Translation Of Interventions Research Articles

A narrative review of the potential role of microaspiration and a dysregulated aerodigestive microbiome in lung disease

: When initiated the human microbiome project did not include the lungs and airways in its sampling sites, indicating an under appreciation of the role of the human lung microbiome in health and disease. This paradigm has recently changed through the use of culture independent methods to characterise the human lung microbiome. The original thinking, that the normal lung was essentially sterile, had previously been challenged by findings of microaspiration in normal volunteers and in patients with decreased levels of consciousness. The sterile lung was also questioned by findings of clinically occult infection markers in lung allograft recipients. What is arguably a “rediscovery” of the importance of the human lung microbiome may still underappreciate physiological and patho-physiological inter-relationships between organ systems, studied in separate research disciplines. In particular, microaspiration may be an important, direct mechanism through which the lung microbiome is modulated. As well as aspiration related to gastro-oesophageal reflux and microaspiration the authors feel that the importance of dysphagia in chronic lung disease, will be increasingly recognised in frailty related microbiome exchange between the oropharynx into the lung. This review therefore discusses interconnections in the human microbiome, with a focus on the potential for aerodigestive pathophysiology and microaspiration. Potential connections with human lung disease are discussed and contextualised within a developing literature. This review therefore highlights much needed new targets for translational intervention in lung pathophysiology and underlies the importance of a mixed disciplinary team approach for the future.

A clinical review of the potential role of microaspiration and a dysregulated aerodigestive microbiome in lung disease

: When initiated the human microbiome project did not include the lungs and airways in its sampling sites, indicating an under appreciation of the role of the human lung microbiome in health and disease. This paradigm has recently changed through the use of culture independent methods to characterise the human lung microbiome. The original thinking, that the normal lung was essentially sterile, had previously been challenged by findings of microaspiration in normal volunteers and in patients with decreased levels of consciousness. The sterile lung was also questioned by findings of clinically occult infection markers in lung allograft recipients. What is arguably a “rediscovery” of the importance of the human lung microbiome may still underappreciate physiological and patho-physiological inter-relationships between organ systems, studied in separate research disciplines. In particular, microaspiration may be an important, direct mechanism through which the lung microbiome is modulated. As well as aspiration related to gastro-oesophageal reflux and microaspiration the authors feel that the importance of dysphagia in chronic lung disease, will be increasingly recognised in frailty related microbiome exchange between the oropharynx into the lung. This review therefore discusses interconnections in the human microbiome, with a focus on the potential for aerodigestive pathophysiology and microaspiration. Potential connections with human lung disease are discussed and contextualised within a developing literature. This review therefore highlights much needed new targets for translational intervention in lung pathophysiology and underlies the importance of a mixed disciplinary team approach for the future.

Prenatal methadone exposure selectively alters protein expression in primary motor cortex: Implications for synaptic function.

As problematic opioid use has reached epidemic levels over the past 2decades, the annual prevalence of opioid use disorder (OUD) in pregnant women has also increased 333%. Yet, how opioids affect the developing brain of offspring from mothers experiencing OUD remains understudied and not fully understood. Animal models of prenatal opioid exposure have discovered many deficits in the offspring of prenatal opioid exposed mothers, such as delays in the development of sensorimotor function and long-term locomotive hyperactivity. In attempt to further understand these deficits and link them with protein changes driven by prenatal opioid exposure, we used a mouse model of prenatal methadone exposure (PME) and preformed an unbiased multi-omic analysis across many sensoriomotor brain regions known to interact with opioid exposure. The effects of PME exposure on the primary motor cortex (M1), primary somatosensory cortex (S1), the dorsomedial striatum (DMS), and dorsolateral striatum (DLS) were assessed using quantitative proteomics and phosphoproteomics. PME drove many changes in protein and phosphopeptide abundance across all brain regions sampled. Gene and gene ontology enrichments were used to assess how protein and phosphopeptide changes in each brain region were altered. Our findings showed that M1 was uniquely affected by PME in comparison to other brain regions. PME uniquely drove changes in M1 glutamatergic synapses and synaptic function. Immunohistochemical analysis also identified anatomical differences in M1 for upregulating the density of glutamatergic and downregulating the density of GABAergic synapses due to PME. Lastly, comparisons between M1 and non-M1 multi-omics revealed conserved brain wide changes in phosphopeptides associated with synaptic activity and assembly, but only specific protein changes in synapse activity and assembly were represented in M1. Together, our studies show that lasting changes in synaptic function driven by PME are largely represented by protein and anatomical changes in M1, which may serve as a starting point for future experimental and translational interventions that aim to reverse the adverse effects of PME on offspring.

