Opioid Prescribing Rate for Nonoperative Distal Radius Fractures and Clinician Response to a Clinical Decision Support Alert.

BACKGROUND: Opioids are commonly prescribed for the management of acute orthopedic trauma pain, including nonoperative distal radius fractures. OBJECTIVES: This prospective study aimed to determine if a clinical decision support intervention influenced prescribing decisions for patients with known risk factors. We sought to quantify frequency of opioid prescriptions for acute nonoperative distal radius fractures treated. METHODS: We performed a prospective study at one large health care system. Utilizing umbrella code S52.5, we identified all distal radius fractures treated nonoperatively, and the encounters were merged with the Prescription Reporting with Immediate Medication Mapping (PRIMUM) database to identify encounters with opioid prescriptions and patients with risk factors for opioid use disorder. We used multivariable logistic regression to determine patient characteristics associated with the prescription of an opioid. Among encounters that triggered the PRIMUM alert, we calculated the percentage of encounters where the PRIMUM alert influenced the prescribing decision. RESULTS: Of 2984 encounters, 1244 (41.7%) included an opioid prescription. Age increment is a significant factor to more likely receive opioid prescriptions (p < 0.0001) after adjusting for other factors. Among encounters where the physician received an alert, those that triggered the alert for early refill were more likely to influence physicians' opioid prescribing when compared with other risk factors (p = 0.0088). CONCLUSION: Over 90% of patients (106/118) continued to receive an opioid medication despite having a known risk factor for abuse. Additionally, we found older patients were more likely to be prescribed opioids for nonoperatively managed distal radius fractures.

Use of kidney failure risk equation as a tool to evaluate referrals from primary care to specialist nephrology care.

BACKGROUND: With rising costs and burden of chronic kidney disease (CKD), timely referral of patients to a kidney specialist is crucial. Currently, Kidney Health Australia (KHA) uses a 'heat map' based on severity and not future risk of kidney failure, whereas the kidney failure risk equation (KFRE) score predicts future risk of progression. AIMS: Evaluate whether a KFRE score assists with timing of CKD referrals. METHODS: Retrospective cohort of 2137 adult patients, referred to tertiary hospital outpatient nephrologist between 2012 and 2020, were analysed. Referrals were analysed for concordance with the KHA referral guidelines and, with the KFRE score, a recommended practice. RESULTS: Of 2137 patients, 626 (29%) did not have urine albumin-to-creatinine ratio (UACR) measurement at referral. For those who had a UACR, the number who met KFRE preferred referral criteria was 36% less than KHA criteria. If the recommended KFRE score was used, then fewer older patients (≥40 years) needed referral. Positively, many diabetes patients were referred, even if their risk of kidney failure was low, and 29% had a KFRE over 3%. For patients evaluated meeting KFRE criteria, a larger proportion (76%) remained in follow-up, with only 8% being discharged. CONCLUSIONS: KFRE could reduce referrals and be a useful tool to assist timely referrals. Using KFRE for triage may allow those patients with very low risk of future kidney failure not be referred, remaining longer in primary care, saving health resources and reducing patients' stress and wait times. Using KFRE encourages albuminuria measurement.

Oh I remember the beauty and aesthetics of guilin!: Exploring the implications of memorability on tourist loyalty through a two-wave panel data.

The travel and tourism industry is among most severely impacted by natural disasters, terrorism, financial crises, and pandemics. Scholars are currently paying attention to how to revive tourism and establish tourist loyalty in the post-pandemic era. Aesthetics is a fundamental component of the tourist experience, and significantly affects tourist loyalty, intention, and behavior. However, research on destination aesthetics is limited, with most studies neglecting the role of memorability in the outcomes of aesthetics, particularly after the pandemic. Therefore, this study explores the mediating role of memorability in the effects of the aesthetic experiential qualities (scenery, cleanliness, harmony, art/architecture, and genuineness) of a nature-based tourism destination on tourist loyalty. Based on a two-wave panel data approach, 509 survey responses were collected and analyzed using Smarts. The findings indicate that the aesthetic experiential qualities positively affect tourists' memorability. Although three of the five aesthetic qualities (scenery, harmony, art/architecture) demonstrated no direct impact on loyalty, all the qualities had significant indirect effects on loyalty through the mediation of memorability. This study provides insights and new perspectives for promoting tourist loyalty in the context of post-pandemic tourism recovery.

