Medicine and Health Sciences Commons^™

Candidate Interventions For Integrating Hypertension And Cardiovascular-Kidney-Metabolic Care In Primary Health Settings: Hearts 2.0 Phase 1, Andres Rosende, Mark D Huffman, Et Al.

2020-Current year OA Pubs

BACKGROUND: HEARTS in the Americas is the regional adaptation of the WHO Global HEARTS Initiative, aimed at helping countries enhance hypertension and cardiovascular disease (CVD) risk management in primary care settings. Its core implementation tool, the HEARTS Clinical Pathway, has been adopted by 28 countries. To improve the care of hypertension, diabetes, and chronic kidney disease (CKD), HEARTS 2.0 was developed as a three-phase process to integrate evidence-based interventions into a unified care pathway, ensuring consistency across fragmented guidelines. This paper focuses on Phase 1, highlighting targeted interventions to improve and update the HEARTS Clinical Pathway.

METHODS: First, the coordinating …

Cytogenetic Annotation Automation In Myelodysplastic Syndrome Research Databases, Samuel Urrutia, Kelly S Chien, Ziyi Li, Alexandre Bazinet, Guilin Tang, Guillermo Garcia-Manero

2020-Current year OA Pubs

No abstract provided.

Mechanisms Of Photoreceptor Protection Upon Targeting The Nrl-Nr2e3 Pathway, Daniel P Murphy, Alexander V Kolesnikov, Cynthia L Montana, Zaid M Khaja, Yu Liu, Vladimir J Kefalov, Joseph C Corbo

2020-Current year OA Pubs

Acute knockout of the rod photoreceptor transcription factor

Methods For Joint Modeling Of Longitudinal Omics Data And Time-To-Event Outcomes: Applications To Lysophosphatidylcholines In Connection To Aging And Mortality In The Long Life Family Study, Konstantin G Arbeev, Olivia Bagley, Svetlana V Ukraintseva, Alexander Kulminski, Eric Stallard, Michaela Schwaiger-Haber, Gary J Patti, Yian Gu, Anatoliy I Yashin, Michael A Province

2020-Current year OA Pubs

Studying the relationships between longitudinal changes in omics variables and event risks requires specific methodologies for joint analyses of longitudinal and time-to-event outcomes. We applied two such approaches (joint models [JM], stochastic process models [SPM]) to longitudinal metabolomics data from the Long Life Family Study, focusing on the understudied associations of longitudinal changes in lysophosphatidylcholines (LPCs) with mortality and aging-related outcomes. We analyzed 23 LPC species, with 5,066 measurements of each in 3,462 participants, 1,245 of whom died during follow-up. JM analyses found that higher levels of the majority of LPC species were associated with lower mortality risks, with the …

Dna Repair And The Contribution To Chemotherapy Resistance, Ksenija Nesic, Phoebe Parker, Elizabeth M Swisher, John J Krais

2020-Current year OA Pubs

The DNA damage response comprises a set of imperfect pathways that maintain cell survival following exposure to DNA damaging agents. Cancers frequently exhibit DNA repair pathway alterations that contribute to their intrinsic genome instability. This, in part, facilitates a therapeutic window for many chemotherapeutic agents whose mechanisms of action often converge at the generation of a double-strand DNA break. The development of therapy resistance occurs through countless molecular mechanisms that promote tolerance to DNA damage, often by preventing break formation or increasing repair capacity. This review broadly discusses the DNA damaging mechanisms of action for different classes of chemotherapeutics, how …

Diverse Cell Types Establish A Pathogenic Immune Environment In Peripheral Neuropathy, Julie Choi, Amy Strickland, Hui Qi Loo, Wendy Dong, Lilianne Barbar, A Joseph Bloom, Yo Sasaki, Sheng Chih Jin, Aaron Diantonio, Jeffrey Milbrandt

2020-Current year OA Pubs

Neuroinflammation plays a complex and context-dependent role in many neurodegenerative diseases. We identified a key pathogenic function of macrophages in a mouse model of a rare human congenital neuropathy in which SARM1, the central executioner of axon degeneration, is activated by hypomorphic mutations in the axon survival factor NMNAT2. Macrophage depletion blocked and reversed neuropathic phenotypes in this sarmopathy model, revealing SARM1-dependent neuroimmune mechanisms as key drivers of disease pathogenesis. In this study, we investigated the impact of chronic subacute SARM1 activation on the peripheral nerve milieu using single cell/nucleus RNA-sequencing (sc/snRNA-seq). Our analyses reveal an expansion of immune cells …

