Systemic immune-inflammation index, neutrophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio in patients with type 2 diabetes at different stages of diabetic retinopathy.

AIM: To investigate systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) levels in patients with type 2 diabetes at different stages of diabetic retinopathy (DR). METHODS: This retrospective study included 141 patients with type 2 diabetes mellitus (DM): 45 without diabetic retinopathy (NDR), 47 with non-proliferative diabetic retinopathy (NPDR), and 49 with proliferative diabetic retinopathy (PDR). Complete blood counts were obtained, and NLR, PLR, and SII were calculated. The study analysed the ability of inflammatory markers to predict DR using receiver operating characteristic (ROC) curves. The relationships between DR stages and SII, PLR, and NLP were assessed using multivariate logistic regression. RESULTS: The average NLR, PLR, and SII were higher in the PDR group than in the NPDR group (P=0.011, 0.043, 0.009, respectively); higher in the NPDR group than in the NDR group (P<0.001 for all); and higher in the PDR group than in the NDR group (P<0.001 for all). In the ROC curve analysis, the NLR, PLR, and SII were significant predictors of DR (P<0.001 for all). The highest area under the curve (AUC) was for the PLR (0.929 for PLR, 0.925 for SII, and 0.821 for NLR). Multivariate regression analysis indicated that NLR, PLR, and SII were statistically significantly positive and independent predictors for the DR stages in patients with DM [odds ratio (OR)=1.122, 95% confidence interval (CI): 0.200-2.043, P<0.05; OR=0.038, 95%CI: 0.018-0.058, P<0.05; OR=0.007, 95%CI: 0.001-0.01, P<0.05, respectively). CONCLUSION: The NLR, PLR, and SII may be used as predictors of DR.

Development of a Decision Aid for Family Surrogate Decision Makers of Critically Ill Patients Requiring Renal Replacement Therapy in ICU: User-Centered Design for Rapid Prototyping.

Objectives Renal replacement therapy (RRT) is increasingly adopted for critically ill patients diagnosed with acute kidney injury, but the optimal time for initiation remains unclear and prognosis is uncertain, leading to medical complexity, ethical conflicts, and decision dilemmas in intensive care unit (ICU) settings. This study aimed to develop a decision aid (DA) for family surrogate of critically ill patients to support their engagement in shared decision-making process with clinicians. Methods Development of DA employed a systematic process with user-centered design (UCD) principle, which included: (i) competitive analysis: searched, screened, and assessed the existing DAs to gather insights for design strategies, developmental techniques, and functionalities; (ii) user needs assessment: interviewed family surrogates to explore target user group's decision-making experience and identify their unmet needs; (iii) evidence syntheses: integrate latest clinical evidence and pertinent information to inform the content development of DA.Results The competitive analysis included 16 relevant DAs, from which we derived valuable insights from existing resources. User decision needs were explored among a cohort of 15 family surrogates, revealing four thematic issues in decision-making, including stuck into dilemmas, sense of uncertainty, limited capacity, and delayed decision confirmation. A total of 27 articles were included for evidence syntheses. Relevant decision-making knowledge on disease and treatment, as delineated in the literature sourced from decision support system or clinical guidelines, were formatted as the foundational knowledge base. Twenty-one items of evidence were extracted and integrated into the content panels of benefits and risks of RRT, possible outcomes, and reasons to choose. The DA was drafted into a web-based phototype using the elements of UCD. This platform could guide users make preparation of decision-making through a sequential four-step progress: identifying treatment options, weighing the benefits and risks, clarifying personal preferences and values, and formulating a schedule for formal shared decision-making with clinicians.Conclusions We developed a rapid prototype of DA tailored for family surrogate decision makers of critically ill patients in need of RRT in ICU setting. Future studies are needed to evaluate its usability, feasibility, and clinical effects of this intervene.

Bioengineered vascular grafts with a pathogenic TGFBR1 variant model aneurysm formation in vivo and reveal underlying collagen defects.

