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Abstract Medulla Tetrapanacis (MT) is a commonly used herbal ingredient in soup to promote lactation and management of mastitis among lactating mothers worldwide, particularly in Asian countries. However, scientific evidence to support its usage in the management of mastitis is limited. This study aimed to investigate the effects of MT water extract and its underlying mechanisms in Staphylococcus aureus (SA)–induced mastitis in human mammary epithelial cells (HuMEC) and lipopolysaccharide (LPS)–induced mastitis in lactating Sprague–Dawley (SD) rats. The anti‐inflammatory and antibacterial effects of MT water extract were examined in SA‐infected HuMEC by ELISA and plate counting, respectively. The effects of MT water extract on blood‐milk barrier and the underlying mechanism of action of the MT water extract were also investigated by transendothelial electrical resistance assay and western blot. The effects and mechanisms of MT water extract on alleviating mastitis on SD rats were evaluated using LPS‐induced mastitis rat model. Our results showed that MT water extract could suppress SA‐induced mastitis by reducing SA internalization and growth, protecting blood‐milk barrier integrity, and attenuating release of cytokines (interleukin 6 [IL‐6] and tumor necrosis factor‐alpha [TNF‐α]) in HuEMC. Furthermore, the antibacterial effect might be related to the increase of antimicrobial peptides transcription, and the anti‐inflammatory effect is at least partly mediated by inactivation of p38 and JNK signaling pathways. Finally, our in vivo results showed that MT water extract ameliorated LPS‐induced mastitis in SD rats via suppressing inflammatory cytokine release (TNF‐α, IL‐6, and interleukin‐1 beta), myeloperoxidase, and alleviating pathohistological damage by downregulation of JNK signaling pathway.

The genus Sarocladium comprises fungal species closely related to Acremonium, with S. kiliense and S. strictum being medically important. These species can cause infections in both immunocompetent and immunocompromised individuals. The current detection methods are limited, prompting the need for rapid and specific diagnostic tools. We developed a colorimetric loop-mediated isothermal amplification (LAMP) assay targeting S. kiliense (SK-LAMP). The initial prototype assay faced challenges with cross-reactivities with closely related species. To address this, we incorporated two additives, pullulan and tetramethylammonium chloride (TMAC), which are known to reduce non-specific signals in amplification assays. Our study found that a combination of 1% (v/v) pullulan and 0.03 M TMAC enhanced the specific detection of S. kiliense in a 45 min reaction, without non-specific false-positive results for other fungal species. This optimised LAMP assay demonstrated high sensitivity and specificity, offering a reliable and rapid method for detecting S. kiliense. The novel approach of combining additives to enhance assay specificity presents a promising strategy for improving LAMP assays targeting closely related fungal species. This advancement can aid in the timely diagnosis and management of infections caused by S. kiliense, contributing to better patient outcomes and infection control.

While mangrove ecosystems are rich in biodiversity, they are increasingly impacted by climate change and urban pollutants. The current study provides first insights into the emergence of potentially pathogenic yeasts in Hong Kong’s mangroves. Sediment and water samples were collected from ten urban and rural mangroves sites. Initial CHROMagarTM Candida Plus screening, representing the first application of this differential medium for water and soil samples collected from a non-clinical environment, enabled the rapid, preliminary phenotypic identification of yeast isolates from mangroves. Subsequent molecular profiling (ITS and/or 28S nrDNA sequencing) and antifungal drug susceptibility tests were conducted to further elucidate yeast diversity and drug resistance. A diversity of yeasts, including 45 isolates of 18 distinct species across 13 genera/clades, was isolated from sediments and waters from Hong Kong mangroves. Molecular profiling revealed a dominance of the Candida/Lodderomyces clade (44.4%), a group of notorious opportunistic pathogens. The findings also reveal a rich biodiversity of non-Candida/Lodderomyces yeasts in mangroves, including the first reported presence of Apiotrichum domesticum and Crinitomyces flavificans. A potentially novel Yamadazyma species was also discovered. Remarkably, 14.3% of the ubiquitous Candida parapsilosis isolates displayed resistance to multiple antifungal drugs, suggesting that mangroves may be reservoirs of multi-drug resistance. Wildlife, especially migratory birds, may disseminate these hidden threats. With significant knowledge gaps regarding the environmental origins, drug resistance, and public health impacts of pathogenic yeasts, urgent surveillance is needed from a One Health perspective. This study provides an early warning that unrestrained urbanization can unleash resistant pathogens from coastal ecosystems globally. It underscores the necessity for enhanced surveillance studies and interdisciplinary collaboration between clinicians, ornithologists, and environmental microbiologists to effectively monitor and manage this environmental health risk, ensuring the maintenance of ‘One Health’.