Active Transport Enables Protein Condensation In Cells, Gaurav Chauhan, Edward G Wilkinson, Yaning Yuan, Samuel R Cohen, Masayuki Onishi, Rohit V Pappu, Lucia C Strader

2020-Current year OA Pubs

Multiple factors drive biomolecular condensate formation. In plants, condensation of the transcription factors AUXIN RESPONSE FACTOR 7 (ARF7) and ARF19 attenuates response to the plant hormone auxin. Here, we report that actin-mediated movement of cytoplasmic ARF condensates enhances condensation. Coarse-grained molecular simulations of active polymers reveal that applied forces drive the associations of macromolecules to enhance phase separation while giving rise to dense phases that preferentially accumulate motile molecules. Our study highlights how molecular motility can drive phase separation, with implications for motile condensates while offering insights into cellular mechanisms that can regulate condensate dynamics.

Subcortical Correlates Of Consciousness With Human Single Neuron Recordings, Michael Pereira, Nathan Faivre, Fosco Bernasconi, Nicholas Brandmeir, Jacob E Suffridge, Kaylee Tran, Shuo Wang, Victor Finomore, Peter Konrad, Ali Rezai, Olaf Blanke

2020-Current year OA Pubs

Subcortical brain structures such as the subthalamic nucleus or the thalamus are involved in regulating motor and cognitive behavior. However, their contribution to perceptual consciousness remains unclear, due to the inherent difficulties of recording subcortical neuronal activity in humans. Here, we asked neurological patients undergoing surgery for deep brain stimulation to detect weak vibrotactile stimuli applied on their hand while recording single neuron activity from the tip of a microelectrode. We isolated putative single neurons in the subthalamic nucleus and thalamus. A significant proportion of neurons modulated their activity while participants were expecting a stimulus. We found that the firing …

A Cross-Sectional Study Of The Role Of Epithelial Cell Injury In Kidney Transplant Outcomes, Philip F. Halloran, Tarek Alhamad, Et Al.

2020-Current year OA Pubs

BACKGROUND: Expression of acute kidney injury-associated (AKI-associated) transcripts in kidney transplants may reflect recent injury and accumulation of epithelial cells in "failed repair" states. We hypothesized that the phenomenon of failed repair could be associated with deterioration and failure in kidney transplants.

METHODS: We defined injury-induced transcriptome states in 4,502 kidney transplant biopsies injury-induced gene sets and classifiers previously developed in transplants.

RESULTS: In principal component analysis (PCA), PC1 correlated with both acute and chronic kidney injury and related inflammation and PC2 with time posttransplant. Positive PC3 was a dimension that correlated with epithelial remodeling pathways and anticorrelated with inflammation. …

Treatment Of Overactive Katp Channels With Glibenclamide In A Zebrafish Model And A Clinical Trial In Humans With Cantú Syndrome, Lotte Kleinendorst, Sarah E Siegelaar, Helen I Roessler, Lema Meiwand, Malou Van Den Boogaard, Rianne H A C M De Bruin-Bon, Kirsten F Van Duinen, R Nils Planken, Elisabeth H Jaspars, Patrick M J H Kemperman, Berto J Bouma, Colin G Nichols, Marcel W Bekkenk, Gijs W Van Haaften, Mieke M Van Haelst

2020-Current year OA Pubs

This study explores the efficacy of glibenclamide, a K

Patient-Reported Social Determinants Of Health In Patients With Heart Failure, Kenneth E Freedland, Brian C Steinmeyer, Judith A Skala, Robert M Carney, Michael W Rich

2020-Current year OA Pubs

BACKGROUND: Social determinants of health (SDOH) complicate medical care and affect clinical outcomes, but the lack of a reliable structured interview for medical patients has impeded clinical assessment and research on SDOH. We assessed the reliability and validity of a newly developed SDOH Patient Interview Form and investigated SDOH in patients with heart failure.

METHODS: The SDOH Patient Interview Form was administered to recently hospitalized patients with heart failure between January 2021 and April 2024. The interviews were recorded, and 50 were randomly selected for the interrater reliability analysis.