Thoracic aortic aneurysm (TAA) is a life-threatening vascular disease frequently associated with underlying genetic causes. An inadequate understanding of human TAA pathogenesis highlights the need for better disease models. Here, we established a functional human TAA model in an animal host by combining human induced pluripotent stem cells (hiPSCs), bioengineered vascular grafts (BVGs), and gene editing. We generated BVGs from isogenic control hiPSC-derived vascular smooth muscle cells (SMCs) and mutant SMCs gene-edited to carry a Loeys-Dietz syndrome (LDS)-associated pathogenic variant (TGFBR1A230T). We also generated hiPSC-derived BVGs using cells from a patient with LDS (PatientA230T/+) and using genetically corrected cells (Patient+/+). Control and experimental BVGs were then implanted into the common carotid arteries of nude rats. The TGFBR1A230T variant led to impaired mechanical properties of BVGs, resulting in lower burst pressure and suture retention strength. BVGs carrying the variant dilated over time in vivo, resembling human TAA formation. Spatial transcriptomics profiling revealed defective expression of extracellular matrix (ECM) formation genes in PatientA230T/+ BVGs compared with Patient+/+ BVGs. Histological analysis and protein assays validated quantitative and qualitative ECM defects in PatientA230T/+ BVGs and patient tissue, including decreased collagen hydroxylation. SMC organization was also impaired in PatientA230T/+ BVGs as confirmed by vascular contraction testing. Silencing of collagen-modifying enzymes with small interfering RNAs reduced collagen proline hydroxylation in SMC-derived tissue constructs. These studies demonstrated the utility of BVGs to model human TAA formation in an animal host and highlighted the role of reduced collagen modifying enzyme activity in human TAA formation.

Bifunctional Squaramide-Catalyzed Oxidative Kinetic Resolution: Simultaneous Access to Axially Chiral Thioether and Sulfoxide.

Axially chiral thioethers and sulfoxides emerge as two pivotal classes of ligands and organocatalysts, which have remarkable features in the stereoinduction of various asymmetric transformations. However, the lack of easy methods to access such molecules with diverse structures has hampered their broader utilization. Herein, an oxidative kinetic resolution for sulfides using a chiral bifunctional squaramide as the catalyst with cumene hydroperoxide as the terminal oxidant is established. This asymmetric approach provides a variety of axially chiral thioethers as well as sulfoxides bearing both axial and central chirality, with excellent diastereo- and enantioselectivities. This catalytic system also successfully extends to the kinetic resolution of benzothiophene-based sulfides. Preliminary mechanism investigation indicates that the multiple hydrogen bonding interactions between the bifunctional squaramide catalyst and substrates play a crucial role in determining the enantioselectivity and reactivity.

A randomized, double-blind, placebo-controlled, phase IIa, clinical study on investigating the efficacy and safety of SPH3127 tablet in patients with essential hypertension.

Around 70% of patients diagnosed with hypertension exhibit increased levels of renin. SPH3127, an inventive renin inhibitor, has shown favorable tolerability and sustained pharmacodynamic inhibitory impact on plasma renin activity (PRA) during previous phase I trials. This phase II study was conducted to investigate the efficacy and safety of SPH3127 in patients with essential hypertension. This study was conducted in patients with mild to moderate essential hypertension, utilizing a randomized, double-blind, placebo-controlled design. The patients were administered either tablet of SPH3127 at doses of 50 mg, 100 mg, or 200 mg, or a placebo. A total of 122 patients were included in the study, with 121 patients included in the full analysis set. Among these patients, there were 30 individuals in each subgroup receiving different dosage regimens of SPH3127, and 31 patients in the placebo group. The reductions in mean sitting diastolic blood pressure (msDBP) after 8 weeks compared to baseline were 5.7 ± 9.5, 8.6 ± 8.8, and 3.8 ± 10.6 mmHg in the SPH3127 50-, 100-, and 200 mg groups, respectively. In the placebo group, the reduction was 3.1 ± 8.4 mmHg. The corresponding reductions in mean sitting systolic blood pressure (msSBP) were 11.8 ± 13.0, 13.8 ± 11.2, 11.1 ± 13.1, and 7.7 ± 9.7 mmHg in each respective group. SPH3127 is a promising drug for the treatment of patients with essential hypertension. The recommended dosage is 100 mg daily.Clinical trial registration: This study was registered in ClinicalTrials.gov (NCT03756103).