Changes in the Vaginal Microbiome During Pregnancy and the Postpartum Period in South African Women: a Longitudinal Study.

Pregnant women in sub-Saharan Africa have high rates of maternal morbidity. There is interest in the impact of the vaginal microbiome on maternal health, including HIV and sexually transmitted infection (STI) acquisition. We characterized the vaginal microbiota of South African women ≥ 18 years with and without HIV in a longitudinal cohort over two visits during pregnancy and one visit postpartum. At each visit, we obtained HIV testing and self-collected vaginal swabs for point-of-care testing for STIs and microbiota sequencing. We categorized microbial communities and evaluated changes over pregnancy and associations with HIV status and STI diagnosis. Across 242 women (mean age 29, 44% living with HIV, 33% diagnosed with STIs), we identified four main community state types (CSTs): two lactobacillus-dominant CSTs (dominated by Lactobacillus crispatus and Lactobacillus iners respectively) and two diverse, non-lactobacillus-dominant CSTs (one dominated by Gardnerella vaginalis and one by diverse facultative anaerobes). From the first antenatal visit to the third trimester (24-36 weeks gestation), 60% of women in the Gardnerella-dominant CST shifted to lactobacillus-dominant CSTs. From the third trimester to postpartum (mean 17 days post-delivery), 80% of women in lactobacillus-dominant CSTs shifted to non-lactobacillus-dominant CSTs with a large proportion in the facultative anaerobe-dominant CST. Microbial composition differed by STI diagnosis (PERMANOVA R2 = 0.002, p = 0.004), and women diagnosed with an STI were more likely to be categorized as L. iners-dominant or Gardnerella-dominant CSTs. Overall, we found a shift toward lactobacillus dominance during pregnancy and the emergence of a distinct, highly diverse anaerobe-dominant microbiota profile in the postpartum period.

Embedded multilevel regression and poststratification: Model-based inference with incomplete auxiliary information.

Health disparity research often evaluates health outcomes across demographic subgroups. Multilevel regression and poststratification (MRP) is a popular approach for small subgroup estimation as it can stabilize estimates by fitting multilevel models and adjust for selection bias by poststratifying on auxiliary variables, which are population characteristics predictive of the analytic outcome. However, the granularity and quality of the estimates produced by MRP are limited by the availability of the auxiliary variables' joint distribution; data analysts often only have access to the marginal distributions. To overcome this limitation, we embed the estimation of population cell counts needed for poststratification into the MRP workflow: embedded MRP (EMRP). Under EMRP, we generate synthetic populations of the auxiliary variables before implementing MRP. All sources of estimation uncertainty are propagated with a fully Bayesian framework. Through simulation studies, we compare different methods of generating the synthetic populations and demonstrate EMRP's improvements over alternatives on the bias-variance tradeoff to yield valid subpopulation inferences of interest. We apply EMRP to the Longitudinal Survey of Wellbeing and estimate food insecurity prevalence among vulnerable groups in New York City. We find that all EMRP estimators can correct for the bias in classical MRP while maintaining lower standard errors and narrower confidence intervals than directly imputing with the weighted finite population Bayesian bootstrap (WFPBB) and design-based estimates. Performances from the EMRP estimators do not differ substantially from each other, though we would generally recommend using the WFPBB-MRP for its consistently high coverage rates.

Recurrent amebic liver abscesses despite metronidazole treatment: A rare case report.