Abstract Background Chronic obstructive pulmonary disease (COPD) is the third leading cause of death globally. COPD patients with cachexia or weight loss have increased risk of death independent of body mass index (BMI) and lung function. We tested the hypothesis genetic variation is associated with weight loss in COPD using a genome‐wide association study approach. Methods Participants with COPD (N = 4308) from three studies (COPDGene, ECLIPSE, and SPIROMICS) were analysed. Discovery analyses were performed in COPDGene with replication in SPIROMICS and ECLIPSE. In COPDGene, weight loss was defined as self‐reported unintentional weight loss > 5% in the past year or low BMI (BMI

The genus Sarocladium comprises fungal species closely related to Acremonium, with S. kiliense and S. strictum being medically important. These species can cause infections in both immunocompetent and immunocompromised individuals. The current detection methods are limited, prompting the need for rapid and specific diagnostic tools. We developed a colorimetric loop-mediated isothermal amplification (LAMP) assay targeting S. kiliense (SK-LAMP). The initial prototype assay faced challenges with cross-reactivities with closely related species. To address this, we incorporated two additives, pullulan and tetramethylammonium chloride (TMAC), which are known to reduce non-specific signals in amplification assays. Our study found that a combination of 1% (v/v) pullulan and 0.03 M TMAC enhanced the specific detection of S. kiliense in a 45 min reaction, without non-specific false-positive results for other fungal species. This optimised LAMP assay demonstrated high sensitivity and specificity, offering a reliable and rapid method for detecting S. kiliense. The novel approach of combining additives to enhance assay specificity presents a promising strategy for improving LAMP assays targeting closely related fungal species. This advancement can aid in the timely diagnosis and management of infections caused by S. kiliense, contributing to better patient outcomes and infection control. [ABSTRACT FROM AUTHOR]

While mangrove ecosystems are rich in biodiversity, they are increasingly impacted by climate change and urban pollutants. The current study provides first insights into the emergence of potentially pathogenic yeasts in Hong Kong's mangroves. Sediment and water samples were collected from ten urban and rural mangroves sites. Initial CHROMagarTM Candida Plus screening, representing the first application of this differential medium for water and soil samples collected from a non-clinical environment, enabled the rapid, preliminary phenotypic identification of yeast isolates from mangroves. Subsequent molecular profiling (ITS and/or 28S nrDNA sequencing) and antifungal drug susceptibility tests were conducted to further elucidate yeast diversity and drug resistance. A diversity of yeasts, including 45 isolates of 18 distinct species across 13 genera/clades, was isolated from sediments and waters from Hong Kong mangroves. Molecular profiling revealed a dominance of the Candida/Lodderomyces clade (44.4%), a group of notorious opportunistic pathogens. The findings also reveal a rich biodiversity of non-Candida/Lodderomyces yeasts in mangroves, including the first reported presence of Apiotrichum domesticum and Crinitomyces flavificans. A potentially novel Yamadazyma species was also discovered. Remarkably, 14.3% of the ubiquitous Candida parapsilosis isolates displayed resistance to multiple antifungal drugs, suggesting that mangroves may be reservoirs of multi-drug resistance. Wildlife, especially migratory birds, may disseminate these hidden threats. With significant knowledge gaps regarding the environmental origins, drug resistance, and public health impacts of pathogenic yeasts, urgent surveillance is needed from a One Health perspective. This study provides an early warning that unrestrained urbanization can unleash resistant pathogens from coastal ecosystems globally. It underscores the necessity for enhanced surveillance studies and interdisciplinary collaboration between clinicians, ornithologists, and environmental microbiologists to effectively monitor and manage this environmental health risk, ensuring the maintenance of 'One Health'. [ABSTRACT FROM AUTHOR]

