A hybrid digital parenting programme to prevent abuse of adolescents in Tanzania: study protocol for a pragmatic cluster-randomised controlled trial.

BACKGROUND: Evidence-based parenting programmes have strong evidence in preventing and mitigating violence, but in-person programmes are challenging to deliver at scale. ParentApp is an open-source, offline-first app-based adaptation of the Parenting for Lifelong Health for Parents and Teens programme to promote playful and positive parenting, reduce risks for sexual violence victimisation, and prevent violence against adolescents. This study aims to evaluate the effectiveness and cost-effectiveness of ParentApp compared to an attention-control group. METHODS: This study is a two-arm pragmatic cluster-randomised controlled trial to test whether ParentApp reduces adolescent physical abuse, emotional abuse, and sexual violence risks and victimisation at 1 month and 12 months post-intervention. Caregivers of adolescents aged 10-17 years and their adolescent children (N = 2400 caregiver-adolescent dyads) will be recruited in urban and peri-urban communities in the Mwanza region of Tanzania. A total of 80 study clusters will be stratified and randomised (1:1) to the intervention group, who will receive ParentApp with support through a WhatsApp group, or to an attention-control group, who will receive a water, sanitation, and hygiene app. Quantitative data will be collected through outcomes questionnaires with caregivers and adolescents, administered at baseline, 4 months post-baseline, and 16 months post-baseline, as well as through routine implementation data and ParentApp engagement data. Qualitative data will be collected through individual interviews and focus groups with caregivers, adolescents, and implementing partner staff. DISCUSSION: App-based interventions have the potential to expand access to evidence-based parenting support, but currently lack rigorous evidence in low- and middle-income countries. This is the first known randomised control trial of a hybrid digital parenting programme to prevent the abuse of adolescents in low- and middle-income settings. TRIAL REGISTRATION: The trial was registered on the Open Science Framework on 14 March 2023, registration: OSF.IO/T9FXZ .

The Case for Assessing and Reporting on Facilitator Fidelity: Introducing the Fidelity of Implementation in Parenting Programs Guideline.

The sizeable body of evidence indicating that parenting programs have a positive impact on children and families highlights the potential public health benefits of their implementation on a large scale. Despite evidence and global attention, beyond the highly controlled delivery of parenting programs via randomized trials, little is known about program effectiveness or how to explain the poorer results commonly observed when implemented in community settings. Researchers, practitioners, and policymakers must work together to identify what is needed to spur adoption and sustainment of evidence-based parenting programs in real-world service systems and how to enhance program effectiveness when delivered via these systems. Collecting, analyzing, and using facilitator fidelity data is an important frontier through which researchers and practitioners can contribute. In this commentary, we outline the value of assessing facilitator fidelity and utilizing the data generated from these assessments; describe gaps in research, knowledge, and practice; and recommend directions for research and practice. In making recommendations, we describe a collaborative process to develop a preliminary guideline-the Fidelity of Implementation in Parenting Programs Guideline or FIPP-to use when reporting on facilitator fidelity. Readers are invited to complete an online survey to provide comments and feedback on the first draft of the guideline. Supplementary Information: The online version contains supplementary material available at 10.1007/s43477-023-00092-5.

The Prevalence of Sexual Assault Among Higher Education Students: A Systematic Review With Meta-Analyses.

Sexual assault among higher education students has detrimental impacts on the health and educational outcomes of survivors. This systematic review aims to describe and synthesize the available quantitative evidence on sexual assault prevalence among this population. We searched Medline, EMBASE, Global Health, PsycINFO, Web of Science, ERIC, and CINAHL for studies published in English, French, Italian, and Spanish from database inception to August 2020 (updated May 2022). We screened studies using prespecified inclusion criteria for the population and context (registered higher education students), condition (self-reported sexual assault), and study design (quantitative survey). The Joanna Briggs Institute Critical Appraisal Checklist was used to assess study quality. Prevalence estimates disaggregated by type of sexual assault, gender identity, and world region were meta-analyzed using a random-effects model and reported following PRISMA guidance. We identified 131 articles, from 21 different countries. The meta-analyzed prevalence of sexual assault was 17.5% for women, 7.8% for men, and 18.1% for transgender and gender diverse people. Four types of sexual assault were identified: rape, attempted rape, forced sexual touching, and coercive sex. Forced sexual touching was the most common act experienced. The African Region had the highest prevalence estimates for women's sexual assault, and the Western Pacific region had the highest prevalence estimates for men's sexual assault. Higher education institutions, especially those outside of the United States, should commit to the implementation of surveys to monitor sexual assault prevalence and dedicate increased resources to supporting student survivors of sexual assault.