RESULTS: The sample included 367 participants (mean age, 61.2±12.1 years; 42.5% …

Rationale And Design Of The Repeat Trial: A Multicenter Randomized Trial Comparing Redo Surgical Aortic Valve Replacement To Valve-In-Valve Transcatheter Aortic Valve Replacement, Matthias Raschpichler, Suzanne De Waha, Stefan Blankenberg, Marcio A Diniz, Emilia Bagiella, Annetine C Gelijns, Vinicius F Calsavara, Aakriti Gupta, Niklas Schofer, Tsuyoshi Kaneko, Mohamed Abdel-Wahab, Holger Thiele, Raj Makkar, Michael A Borger

2020-Current year OA Pubs

BACKGROUND: Redo surgical aortic valve replacement (rSAVR) has for long been the therapeutic reference standard for degenerated surgical aortic bioprostheses. Valve-in-valve transcatheter aortic valve replacement (ViV-TAVR) has emerged as an alternative for patients at high surgical risk due to its lower invasiveness. The long-term clinical efficacy of ViV-TAVR in patients at low to intermediate surgical risk remains unknown.

METHODS AND RESULTS: To compare clinical outcomes of redo surgical aortic valve replacement versus ViV-TAVR in low- to intermediate-risk patients with degenerated surgical aortic bioprostheses. REPEAT (Repeat Intervention for Deteriorated Surgical Bioprosthetic Aortic Valves) is an investigator-initiated, international, multicenter, randomized, parallel, open-label …

Sksr1 Identified As Key Virulence Factor In Cryptosporidium By Genetic Crossing, Wei He, Lianbei Sun, Tianyi Hou, Zuwei Yang, Fuxian Yang, Shengchen Zhang, Tianpeng Wang, Xinran Wang, Na Li, Yaqiong Guo, L David Sibley, Yaoyu Feng, Lihua Xiao

2020-Current year OA Pubs

Cryptosporidium is a major cause of severe diarrhea. Although Cryptosporidium isolates exhibit significant differences in infectivity and virulence, the genetic determinants for these traits are not clear. In this study, we use classical genetics to cross two Cryptosporidium parvum isolates of different virulence and use bulk segregant analysis of whole-genome sequences from the progeny to identify quantitative trait loci (QTL) associated with Cryptosporidium infectivity and virulence. Of the 23 genes in three QTL, two have loss-of-function mutations in the low-virulence isolates, including the SKSR1 gene encoding a variant secretory protein. Deletion of the SKSR1 gene or expression of the frame-shifted …

Rapamycin Treatment For Alzheimer's Disease And Related Dementias: A Pilot Phase 1 Clinical Trial, Mitzi M Gonzales, Miranda E Orr, Yingxin He, Randall J Bateman, Et Al.

2020-Current year OA Pubs

BACKGROUND: Rapamycin has been shown to extend lifespan and acts on pathologies underlying Alzheimer's disease and related dementias in animal models. However, rapamycin's clinical application remains underexplored.

METHODS: We conducted a single-site open-label phase 1 clinical trial (ClinicalTrials.gov: NCT04200911) to examine the effects of rapamycin in humans. Eligible participants were people 55-85 years old with mild cognitive impairment or early-stage dementia, which was defined as having a Global Clinical Dementia Rating Scale Score of 0.5-1. All participants received rapamycin (1 mg/day) for eight weeks. The primary aim was to evaluate rapamycin's central nervous system penetrance by assaying drug levels in …

Dual-Responsive Synthetic Gene Circuit For Dynamic Biologic Drug Delivery Via Inflammatory And Circadian Signaling Pathways, Amanda Cimino, Fiona Pat, Omolabake Oyebamiji, Christine T N Pham, Erik D Herzog, Farshid Guilak

2020-Current year OA Pubs

BACKGROUND: Engineered cells provide versatile tools for precise, tunable drug delivery, especially when synthetic stimulus-responsive gene circuits are incorporated. In many complex disease conditions, endogenous pathologic signals such as inflammation can vary dynamically over different time scales. For example, in autoimmune conditions such as rheumatoid arthritis or juvenile idiopathic arthritis, local (joint) and systemic inflammatory signals fluctuate daily, peaking in the early morning, but can also persist over long periods of time, triggering flare-ups that can last weeks to months. However, treatment with disease-modifying anti-rheumatic drugs is typically provided at continuous high doses, regardless of disease activity and without consideration …

The Role Of Organizational Characteristics In Intervention Sustainment: Findings From A Quantitative Analysis In 42 Hiv Testing Clinics In Vietnam, Sophia M Bartels, Byron J Powell, Et Al.