Abstract The KRAS oncogene drives many common and highly fatal malignancies. These include pancreatic, lung, and colorectal cancer, where various activating KRAS mutations have made the development of KRAS inhibitors difficult. Here we identify the scaffold protein SH3 and multiple ankyrin repeat domain 3 (SHANK3) as a RAS interactor that binds active KRAS, including mutant forms, competes with RAF and limits oncogenic KRAS downstream signalling, maintaining mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) activity at an optimal level. SHANK3 depletion breaches this threshold, triggering MAPK/ERK signalling hyperactivation and MAPK/ERK-dependent cell death in KRAS-mutant cancers. Targeting this vulnerability through RNA interference or nanobody-mediated disruption of the SHANK3–KRAS interaction constrains tumour growth in vivo in female mice. Thus, inhibition of SHANK3–KRAS interaction represents an alternative strategy for selective killing of KRAS-mutant cancer cells through excessive signalling.

In the past decade, the use of immune checkpoint therapy (ICT) has increased across many malignancies, including metastatic renal cell carcinoma as an option for frontline and subsequent lines of therapy. Despite the many therapeutic benefits of ICT, its use is complicated by the potential risk of immune-related adverse events (irAEs). One rare but potentially life-threatening irAE is hemophagocytic lymphohistiocytosis (HLH). HLH is a systemic inflammatory disorder resulting in multiorgan failure. The diagnosis of HLH is a challenge due to nonspecific symptoms and overlap with other systemic conditions, which can lead to delays in receiving appropriate treatment and potentially poor patient outcomes. This case illustrates the management of HLH caused by nivolumab plus ipilimumab combination therapy through the use of corticosteroids and tocilizumab in a patient with metastatic clear cell renal cell carcinoma.

Abstract Belief in powerful supernatural agents that enforce moral norms has been theoretically linked with cooperative altruism and prosociality. Correspondingly, prior research reveals an implicit association between atheism and extreme antisociality (e.g., serial murder). However, findings centered on associations between lack of faith and moral transgression do not directly address the hypothesized conceptual association between religious belief and prosociality. Accordingly, we conducted two pre-registered experiments depicting a “serial helper” to assess biases related to extraordinary helpfulness, mirroring designs depicting a serial killer used in prior cross-cultural work. In both a predominantly religious society (the U.S., Study 1) and a predominantly secular society (New Zealand, Study 2), we successfully replicated previous research linking atheism with transgression, and obtained evidence for a substantially stronger conceptual association between religiosity and virtue. The results suggest that stereotypes linking religiosity with prosociality are both real and global in scale.