An Overview of the Effects of Tenapanor on Visceral Hypersensitivity in the Treatment of Irritable Bowel Syndrome with Constipation.

Background: Patients with irritable bowel syndrome with constipation (IBS-C) experience persistent abdominal pain, a common symptom leading to greater healthcare utilization and reports of treatment non-response. Clinically significant improvements in abdominal pain were observed in clinical trials of tenapanor, a first-in-class inhibitor of sodium/hydrogen exchanger isoform 3 (NHE3), for the treatment of IBS-C in adults. Aim: This narrative review reports the current knowledge about visceral hypersensitivity as a mechanism for abdominal pain in patients with IBS-C and explores the published evidence for hypothesized mechanisms by which tenapanor may reduce visceral hypersensitivity leading to the observed clinical response of decreased abdominal pain. Findings: Abdominal pain is experienced through activation and signaling of nociceptive dorsal root ganglia that innervate the gut. These sensory afferent neurons may become hypersensitized through signaling of transient receptor potential cation channel subfamily V member 1 (TRPV1), resulting in reduced action potential thresholds. TRPV1 signaling is also a key component of the proinflammatory cascade involving mast cell responses to macromolecule exposure following permeation through the intestinal epithelium. Indirect evidence of this pathway is supported by observations of higher pain in association with increased intestinal permeability in patients with IBS. Tenapanor reduces intestinal sodium absorption, leading to increased water retention in the intestinal lumen, thereby improving gastrointestinal motility. In animal models of visceral hypersensitivity, tenapanor normalized visceromotor responses and normalized TRPV1-mediated nociceptive signaling. Conclusion: By improving gastrointestinal motility, decreasing intestinal permeability and inflammation, and normalizing nociception through decreased TRPV1 signaling, tenapanor may reduce visceral hypersensitivity, leading to less abdominal pain in patients with IBS-C. Therapies that have demonstrated effects on visceral hypersensitivity may be the future direction for meaningful abdominal pain relief for patients with IBS-C.

[The Role of NK Cells in Allogeneic Hematopoietic Stem Cell Micro-Transplantation for Acute Myeloid leukemia].

OBJECTIVE: To explore the role of NK cells in allogeneic hematopoietic stem cell micro-transplantation(MST) in the treatment of patients with acute myeloid leukemia(AML). METHODS: Data from 93 AML patients treated with MST at our center from 2013-2018 were retrospectively analyzed. The induction regimen was anthracycline and cytarabine combined with peripheral blood stem cells transplantation mobilization by granulocyte colony stimulating factor (GPBSC), followed by 2-4 courses of intensive treatment with medium to high doses of cytarabine combined with GPBSC after achieving complete remission (CR). The therapeutic effects of one and two courses of MST induction therapy on 42 patients who did not reach CR before transplantation were evaluated. Cox proportional hazards regression analysis was used to analyze the impact of donor NK cell dose and KIR genotype, including KIR ligand mismatch, 2DS1, haplotype, and HLA-Cw ligands on survival prognosis of patients. RESULTS: Forty-two patients received MST induction therapy, and the CR rate was 57.1% after 1 course and 73.7% after 2 courses. Multivariate analysis showed that, medium and high doses of NK cells was significantly associated with improved disease-free survival (DFS) of patients (HR=0.27, P =0.005; HR=0.21, P =0.001), and high doses of NK cells was significantly associated with improved overall survival (OS) of patients (HR=0.15, P =0.000). Donor 2DS1 positive significantly increases OS of patients (HR=0.25, P =0.011). For high-risk patients under 60 years old, patients of the donor-recipient KIR ligand mismatch group had longer DFS compared to the nonmismatch group (P =0.036); donor 2DS1 positive significantly prolonged OS of patients (P =0.009). CONCLUSION: NK cell dose, KIR ligand mismatch and 2DS1 influence the therapeutic effect of MST, improve the survival of AML patients.

The impact of the fluconazole trailing effect on the persistence of Candida albicans bloodstream infection when treated with fluconazole.