Benzothiazole Substitution Analogs of Rhodacyanine Hsp70 Inhibitors Modulate Tau Accumulation.

The accumulation and aggregation of the microtubule-associated protein tau (tau) into intracellular neuronal tangles are a hallmark of a range of progressive neurodegenerative tauopathies, including Alzheimer's disease (AD), frontotemporal dementia, Pick's disease, and progressive supranuclear palsy. The aberrant phosphorylation of tau is associated with tau aggregates in AD. Members of the heat shock protein 70 kDa (Hsp70) family of chaperones bind directly to tau and modulate tau clearance and aggregation. Small molecules that inhibit the Hsp70 family of chaperones have been shown to reduce the accumulation of tau, including phosphorylated tau. Here, eight analogs of the rhodacyanine inhibitor, JG-98, were synthesized and evaluated. Like JG-98, many of the compounds inhibited ATPase activity of the cytosolic heat shock cognate 70 protein (Hsc70) and reduced total, aggregated, and phosphorylated tau accumulation in cultured cells. Three compounds, representing divergent clogP values, were evaluated for in vivo blood-brain barrier penetration and tau reduction in an ex vivo brain slice model. AL69, the compound with the lowest clogP and the lowest membrane retention in a parallel artificial membrane permeability assay (PAMPA), reduced phosphorylated tau accumulation. Our results suggest that benzothiazole substitutions of JG-98 that increase hydrophilicity may increase the efficacy of these Hsp70 inhibitors to reduce phosphorylated tau.

Differences in Merkel Cell Carcinoma Presentation and Outcomes Among Racial and Ethnic Groups.

Importance: Racial and ethnic differences in skin cancer outcomes are understudied. Delineating these differences in Merkel cell carcinoma (MCC) is needed to better understand this rare disease. Objective: To determine how MCC presentation and outcomes differ across racial and ethnic groups. Design, Setting, and Participants: This retrospective cohort study included patients diagnosed with MCC and followed up from 2000 through 2018 in the 18 population-based cancer registries of the National Cancer Institute's Surveillance, Epidemiology, and End Results Program. Patients without follow-up data were excluded. Data analysis occurred from March 12 to November 30, 2022. Main Outcomes and Measures: A Cox proportional hazards regression was conducted to determine associations between demographic variables (race and ethnicity, age, sex, and income) and clinical variables (stage at diagnosis, primary site, and diagnosis year) with MCC-specific survival. Results: Of the 9557 patients with MCC identified (6758 [70.7%] aged ≥70 years; 6008 [62.9%] male), 222 (2.3%) were Asian American or Pacific Islander, 146 (1.5%) Black, 541 (5.7%) Hispanic, and 8590 (89.9%) White. Hispanic patients had improved MCC-specific survival compared with White patients (hazard ratio, 0.82; 95% CI, 0.67-0.99; P = .04). Black patients had the lowest MCC-specific survival, but it was not statistically different from White patients (hazard ratio, 1.19; 95% CI, 0.86-1.60; P = .28). Hispanic and Black patients were less likely to present with a primary site of the head and neck than White patients (183 of 541 [33.8%] Hispanic patients and 45 of 146 [30.8%] Black patients vs 3736 of 8590 [43.5%] White patients; P < .001 and P = .002, respectively). Black patients presented more often than White patients with advanced disease at diagnosis (59 of 146 [40.4%] vs 2510 of 8590 [29.2%]; P = .004). Conclusions and Relevance: In this cohort study, there were differences between racial and ethnic groups in observed MCC outcomes and disease characteristics. Further investigations are warranted into the findings that, compared with White patients, Hispanic patients with MCC had improved outcomes and Black patients did not have worse outcomes despite presenting with more advanced disease.