Testing a novel knowledge translation intervention for motor learning practice in physical therapy

Testing a novel knowledge translation intervention for motor learning practice in physical therapy

Evaluation of Gait Development Trajectory in Mice

Background/Objective: Movement and walking are huge facets in how we go about our lives and experience the world. Gait is compromised in numerous conditions, from injury and chronic pain to neurological conditions and arthritis. Movement biomechanics have therefore been studied extensively in humans for decades. Although animal models are often used to examine the progression of various health conditions, translational gait research in animal models are less complete, and there is limited information on gait changes as mice grow.
 Methods: We recorded video segments of wild-type C57Bl/6J mice during skeletal growth (5 weeks to 16 weeks) walking (n = 4 Female, n = 2 Male) at 20 cm/s on the DigiGait system, a transparent treadmill equipped with a high-speed camera. Videos captured a ventral view of the mouse and were processed using DigiGait Analysis software, which uses local thresholding and position-finding algorithms to examine paw placement on the treadmill belt. Manual adjustments were made to eliminate artifacts and confirm heel-strike and toe-off times. After these corrections, the software returns stride parameters that were compared between sexes.
 Results: Over 30 gait metrics, including stride length, frequency, stance/swing times, and stance width, were calculated for all four limbs per animal for several time points. Stride length increased from 4.5 ± .5 cm at week 5 to 5.0 ± .8 cm at week 16, and frequency decreased from 4.6 ± .6 to 4.2 ± .6 steps per second. No notable changes in stance width, symmetry, or stance/swing ratio were identified.
 Conclusion and Potential Impact: Future directions for this research include conducting a principal component analysis to investigate the variability within the gait data. Identifying trends in gait parameters will help create a more complete picture of gait maturation. Establishing this baseline data allows for its comparison against treatment groups and the potentially meaningful investigation of translatable therapeutics and interventions.

Allostatic Mechanism of Mind-Body Medicine for Neuroinflammation

Chronic inflammatory diseases are the most significant cause of death in the world and entail severe impairment to quality of life. The World Health Organization (WHO) ranks chronic inflammatory diseases as the greatest threat to human health and wellbeing. Inflammation is epicentral to many clinical conditions and symptoms, and it is anticipated that the health, economic, and mortality burdens associated with chronic inflammation will steadily increase in the United States over the next 30 years. An inflammatory model of disease premises that peripheral injury/trauma/toxins release signaling mediators that activate glial components of peripheral and central cellular circuitry which if prolonged causes toxification of the central nervous system, or neuroinflammation. This inflammatory process is associated with an array of systemic symptomatology affecting somatic, neurocognitive, and affective domains, that can often be misdiagnosed and/or ineffectively treated in the clinic. Centralized neuroinflammation determines a range of conditions and their clinical trajectories, from autoimmune diseases, cancers, cardiovascular diseases, chronic pain, to neurological and psychiatric disorders. It is coming to light that mind-body medicine, defined here as mindfulness- and yoga-based interventions, appear to modulate peripheral cell signaling involved with inflammatory response. Translational mechanism nor intervention specificity of this early data is currently clearly delineated, posing an exciting and highly beneficial frontier for further empirical exploration in the field of integrative mind-body medicine. Here we initiate an allostasis model of working mechanism that aims to inform methodological design and ensuing empirical perspectives.

Risk Factors, Pathophysiologic Mechanisms, and Potential Treatment Strategies of Futile Recanalization after Endovascular Therapy in Acute Ischemic Stroke.

Endovascular therapy is the first-line treatment for acute ischemic stroke. However, studies have shown that, even with the timely opening of occluded blood vessels, nearly half of all patients treated with endovascular therapy for acute ischemic stroke still have poor functional recovery, a phenomenon called "futile recanalization.". The pathophysiology of futile recanalization is complex and may include tissue no-reflow (microcirculation reperfusion failure despite recanalization of the occluded large artery), early arterial reocclusion (reocclusion of the recanalized artery 24-48 hours post endovascular therapy), poor collateral circulation, hemorrhagic transformation (cerebral bleeding following primary ischemic stroke), impaired cerebrovascular autoregulation, and large hypoperfusion volume. Therapeutic strategies targeting these mechanisms have been attempted in preclinical research; however, translation to the bedside remains to be explored. This review summarizes the risk factors, pathophysiological mechanisms, and targeted therapy strategies of futile recanalization, focusing on the mechanisms and targeted therapy strategies of no-reflow to deepen the understanding of this phenomenon and provide new translational research ideas and potential intervention targets for improving the efficacy of endovascular therapy for acute ischemic stroke.

Identifying candidate quality indicators of tools that support the practice of knowledge translation: a scoping review protocol.

The objective of this scoping review is to identify and characterize relevant knowledge translation methods tools (those that provide guidance for optimized knowledge translation practice) to uncover candidate quality indicators to inform a future quality assessment tool for knowledge translation strategies. Knowledge translation strategies (defined as including knowledge translation interventions, tools, and products) target various knowledge users, including patients, clinicians, researchers, and policy-makers. The development and use of strategies that support knowledge translation practice have been rapidly increasing, making it difficult for knowledge users to decide which to use. There is limited evidence-based guidance or measures to help assess the overall quality of knowledge translation strategies. Empirical and non-empirical documents will be considered if they explicitly describe a knowledge translation methods tool and its development, evaluation or validation, methodological strengths or limitations, and/or use over time. The review will consider a knowledge translation methods tool if it falls within at least one knowledge translation domain (ie, implementation, dissemination, sustainability, scalability, integrated knowledge translation) in the health field. We will conduct a systematic search of relevant electronic databases and gray literature. The search strategy will be developed iteratively by an experienced medical information specialist and peer-reviewed with the PRESS checklist. The search will be limited to English-only documents published from 2005 onward. Documents will be independently screened, selected, and extracted by 2 researchers. Data will be analyzed and summarized descriptively, including the characteristics of the included documents, knowledge translation methods tools, and candidate quality indicators. Open Science Framework ( https://osf.io/chxvq ).