Amebic liver abscesses should be considered in adult males with a liver abscess and a history of travel to endemic areas. Effective treatment includes metronidazole, followed by paromomycin.

IP-DNQ induces mitochondrial dysfunction and G2/M phase cell cycle arrest to selectively kill NQO1-positive pancreatic cancer cells.

Pancreatic cancer is among the top five leading causes of cancer-related deaths worldwide, with low survival rates. Current therapies for pancreatic cancer lack tumor specificity, resulting in harmful effects on normal tissues. Therefore, developing tumor-specific agents for the treatment of pancreatic cancer is critical. NAD(P)H:quinone oxidoreductase 1 (NQO1), highly expressed in pancreatic cancers but not in normal tissues, makes NQO1 bioactivatable drugs a potential therapy for selectively killing NQO1-positive cancer cells. Our previous studies have revealed that novel NQO1 bioactivatable drug deoxynyboquinone (DNQ) is ten-fold more potent than the prototypic NQO1 bioactivatable drug ß-lapachone in killing of NQO1-positive cancer cells. However, DNQ treatment results in high-grade methemoglobinemia, a significant side effect that limits clinical development. Here, we report for the first time on a DNQ derivative, isopentyl-deoxynboquinone (IP-DNQ), which selectively kills pancreatic ductal adenocarcinoma cells in an NQO1-dependent manner with equal potency to the parent DNQ. IP-DNQ evokes massive ROS production and oxidative DNA lesions that results in PARP1 hyperactivation, mitochondrial catastrophe and G2/M-phase arrest, leading to apoptotic and necrotic programmed cell death. Importantly, IP-DNQ treatment causes mild methemoglobinemia in vivo, with a three-fold improvement in the maximum tolerated dose compared to DNQ, while significantly suppresses tumor growth and extends the lifespan of mice in subcutaneous and orthotopic pancreatic cancer xenograft models. Our study demonstrates that IP-DNQ is a promising therapy for NQO1-positive pancreatic cancers and may enhance the efficacy of other anticancer drugs. IP-DNQ represents a novel approach to treating pancreatic cancer with the potential to improve patient outcomes.

Deep learning models capture histological disease activity in Crohn's Disease and Ulcerative Colitis with high fidelity.

BACKGROUND AND AIMS: Histologic disease activity in Inflammatory Bowel Disease (IBD) is associated with clinical outcomes and is an important endpoint in drug development. We developed deep learning models for automating histological assessments in IBD. METHODS: Histology images of intestinal mucosa from phase 2 and phase 3 clinical trials in Crohn's disease (CD) and Ulcerative Colitis (UC) were used to train artificial intelligence (AI) models to predict the Global Histology Activity Score (GHAS) for CD and Geboes histopathology score for UC. Three AI methods were compared. AI models were evaluated on held-back testing sets and model predictions were compared against an expert central reader and five independent pathologists. RESULTS: The model based on multiple instance learning and the attention mechanism (SA-AbMILP) demonstrated the best performance among competing models. AI modeled GHAS and Geboes sub-grades matched central readings with moderate to substantial agreement, with accuracies ranging from 65% to 89%. Furthermore, the model was able to distinguish the presence and absence of pathology across four selected histological features with accuracies for colon, in both CD and UC, ranging from 87% to 94% and, for CD ileum, ranging from 76% to 83%. For both CD and UC, and across anatomical compartments (ileum and colon) in CD, comparable accuracies against central readings were found between the model assigned scores and scores by an independent set of pathologists. CONCLUSIONS: Deep learning models based upon GHAS and Geboes scoring systems were effective at distinguishing between the presence and absence of IBD microscopic disease activity.

Tracking the evolution of the SARS-CoV-2 Delta variant of concern: analysis of genetic diversity and selection across the whole viral genome.