Quantitative differentiation of benign and misfolded glaucoma-causing myocilin variants on the basis of protein thermal stability.

Accurate predictions of the pathogenicity of mutations associated with genetic diseases are key to the success of precision medicine. Inherited missense mutations in the myocilin (MYOC) gene, within its olfactomedin (OLF) domain, constitute the strongest genetic link to primary open-angle glaucoma via a toxic gain of function, and thus MYOC is an attractive precision-medicine target. However, not all mutations in MYOC cause glaucoma, and common variants are expected to be neutral polymorphisms. The Genome Aggregation Database (gnomAD) lists ∼100 missense variants documented within OLF, all of which are relatively rare (allele frequency <0.001%) and nearly all are of unknown pathogenicity. To distinguish disease-causing OLF variants from benign OLF variants, we first characterized the most prevalent population-based variants using a suite of cellular and biophysical assays, and identified two variants with features of aggregation-prone familial disease variants. Next, we considered all available biochemical and clinical data to demonstrate that pathogenic and benign variants can be differentiated statistically based on a single metric: the thermal stability of OLF. Our results motivate genotyping MYOC in patients for clinical monitoring of this widespread, painless and irreversible ocular disease.

The development, reliability, and validity of the Facilitator Assessment Tool: An implementation fidelity measure used in Parenting for Lifelong Health for Young Children.

BACKGROUND: The Parenting for Lifelong Health for Young Children (PLH-YC) programme aims to reduce violence against children and child behaviour problems among families in low- and middle-income countries (LMICs). Although the programme has been tested in four randomised controlled trials and delivered in over 25 countries, there are gaps in understanding regarding the programme's implementation fidelity and, more generally, concerning the implementation fidelity of parenting programmes in LMICs. AIMS: This study aims to address these gaps by examining the psychometric properties of the PLH-YC-Facilitator Assessment Tool (FAT)-an observational tool used to measure the competent adherence of PLH-YC facilitators. Examining the psychometric properties of the FAT is important in order to determine whether there is an association between facilitator competent adherence and programme outcomes and, if correlated, to improve facilitator performance. It is also important to develop the implementation literature among parenting interventions in LMICs. METHODS: The study examined the content validity, intra-rater reliability, and inter-rater reliability of the FAT. Revision of the tool was based on consultation with programme trainers, experts, and assessors. A training curriculum and assessment manual was created. Assessors were trained in Southeastern Europe and their assessments of facilitator delivery were analysed as part of a large-scale factorial experiment (N = 79 facilitators). RESULTS: The content validity process with PLH-YC trainers, experts, and assessors resulted in substantial improvements to the tool. Analyses of percentage agreements and intraclass correlations found that, even with practical challenges, assessments were completed with adequate yet not strong intra- and inter-rater reliability. CONCLUSIONS: This study contributes to the literature on the implementation of parenting programmes in LMICs. The study found that the FAT appears to capture its intended constructs and can be used with an acceptable degree of consistency. Further research on the tool's reliability and validity-specifically, its internal consistency, construct validity, and predictive validity-is recommended.

Challenges documenting racial disparities in Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine skin cancer that predominantly impacts White patients. Overall incidence and the proportion of minority patients with MCC are both rising. In the more common skin cancer, melanoma, racial disparities are well-documented in stage at presentation and patient survival. Whether racial and ethnic disparities exist in MCC remains unclear. The study of MCC disparities is hampered by limitations in data registries, including SEER and NCDB, and an evolving natural history due to the advent of immunotherapy. Published MCC immunotherapy clinical trials consistently reported the racial diversity among enrolled subjects but failed to include patients' ethnicities. Efforts to improve data capture in cancer registries and create multi-institutional clinical databases will allow for more effective study of racial and ethnic disparities in rare cancers like MCC. Such studies are needed to advance policies promoting equity in care.