OBJECTIVES: The trailing effect of Candida species is a phenomenon characterized by reduced but persistent growth at antifungal concentrations above the MIC. We assessed the impact of trailing growth on the persistence of Candida albicans candidemia in patients receiving fluconazole (FLC) therapy. METHODS: We retrospectively investigated candidemia isolates at three hospitals in southern Taiwan between 2013 and 2020. Patients treated with FLC for FLC-susceptible C. albicans candidemia were enrolled. The degree of trailing was determined as the average growth above the MIC divided by the measured growth at the lowest drug concentration using the EUCAST method and classified into four categories: residual (0.1-5%), slight (6-10%), moderate (11-15%), and heavy trailers (>15%). RESULTS: Among isolates from 190 patients, the proportions of heavy trailers at 24 hours, 48 hours, and 72 hours were 63.7% (121/190), 63.2% (120/190), and 74.7% (142/190), respectively. Persistent candidemia was observed in 17 (8.9 %) patients. The proportion of persistent C. albicans candidemia in heavy trailing isolates at 48 hours was higher than in isolates without heavy trailing (13.3% [16/120] vs. 1.4% [1/70], p = 0.007). A multivariate analysis showed that immunosuppression (OR = 7.92; 95% CI: 2.38-26.39, p = 0.001), hospitalization days after the index date of C. albicans identification (OR = 1.03; 95% CI: 1.01-1.05, p = 0.011), and heavy trailing isolates at 48 hours (OR = 10.04; 95% CI: 1.27-79.88, p = 0.029) were independent factors for persistent candidemia. DISCUSSION: The current study revealed that heavy trailing in C. albicans isolates is associated with persistent candidemia in patients receiving FLC treatment.

Identification of COQ2 as a regulator of proliferation and lipid peroxidation through genome-scale CRISPR-Cas9 screening in myeloma cells.

Multiple myeloma (MM) is the second most common malignant haematological disease with a poor prognosis. The limit therapeutic progress has been made in MM patients with cancer relapse, necessitating deeper research into the molecular mechanisms underlying its occurrence and development. A genome-wide CRISPR-Cas9 loss-of-function screening was utilized to identify potential therapeutic targets in our research. We revealed that COQ2 plays a crucial role in regulating MM cell proliferation and lipid peroxidation (LPO). Knockout of COQ2 inhibited cell proliferation, induced cell cycle arrest and reduced tumour growth in vivo. Mechanistically, COQ2 promoted the activation of the MEK/ERK cascade, which in turn stabilized and activated MYC protein. Moreover, we found that COQ2-deficient MM cells increased sensitivity to the LPO activator, RSL3. Using an inhibitor targeting COQ2 by 4-CBA enhanced the sensitivity to RSL3 in primary CD138+ myeloma cells and in a xenograft mouse model. Nevertheless, co-treatment of 4-CBA and RSL3 induced cell death in bortezomib-resistant MM cells. Together, our findings suggest that COQ2 promotes cell proliferation and tumour growth through the activation of the MEK/ERK/MYC axis and targeting COQ2 could enhance the sensitivity to ferroptosis in MM cells, which may be a promising therapeutic strategy for the treatment of MM patients.

To explore the pathogenesis of anterior resection syndrome by magnetic resonance imaging rectal defecography.

BACKGROUND: Over 90% of rectal cancer patients develop low anterior resection syndrome (LARS) after sphincter-preserving resection. The current globally recognized evaluation method has many drawbacks and its subjectivity is too strong, which hinders the research and treatment of LARS. AIM: To evaluate the anorectal function after colorectal cancer surgery by quantifying the index of magnetic resonance imaging (MRI) defecography, and pathogenesis of LARS. METHODS: We evaluated 34 patients using the standard LARS score, and a new LARS evaluation index was established using the dynamic images of MRI defecography to verify the LARS score. RESULTS: In the LARS score model, there were 10 (29.41%) mild and 24 (70.58%) severe cases of LARS. The comparison of defecation rate between the two groups was 29.36 ± 14.17% versus 46.83 ± 18.62% (P = 0.004); and MRI-rectal compliance (MRI-RC) score was 3.63 ± 1.96 versus 7.0 ± 3.21 (P = 0.001). Severe and mild LARS had significant differences using the two evaluation methods. There was a significant negative correlation between LARS and MRI-RC score (P < 0.001), and they had a negative correlation with defecation rate (P = 0.028). CONCLUSION: MRI defecography and standard LARS score can both be used as an evaluation index to study the pathogenesis of LARS.

