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HMMR mediates progression of nasopharyngeal carcinoma by inhibiting FAM83D ubiquitination and activating beta-catenin signaling pathway
Get PDFThe hyaluronan-mediated motility receptor (HMMR) is widely expressed across various species and plays a crucial role in cancer progression. However, its role in nasopharyngeal carcinoma (NPC) remains unexplored. Here, we identified a novel HMMR-FAM83D-β-catenin axis, which drives NPC progression through β-catenin signaling. Using bulk RNA sequencing, single-cell RNA-sequencing, and immunohistochemistry, we determined that HMMR is highly expressed in NPC tissues, correlating with poor survival in NPC patients. In vitro assays demonstrated that modulating HMMR expression influenced NPC cell proliferation, migration, and invasion. In vivo, HMMR knockdown significantly inhibited tumor growth and metastasis in NPC models. HMMR was significantly upregulated in NPC tissues and correlated with worse patient survival. Mechanistically, HMMR was found to interact with the Wnt/β-catenin signaling pathway, affecting both pathway activation and β-catenin expression, as evidenced by RNA-seq and western blotting. Co-immunoprecipitation, mass spectrometry, and western blot analyses further revealed that HMMR interacts with Family with Sequence Similarity 83 Member D (FAM83D), stabilizing its expression by inhibiting its ubiquitination. This interaction, in turn, modulates β-catenin levels, driving NPC progression. Our findings reveal a novel HMMR-FAM83D-β-catenin axis that promotes NPC cell progression through Wnt/β-catenin signaling by modulating β-catenin signaling. HMMR could serve as a potential prognostic biomarker and therapeutic target for NPC, deepening our understanding of its role in disease progression
Enhancing maternal and newborn outcomes in Ghana: a comprehensive randomized controlled trial evaluation of obstetric triage effectiveness and midwives training
Get PDFBackground Ghana has made progress in maternal and newborn health, but significant challenges remain, with maternal mortality at 263 per 100,000 live births and neonatal mortality at 22.8 per 1,000 live births. The Obstetric Triage Implementation Package (OTIP), which includes rapid triage protocols and midwife-led peer training, aims to improve the quality of care in a context of scarce resources. This study evaluates the effectiveness of OTIP in improving maternal and neonatal outcomes and assesses the mechanisms behind the observed effects. Methods A cluster randomized controlled trial will assess the impact of OTIP in 25 high-volume hospitals across Ghana during the final phase of its national roll-out. Hospitals will be randomized into early and late intervention groups. A complementary regression discontinuity analysis will assess the impact of OTIP at the national level. Primary outcomes include process improvements and maternal and neonatal outcomes. Secondary outcomes will assess midwives’ knowledge and attitudes. Data sources include primary surveys of 1,250 mother-newborn pairs and 750 midwives, and administrative records from the Ghana Health Service, Ministry of Health. Discussion A rigorous evaluation of OTIP would be crucial, not only to assess the effectiveness of a program in which the Government of Ghana is already investing, but also to assess the potential applicability of this training model to other areas, and to contribute to the academic literature by filling gaps in our understanding of how different training methods can overcome barriers to the diffusion of new practices. Trial registration Study protocols have been approved by the Ghana Health Service (GHS) Ethics Review Committee (GHS-ERC: 022/05/24). Trial registration number: ISRCTN15629047. Registered on 04/11/2024 while participant enrollment was ongoing, https://doi.org/10.1186/ISRCTN15629047. The study is hence retrospectively registered
Emergence of Medetomidine in the Unregulated Drug Supply and Its Association With Hallucinogenic Effects
Get PDFThe unregulated drug supply in the United States is rapidly evolving, and veterinary tranquillisers have emerged as adulterants of concern, especially in illicitly‐manufactured fentanyl. Following the proliferation of xylazine, medetomidine, a more potent sedative, has recently appeared in multiple US states. This study describes the characteristics of medetomidine samples from a national mail‐based drug checking program and aims to determine whether medetomidine is associated with hallucinogenic effects. We conducted a retrospective analysis of 11,363 drug samples between December 2022 and April 2025. Samples were sent voluntarily by people who use drugs. Participant‐reported sensations and sample characteristics (e.g., colour, texture) were gathered at point‐of‐contact. Composition was analysed using gas‐chromatography mass spectrometry. We estimated adjusted prevalence ratios for hallucinations in medetomidine‐containing samples using generalised estimating equations. Medetomidine was identified in 278 samples (2.4%), with pronounced growth beginning June 2024. Medetomidine commonly appeared with fentanyl (58.8%) and/or xylazine (55.9%). Most samples were powders (85.3%). Among all 11,363 samples, those containing medetomidine in primary abundance (n = 136) were more likely to be associated with reported hallucinations (17.6%) compared to all other samples (1.2%; adjusted prevalence ratio: 11.95, 95% confidence interval 6.36, 22.44). Medetomidine is an emerging adulterant, although its risk profile is under‐described. Our findings suggest medetomidine may cause hallucinogenic effects, contradicting clinical use for preventing delirium in postsurgical settings. Unexpected hallucinations may serve as a sentinel signal for medetomidine's presence in local drug markets. Education is needed for people who use drugs and clinicians about novel adverse effects of medetomidine