Calcium dysregulation potentiates wild-type myocilin misfolding: implications for glaucoma pathogenesis.

Myocilin is secreted from trabecular meshwork cells to an eponymous extracellular matrix that is critical for maintaining intraocular pressure. Missense mutations found in the myocilin olfactomedin domain (OLF) lead to intracellular myocilin misfolding and are causative for the heritable form of early-onset glaucoma. The OLF domain contains a unique internal, hetero-dinuclear calcium site. Here, we tested the hypothesis that calcium dysregulation causes wild-type (WT) myocilin misfolding reminiscent of that observed for disease variants. Using two cellular models expressing WT myocilin, we show that the Ca2+ ATPase channel blocker thapsigargin inhibits WT myocilin secretion. Intracellular WT myocilin is at least partly insoluble and aggregated in the endoplasmic reticulum (ER), and stains positively with an amyloid dye. By comparing the effect of thapsigargin on WT myocilin to that on a de novo secretion-competent Ca2+-free variant D478S, we discern that non-secretion of WT myocilin is due initially to calcium dysregulation, and is potentiated further by resultant ER stress. In E. coli, depletion of calcium leads to recombinant expression of misfolded isolated WT OLF but the D478S variant is still produced as a folded monomer. Treatment of cells expressing a double mutant composed of D478S and either disease variants P370L or Y437H with thapsigargin promotes its misfolding and aggregation, demonstrating the limits of D478S to correct secretion defects. Taken together, the heterodinuclear calcium site is a liability for proper folding of myocilin. Our study suggests a molecular mechanism by which WT myocilin misfolding may contribute broadly to glaucoma-associated ER stress. This study explores the effect of calcium depletion on myocilin olfactomedin domain folding.

Acne treatment review and future perspectives.

Acne affects approximately 9% of people worldwide and is the most common skin condition in the USA. There are abundant topical and oral treatment options available for patients with acne. First-line agents include topical retinoids, azelaic acid, benzoyl peroxide, and combinations of these agents. For recalcitrant or more severe acne, oral medications, including oral antibiotics, isotretinoin, or hormonal therapy, may be considered. This review will also discuss the many advances being made in the treatment of acne vulgaris, from the development of microencapsulated medications to targeted treatments.

Risk and Protective Factors for Men's Sexual Violence Against Women at Higher Education Institutions: A Systematic and Meta-Analytic Review of the Longitudinal Evidence.

Sexual violence among higher education institution (HEI) students is a growing public health concern. To date, there is little evidence on how to effectively prevent sexual violence among this demographic. This study is the first systematic review to meta-analyze all available evidence for risk and protective factors of sexual violence perpetrated by men at HEIs. We searched four electronic databases and multiple gray literature sources. We screened studies using prespecified selection criteria for the sample (HEI students who identify as men), outcome (sexual violence perpetration against peers), and study design (quantitative and longitudinal). Longitudinal studies provide the most rigorous available evidence on risk and protective factors. We identified 16 studies and meta-analyzed eight different risk factors: alcohol consumption, hostility toward women, delinquency, fraternity membership, history of sexual violence perpetration, rape myth acceptance, age at first sex, and peer approval of sexual violence. We deemed included studies to have a varied risk of bias and the overall quality of evidence to range from moderate to high. History of sexual violence perpetration (perpetration prior to entering an HEI) emerged as the strongest predictor of sexual violence perpetration at HEIs, complicating the notion that HEI environments themselves foster a culture of sexual violence. Peer support for sexual violence predicted perpetration while individual rape-supporting beliefs did not. Our findings suggest that interventions targeting peer norms (e.g., bystander interventions) and early sexual violence prevention and consent interventions for high school and elementary school students could be effective in reducing and preventing sexual violence at HEIs.