2020-Current year OA Pubs

BACKGROUND: Evidence-based intervention (EBI) sustainment is one of public health's largest translational research problems. Fewer than half of public health EBIs are sustained long-term, and sustainment challenges are even more pressing in low and middle-income countries (LMICs). Organizational characteristics, including organizations' inner structures, culture, and climate, may play a key role in EBI sustainment. However, little quantitative research has examined these relationships, particularly in LMICs.

METHODS: In this observational study, we assessed the association between baseline organizational characteristics and EBI sustainment within a cluster randomized implementation trial in Vietnam testing strategies to scale-up Systems Navigation and Psychosocial Counseling (SNaP) for …

Psychiatric Genome-Wide Association Study Enrichment Shows Promise For Future Psychopharmaceutical Discoveries, Alexander S Hatoum, Aaron J Gorelik, Lauren Blaydon, Spencer B Huggett, Tingying Chi, David A A Baranger, Alex P Miller, Emma C Johnson, Arpana Agrawal, Ryan Bogdan

2020-Current year OA Pubs

BACKGROUND: Innovation in psychiatric therapeutics has stagnated on known mechanisms. Psychiatric genome-wide association studies (GWAS) have identified hundreds of genome-wide significant (GWS) loci that have rapidly advanced our understanding of disease etiology. However, whether these results can be leveraged to improve clinical treatment for specific psychiatric disorders remains poorly understood.

METHODS: In this proof-of-principal evaluation of GWAS clinical utility, we test whether the targets of drugs used to treat Attention Deficit Hyperactivity Disorder (ADHD), Bipolar Disorder (BiP), Generalized Anxiety Disorder (GAD), Major Depressive Disorder (MDD), Post-Traumatic Stress Disorder (PTSD), Schizophrenia (SCZ), Substance Use Disorders (SUDs), and insomnia (INS), are enriched …

Label-Free Multimodal Optical Biopsy Reveals Biomolecular And Morphological Features Of Diabetic Kidney Tissue In 2d And 3d, Anthony A Fung, Zhi Li, Craig Boote, Petar Markov, Joseph P Gaut, Sanjay Jain, Lingyan Shi

2020-Current year OA Pubs

Kidney disease, the ninth leading cause of death in the United States, suffers from poor diagnostic efficiency (10%). Traditional biopsies use molecular reagents to enhance diagnostic power but are limited by overlapping spatial and chromatic signals, product quality variability, and additional processing. To address these challenges without disrupting routine diagnostics, we implement label-free imaging modalities-stimulated Raman scattering (SRS), second harmonic generation (SHG), and two-photon fluorescence (TPF)-within a single setup. We identify morphological, lipidomic, and metabolic biomarkers in control and diabetic kidney samples at subcellular resolution. Label-free Stimulated Raman Histology (SRH) reveals distinct collagen morphology, mesangial-glomerular volumes, lipid saturation, redox status, …

A Phase I Dose-Escalation Study Of The Hif-2 Alpha Inhibitor Dff332 In Patients With Advanced Clear-Cell Renal Cell Carcinoma, Sumanta K Pal, Joel Picus, Et Al.

2020-Current year OA Pubs

PURPOSE: Mutations or silencing of the von Hippel-Lindau tumor suppressor gene accumulate hypoxia-inducible factors (HIF). HIF-2α is implicated in the oncogenesis of ∼50% of patients with clear-cell renal cell carcinoma (ccRCC) but has been considered "undruggable." DFF332, an orally administered novel allosteric inhibitor of HIF-2α, showed dose-dependent antitumor efficacy in preclinical models of ccRCC.

