UC San Diego Health System

Hereditary angioedema is a bradykinin-mediated, rare condition characterised by recurrent and potentially life-threatening attacks of subcutaneous and submucosal swelling. Bradykinin B2 receptor antagonism is a proven mechanism for on-demand treatment of attacks, but no evidence exists on its effects when used prophylactically. Deucrictibant is an investigational orally bioavailable bradykinin B2 receptor antagonist. We aimed to evaluate the efficacy, safety, and tolerability of two dose regimens of oral deucrictibant administered as prophylaxis against hereditary angioedema attacks. CHAPTER-1 was a multicentre, double-blind, placebo-controlled, randomised, phase 2 trial conducted in two parts, a double-blind placebo controlled first part and an open-label second part, with only part 1 reported here. Part 1 recruited adults (aged 18-75 years) with hereditary angioedema type 1 or 2 from 37 sites (university hospitals and accredited angioedema centres) across North America, Europe, and Israel. Patients required a documented history of three or more attacks within the last 3 consecutive months before screening or two or more during the screening period (up to 8 weeks) to be eligible. An interactive response technology system randomised eligible patients 1:1:1 to receive oral deucrictibant 20 mg daily, 40 mg daily, or matching placebo for 12 weeks. Randomisation to treatment groups was stratified by the baseline attack rate. Patients, investigators, site personnel, and the sponsor were blinded to treatment assignment. Masking was achieved with identically appearing deucrictibant and placebo capsules. The primary endpoint was the time-normalised number of investigator-confirmed attacks per 4 weeks (monthly attack rate) from weeks 1 to 12 and was assessed using the intention-to-treat set. The endpoint was analysed by comparing each deucrictibant group with the placebo group using a Poisson generalised linear model with a log link function and Pearson's χ2 scaling of SEs to account for potential dispersion. The safety analysis set included all patients who were randomly assigned and who received one or more doses of study drug (deucrictibant or placebo). CHAPTER-1 is registered with ClinicalTrials.gov (NCT05047185) and is now complete. Between March 9, 2022, and June 19, 2023, 44 patients were screened. Of 34 patients who were randomly assigned, 11 patients received deucrictibant 20 mg, 12 patients received deucrictibant 40 mg, and 11 patients received the placebo, with a median follow-up of 85·0 days (IQR 84·0-86·0). 21 (62%) patients were female, 13 (38%) were male, and 34 (100%) patients were White. The least squares mean monthly attack rate (primary analysis) was 0·40 (95% CI 0·18-0·92) for deucrictibant 20 mg, 0·30 (0·11-0·81) for deucrictibant 40 mg, and 1·93 (1·30-2·88) for placebo; percent reduction in attack rate compared with placebo was 79·2% (95% CI 47·2-91·8) for deucrictibant 20 mg (p=0·0010) and 84·5% (95% CI 53·8-94·8) for deucrictibant 40 mg (p=0·0008). Treatment-related treatment-emergent adverse events were experienced by two (18%) patients receiving deucrictibant 20 mg, one (8%) patient receiving deucrictibant 40 mg, and one (9%) patient receiving the placebo; all were mild in severity (grade 1) and did not require dosing modification of the study drug. There were no serious adverse events or deaths in any treatment group. To the best of our knowledge, this trial provides the first clinical evidence and proof-of-concept for bradykinin B2 receptor antagonism as a therapeutic approach for the prevention of hereditary angioedema attacks and supports further investigation of oral deucrictibant for bradykinin-mediated angioedema. Pharvaris.

The opioid epidemic and limitations of current nonopioid analgesics have created a need for safer, effective pain therapies. Suzetrigine, a first-in-class selective NaV1.8 inhibitor, was approved by the Food and Drug Administration in 2025 for the treatment of moderate to severe acute pain. The purpose of this review is to discuss the mechanism and clinical efficacy of suzetrigine and its potential for addressing existing therapeutic gaps in pain management. Phase 3 trials have demonstrated that suzetrigine provides a statistically significant and clinically meaningful reduction in acute postoperative pain compared to placebo, with efficacy similar to hydrocodone/acetaminophen and a favorable safety profile. Mechanistic studies confirm selective peripheral NaV1.8 inhibition, minimizing central nervous system effects and abuse potential. Ongoing research is evaluating suzetrigine for chronic pain conditions including diabetic peripheral neuropathy and lumbosacral radiculopathy, though long-term efficacy and safety remain to be established. Suzetrigine represents a promising nonopioid alternative for acute pain and has the potential to fill a significant gap in pain management. While initial results are encouraging, future studies are needed to define its role in chronic pain and multimodal analgesia, and to establish long-term safety.