Rationale and design of the preserved versus reduced ejection fraction biomarker registry and precision medicine database for ambulatory patients with heart failure (PREFER-HF) study.

INTRODUCTION: Patients with heart failure (HF) are classically categorised by left ventricular ejection fraction (LVEF). Efforts to predict outcomes and response to specific therapy among LVEF-based groups may be suboptimal, in part due to the underlying heterogeneity within clinical HF phenotypes. A multidimensional characterisation of ambulatory patients with and without HF across LVEF groups is needed to better understand and manage patients with HF in a more precise manner. METHODS AND ANALYSIS: To date, the first cohort of 1313 out of total planned 3000 patients with and without HF has been enroled in this single-centre, longitudinal observational cohort study. Baseline and 1-year follow-up blood samples and clinical characteristics, the presence and duration of comorbidities, serial laboratory, echocardiographic data and images and therapy information will be obtained. HF diagnosis, aetiology of disease, symptom onset and clinical outcomes at 1 and 5 years will be adjudicated by a team of clinicians. Clinical outcomes of interest include all-cause mortality, cardiovascular mortality, all-cause hospitalisation, cardiovascular hospitalisation, HF hospitalisation, right-sided HF and acute kidney injury. Results from the Preserved versus Reduced Ejection Fraction Biomarker Registry and Precision Medicine Database for Ambulatory Patients with Heart Failure (PREFER-HF) trial will examine longitudinal clinical characteristics, proteomic, metabolomic, genomic and imaging data to better understand HF phenotypes, with the ultimate goal of improving precision medicine and clinical outcomes for patients with HF. ETHICS AND DISSEMINATION: Information gathered in this research will be published in peer-reviewed journals. Written informed consent for PREFER-HF was obtained from all participants. All study procedures were approved by the Mass General Brigham Institutional Review Board in Boston, Massachusetts and performed in accordance with the Declaration of Helsinki (Protocol Number: 2016P000339). TRIAL REGISTRATION NUMBER: PREFER-HF ClinicalTrials.gov identifier: NCT03480633.

Molecular architecture and modifications of full-length myocilin.

Myocilin, a modular multidomain protein, is expressed broadly in the human body but is best known for its presence in the trabecular meshwork extracellular matrix, and myocilin misfolding is associated with glaucoma. Despite progress in comprehending the structure and misfolding of the myocilin olfactomedin domain, the structure and function of full-length myocilin, and contextual changes in glaucoma, remain unknown. Here we expressed and purified milligram-scale quantities of full-length myocilin from suspension mammalian cell culture (Expi293F), enabling molecular characterization in detail not previously accessible. We systematically characterized disulfide-dependent and -independent oligomerization as well as confirmed glycosylation and susceptibility to proteolysis. We identified oligomeric states with glycosylation sites that are inaccessible to enzymatic removal. Low-resolution single particle 2D class averaging from conventional transmission electron microscopy imaging confirms an extended arrangement of tetramers, truncated products consistent with dimers, and a higher-ordered state consistent with octamer. Taken together, our study reveals new myocilin misfolded states and layers of intrinsic heterogeneity, expands our knowledge of olfactomedin-family proteins and lays the foundation for a better molecular understanding of myocilin structure and its still enigmatic biological function.

Measures of Facilitator Competent Adherence Used in Parenting Programs and Their Psychometric Properties: A Systematic Review.