Background This study explored the lived experiences and perspectives of women who had suffered a perinatal loss in Nairobi county, Kenya. Existing research works have established that perinatal loss often comes with a significant psychosocial burden, which has been made worse by negative cultural beliefs and practices. Despite this, perinatal loss grieving is rarely recognised or socially legitimated in many countries. This study aimed to shed light on the experiences of bereaved women to come up with effective interventions and combat the stigma associated with perinatal loss.Methods The study used a qualitative research design employing a descriptive phenomenological approach targeting women of reproductive age who had experienced perinatal loss within the previous 3 years. The study was conducted in three subcounties of Nairobi. Purposive sampling was used to identify and recruit 22 women to participate in focus group discussions. After the discussions, the audio recordings were transcribed, translated and analysed thematically. Triangulation was then done per thematic area to allow for a deeper understanding of the experiences and perceptions of the study participants.Results The research identified 3 themes and 7 subthemes: (1) ‘Psychosocial challenges of perinatal loss’ with five subthemes;—‘Emotional trauma and grief’, ‘Multiple losses and reproductive pressure’, ‘Broken relationships,’ ‘Violence and abuse’ and ‘Familial stigmatization’. (2) ‘Healthcare experiences.’ (3) ‘Stigma and cultural influences’ with 2 subthemes ‘Societal stigmatisation’, and ‘Cultural perceptions and norms surrounding perinatal loss’.Conclusion Women who have experienced perinatal loss often suffer psychological torture, discrimination, abuse, stigma and trauma. The findings from this study highlight the urgent need to set-up robust support systems to assist individuals coping with perinatal loss. This will require a range of interventions, including implementing trauma management programmes, training of healthcare workers, advocacy, sensitisation and establishing support networks to address discrimination and stigma faced by those affected.

Summary: Autophagosome formation initiated on the endoplasmic reticulum (ER)-associated omegasome requires LC3. Translational regulation of LC3 biosynthesis is unexplored. Here we demonstrate that LC3 mRNA is recruited to omegasomes by directly binding to the ER transmembrane Sigma-1 receptor (S1R). Cell-based and in vitro reconstitution experiments show that S1R interacts with the 3′ UTR of LC3 mRNA and ribosomes to promote LC3 translation. Strikingly, the 3′ UTR of LC3 is also required for LC3 protein lipidation, thereby linking the mRNA-3′ UTR to LC3 function. An autophagy-defective S1R mutant responsible for amyotrophic lateral sclerosis cannot bind LC3 mRNA or induce LC3 translation. We propose a model wherein S1R de-represses LC3 mRNA via its 3′ UTR at the ER, enabling LC3 biosynthesis and lipidation. Because several other LC3-related proteins use the same mechanism, our data reveal a conserved pathway for localized translation essential for autophagosome biogenesis with insights illuminating the molecular basis of a neurodegenerative disease.

Background: Treatment-Resistant Depression (TRD) is a poorly understood but prevalent clinical phenomenon that lacks a widely accepted definition, explanatory model, or set of practice recommendations. It involves a chronic form of unipolar Major Depressive Disorder (MDD) that fails to respond to at least two first-line clinical treatments. TRD affects as many as 70 % of patients who fail to respond to their first trial of antidepressant medication and 60 % of patients who fail to respond to their first phase of psychotherapy. Purpose: This qualitative study aims to develop a model for understanding the phenomenon of unipolar TRD and the practices involved in its effective treatment. Methods: This study involved a grounded theory analysis of interviews with four adult-American patients with unipolar TRD and five American providers who routinely treat such patients. Results: A model of unipolar TRD was developed, explaining common etiological and maintaining factors of unipolar TRD and offering recommendations for guiding effective treatment. Limitations: This study had a small sample size (N = 9) with limited sociodemographic diversity (all Americans; only two females; one racial/ethnic minority; no sexual minorities), which may limit its generalizability. Conclusions: Nevertheless, its emergent theory underscores the importance of TRD patients cultivating positive views of medication and psychotherapy while collaborating with their providers to obtain psychoeducation, build mindfulness/coping skills, enhance social support, and re-engage with pleasurable activities. It recommends that mental health providers focus on processing TRD patients’ subjective experiences, validating patients’ frustrations, and monitoring and calibrating patients’ expectations.