Background: Since 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has diversified extensively, producing five highly virulent lineages designated as variants of concern (VOCs). The Delta VOC emerged in India with increased transmission, immune evasion, and mortality, causing a massive global case surge in 2021. This study aims to understand how the Delta VOC evolved by characterizing mutation patterns in the viral population before and after its emergence. Furthermore, we aim to identify the influence of positive and negative selection on VOC evolution and understand the prevalence of different mutation types in the viral genome. Methods: Three groups of whole viral genomes were retrieved from GISAID, sourced from India, with collection periods as follows: Group A-during the initial appearance of SARS-CoV-2; Group B-just before the emergence of the Delta variant; Group C-after the establishment of the Delta variant in India. Mutations in >1% of each group were identified with BioEdit to reveal differences in mutation quantity and type. Sites under positive or negative selection were identified with FUBAR. The results were compared to determine how mutations correspond with selective pressures and how viral mutation profiles changed to reflect genetic diversity before and after VOC emergence. Results: The number of mutations increased progressively in Groups A-C, with Group C reporting a 2.2- and 1.9-fold increase from Groups A and B, respectively. Among all the observed mutations, Group C had the highest percentage of deletions (22.7%; vs. 4.2% and 2.6% in Groups A and B, respectively), and most mutations altered the final amino acid code, such as non-synonymous substitutions and deletions. Conversely, Group B had the most synonymous substitutions that are effectively silent. The number of sites experiencing positive selection increased in Groups A-C, but Group B had 2.4- and 2.6 times more sites under negative selection compared to Groups A and C, respectively. Conclusion: Our findings demonstrated that viral genetic diversity continuously increased during and after the emergence of the Delta VOC. Despite this, Group B reports heightened negative selection, which potentially preserves important gene regions during evolution. Group C contains an unprecedented quantity of mutations and positively selected sites, providing strong evidence of active viral adaptation in the population.

Direct oral anticoagulants for the treatment of splanchnic vein thrombosis - A systematic review and meta-analysis.

BACKGROUND: Splanchnic vein thrombosis (SVT) is an uncommon manifestation of venous thromboembolism in the splanchnic venous system, with scarce evidence surrounding its management. We assessed the efficacy and safety of direct oral anticoagulant (DOAC) to low-molecular-weight heparins (LMWH), vitamin-k antagonists (VKAs), or no anticoagulation. METHODS: We conducted a systematic review and meta-analysis with the primary efficacy outcome being complete recanalization of affected vessels and primary safety outcome being major bleeding. Meta-analysis was done using a random-effects model, with dichotomous outcomes being synthesized with odds ratios (ORs) and corresponding 95 % CIs. RESULTS: Seven non-randomized and one randomized study involving 883 participants were included for analysis. DOACs were more effective than VKAs (OR = 4.33; 95 % CI: 2.4, 7.83; n = 1 study) in non-cirrhotic patients and no anticoagulation in cirrhotic patients (OR = 3.86; 95 % CI: 1.49, 10.03; n = 3 studies). DOACs had a statistically significant reduction in major bleeding compared to observation [OR = 0.09; 95 % CI: 0.03, 0.29; n = 3 studies], LMWHs [OR = 0.13; 95 % CI: 0.03, 0.29; n = 1 study] and VKAs [OR = 0.12; 95 % CI: 0.02, 0.69; n = 2 studies] in non-cirrhotic patients. No difference in major bleeding was found between DOACs and observation, LMWH, or VKAs in cirrhotic patients. CONCLUSION: DOACs appear to be a favorable alternative to VKAs and LMWHs in non-cirrhotic patients. This avenue of research would benefit from larger studies that adjust for SVT etiologies, patient risk factors, and overall bleeding risk.

Cilta-cel or Standard Care in Lenalidomide-Refractory Multiple Myeloma.