Implementation fidelity is a critical component of intervention science, which aims to understand how interventions unfold in practice to improve outcomes. A key element of fidelity is facilitator competent adherence-the extent to which a program is delivered as prescribed with the specified level of quality. We conducted a two-part systematic review examining these aspects in parenting programs aiming to reduce child behavior problems and maltreatment. Part One reviews measures of facilitator competent adherence and Part Two examines the psychometric properties of the observational measures found. Searches identified 9153 articles from electronic databases, citation tracking, and expert input. After screening using pre-specified criteria, 156 (Part One) and 41 (Part Two) articles remained. In Part One, measure, facilitator, and intervention characteristics were extracted and synthesized from 65 measures. Most measures were observational, used by facilitators and researchers, and employed Likert-scale ratings. In Part Two, evidence on the reliability (internal consistency, inter-rater, intra-rater, test-retest) and validity (content, construct, convergent/divergent, criterion) of 30 observational measures identified from Part One was synthesized and evaluated. An adapted COSMIN checklist was used to assess study and measure quality. We found most studies to be of reasonably high quality. This is the first review to summarize and critically appraise measures of facilitator competent adherence used in the parenting program literature and establish their psychometric properties. The findings underscore the need to advance research on measures of facilitator competent adherence; reliable, valid, and high-quality implementation measures allow for evidence-based decisions regarding the delivery and scale-up of parenting programs. PROSPERO Registration Number: CRD42020167872.

A mixed methods evaluation of the large-scale implementation of a school- and community-based parenting program to reduce violence against children in Tanzania: a study protocol.

BACKGROUND: Despite the rapid dissemination of parenting programs aiming to reduce and prevent violence against children (VAC) worldwide, there is limited knowledge about and evidence of the implementation of these programs at scale. This study addresses this gap by assessing the quality of delivery and impact of an evidence-based parenting program for parents/caregivers and their adolescent girls aged 9 to 14-Parenting for Lifelong Health Teens (PLH-Teens), known locally as Furaha Teens-on reducing VAC at scale in Tanzania. The study will explore participating family and staff perspectives on program implementation and examine factors associated with implementation and how implementation quality is associated with intervention outcomes when the program is delivered to approximately 50,000 parent-child dyads (N = 100,000) in schools and community centers across eight districts of Tanzania. METHODS: This mixed-methods study will answer the following research questions: (1) what is the implementation quality and fidelity of PLH-Teens at scale in Tanzania; (2) what factors are associated with the quality of delivery and implementation fidelity of PLH-Teens; (3) how are implementation quality and fidelity associated with intervention outcomes; (4) what are participant and implementing staff perspectives on the acceptability, appropriateness, feasibility, benefits, and challenges of delivering PLH-Teens in their schools and communities; (5) what is the impact of PLH-Teens on VAC and participant well-being; and (6) how much does it cost to deliver PLH-Teens at scale? Qualitative and quantitative data will be collected directly from implementers, parents/caregivers, and adolescents using pre-post questionnaires, observational assessments, cost surveys, focus groups, and interviews. Qualitative data will be analyzed thematically with the aid of NVIVO software. Quantitative data will be cleaned and analyzed using methods such as correlation, regression, and structural equation models using Stata and R. COREQ and TREND guidelines will be used, where appropriate. DISCUSSION: Findings will provide vital insights into some of the factors related to quality implementation at scale. Lessons learned regarding the implementation of PLH-Teens at scale will be applied in Tanzania, and also in the delivery of PLH parenting programs globally.

The Science of Scale for Violence Prevention: A New Agenda for Family Strengthening in Low- and Middle-Income Countries.

Ending all violence against children by 2030 is a core part of Sustainable Development Goals 5 and 16. A number of promising violence reduction strategies have been identified in research studies. However, we lack an understanding of the implementation and impact of these programs in respect to their delivery at a large scale or within existing service systems, particularly in low- and middle-income countries (LMICs). We advocate for greater collaboration between researchers, policymakers, donors, governments, non-governmental organizations, and program managers and staff to study how violence prevention programs operate on a large scale. We describe a new initiative aiming to foster such collaborations in the field of family strengthening programs.

A Systematic Review of Caregiver-Implemented Functional Analyses.

The purpose of this systematic review was to systematically locate and analyze the research on caregiver-implemented functional analyses and subsequent function-based interventions. We included 36 studies and examined multiple features of the studies, including participant demographics, functional analysis characteristics, intervention characteristics, procedural fidelity, risks of bias, and social validity. Overall, the studies showed that caregivers were able to implement functional analyses that yielded differential responding, although few studies reported procedural fidelity data. Caregivers were also able to implement function-based interventions that led to socially significant changes in challenging behavior. Implications for practice and future research are discussed.