Behavioral alignment in social networks
Get PDFThe orderly behaviors observed in large-scale groups, such as fish schooling and the organized movement of crowds, are both ubiquitous and essential for the survival and stability of these systems. Understanding how such complex collective behaviors emerge from simple local interactions and behavioral adjustments is a significant scientific challenge. Historically, research has predominantly focused on imitation and social learning, where individuals adopt the strategies of more successful peers to refine their behavior. However, in recent years, an alternative learning approach based on self-exploration and introspective learning has garnered increasing attention. In this paradigm, individuals assess their own circumstances and select strategies that best align with their specific conditions. Two examples are coordination and anti-coordination, where individuals align with and diverge from the local majority, respectively. In this study, we analyze networked systems of coordinating and anti-coordinating individuals, exploring the combined effects of system dynamics, network structure, and behavioral patterns. We address several practical questions, including the number of equilibria, their characteristics, the equilibrium time, and the resilience of the system. We find that the number of equilibrium states can be extremely large, even increasing exponentially with minor alternations to the network structure. Moreover, the network structure has a significant impact on the average equilibrium time. Despite the complexity of these findings, we find that variations can be captured by a single, simple network characteristic (the average path length), which we illustrate in both synthetic and empirical networks
Sources of stress among caregivers receiving diaper assistance
Get PDFBackground: Diaper insecurity is a major financial burden for many families with young children.
Objectives: We aimed to describe the most frequently occurring stressors among caregivers receiving diaper assistance.
Design: Caregivers receiving diaper assistance at community-based organizations in North Carolina completed surveys, including a modified Everyday Stressors Index.
Methods: We conducted a descriptive, cross-sectional study, calculating the number and percent of caregivers reporting that each stressor caused them “a lot of” or “some” stress.
Results: More than half of participants reported “a lot of” or “some” stress about not having enough time to do the things they want (58.5%), affording diapers (58.3%), affording rent or mortgage (54.1%), having too many responsibilities or things to do (53.1%), and affording utility bills (51.0%).
Conclusions: Caregivers need support having enough money to meet basic needs and having sufficient time to meet their responsibilities and goals. Potential strategies include repealing the state sales tax on diapers and increasing state and federal tax credits and minimum wage.Plain Language Summary
Why did we conduct this study? Diapers represent a significant cost for families with young children. As many as 50% of families with young children report diaper insecurity (also referred to as diaper need), or difficulty affording enough diapers to keep their child clean, dry, and healthy. We wanted to describe the different types of stressors experienced by caregivers with diaper insecurity to understand additional supports these families may need to ensure both caregiver and child wellbeing. What did we find? Among caregivers receiving diaper assistance from local organizations, most had at least one adult in the household working for pay, and most had household incomes <$35,000. More than half reported substantial stress not having enough time to do the things they want, affording diapers, affording rent or mortgage, having too many responsibilities or things to do, and affording utility bills like water and electricity. What do the findings mean? Frequently reported stressors among caregivers receiving diaper assistance revealed two themes: caregivers need more money to meet basic needs and more time to meet their responsibilities and goals. Potential program and policy solutions include directly funding diaper banks, using Temporary Assistance for Needy Families (TANF) funds to cover the cost of diapers, repealing state sales tax on diapers, designating diapers as a medical necessity so they can be covered by Medicaid, allowing diapers to be purchased through health savings or flexible spending accounts, increasing minimum wage, increasing tax credits to families through the Child Tax Credit or Earned Income Tax credit, and increasing benefits in social safety net programs, such as the Supplemental Nutrition Assistance Program, among others
Esophageal cancer staging in Malawi: the feasibility of chest radiography and abdominal ultrasound for initial evaluation
Get PDFBackground Esophageal cancer (EC) is the third leading cause of cancer-related morbidity and mortality in Malawi. Given limited imaging capacity and high costs, staging is not routinely performed. One proposed staging algorithm is to first evaluate for metastatic disease using low-cost chest radiography (CXR) and abdominal ultrasound (US) followed by confirmatory computerized tomography (CT) of the chest and abdomen if no metastases identified on initial screening. The feasibility of this approach is unknown for EC in sub–Saharan Africa and was studied in the context of a larger prospective observational cohort study of EC in Malawi.