This review summarizes the pathophysiology, clinical presentation, and evidence-based management of pelvic floor disorders (PFDs) during pregnancy, birth, and the postpartum period. It highlights current knowledge on prevention, diagnosis, treatment, and long-term outcomes, with particular focus on urinary incontinence, fecal incontinence, pelvic organ prolapse, and perineal wound-related complications. Pregnancy induces hormonal and mechanical changes that predispose to PFDs, including urinary incontinence, fecal incontinence, and pelvic organ prolapse. Vaginal birth, especially with operative assistance and/or resulting in obstetric anal sphincter injury (OASI), significantly increases the risk of long-term pelvic floor dysfunction. Preventative strategies—such as antenatal perineal massage, pelvic floor muscle training (PFMT), perineal application of warm compresses in labor, manual perineal protection during birth, and restricted use of episiotomy—can reduce severe lacerations and future PFDs. Conservative postpartum management of PFDs includes PFMT, biofeedback, pessaries; and newer digital tools may improve adherence and outcomes. Although surgical interventions are typically delayed until after childbearing, emerging evidence supports select procedures even if future childbearing is desired. Myofascial pain and wound complications require tailored management with physical therapy and, in some cases, local injections. Counseling on subsequent mode of birth after prior OASI remains individualized. Pelvic floor disorders are common and often underrecognized sequelae of pregnancy and childbirth. Optimizing prevention and early postpartum care can reduce symptom burden and improve quality of life. Individualized counseling, shared decision-making, and multidisciplinary management are essential to address the complex interplay of delivery-related injury, pelvic floor dysfunction, and patient goals.

Given a set of overlapping local views (patches) of a dataset, we consider the problem of finding a rigid alignment of the views that minimizes a $2$-norm based alignment error. In general, the views are noisy and a perfect alignment may not exist. In this work, we characterize the non-degeneracy of an alignment in the noisy setting based on the kernel and positivity of a certain matrix. This leads to a polynomial time algorithm for testing the non-degeneracy of a given alignment. Subsequently, we focus on Riemannian gradient descent for minimizing the alignment error, providing a sufficient condition on an alignment for the algorithm to converge (locally) linearly to it. \revadd{Additionally, we provide an exact recovery and noise stability analysis of the algorithm}. In the case of noiseless views, a perfect alignment exists, resulting in a realization of the points that respects the geometry of the views. Under a mild condition on the views, we show that a non-degenerate perfect alignment \revadd{characterizes the infinitesimally rigidity of a realization, and thus the local rigidity of a generic realization}. By specializing the non-degeneracy conditions to the noiseless case, we derive necessary and sufficient conditions on the overlapping structure of the views for \revadd{a perfect alignment to be non-degenerate and equivalently, for the resulting realization to be infinitesimally rigid}. Similar results are also derived regarding the uniqueness of a perfect alignment and global rigidity.

Artificial sweeteners (AS) are widely used as sugar substitutes, particularly among individuals with metabolic disorders. Although AS are approved by regulatory authorities, concerns regarding their potential association with cancer risk persist due to inconsistent findings across studies. This umbrella review aimed to comprehensively synthesize evidence from published meta-analyses evaluating the association between AS consumption and cancer risk. A systematic search of PubMed, Web of Science, and Scopus was conducted to identify meta-analyses examining the association between AS consumption and cancer outcomes in human populations. Data synthesis was performed using random-effects models, and evidence certainty was evaluated using the GRADE framework. Sensitivity analyses, prediction intervals, and publication bias assessments were conducted when applicable. Overall AS consumption was not significantly associated with breast cancer (OR = 0.99, 95% CI 0.92–1.08, P = 0.99), colorectal cancer (CRC) (OR = 0.90, 95% CI 0.76–1.05, P = 0.18), pancreatic cancer (OR = 1.04, 95% CI 0.93–1.17, P = 0.44), gastric cancer (OR = 0.93, 95% CI 0.63–1.36, P = 0.71), or bladder cancer (OR = 1.19, 95% CI 0.75–1.88, P = 0.44). Dose-specific analyses showed no significant associations between AS consumption and breast cancer across low-dose (OR = 1.00, 95% CI 0.95–1.06, P = 0.83), moderate-dose (OR = 0.97, 95% CI 0.94–1.01, P = 0.21), or high-dose categories (OR = 0.88, 95% CI 0.73–1.06, P = 0.18). For CRC, low-dose AS consumption was associated with a reduced risk (OR = 0.87, 95% CI 0.76–0.99, P = 0.04; GRADE: low), whereas moderate-dose (OR = 1.11, 95% CI 0.92–1.33, P = 0.25) and high-dose AS consumption (OR = 0.89, 95% CI 0.79–1.00, P = 0.05) showed no significant associations with CRC risk. Based on the GRADE framework, the certainty of evidence was rated as low for breast cancer, CRC, and pancreatic cancer, very low for bladder cancer, and not assessable for gastric cancer due to the limited number of studies. Although no significant cancer risks were identified, the overall strength of the evidence was weak. More well-designed, high-quality studies are necessary to further explore and clarify the long-term impact of AS on cancer risk. Additionally, there is insufficient evidence available to assess the effects of AS on other cancer types, and further research is needed in this area.