Stable calcium-free myocilin olfactomedin domain variants reveal challenges in differentiating between benign and glaucoma-causing mutations.

Nonsynonymous gene mutations can be beneficial, neutral, or detrimental to the stability, structure, and biological function of the encoded protein, but the effects of these mutations are often not readily predictable. For example, the ß-propeller olfactomedin domain of myocilin (mOLF) exhibits a complex interrelationship among structure(s), stability, and aggregation. Numerous mutations within mOLF are linked to glaucoma; the resulting variants are less stable, aggregation-prone, and sequestered intracellularly, causing cytotoxicity. Here, we report the first stable mOLF variants carrying substitutions in the calcium-binding site that exhibit solution characteristics indistinguishable from those of glaucoma variants. Crystal structures of these stable variants at 1.8-2.0-Å resolution revealed features that we could not predict by molecular dynamics simulations, including loss of loop structure, helix unwinding, and a blade shift. Double mutants that combined a stabilizing substitution and a selected glaucoma-causing single-point mutant rescued in vitro folding and stability defects. In the context of full-length myocilin, secretion of stable single variants was indistinguishable from that of the WT protein, and the double mutants were secreted to varying extents. In summary, our finding that mOLF can tolerate particular substitutions that render the protein stable despite a conformational switch emphasizes the complexities in differentiating between benign and glaucoma-causing variants and provides new insight into the possible biological function of myocilin.

Spermidine/spermine-N1-acetyltransferase ablation impacts tauopathy-induced polyamine stress response.

BACKGROUND: Tau stabilizes microtubules; however, in Alzheimer's disease (AD) and tauopathies, tau becomes hyperphosphorylated, aggregates, and results in neuronal death. Our group recently uncovered a unique interaction between polyamine metabolism and tau fate. Polyamines exert an array of physiological effects that support neuronal function and cognitive processing. Specific stimuli can elicit a polyamine stress response (PSR), resulting in altered central polyamine homeostasis. Evidence suggests that elevations in polyamines following a short-term stressor are beneficial; however, persistent stress and subsequent PSR activation may lead to maladaptive polyamine dysregulation, which is observed in AD, and may contribute to neuropathology and disease progression. METHODS: Male and female mice harboring tau P301L mutation (rTg4510) were examined for a tau-induced central polyamine stress response (tau-PSR). The direct effect of tau-PSR byproducts on tau fibrillization and oligomerization were measured using a thioflavin T assay and a N2a split superfolder GFP-Tau (N2a-ssGT) cell line, respectively. To therapeutically target the tau-PSR, we bilaterally injected caspase 3-cleaved tau truncated at aspartate 421 (AAV9 Tau ΔD421) into the hippocampus and cortex of spermidine/spermine-N1-acetyltransferase (SSAT), a key regulator of the tau-PSR, knock out (SSAT-/-), and wild type littermates, and the effects on tau neuropathology, polyamine dysregulation, and behavior were measured. Lastly, cellular models were employed to further examine how SSAT repression impacted tau biology. RESULTS: Tau induced a unique tau-PSR signature in rTg4510 mice, notably in the accumulation of acetylated spermidine. In vitro, higher-order polyamines prevented tau fibrillization but acetylated spermidine failed to mimic this effect and even promoted fibrillization and oligomerization. AAV9 Tau ΔD421 also elicited a unique tau-PSR in vivo, and targeted disruption of SSAT prevented the accumulation of acetylated polyamines and impacted several tau phospho-epitopes. Interestingly, SSAT knockout mice presented with altered behavior in the rotarod task, the elevated plus maze, and marble burying task, thus highlighting the impact of polyamine homeostasis within the brain. CONCLUSION: These data represent a novel paradigm linking tau pathology and polyamine dysfunction and that targeting specific arms within the polyamine pathway may serve as new targets to mitigate certain components of the tau phenotype.