PATIENTS AND METHODS: This first-in-human study evaluated the safety, tolerability, antitumor activity, pharmacokinetics, and pharmacodynamics of DFF332 in patients with heavily pretreated advanced ccRCC. Preliminary data from the dose escalation of DFF332 monotherapy, administered orally at 50 or 100 mg weekly or 25, 50, 100, or …

Meningeal Lymphatics-Microglia Axis Regulates Synaptic Physiology, Kyungdeok Kim, Daviti Abramishvili, Siling Du, Zachary Papadopoulos, Jay Cao, Jasmin Herz, Igor Smirnov, Jean-Leon Thomas, Marco Colonna, Jonathan Kipnis

2020-Current year OA Pubs

Meningeal lymphatics serve as an outlet for cerebrospinal fluid, and their dysfunction is associated with various neurodegenerative conditions. Previous studies have demonstrated that dysfunctional meningeal lymphatics evoke behavioral changes, but the neural mechanisms underlying these changes have remained elusive. Here, we show that prolonged impairment of meningeal lymphatics alters the balance of cortical excitatory and inhibitory synaptic inputs, accompanied by deficits in memory tasks. These synaptic and behavioral alterations induced by lymphatic dysfunction are mediated by microglia, leading to increased expression of the interleukin 6 gene (Il6). IL-6 drives inhibitory synapse phenotypes via a combination of trans- and classical IL-6 …

Network Analysis Of The Cerebrospinal Fluid Proteome Reveals Shared And Unique Differences Between Sporadic And Familial Forms Of Amyotrophic Lateral Sclerosis, Adam N Trautwig, Cindy V Ly, Timothy M Miller, Et Al.

2020-Current year OA Pubs

BACKGROUND: Amyotrophic Lateral Sclerosis (ALS), a neurodegenerative disease involving loss of motor neurons, typically results in death within 3-5 years of disease onset. Although roughly 10% of cases can be linked to a specific inherited mutation (e.g., C9orf72 hexanucleotide repeat expansion or SOD1 mutation), the cause(s) of most cases are unknown. Consequently, there is a critical need for biomarkers that reflect disease onset and progression across ALS subgroups.

METHODS: We employed tandem mass tag mass spectrometry (TMT-MS) based proteomics on cerebrospinal fluid (CSF) to identify and quantify 2105 proteins from sporadic, C9orf72, and SOD1 ALS patients, asymptomatic C9orf72 expansion carriers, …

Modulation Of Her2 Internalization Enhances Single-Dose Antibody-Drug Potency In Her2+ Gastric Cancer, Abbey Zidel, Alex Benton, Emma Brown, Shayla Shmuel, Alex Vanover, Sandeep Surendra Panikar, Ron Bose, Haeseong Park, Andrew A Davis, Patrícia M R Pereira

2020-Current year OA Pubs

HER2 is a membrane receptor tyrosine kinase overexpressed in 18-20% of gastric tumors. Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate (ADC) that targets HER2-positive (HER2

Acute Kidney Injury Triggers Hypoxemia By Lung Intravascular Neutrophil Retention That Reduces Capillary Blood Flow, Yohei Komaru, Liang Ning, Carine Lama, Anusha Suresh, Eirini Kefaloyianni, Mark J. Miller, Shinichi Kawana, Hailey M Shepherd, Wenjun Li, Daniel Kreisel, Andreas Herrlich

2020-Current year OA Pubs

Sterile acute kidney injury (AKI) is common in the clinic and frequently associated with unexplained hypoxemia that does not improve with dialysis. AKI induces remote lung inflammation with neutrophil recruitment in mice and humans, but which cellular cues establish neutrophilic inflammation and how it contributes to hypoxemia is not known. Here we report that AKI induced rapid intravascular neutrophil retention in lung alveolar capillaries without extravasation into tissue or alveoli, causing hypoxemia by reducing lung capillary blood flow in the absence of substantial lung interstitial or alveolar edema. In contrast to direct ischemic lung injury, lung neutrophil recruitment during remote …

Maintenance Of Graft Tissue-Resident Foxp3+ Cells Is Necessary For Lung Transplant Tolerance In Mice, Wenjun Li, Yuriko Terada, Yun Zhu Bai, Yuhei Yokoyama, Hailey M. Shepherd, Junedh M. Amrute, Amit I. Bery, Zhiyi Liu, Jason M. Gauthier, Marina Terekhova, Jon H. Ritter, Varun Puri, Ramsey R. Hachem, Maxim N. Artyomov, Kory J. Lavine, Ruben G. Nava, Andrew E. Gelman, Daniel Kreisel, Et Al.