Methods From 2021 to 2022, EC patients at Kamuzu Central Hospital in Lilongwe, Malawi enrolled in the Treatment Outcomes of Esophageal Cancer in Malawi (TOEC-M) study were recruited. Participants were scheduled for a CXR, US, and CT scan as part of this sub-study. Participant characteristics, completion rates, imaging findings, and barriers to completion were documented. For participants undergoing all three imaging studies, sensitivity and specificity were calculated.
Results Of 150 patients in TOEC-M, 67 (44.7%) enrolled in this sub-study. Mean age was 55.4 years and 50.8% were males. The majority had mid-esophageal (38 [56.7%]) squamous cell carcinomas (54 [80.6%]). CXR was completed in 54 (80.6%) study participants, US in 43 (64.2%), CT chest in 29 (43.3%), and CT abdomen in 24 (35.8%). Sixteen (23.9%) completed all studies and 4 (6.0%) did not undergo any imaging. Of the 63 patients that were imaged, metastatic disease was identified in 18 (28.6%) by any modality. Positive findings were identified on 3 (5.6%) CXRs, 4 (9.3%) US, and 18 (62.1%) CTs, most frequently liver masses followed by lung nodules and adenopathy. Barriers to imaging completion included participant functional status and scanner availability.
Conclusions As access to EC treatment modalities expands, feasible and accurate staging will become increasingly important to guide clinical management. Our results suggest that CXR and US may serve as useful initial tools for assessing metastatic disease. In patients not medically fit for oncologic treatment, positive findings on CXR and US may allow CT to be deferred. Barriers to implementation of a pragmatic stepwise staging algorithm identified in this study can inform future research and care for patients with EC in similar resource-limited settings
Differential BK channel potentiation by vanzacaftor enantiomers enables therapy for modulator-ineligible people with cystic fibrosis
Get PDFTo the Editor: Cystic fibrosis transmembrane conductance regulator (CFTR) modulators have significantly improved outcomes for people with cystic fibrosis (pwCF), yet those with unresponsive mutations remain without effective treatments. One promising strategy involves enhancing ion channels alternative to CFTR (reviewed in ref. 1), including apically expressed large conductance, calcium-activated potassium (BK) channels. BK channels, composed of the pore-forming subunit KCNMA1 (Slo1) and the regulatory subunit LRRC26 (γ1), are critical for airway surface hydration and mucociliary transport (MCT). Inhibition or knockdown of these components leads to reduced airway surface liquid, increased mucus concentration, and impaired MCT in CF models in vitro and in vivo. BK plays a crucial role in enhancing chloride exit, a phenomenon called apical loop current. Our simulations indicated that small apical increases in potassium conductance (from 0 to 0.002 S/cm2) enhance Cl– efflux approximately 3-fold. Reanalyzing airway single cell RNA-seq data from ref. 4, we show KCNMA1, LRRC26, and ANO1 expression in secretory cells. Among BK β-subunits, only KCNMB2/4 are detected, with KCNMB2 in ciliated cells and KCNMB4 in large airways, supporting the hypothesis that, in peripheral airways where CF disease starts, apical loop currents between ANO1 and BK, made of KCMNA1/LRRC26, can be enhanced therapeutically
E-cigarette, or Vaping, Product Use Associated Lung Injury: Epidemiology, Challenges, and Implications With COVID-19
Get PDFBackground: E-cigarette, or vaping products produce an aerosol by heating nicotine, or cannabis including tetrahydrocannabinol (THC) and cannabidiol (CBD), mixed with other chemicals that help make the aerosol. They are increasingly popular among teenagers and young adults, with a 2023 survey reporting that 2.13 million middle and high school students in the United States used e-cigarettes within the last 30 days. The use of e-cigarette, or vaping products could lead to an acute pulmonary inflammatory syndrome called e-cigarette, or vaping, product use-associated lung injury (EVALI). We review the challenges in diagnosing and treating EVALI, especially during the COVID-19 pandemic. Methods: We conducted a literature search on June 10, 2024 using the PubMed database. We searched for articles, case reports and CDC reports investigating the pathogenesis, treatment, and challenges of diagnosing EVALI during the COVID-19 pandemic. Results: The exact causes of EVALI are not completely understood, although it has been linked to the use of THC and vitamin E acetate. There are no specific biomarkers to diagnose EVALI and it is typically diagnosed through a process of eliminating other possible conditions. Eight studies detailed cases where pediatric patients were initially diagnosed with COVID-19 or community-acquired pneumonia, despite multiple negative COVID-19 tests, and were later found to have EVALI. Conclusions: After alerting the public about the removal of vitamin E acetate from vape liquids in 2020, there has been a decline in cases of EVALI, although they are still detected. Therefore, it is necessary to continue looking for diagnostic markers of EVALI and further investigate the toxicity of vapes and e-cigarettes to prevent the recurrence of another EVALI epidemic, especially among teenagers and young adults