BACKGROUND: Ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen (BCMA)-directed CAR T-cell therapy, is effective in heavily pretreated patients with relapsed or refractory multiple myeloma. We investigated cilta-cel in earlier treatment lines in patients with lenalidomide-refractory disease. METHODS: In this phase 3, randomized, open-label trial, we assigned patients with lenalidomide-refractory multiple myeloma to receive cilta-cel or the physician's choice of effective standard care. All the patients had received one to three previous lines of treatment. The primary outcome was progression-free survival. RESULTS: A total of 419 patients underwent randomization (208 to receive cilta-cel and 211 to receive standard care). At a median follow-up of 15.9 months (range, 0.1 to 27.3), the median progression-free survival was not reached in the cilta-cel group and was 11.8 months in the standard-care group (hazard ratio, 0.26; 95% confidence interval [CI], 0.18 to 0.38; P<0.001). Progression-free survival at 12 months was 75.9% (95% CI, 69.4 to 81.1) in the cilta-cel group and 48.6% (95% CI, 41.5 to 55.3) in the standard-care group. More patients in the cilta-cel group than in the standard-care group had an overall response (84.6% vs. 67.3%), a complete response or better (73.1% vs. 21.8%), and an absence of minimal residual disease (60.6% vs. 15.6%). Death from any cause was reported in 39 patients and 46 patients, respectively (hazard ratio, 0.78; 95% CI, 0.5 to 1.2). Most patients reported grade 3 or 4 adverse events during treatment. Among the 176 patients who received cilta-cel in the as-treated population, 134 (76.1%) had cytokine release syndrome (grade 3 or 4, 1.1%; no grade 5), 8 (4.5%) had immune effector cell-associated neurotoxicity syndrome (all grade 1 or 2), 1 had movement and neurocognitive symptoms (grade 1), 16 (9.1%) had cranial nerve palsy (grade 2, 8.0%; grade 3, 1.1%), and 5 (2.8%) had CAR-T-related peripheral neuropathy (grade 1 or 2, 2.3%; grade 3, 0.6%). CONCLUSIONS: A single cilta-cel infusion resulted in a lower risk of disease progression or death than standard care in lenalidomide-refractory patients with multiple myeloma who had received one to three previous therapies. (Funded by Janssen and Legend Biotech; CARTITUDE-4 ClinicalTrials.gov number, NCT04181827.).

Complications After Renal Mass Biopsy: Frequency, Nature, Timing, and Associated Characteristics.

BACKGROUND. Observation periods after renal mass biopsy (RMB) range from 1 hour to overnight hospitalization. Short observation may improve efficiency by allowing use of the same recovery bed and other resources for RMBs in additional patients. OBJECTIVE. The purpose of this study was to evaluate the frequency, timing, and nature of complications after RMB, as well as to identify characteristics associated with such complications. METHODS. This retrospective study included 576 patients (mean age, 64.9 years; 345 men, 231 women) who underwent percutaneous ultrasound- or CT-guided RMB at one of three hospitals, performed by 22 radiologists, between January 1, 2008, and June 1, 2020. The EHR was reviewed to identify postbiopsy complications, which were classified as bleeding-related or non-bleeding-related and as acute (< 24 hours), subacute (24 hours to 30 days), or delayed (> 30 days). Deviations from normal clinical management (analgesia, unplanned laboratory testing, or additional imaging) were identified. RESULTS. Acute and subacute complications occurred after 3.6% (21/576) and 0.7% (4/576) of RMBs, respectively. No delayed complication or patient death occurred. A total of 76.2% (16/21) of acute complications were bleeding-related. A deviation from normal clinical management occurred after 1.6% (9/551) of RMBs that had no associated postbiopsy complication. Among the 16 patients with bleeding-related acute complications, all experienced a deviation, with mean time to deviation of 56 ± 47 (SD) minutes (range, 10-162 minutes; ≤ 120 minutes in 13/16 patients). The five non-bleeding-related acute complications all presented at the time of RMB completion. The four subacute complications occurred from 28 hours to 18 days after RMB. Patients with, versus those without, a bleeding-related complication had a lower platelet count (mean, 197.7 vs 250.4 × 109/L, p = .01) and greater frequency of entirely endophytic renal masses (47.4% vs 19.6%, p = .01). CONCLUSION. Complications after RMB were uncommon and presented either within 3 hours after biopsy or more than 24 hours after biopsy. CLINICAL IMPACT. A 3-hour monitoring window after RMB before patient discharge (in the absence of deviation from normal clinical management and complemented by informing patients of the low risk of a subacute complication) may provide both safe patient management and appropriate resource utilization.