2020-Current year OA Pubs

Mechanisms that mediate allograft tolerance differ between organs. We have previously shown that Foxp3+ T cell-enriched bronchus-associated lymphoid tissue (BALT) is induced in tolerant murine lung allografts and that these Foxp3+ cells suppress alloimmune responses locally and systemically. Here, we demonstrated that Foxp3+ cells that reside in tolerant lung allografts differed phenotypically and transcriptionally from those in the periphery and were clonally expanded. Using a mouse lung retransplant model, we showed that recipient Foxp3+ cells were continuously recruited to the BALT within tolerant allografts. We identified distinguishing features of graft-resident and newly recruited Foxp3+ cells and showed that graft-infiltrating Foxp3+ …

Radiation Dosimetry Of [11c]Tz1964b As Determined By Whole-Body Pet Imaging Of Nonhuman Primates, Baijayanta Maiti, Noah L Goldman, Mahdjoub Hamdi, Jason Lenox-Krug, Morvarid Karimi, Stephen M Moerlein, Richard Laforest, Tianyu Huang, Zhude Tu, Joel S Perlmutter, Scott A Norris

2020-Current year OA Pubs

BACKGROUND: Phosphodiesterase 10A (PDE10A) is a postsynaptic, membrane bound cyclic nucleotide phosphodiesterase that is highly enriched in the striatal medium spiny neurons and regulates dopaminergic neurotransmission. The objective of this study is to determine the absorbed radiation dosimetry of a novel radiotracer for PDE10A: 3-(Methoxy-

RESULTS: Highest retention was observed in the liver with total time-integrated activity of ~ 0.23 h. Absorbed organ dosimetry was highest in the liver (53.3 μGy/MBq), making it the critical organ. Gallbladder (35.9 μGy/MBq) and spleen (35.4 μGy/MBq) were the next highest organs for absorbed radiation dose. Effective doses were estimated to be 5.02 and …

Autophagy Is Required For The Therapeutic Effects Of The Nad+ Precursor Nicotinamide In Obesity-Related Heart Failure With Preserved Ejection Fraction, Mahmoud Abdellatif, Moydul Islam, Abhinav Diwan, Et Al.

2020-Current year OA Pubs

No abstract provided.

A Role For Δ Subunit-Containing Gabaa Receptors On Parvalbumin-Positive Neurons In Maintaining Electrocortical Signatures Of Sleep States, Peter M Lambert, Sofia V Salvatore, Xinguo Lu, Hong-Jin Shu, Ann Benz, Nicholas Rensing, Carla M Yuede, Michael Wong, Charles F Zorumski, Steven Mennerick

2020-Current year OA Pubs

GABA

Comparison Of Broad-Spectrum Anti-Pseudomonal Beta-Lactam Antibiotics Versus Targeted Therapy For Neutropenic Patients With Methicillin-Susceptible, Lauren C Russell, Jeff Klaus, Miguel A Chavez, Erik R Dubberke, Tamara Krekel

2020-Current year OA Pubs

The safety of the utilization of methicillin-susceptible

Novel Treatment Approaches Utilizing Antibody-Drug Conjugates In Breast Cancer, Andrew A Davis, Jennifer Hesse, Patrícia M R Pereira, Cynthia X Ma

2020-Current year OA Pubs

Antibody-drug conjugates (ADCs) are rapidly changing the way we treat patients with breast cancer. Despite this progress, many unanswered questions remain regarding the sequencing of different ADCs with similar payloads, optimal combinations, drug design strategies to limit off-target toxicities, biomarkers to define antigen positivity, and the use of ADCs in the neoadjuvant and adjuvant settings. In this review, we summarize novel ADC approaches in breast cancer treatment, including potential improvements in ADC payloads, linkers, targets, and drug delivery. We also evaluate novel strategies to combine ADCs with other agents, such as targeted drugs and immune checkpoint inhibitors. To improve patient …

When The Parts Are Greater Than The Whole: How Understanding Mechanisms Can Advance Implementation Research, Elvin H Geng, Byron J Powell, Charles W Goss, Cara C Lewis, Anne E Sales, Bo Kim

2020-Current year OA Pubs

BACKGROUND: Does the importance of context in implementation imply that generalizing about the effects of strategies is ultimately limited? Conceptual approaches for generalizing in the presence of significant contextual heterogeneity could advance implementation research but require novel perspectives.

MAIN BODY: Drawing from perspectives from Realist approaches, Pearl's transportability framework and philosophy of science, this paper outlines a mechanism-based approach to generalizing about the effects of implementation strategies. We suggest that understanding mechanisms creates a conceptual bridge between the effects of a strategy and the influence of the implementation context. Using directed acyclic graphs to represent the mechanisms of strategies, we …