Case Study Analysis of a Decision Coaching Intervention for Young Adults with Early Psychosis
Get PDFYoung adults with early psychosis often disengage from essential early intervention services (i.e., Coordinated Specialty Care or CSC in the United States). While decision support interventions improve service engagement, their use in this population is underexplored. This study evaluated the feasibility, acceptability, fidelity, and potential impact of a decision coaching intervention for young adults with early psychosis in CSC services. Using a mixed-method, longitudinal, collective case study design, we assessed the intervention's impact on decision-making needs through the Decisional Conflict Scale and qualitative interviews. We also evaluated feasibility, fidelity, and acceptability through observations and feedback from interventionists and participants. Eight young adults from three CSC programs participated, showing variable engagement, with generally favorable fidelity and acceptability ratings. The Decisional Conflict Scale revealed mixed findings, while four themes from qualitative interviews emerged: Perspective and Information Seeking, Motivation and Prioritization, Empowerment and Confidence, and Critical Thinking and Evaluation. The findings suggest that training CSC providers—including peer specialists and clinicians—to deliver decision coaching with fidelity is feasible, well-received by young adults, and potentially impactful on decision-making. Replication in a larger controlled trial, addressing observed study limitations, is warranted. This trial was registered with ClinicalTrials.gov (Identifier: NCT04532034) on August 28, 2020, as Temple University Protocol Record 261047, Facilitating Engagement in Evidence-Based Treatment for Early Psychosis (https://clinicaltrials.gov/ct2/show/NCT04532034?term=NCT04532034&draw=2&rank=1)
Yes, in my backyard (YIMBY) and yours, too: women entrepreneurs’ leadership for a sustainable future of a small Japanese town
Get PDFWe describe and discuss the narratives and backgrounds of four female entrepreneurs in a small rural town in Japan (Chizu, Tottori prefecture) who are working to foster emergent cultures of sustainability. The narratives concern their individual and group paths towards an entrepreneurial ecosystem that functions in tandem with the local socio-ecological system (SES) in strengthening the long-term vitality of a rural town. This paper was developed from the individual and collective narratives of these women entrepreneurs (all co-authors of this paper) which reflect their efforts to foster dialogues and form a community of purpose that enlists and expands upon a pre-existing movement of “small, lively communities” (ikita chiiona komyunitii) and the “zero-to-one movement” in Chizu Okada (Contemp Japan 34:210-227, 2022). The narratives connect not only to changing demographics in other small, rural communities in Japan and across the world, but also to women taking the initiative to actively engage economically, socially, and politically, despite cultures that have not usually been supportive of women’s initiatives and activist roles. In this paper, we highlight the importance of local initiatives led by women to build and share visions for sustainable futures for their communities. We explore narratives that reflect impacts of acute shocks and chronic stressors on the community (e.g., extreme weather events, as well as climate change and the COVID-19 pandemic) and express visions of sustainability. These narratives of a community as an integral part of its ecosystem influence the process of making decisions to mitigate or adapt to improve the well-being of the community for present and future generations. The women’s group and the individual women within the group hold visions of community sustainability goals that largely fit within Chizu’s culture, as it has been over the last several decades. However, the unique pathway(s) and futures-oriented thinking of these women differ in some ways from social norms in Japan. This distinction is especially notable as a change from, as well as beneficiary of the “zero-to-one movement” Okada (Contemp Japan 34:210-227, 2022). This was a very important and influential decades-long effort to revitalize Chizu, an effort largely organized and operated by men in authority in the area. Thus, there is tension within the complex system that includes entrepreneurial ecosystems and SES functioning within Chizu and the aspiration for forming a culture of sustainability. This paper offers a window into a local effort that can inspire action in other communities to shape constructive responses to a changing climate, changing demographic, and changing role for women acting to support the multi-generational well-being of the community in its socio-ecological system. Understanding the efforts of individual citizens for environmental sustainability and in support of the vitality of their community in the small town of Chizu, Japan may help understand the potential for similar efforts in other communities