Changes in the vaginal microbiome during pregnancy and the postpartum period in South African women: a longitudinal study.

African women have more diverse vaginal microbiota than women of European descent, and there is interest in the impact of this diversity on maternal health, including HIV and STI acquisition. We characterized the vaginal microbiota in a cohort of women ≥ 18 years with and without HIV in a longitudinal cohort over two visits during pregnancy and one visit postpartum. At each visit we obtained HIV testing and self-collected vaginal swabs for point of care testing for STIs and microbiome sequencing. We categorized microbial communities and evaluated changes over pregnancy and associations with HIV status and STI diagnosis. Across 242 women (mean age 29, 44% living with HIV, 33% diagnosed with STIs), we identified four main community state types (CSTs): two lactobacillus-dominant CSTs (dominated by Lactobacillus crispatus and Lactobacillus iners respectively) and two diverse, non-lactobacillus-dominant CSTs (one dominated by Gardnerella vaginalis and one by other facultative anaerobes). From first antenatal visit to third trimester (24-36 weeks gestation), 60% of women in the Gardnerella -dominant CST shifted to L actobacillus -dominant CSTs. From third trimester to postpartum (mean 17 days post-delivery), 80% of women in Lactobacillus -dominant CSTs shifted to non-lactobacillus-dominant CSTs with a large proportion in the facultative anaerobe-dominant CST. Microbial composition differed by STI diagnosis (PERMANOVA R 2 = 0.002, p = 0.004), and women diagnosed with an STI were more likely to be categorized with L. iners -dominant or Gardnerella -dominant CSTs. Overall we found a shift toward lactobacillus dominance during pregnancy, and the emergence of a distinct, highly diverse anaerobe-dominant microbiome population in the postpartum period.

Guselkumab More Effectively Neutralizes Psoriasis-Associated Histologic, Transcriptomic, and Clinical Measures than Ustekinumab.

Given the key role of the IL-23/Th17 axis in the pathogenesis of moderate-to-severe plaque psoriasis, several specific inhibitors of the p19 subunit of IL-23 have been approved to treat this chronic inflammatory disease. Clinical data indicate that guselkumab, one such selective IL-23 inhibitor, achieves greater clinical efficacy compared with ustekinumab, which inhibits both IL-12 and IL-23 via binding their shared p40 subunit. To understand mechanisms underlying the enhanced efficacy observed with the p19 subunit of IL-23-specific inhibition, we explored cellular and molecular changes in skin of psoriasis patients treated with ustekinumab or guselkumab and in ustekinumab inadequate responders (Investigator's Global Assessment of psoriasis score ≥ 2) subsequently treated with guselkumab (ustekinumab→guselkumab). Skin biopsies were collected pretreatment and posttreatment to assess histologic changes and molecular responses in ustekinumab- and guselkumab-treated patients. Serum cytokines and skin transcriptomics from the subset of ustekinumab→guselkumab-treated patients were also analyzed to characterize differential treatment effects. Ustekinumab and guselkumab demonstrated differential effects on secretion of pathogenic Th17-related cytokines induced by IL-23 in in vitro assays, which suggest guselkumab is a more potent therapeutic agent. Consistent with these findings, guselkumab elicited a significantly greater reduction in cellular and molecular psoriasis-related disease indicators than ustekinumab. In ustekinumab→guselkumab patients, suppression of serum IL-17A and IL-17F levels and neutralization of molecular scar and psoriasis-related gene markers in skin were significantly greater compared with patients continuing ustekinumab. This comparative study demonstrates that guselkumab inhibits psoriasis-associated pathology, suppresses Th17-related serum cytokines, and normalizes the psoriasis skin gene expression profile more effectively than ustekinumab.