Summary: Background: Treatment-simplification strategies are important tools for patient-centred management. We evaluated long-term outcomes from a PI monotherapy switch strategy. Methods: Eligible participants attending 43 UK treatment centres had a viral load (VL) below 50 copies/ml for at least 24 weeks on combination ART. Participants were randomised to maintain ongoing triple therapy (OT) or switch to a strategy of physician-selected PI monotherapy (PI-mono) with prompt return to combination therapy if VL rebounded. The primary outcome, previously reported, was loss of future drug options after 3 years, defined as new intermediate/high level resistance to at least one drug to which the participant's virus was considered sensitive at trial entry. Here we report resistance and disease outcomes after further extended follow-up in routine care. The study was registered as ISRCTN04857074. Findings: We randomised 587 participants to OT (291) or PI-mono (296) between Nov 4, 2008, and July 28, 2010 and followed them for a median of more than 8 years (100 months) until 2018. At the end of this follow-up time, one or more future drug options had been lost in 7 participants in the OT group and 6 in the PI-mono group; estimated cumulative risk by 8 years of 2.7% and 2.1% respectively (difference −0.6%, 95% CI −3.2% to 2.0%). Only one PI-mono participant developed resistance to the protease inhibitor they were taking (atazanavir). Serious clinical events (death, serious AIDS, and serious non-AIDS) were infrequent; reported in a total of 12 (4.1%) participants in the OT group and 23 (7.8%) in the PI-mono group (P = 0.08) over the entire follow-up period. Interpretation: A strategy of PI monotherapy, with regular VL monitoring and prompt reintroduction of combination treatment following rebound, preserved future treatment options. Findings confirm the high genetic barrier to resistance of the PI drug class that makes them well suited for creative, patient-centred, treatment-simplification approaches. The possibility of a small excess risk of serious clinical events with the PI monotherapy strategy cannot be excluded. Funding: The National Institute for Health Research Health Technology Assessment programme.

Caenorhabditis elegans is an instrumental model in aging research due to its large brood size, short lifespan, and malleable genetics. However, maintaining a synchronous nematode population for longevity studies is challenging and time consuming due to their quick rate of development and reproduction. Multiple methods are employed in the field, ranging from worm strains with temperature dependent sterility to DNA replication inhibitors such as 5′-fluorodeoxyuridine (FUdR). In this study, we characterize a small molecule (C22) that impairs eggshell integrity and disrupts early embryogenesis to determine its applicability as a potential FUdR alternative. We find that C22 prevents egg hatching in a concentration dependent manner. However, it extends the lifespan of wild type worms and can induce FMO-2, a longevity regulating enzyme downstream of dietary restriction. Our results suggest that C22 is unlikely to be widely useful as an alternative to FUdR but its mechanism for lifespan extension may be worth further investigation.

Introduction: Sickle cell trait (SCT) has been associated with chronic kidney disease (CKD) in African Americans, although evidence for its impact in Africans and people with HIV is currently lacking. We conducted a cross-sectional study investigating the association between SCT and kidney disease in people of African ancestry with HIV in the UK. Methods: The primary outcome was estimated glomerular filtration rate (eGFR) 50 mg/mmol), and albuminuria (albumin-to-creatinine ratio >3 mg/mmol). Multivariable logistic regression was used to estimate the associations between SCT and kidney disease outcomes. Results: A total of 2895 participants (mean age 48.1 [SD 10.3], 57.2% female) were included, of whom 335 (11.6%) had SCT and 352 (12.2%) had eGFR

Abstract Shank proteins are major scaffolds of the postsynaptic density of excitatory synapses. Mutations in SHANK genes are associated with autism and intellectual disability. The effects of missense mutations on Shank3 function, and therefore the pathomechanisms are unclear. Several missense mutations in SHANK3 affect the N-terminal region, consisting of the Shank/ProSAP N-terminal (SPN) domain and a set of Ankyrin (Ank) repeats. Here we identify a novel SHANK3 missense mutation (p.L270M) in the Ankyrin repeats in patients with an ADHD-like phenotype. We functionally analysed this and a series of other mutations, using biochemical and biophysical techniques. We observe two major effects: (1) a loss of binding to δ-catenin (e.g. in the p.L270M variant), and (2) interference with the intramolecular interaction between N-terminal SPN domain and the Ank repeats. This also interferes with binding to the α-subunit of the calcium-/calmodulin dependent kinase II (αCaMKII), and appears to be associated with a more severe neurodevelopmental pathology.