Photonic chip-based low-noise microwave oscillator.

Numerous modern technologies are reliant on the low-phase noise and exquisite timing stability of microwave signals. Substantial progress has been made in the field of microwave photonics, whereby low-noise microwave signals are generated by the down-conversion of ultrastable optical references using a frequency comb1-3. Such systems, however, are constructed with bulk or fibre optics and are difficult to further reduce in size and power consumption. In this work we address this challenge by leveraging advances in integrated photonics to demonstrate low-noise microwave generation via two-point optical frequency division4,5. Narrow-linewidth self-injection-locked integrated lasers6,7 are stabilized to a miniature Fabry-Pérot cavity8, and the frequency gap between the lasers is divided with an efficient dark soliton frequency comb9. The stabilized output of the microcomb is photodetected to produce a microwave signal at 20 GHz with phase noise of -96 dBc Hz-1 at 100 Hz offset frequency that decreases to -135 dBc Hz-1 at 10 kHz offset-values that are unprecedented for an integrated photonic system. All photonic components can be heterogeneously integrated on a single chip, providing a significant advance for the application of photonics to high-precision navigation, communication and timing systems.

Molecular and Family Analyses of a Novel RHD1058G>C Allele in a Chinese RhD Population.

BACKGROUND: Rh(D) phenotype in a sample from a 19-year-old female patient showed weak positivity (1+). A follow-up sample was requested to further define the Rh(D) phenotype, her Rh(D) phenotype was tested by using another reagent, Rh(D) phenotype still showed weak reactivity (1+), RhCcEe phenotype was Ccee. METHODS: Seven samples from the family members of the proposita were received. The RhDCcEe phenotypes were typed by the microcolumn gel card and the unexpected antibodies were assayed by indirect anti-human globulin test (IAT). Genomic DNA was extracted from the blood sample and the novel RHD1058G>C allele was detected through an established sequence-specific primer PCR (PCR-SSP), RHD exons 1 - 10 were sequenced afterward by exon-specific amplification. The distribution of RHD1058G>C allele and RHD weak positive phenotype were investigated in the pedigrees. RESULTS: The unexpected antibodies all were negative in the family members. The novel RHD1058G>C allele was found in the proposita, her father, and grandfather. Five family members were detected serologically with the common Rh(D)-positive phenotypes either as homozygote of RHD/RHD or heterozygote of RHD/RHd. Two family members were detected as weak D phenotypes in accordance with the genotyping results by PCR-SSP, and both of them have a D1058Ce haplotype and a dce haplotype. One member, her father, was tested common Rh(D)-positive with D1058Ce haplotype and a Dce haplotype. CONCLUSIONS: These data allow us to describe the characteristics of the weak D phenotype with a novel c.RHD-1058G>C allele, which may be partial D and increase the risk of RHD alloantibody. The novel RHD1058G>C allele was inherited in three generations in a family rather than spontaneous mutation in an individual.

Frame-based versus robot-assisted stereo-electro-encephalography for drug-resistant epilepsy.