Identifying Plasma and Urinary Biomarkers of Fermented Food Intake and Their Associations with Cardiometabolic Health in a Dutch Observational Cohort.

Identification of food intake biomarkers (FIBs) for fermented foods could help improve their dietary assessment and clarify their associations with cardiometabolic health. We aimed to identify novel FIBs for fermented foods in the plasma and urine metabolomes of 246 free-living Dutch adults using nontargeted LC-MS and GC-MS. Furthermore, associations between identified metabolites and several cardiometabolic risk factors were explored. In total, 37 metabolites were identified corresponding to the intakes of coffee, wine, and beer (none were identified for cocoa, bread, cheese, or yoghurt intake). While some of these metabolites appeared to originate from raw food (e.g., niacin and trigonelline for coffee), others overlapped different fermented foods (e.g., 4-hydroxybenzeneacetic acid for both wine and beer). In addition, several fermentation-dependent metabolites were identified (erythritol and citramalate). Associations between these identified metabolites with cardiometabolic parameters were weak and inconclusive. Further evaluation is warranted to confirm their relationships with cardiometabolic disease risk.

Acute Transcriptomic and Epigenetic Alterations at T12 After Rat T10 Spinal Cord Contusive Injury.

Spinal cord injury is a severely debilitating condition affecting a significant population in the USA. Spinal cord injury patients often have increased risk of developing persistent neuropathic pain and other neurodegenerative conditions beyond the primary lesion center later in their life. The molecular mechanism conferring to the "latent" damages at distal tissues, however, remains elusive. Here, we studied molecular changes conferring abnormal functionality at distal spinal cord (T12) beyond the lesion center (T10) by combining next-generation sequencing (RNA- and bisulfite sequencing), super-resolution microscopy, and immunofluorescence staining at 7 days post injury. We observed significant transcriptomic changes primarily enriched in neuroinflammation and synaptogenesis associated pathways. Transcription factors (TFs) that regulate neurogenesis and neuron plasticity, including Egr1, Klf4, and Myc, are significantly upregulated. Along with global changes in chromatin arrangements and DNA methylation, including 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC), bisulfite sequencing further reveals the involvement of DNA methylation changes in regulating cytokine, growth factor, and ion channel expression. Collectively, our results pave the way towards understanding transcriptomic and epigenomic mechanism in conferring long-term disease risks at distal tissues away from the primary lesion center and shed light on potential molecular targets that govern the regulatory mechanism at distal spinal cord tissues.

Associations between dairy fat intake, milk-derived free fatty acids, and cardiometabolic risk in Dutch adults.

PURPOSE: Milk-derived free fatty acids (FFAs) may act as both biomarkers of intake and metabolic effect. In this study we explored associations between different types of dairy consumption, a selection of milk-derived free fatty acids, and cardiometabolic disease (CMD) risk factors. METHODS: Sixty-seven FFAs were quantified in the plasma of 131 free-living Dutch adults (median 60 years) using gas chromatography-flame ionization detector. Intakes of different dairy foods and groups were assessed using a food frequency questionnaire. Twelve different CMD risk factors were analyzed. Multiple linear regressions were used to evaluate the associations under study. RESULTS: Based on the fully adjusted models, 5 long-chain unsaturated FFAs (C18:1 t13 + c6 + c7 + u, C18:2 c9t11 + u, C20:1 c11, C20:3 c8c11c14, and C20:4 c5c8c11c14), 2 medium-chain saturated FFAs (C15, C15 iso), and a trans FFA (C16:1 t9) were positively associated with at least one variable of dairy intake, as well as plasma total and LDL cholesterol, blood pressure, and SCORE (p ≤ 0.05). A long-chain PUFA associated with high-fat fermented dairy intake (C18:2 t9t12), was negatively associated with serum triglyceride levels, and a long-chain saturated FFA associated with cheese intake (C18:1 u1) was negatively associated with plasma LDL cholesterol and serum triglyceride levels. No clear associations were observed between dairy intake and CMD risk factors. CONCLUSION: Milk-derived FFAs could act as sensitive biomarkers for dairy intake and metabolism, allowing the association between dairy and CMD risk to be more precisely evaluated.

