lead to bleeding from the bone. The aim of our study, therefore, was to locate the site of the impingement and to determine the width of tolerable osteophytes, which does not induce impingement during activities of daily living (ADL), using a three-dimensional simulation. METHODS: On 35 hip models, virtual THA was performed. The acetabular cups were positioned at 45° abduction and 20° anteversion, and the anteversion of femoral stems was 15°. Circular osteophytes with a 30-mm rim were built around the acetabular cup. Fourteen ADL motions were simulated, and the osteophytes were removed until there was no impingement. A clock face was used to map the location and the width of tolerable osteophytes. RESULTS: The impingement mainly occurred in antero-superior and posterior portions around the acetabular cup. Only 4.2-6.2-mm osteophytes were tolerable at the antero-superior portion (12-3 o'clock) and 6.3-7.2-mm osteophytes at the posterior portion (8-10 o'clock) following a total hip arthroplasty. In antero-inferior and postero-superior portions, over-20-mm osteophytes did not induce any impingement. CONCLUSION: Osteophytes in the antero-superior and posterior portion of the acetabulum should be excised during a THA to avoid impingement of the femur-stem construct on the acetabular osteophytes during ADLs.

Cadiolides J-M, antibacterial polyphenyl butenolides from the Korean tunicate Pseudodistoma antinboja.

Activity-guided fractionations of the tunicate Pseudodistoma antinboja yielded four new compounds of the cadiolide class (cadiolides J-M, 1, 3-5) along with a known one (cadiolide H, 2). The structures were defined by spectroscopic methods including X-ray crystallographic analysis. These compounds were evaluated for their antibacterial activity and exhibited potent antibacterial activity against all of the drug resistant strains tested with MICs comparable to those of marketed drugs such as vancomycin and linezolid.

Saccharomonopyrones A-C, New α-Pyrones from a Marine Sediment-Derived Bacterium Saccharomonospora sp. CNQ-490.

Intensive study of the organic extract of the marine-derived bacterium Saccharomonospora sp. CNQ-490 has yielded three new α-pyrones, saccharomonopyrones A-C (1-3). The chemical structures of these compounds were assigned from the interpretation of 1D, 2D NMR and mass spectrometry data. Saccharomonopyrone A (1) is the first α-pyrone microbial natural product bearing the ethyl-butyl ether chain in the molecule, while saccharomonopyrones B and C possess unusual 3-methyl and a 6-alkyl side-chain within a 3,4,5,6-tetrasubstituted α-pyrone moiety. Saccharomonopyrone A exhibited weak antioxidant activity using a cation radical scavenging activity assay with an IC50 value of 140 µM.

Adoption of virtual prenatal visits linked to recurrent virtual or forgone visits for postpartum care.

BACKGROUND: To investigate the association between prenatal and postpartum visits, with a specific focus on the modality of these visits, and to assess whether barriers to virtual visits experienced during the prenatal period are linked to types of postpartum visits. METHODS: The repeated cross-sectional study used the Pregnancy Risk Assessment Monitoring System from 2020 through 2021. Women who had prenatal visits and who also reported their postpartum visits were included (n = 11,258). The outcome was the modality of postpartum visits, and the key independent variable was virtual prenatal visit experience. Multinomial logistic regression analysis was performed to examine the relationship of postpartum visits with virtual prenatal visit experience. RESULTS: Among those who had virtual prenatal visits, about one-third used virtual visits again for postpartum care. Individuals who had virtual prenatal visits showed greater odds of utilizing virtual visits (OR 8.54, 95%CI 7.05-10.35, p=<0.001) or no office visits (OR 1.61, 95%CI 1.25-2.07, p=<0.001) compared to in-person visits during the postpartum period. Women who reported a lack of virtual appointment availability (OR 0.58, 95%CI 0.40-0.86, P = 0.006) or cellular data (OR 0.18, 95%CI 0.05-0.68, p = 0.012) in their prenatal care had lower odds of virtual postpartum visits. CONCLUSIONS: While virtual prenatal visits are linked to greater virtual visits for postpartum care, they are also associated with increased forgone care. The unavailability of virtual appointments and cellular data is a significant barrier to virtual visits. The findings provide practical implications for advancing equitable and sustainable care in a rapidly changing healthcare landscape.