BACKGROUND: Stereoelectroencephalography (SEEG) is an effective presurgical invasive evaluation for drug-resistant epilepsies. The introduction of robotic devices provides a simplified, accurate, and safe alternative to the conventional SEEG technique. We report our institutional experience with robot-assisted SEEG and compare its in vivo accuracy, operation efficiency, and safety with the more traditional SEEG workflow. METHODS: All patients with medically refractory focal epilepsy who underwent SEEG depth electrode implantation between 2014 and 2022 were included in this study. Technical advancements of the robot-assisted technique are described. Analyses of patient demographics, electrode implantation accuracy, operation time, and procedure-related complications were performed. RESULTS: One hundred and sixty-six patients underwent 167 SEEG procedures. The first 141 procedures were performed using a conventional approach involving a Leksell stereotactic system, and the last 26 procedures were robot-assisted. Among the 1726 depth electrodes that were inserted, the median entry point localization error was as follows: conventional (1.0 mm; range, 0.1-33.5 mm) and robot-assisted (1.1 mm; range, 0-4.8 mm) (P = 0.17). The median target point localization error was as follows: conventional (2.8 mm; range, 0.1-49 mm) and robot-assisted (1.8 mm; range, 0-30.3 mm) (P < 0.001). The median operation time was significantly reduced with the robot-assisted workflow (90 min vs. 77.5 min; P < 0.01). Total complication rates were as follows: conventional (17.7%) and robot-assisted (11.5%) (P = 0.57). Major complication rates were 3.5% and 7.7% (P = 0.77), respectively. CONCLUSIONS: SEEG is a safe and highly accurate method that provides essential guidance for epilepsy surgery. Implementing SEEG in conjunction with multimodal planning systems and robotic devices can further increase safety margin, surgical efficiency, and accuracy.

TXNIP-mediated crosstalk between oxidative stress and glucose metabolism.

Thioredoxin-interacting protein (TXNIP) has emerged as a key player in cancer and diabetes since it targets thioredoxin (TRX)-mediated redox regulation and glucose transporter (GLUT)-mediated metabolism. TXNIP consists of two arrestin (ARR, N-ARR and C-ARR) domains at its amino-terminus and two PPxY (PY) motifs and a di-leucine (LL) motif for endocytosis at its carboxyl-terminus. Here, we report that TXNIP shuffles between TRX and GLUTs to regulate homeostasis of intracellular oxidative stress and glucose metabolism. While TXNIP functions as a gatekeeper of TRX by default, it robustly interacted with class I GLUTs through its C-ARR domain upon increase of intracellular reactive oxygen species. This interaction prompted the surface expression downregulation and lysosomal degradation of GLUTs by its carboxyl-terminal LL endocytic signaling motif to attenuate glucose uptake. Consequently, TXNIP expression significantly limited glucose uptake, leading to the suppression of glycolysis, hexosamine biosynthesis, and the pentose phosphate pathway. Our findings establish a fundamental link between ROS and glucose metabolism through TXNIP and provide a promising target for the drug development against GLUT-related metabolic disorders.

Patient-Reported Outcomes in Disorders of Gut-Brain Interaction.

Disorders of gut-brain interaction are characterized by chronic gastrointestinal symptoms in the absence of abnormal endoscopic or radiologic findings or objective biomarkers that can be identified during routine clinical evaluation. The assessment of the symptom pattern and severity, therefore, is the key modality to evaluate the presence, impact, and evolution of these conditions, for both clinical and regulatory purposes. Patient-reported outcomes are structured symptom assessment questionnaires designed to evaluate symptom patterns, quantify severity of symptoms, and evaluate response to treatment at follow-up. This review provides an overview of currently available patient-reported outcomes for evaluating the main disorders of gut-brain interaction, specifically, functional dyspepsia; irritable bowel syndrome; and chronic constipation. It summarizes their content, level of validation for clinical practice and for research, and the regulatory approach to these conditions. Expected future developments and need for further research on patient-reported outcomes for these and other disorders of gut-brain interaction are highlighted.

NHE3 inhibitor tenapanor maintains intestinal barrier function, decreases visceral hypersensitivity, and attenuates TRPV1 signaling in colonic sensory neurons.