Abstract Introduction:Choosing an appropriate electronic data capture system (EDC) is a critical decision for all randomized controlled trials (RCT). In this paper, we document our process for developing and implementing an EDC for a multisite RCT evaluating the efficacy and implementation of an enhanced primary care model for individuals with opioid use disorder who are returning to the community from incarceration. Methods:Informed by the Knowledge-to-Action conceptual framework and user-centered design principles, we used Claris Filemaker software to design and implement CRICIT, a novel EDC that could meet the varied needs of the many stakeholders involved in our study. Results:CRICIT was deployed in May 2021 and has been continuously iterated and adapted since. CRICIT’s features include extensive participant tracking capabilities, site-specific adaptability, integrated randomization protocols, and the ability to generate both site-specific and study-wide summary reports. Conclusions:CRICIT is highly customizable, adaptable, and secure. Its implementation has enhanced the quality of the study’s data, increased fidelity to a complicated research protocol, and reduced research staff’s administrative burden. CRICIT and similar systems have the potential to streamline research activities and contribute to the efficient collection and utilization of clinical research data.

Postoperative delirium (POD) represents a perioperative neurocognitive disorder that has dreaded ramifications on a patient’s recovery from surgery. Dexmedetomidine displays multiple mechanisms of neuroprotection to assist in preventing POD as a part of a comprehensive anesthetic care plan. This review will cover dexmedetomidine’s pharmacological overlap with the current etiological theories behind POD along with pre-clinical and clinical studies on POD prevention with dexmedetomidine. While the body of evidence surrounding the use of dexmedetomidine for POD prevention still requires further development, promising evidence exists for the use of dexmedetomidine in select dosing and circumstances to enhance recovery from surgery.

IntroductionUntil vaccines became available in late 2020, our ability to prevent the spread of COVID-19 within countries depended largely on voluntary adherence to mitigation measures. However, individual decision-making regarding acceptable COVID-19 risk is complex. To better understand decision-making regarding COVID-19 risk, we conducted a qualitative substudy within a larger Berkeley COVID-19 Safe Campus Initiative (BCSCI) during the summer of 2020, and completed a mixed-methods analysis of factors influencing decision-making.Materials and methodsWe interviewed 20 participants who tested positive for SARS-CoV-2 and 10 who remained negative, and analyzed quantitative survey data from 3,324 BCSCI participants. The BCSCI study enrolled university-affiliated people living in the local area during summer of 2020, collected data on behaviors and attitudes toward COVID-19, and conducted SARS-CoV-2 testing at baseline and endline.ResultsAt baseline, 1362 students (57.5%) and 285 non-students (35.1%) said it had been somewhat or very difficult to comply with COVID-19-related mandates. Most-cited reasons were the need to go out for food/essentials, difficulty of being away from family/friends, and loneliness. Eight interviewees explicitly noted they made decisions partially because of others who may be at high risk. We did not find significant differences between the behaviors of students and non-students.DiscussionDespite prevailing attitudes about irresponsibility of college students during the COVID-19 pandemic, students in our study demonstrated a commitment to making rational choices about risk behavior, not unlike non-students around them. Decision-making was driven by perceived susceptibility to severe disease, need for social interaction, and concern about risk to others. A harm reduction public health approach may be beneficial.