Over 80% of tuberculosis cases in the United States are due to reactivation of untreated latent tuberculosis infection (LTBI), most of whom were foreign born. LTBI treatment can greatly lower the risk of progression to active TB disease, and shorter treatment regimens increase the potential of migrants and other persons in vulnerable conditions, to complete treatment. We conducted across-sectional study to assess willingness to complete a one-month course of LTBI treatment among internal and international migrants living in Tijuana, BC, Mexico, and to identify factors associated with treatment unwillingness between November 2020 and April 2021. Prior to administering TB skin tests (TST), participants were asked if they would accept LTBI treatment if indicated by test results and clinical examination. Recruitment occurred in migrant shelters throughout Tijuana and at a storefront office conducting research and harm reduction services for people who use drugs. Among 595 participants, 80.4% were living in shelters, 3.5% were recruited at shelters but living independently, and 16.1% were recruited through the storefront office. Overall, 71 (11.9%) indicated that they were unwilling to take LTBI treatment and 109 (18.3%) had positive TST results. Unwillingness to take LTBI treatment was more common among participants from the storefront office compared to the shelter (64.6% vs. 1.8%, p<0.001). Since only 1.8% of shelter participants were unwilling to receive treatment, multivariable Poisson regression with robust variance estimation via GEE for identifying factors independently associated with LTBI treatment unwillingness was restricted to storefront participants. Treatment unwillingness among storefront participants was positively associated with perceiving health status as "good" or "very good" (prevalence ratio [PR]=2.37, 95% confidence interval [CI]: 1.52, 3.99) and heroin use in the past six months (PR=1.70; 95% CI: 1.33, 2.19). Unstable housing was reported as a barrier to treatment. These findings suggest that most migrants in Tijuana were willing to receive short-course LTBI treatment if indicated, yet willingness was lower among those at greatest risk of TB. Efforts to increase testing and treatment, as well as further research on overcoming barriers to treatment willingness are needed.

Gastrointestinal (GI) cancers are a heterogeneous group of cancers with high morbidity and mortality rates. Despite advancements in early detection markers and therapy, the outcome remains poor due to high tumor heterogeneity and metastasis. The microenvironment (ME) in GI cancers is highly dynamic and enriched with immune and endothelial cells, extracellular matrix (ECM), and stromal components, including cancer associated fibroblasts (CAFs), which play an essential role in tumor progression. CAFs modulate tumor progression through extensive crosstalk with cancer cells, immune cells, and ECM remodeling. CAFs secrete cytokines, growth factors, and exosomes that modulate tumor progression, epithelial to mesenchymal transition, angiogenesis, immune tolerance, and therapy resistance. By remodeling the ECM, CAFs create a protumorgenic microenvironment through the activation of key signaling pathways such as YAP/TAZ and integrin/FAK. CAFs are also heterogeneous, with diverse subsets exhibiting context-dependent pro- or anti-tumor function, as discussed in this review. Autophagy is a process that removes damaged cellular components to maintain homeostasis. In the early stage of cancer, autophagy suppresses tumor progression. Still, in the later stages of tumors, CAFs support survival, metabolic alterations, therapy resistance, and immune evasion, as such are regulated by signals like TGF-β/IL-6/ROS and pathways including AMPK/STAT3/NF-κB/SMAD and mTOR. The review discusses CAFs and modulation of autophagy in GI cancer progression, metastasis, and resistance to therapy. CAFs remodel the ME and induce immune tolerance, while autophagy in both cancer cells and CAFs allows survival under stress. By showing these interconnected mechanisms, the review identifies CAF autophagy as a critical therapeutic target to overcome resistance in GI cancers.