The pathogenesis of irritable bowel syndrome (IBS) is multifactorial, characterized in part by increased intestinal permeability, and visceral hypersensitivity. Increased permeability is associated with IBS severity and abdominal pain. Tenapanor is FDA-approved for the treatment of IBS with constipation (IBS-C) and has demonstrated improvements in bowel motility and a reduction in IBS-related pain; however, the mechanism by which tenapanor mediates these functions remains unclear. Here, the effects of tenapanor on colonic pain signaling and intestinal permeability were assessed through behavioral, electrophysiological, and cell culture experiments. Intestinal motility studies in rats and humans demonstrated that tenapanor increased luminal sodium and water retention and gastrointestinal transit versus placebo. A significantly reduced visceral motor reflex (VMR) to colonic distension was observed with tenapanor treatment versus vehicle in two rat models of visceral hypersensitivity (neonatal acetic acid sensitization and partial restraint stress; both P < 0.05), returning VMR responses to that of nonsensitized controls. Whole cell voltage patch-clamp recordings of retrogradely labeled colonic dorsal root ganglia (DRG) neurons from sensitized rats found that tenapanor significantly reduced DRG neuron hyperexcitability to capsaicin versus vehicle (P < 0.05), an effect not mediated by epithelial cell secretions. Tenapanor also attenuated increases in intestinal permeability in human colon monolayer cultures caused by incubation with proinflammatory cytokines (P < 0.001) or fecal supernatants from patients with IBS-C (P < 0.005). These results support a model in which tenapanor reduces IBS-related pain by strengthening the intestinal barrier, thereby decreasing permeability to macromolecules and antigens and reducing DRG-mediated pain signaling.NEW & NOTEWORTHY A series of nonclinical experiments support the theory that tenapanor inhibits IBS-C-related pain by strengthening the intestinal barrier. Tenapanor treatment reduced visceral motor responses to nonsensitized levels in two rat models of hypersensitivity and reduced responses to capsaicin in sensitized colonic nociceptive dorsal root ganglia neurons. Intestinal permeability experiments in human colon monolayer cultures found that tenapanor attenuates increases in permeability induced by either inflammatory cytokines or fecal supernatants from patients with IBS-C.

Abdominal Symptom Improvement During Clinical Trials of Tenapanor in Patients With Irritable Bowel Syndrome With Constipation: A Post Hoc Analysis.

INTRODUCTION: This post hoc analysis evaluated the efficacy of tenapanor on abdominal symptoms in patients with irritable bowel syndrome with constipation. Abdominal symptoms assessed included pain, discomfort, bloating, cramping, and fullness. METHODS: The abdominal symptom data were pooled from 3 randomized controlled trials (NCT01923428, T3MPO-1 [NCT02621892], and T3MPO-2 [NCT02686138]). Weekly scores were calculated for each abdominal symptom, and the Abdominal Score (AS) was derived as the average of weekly scores for abdominal pain, discomfort, and bloating. The overall change from baseline during the 12 weeks was assessed for each symptom weekly score and the AS. The AS 6/12-week and 9/12-week response rates (AS improvement of ≥2 points for ≥6/12- or ≥9/12-week) were also evaluated. The association of weekly AS response status (reduction of ≥30%) with weekly complete spontaneous bowel movement (CSBM) status (=0 and >0) was assessed. RESULTS: Among 1,372 patients (684 tenapanor [50 mg twice a day] and 688 placebo), the least squares mean change from baseline in AS was -2.66 for tenapanor vs -2.09 for placebo ( P < 0.0001). The 6/12-week AS response rate was 44.4% for tenapanor vs 32.4% for placebo ( P < 0.0001), and for 9/12-week AS, 30.6% for tenapanor vs 20.5% for placebo ( P < 0.0001). A significant association between weekly CSBM status and weekly AS response status was observed each week ( P < 0.0001), with a greater proportion achieving an AS reduction in patients with >0 CSBMs in a week. DISCUSSION: Tenapanor significantly reduced abdominal symptoms in patients with irritable bowel syndrome with constipation, particularly pain, discomfort, and bloating measured by AS, compared with placebo.

Physiochemical Coupled Dynamic Nanosphere Lithography Enabling Multiple Metastructures from Single Mask.

Metastructures are widely used in photonic devices, energy conversion, and biomedical applications. However, to fabricate multiple patterns continuously in single etching protocol with highly tunable photonic properties is challenging. Here, a simple and robust dynamic nanosphere lithography is proposed by inserting a spacer between the nanosphere assembly and the wafer. The nanosphere diameter decrease and uneven penetration of the spacer during etching lead to a dynamic masking process. Coupled anisotropic physical ion sputtering and ricocheting with isotropic chemical radical etching achieve highly tunable structures with various 3D patterns continuously forming through a single etching process. Specifically, the nanosphere diameters define the periodicity, the etched spacer forms the upper parts, and the wafer forms the lower parts. Each part of the structure is highly tunable through changing nanosphere diameter, spacer thickness, and etch conditions. Using this protocol, numerous structures of varying sizes including nanomushrooms, nanocones, nanopencils, and nanoneedles with diverse shapes are realized as proof of concepts. The broadband antireflection ability of the nanostructures and their use in surface-enhanced Raman spectroscopy are also demonstrated for practical application. This method substantially simplifies the fabrication procedure of various metastructures, paving the way for its application in multiple disciplines especially in photonic devices.