OBJECTIVES/GOALS: Cervical cancer is the fourth most common cancer among women worldwide, with approximately 570,000 newly diagnosed cases and 311,000 related deaths among women in 2018.In the United States, approximately 13,000 new cases of cervical cancer are diagnosed annually with approximately 4,000 women dying each year from cervical cancer. Nearly all cervical cancer is caused by oncogenic strains of the human papillomavirus (HPV). Prevention strategies to reduce cervical cancer after HPV exposure entail treatment of cervical dysplasia at the premalignant state, specifically low-grade squamous intraepithelial lesions (LSIL) and high-grade squamous intraepithelial lesions (HSIL), along with the eventual clearance of HPV.The most common treatment for persistent LSIL or HSIL is the loop electrical excisional procedure (LEEP). This procedure is unfortunately not widely available in resource-limited countries and is associated with potential significant morbidities, including decreased fertility, preterm birth, premature rupture of membranes and cervical incompetence. Despite undergoing standard of care treatment, in certain high-risk populations, specifically HIV-infected women, there is a higher rate of premalignant HPV-related cervical disease persistence, progression and recurrence.There is a paramount need for novel nonsurgical treatments to stabilize or treat precancerous lesions of the cervix and to decrease the persistence of HPV infection. Medical treatment with the natural herb curcumin may allow subjects to receive treatment of cervical lesions without undergoing a surgical procedure.Curcumin is a major active component extracted from turmeric with anti-inflammatory, anti-infectious, and anti-cancer properties.Topical intravaginal curcumin has the promise of delivering this drug directly to the site of disease, ensuring adequate concentrations at the site of disease while avoiding systemic side effects. This proposed study will determine if there are higher rates of HPV clearance after curcumin administration among women with and without HIV who have premalignant HPV-related cervical disease, specifically LSIL or recently treated (with a LEEP) HSIL. METHODS/STUDY POPULATION: We are proposing a prospective double-blind randomized control trial to investigate the utility of topical intra-vaginal curcumin in increasing rates of HPV clearance and mitigating the high rates of disease recurrence in women with and without HIV. A sample of approximately 200 women with and without HIV who have biopsy-proven LSIL or recently treated HSIL will be randomized to one of two arms: 2000 mg of curcumin powder in capsules or placebo inserted intravaginally at bedtime once weekly for 20 weeks (excluding the time of menses). Cervical cytology and HPV testing will be performed at baseline and 6 months post-randomization. If a participant has abnormal cytology or a positive high-risk HPV test 6 months post-randomization, they will be scheduled to undergo a colposcopy with biopsies of all suspicious cervical lesions. If biopsy results are HSIL or greater, subjects will be referred back to routine clinical treatment, which may include a LEEP. Clinicians performing the colposcopies and the study participants will be blinded since the placebo has the same appearance as the curcumin capsules. At the end of the study, study participants will be offered the opportunity to participate in 2-3 hour focus groups to discuss acceptability of the product as a treatment for premalignant HPV-related cervical disease until data saturation is achieved. Power and sample size calculations are based on the primary outcome of interest, which is clearance of HPV at 6 months. Basu et al (2013) documented HPV clearance in as many as 80% of subjects with topical curcumin. To account for an expected lower success rate in HIV-infected women, who will also be included in the study, we intend to power our study to determine a more conservative 20% improvement in clearance rate at 6 months with curcumin treatment, assuming an expected clearance rate of HPV in HIV-infected women of 25%. In order to detect a 20% difference of HPV clearance among those treated with intravaginal curcumin vs. placebo at 6 months, about 80 patients per arm would achieve 80% power at the 5% significance level. To account for up to 20% loss to follow-up or discontinuation, the total sample size in each arm would be 100 subjects with a total of approximately 200 subjects enrolled in both arms. RESULTS/ANTICIPATED RESULTS: We are currently in the process of collecting data for this study. We hypothesize that intravaginal curcumin will have a 20% higher rate of HPV clearance at 6 months as compared to placebo. Primary outcome measures will include clearance of HPV at 6 months in curcumin vs. placebo. Secondary outcomes measures will include recurrence of disease by either cytologic or histologic abnormality requiring further surveillance or treatment at 6 months. We also hypothesize that intravaginal curcumin administered once weekly at bedtime for 20 weeks will be safe, acceptable, and well tolerated. This is based off of previous findings from the Phase 1 trial of intravaginal curcumin that we performed. During this Phase 1 trial, we explored daily intravaginal administration of 2000 mg of curcumin to further understand curcumin’s tolerability. Our focus group participants displayed an overwhelming consensus that daily administration affected quality of life, specifically due to the yellow-colored vaginal discharge from the medication. Study participants expressed that once or twice weekly administration was more tolerable and feasible. Our proposed study would therefore test the tolerability and effects of weekly curcumin administration and its ability to clear HPV infection. The primary outcome measure will be the proportion of study participants who discontinue treatment for any reason (acceptability) and the proportion of study participants who discontinue treatment due to adverse effects (tolerability). DISCUSSION/SIGNIFICANCE OF IMPACT: Non-surgical treatments that decrease the morbidity and risk of progression of premalignant HPV-related cervical disease are greatly needed, especially in low-resource settings and among women experiencing barriers to care and/or at high risk for disease progression. Medical treatment with the natural herb curcumin is an emerging strategy that may allow subjects to receive treatment of cervical lesions without undergoing a surgical procedure.Several preclinical and clinical studies have shown curcumin’s ability to reduce tumors and precancerous lesions in animal and human cancer cells. Curcumin can suppress the activation of transcription factor NF-κB and the expression and activity of VEGF and p16INK4a, biomarkers known to be elevated in premalignant HPV-related cervical disease.Studies have also shown that curcumin alters HPV-associated molecular pathways in cancer cells, suppressing cervical cancer growth by inhibiting the transcription of oncoproteins HPV16 and HPV18 (designated as E6 and E7) and restoring p53 and retinoblastoma function. Our proposed study would therefore test the tolerability and effects of weekly curcumin administration and its ability to clear HPV infection. Our results will generate novel data as to what is an acceptable and well-tolerated dosing regimen of intravaginal curcumin, which would be crucial in designing further curcumin intervention studies. The results of our proposal will explore the effect of intravaginal curcumin as a standalone and adjuvant therapy to a LEEP among women with premalignant HPV-related cervical disease. The potential to not just excise diseased tissue, but to directly augment the clearance of the causative agent HPV, would have profound long-term ramifications in resource-limited settings and among women experiencing barriers to care and/or at high risk for disease progression.