Nontargeted and Targeted Metabolomics Identifies Dietary Exposure Biomarkers for Navy Bean and Rice Bran Consumption in Children and Adults.

Dietary exposure biomarkers are needed for advancing knowledge on healthy foods. This study examined biomarkers for navy beans and rice bran in children and adults. Plasma, urine, stool, and study foods from dietary intervention studies were analyzed by metabolomics. A total of 38 children and 49 adults were assessed after consuming navy beans and/or rice bran for 2-, 4-, 6-, or 12 weeks. From the 138-175 metabolites modulated by diet, 11 were targeted for quantification. Trigonelline and pipecolate concentrations increased in children and adult plasma after 4 weeks compared to baseline. Increased xanthurenate (46%) was observed in children plasma after rice bran intake for 4 weeks. Study foods with navy beans had higher S-methylcysteine compared to control and supported the increased urine S-methylcysteine sulfoxide. Nontargeted metabolomics was moderately effective to identify target molecules as candidate biomarkers. Study limitations include interindividual metabolite variations before diet intervention. Validation is warranted using cross-over designs and larger sample sizes.

Promoting Bone Formation and Healing in Segmental Defects Through Ectopic Induced Membrane.

We aimed to determine whether addition of an in vivo ectopic induced membrane (EM) to the Masquelet Technique enhanced angiogenesis and bone formation in a segmental defect. After generating and stabilizing a diaphyseal femur defect, 10 rats received a polymethylmethacrylate (PMMA) spacer within the defect (control); 10 received another PMMA spacer implanted subcutaneously (EM). We removed the spacers and added autograft; the excised EM was added to their autograft (EM group). Post-mortem x-rays assessed bone formation and bridging. Osteogenesis in the proximal defect was significantly more uniform (p < 0.01), and there was greater amount of bone remodeling distally in the EM group (p < 0.05). There was no difference in bone formation (p = 0.19) but greater degrees of bridging in the EM group (2.20 vs. 1.20, p = 0.09). The EM resulted in more homogeneous proximal osteogenesis and increased bone remodeling distally. These findings could lead to more consistent and predictable bone healing. (Journal of Surgical Orthopaedic Advances 31(3):161-165, 2022).

Interleukin-22 regulates neutrophil recruitment in ulcerative colitis and is associated with resistance to ustekinumab therapy.

The function of interleukin-22 (IL-22) in intestinal barrier homeostasis remains controversial. Here, we map the transcriptional landscape regulated by IL-22 in human colonic epithelial organoids and evaluate the biological, functional and clinical significance of the IL-22 mediated pathways in ulcerative colitis (UC). We show that IL-22 regulated pro-inflammatory pathways are involved in microbial recognition, cancer and immune cell chemotaxis; most prominently those involving CXCR2+ neutrophils. IL-22-mediated transcriptional regulation of CXC-family neutrophil-active chemokine expression is highly conserved across species, is dependent on STAT3 signaling, and is functionally and pathologically important in the recruitment of CXCR2+ neutrophils into colonic tissue. In UC patients, the magnitude of enrichment of the IL-22 regulated transcripts in colonic biopsies correlates with colonic neutrophil infiltration and is enriched in non-responders to ustekinumab therapy. Our data provide further insights into the biology of IL-22 in human disease and highlight its function in the regulation of pathogenic immune pathways, including neutrophil chemotaxis. The transcriptional networks regulated by IL-22 are functionally and clinically important in UC, impacting patient trajectories and responsiveness to biological intervention.