Neural correlates of perceived and relative resilience in male and female patients with irritable bowel syndrome.

BACKGROUND: Patients with irritable bowel syndrome (IBS) show lower resilience than healthy controls (HCs), associated with greater symptom severity and worse quality of life. However, little is known about affected markers of resilience or the influence of sex. Furthermore, as resilience is complex, a comprehensive assessment, with multiple resilience measures, is needed. Therefore, we aimed to evaluate perceived and relative resilience and their neural correlates in men and women with IBS. METHODS: In 402 individuals (232 IBS [73.3% women] and 170 HCs [61.2% women]), perceived resilience was assessed by the Connor-Davidson Resilience Scale (CDRISC) and Brief Resilience Scale (BRS); relative resilience was assessed by the standardized residual of the Short Form-12 mental component summary score predicted by the Adverse Childhood Experiences score. Non-rotated partial least squares analysis of region-to-region resting-state connectivity data was used to define resilience-related signatures in HCs. Disease and sex-related differences within these signatures were investigated. KEY RESULTS: Scores on all resilience measures were lower in IBS than in HCs (p's < 0.05). In all three resilience-related signatures, patients with IBS showed reduced connectivity largely involving the central autonomic network (p's < 0.001). Men with IBS showed lower CDRISC scores than women with IBS, and greater reductions in CDRISC-related connectivity, associated with worse symptom severity (p < 0.05). CONCLUSIONS AND INFERENCES: Individuals with IBS show reduced perceived and relative resilience, with reduced connectivity suggesting impaired homeostasis maintenance. Men with IBS may show additional impairment in specific aspects of resilience. Treatments aimed at improving resilience may benefit patients with IBS, especially men with IBS.

Novel endomorphin analogues CEMR-1 and CEMR-2 produce potent and long-lasting antinociception with a favourable side effect profile at the spinal level.

BACKGROUND AND PURPOSE: Endomorphins have shown great promise as pharmaceutics for the treatment of pain. We have previously confirmed that novel endomorphin analogues CEMR-1 and CEMR-2 behaved as potent µ agonists and displayed potent antinociceptive activities at the supraspinal and peripheral levels. The present study was undertaken to evaluate the antinociceptive properties of CEMR-1 and CEMR-2 following intrathecal (i.t.) administration. Furthermore, their antinociceptive tolerance and opioid-like side effects were also determined. EXPERIMENTAL APPROACH: The spinal antinociceptive effects of CEMR-1 and CEMR-2 were determined in a series of pain models, including acute radiant heat paw withdrawal test, spared nerve injury-induced neuropathic pain, complete Freund's adjuvant-induced inflammatory pain, visceral pain and formalin pain. Antinociceptive tolerance was evaluated in radiant heat paw withdrawal test. KEY RESULTS: Spinal administration of CEMR-1 and CEMR-2 produced potent and prolonged antinociceptive effects in acute pain. CEMR-1 and CEMR-2 may produce their antinociception through distinct µ receptor subtypes. These two analogues also exhibited significant analgesic activities in neuropathic, inflammatory, visceral and formalin pain at the spinal level. It is noteworthy that CEMR-1 showed non-tolerance-forming analgesic properties, while CEMR-2 exhibited substantially reduced antinociceptive tolerance. Furthermore, both analogues displayed no or reduced side effects on conditioned place preference response, physical dependence, locomotor activity and gastrointestinal transit. CONCLUSIONS AND IMPLICATIONS: The present investigation demonstrated that CEMR-1 and CEMR-2 displayed potent and long-lasting antinociception with a favourable side effect profile at the spinal level. Therefore, CEMR-1 and CEMR-2 might serve as promising analgesic compounds with minimal opioid-like side effects.