The objective was to evaluate the association of peripheral and central hearing abilities with cognitive function in older adults.Recruited from epidemiological studies of aging and cognition at the Rush Alzheimer's Disease Center, participants were a community-dwelling cohort of older adults (range 63-98 years) without diagnosis of dementia. The cohort contained roughly equal numbers of Black (n=61) and White (n=63) subjects with groups similar in terms of age, gender, and years of education. Auditory abilities were measured with pure-tone audiometry, speech-in-noise perception, and discrimination thresholds for both static and dynamic spectral patterns. Cognitive performance was evaluated with a 12-test battery assessing episodic, semantic, and working memory, perceptual speed, and visuospatial abilities.Among the auditory measures, only the static and dynamic spectral-pattern discrimination thresholds were associated with cognitive performance in a regression model that included the demographic covariates race, age, gender, and years of education. Subsequent analysis indicated substantial shared variance among the covariates race and both measures of spectral-pattern discrimination in accounting for cognitive performance. Among cognitive measures, working memory and visuospatial abilities showed the strongest interrelationship to spectral-pattern discrimination performance.For a cohort of older adults without diagnosis of dementia, neither hearing thresholds nor speech-in-noise ability showed significant association with a summary measure of global cognition. In contrast, the two auditory metrics of spectral-pattern discrimination ability significantly contributed to a regression model prediction of cognitive performance, demonstrating association of central auditory ability to cognitive status using auditory metrics that avoided the confounding effect of speech materials.