Complex interactive multimodal intervention to improve personalized stress management among healthcare workers in China: A knowledge translation protocol.

Numerous stress management interventions have been implemented in the workplace, but few are adapted to the healthcare setting. Due to the nature of their jobs, healthcare workers (HCWs) may find it difficult to adopt recommended stress management strategies. We present the protocol for a 12-week personalized stress management intervention among HCWs to change their behavior as well as improve physiological/psychological outcomes. It is a pragmatic quasi-experimental study involving stressed HCWs from two general hospitals in Wuhan, China. The intervention group will receive a complex interactive multimodal intervention, including advanced education via mobile connection, participation in a web-based social network, tailored feedback, and the support of a nurse coach, while the control group will engage in self-guided stress management. The primary outcome is centered on behavioral measures, namely improvements in stress management practice frequency after a 12-week intervention. The secondary outcomes are the changes in stress-related physiological indices (i.e. high frequency variability and normalized unit assessed by Holter) and psychological indicators (scores on the Perceived Stress Scale and Depression, Anxiety, Stress Scale) following 12 weeks of treatment. The knowledge translation intervention builds on a body of work defining the role of individualized instruction and feedback intervention, as well as group intervention through WeChat social network and personalized coaching. We believe this novel intervention will help HCWs promote their stress management awareness and skills, and ultimately benefit their long-term health. ClinicalTrials.gov., NCT05239065. Registered 14 February 2022-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT05239065.

Sex‐specific molecular profiling to understand pathology and identify causal genes and drug targets for Alzheimer’s disease

AbstractBackgroundAlzheimer’s disease (AD) is a highly heterogeneous multifactorial disease. Genetic influences on AD are strong as shown by several pathogenic genes and over 50 AD GWAS loci. There are also clear sex differences in AD risk and progression. Women are at a higher risk of developing AD and present faster progression. A recent GTEx study also highlights sex differences in the genetic regulation of gene expression. Despite these established sex differences, sex‐specific molecular findings in AD are still limited.MethodWe generated and performed analysis using 713 CSF proteomic data that passed QC obtained from Knight‐ADRC and DIAN samples. The sample includes 190 late onset clinical AD patients and 509 age‐ and gender‐matched cognitively healthy individuals. Age at lumbar puncture and surrogate variables (to account for unmeasured heterogeneity) were included as covariates. To evaluate sex‐specific molecular signatures, we performed sex‐stratified analysis by separately analyzing 333 males and 366 females.ResultIn male CSF tissues, 99 proteins significantly associated with late onset AD status (FDR P < 0.05) and 131 proteins in female CSF tissues. Those proteins were enriched in pathways involved in the endolysosome and proteasome pathway including HSP70. We identified 44 proteins presenting a suggestive evidence of sex‐specific effects on AD status. In particular, several proteins that were previously reported to be associated with AD risk show sex‐specific effects. Downregulation of LRIG3 improves cognitive impairment and alleviate neuronal damage in hippocampus tissues in AD rats through modulating the PI3K/Akt pathway. We found that LRIG3 was associated in males only and would not have been identified through a combined analysis that simply included sex as a covariate (P = 3.4×10‐3 in males; P > 0.5 in females; P = 0.067 in all).ConclusionThis study demonstrates that 800 proteins in 700 CSF tissues can provide a suggestive information on sex‐specific proteomic profiles. We will extend our sex‐specific analysis using our recently generated 7000 proteomic data to fully understand the biology of the disease and determine the role of sex in disease, create sex‐specific genes and prediction models. This will provides insights for clinically translatable interventions for prevention and treatment.

Implementation of Subluxation Stimulation Protocol post stroke in Inpatient Rehabilitation setting

<h3>Research Objectives</h3> Glenohumeral subluxation is a common post-stroke complication, affecting up to 80% of patients. Long duration neuromuscular electrical stimulation has been shown to reduce subluxation, decrease shoulder pain, and can improve motor outcomes for the affected extremity. This poster aims to investigate the feasibility of implementing a long duration subluxation stimulation protocol for the hemiparetic upper extremity post stroke while in inpatient rehabilitation. <h3>Design</h3> Feasibility study 12-month period. <h3>Setting</h3> Inpatient rehabilitation hospital. <h3>Participants</h3> 9 occupational therapists serving dedicated stroke unit. <h3>Interventions</h3> 1 year, 2 phase multicomponent knowledge translation interventions. Attended and unattended neuromuscular electrical stimulation to support glenohumeral subluxation for 3 – 6 hours, 5 days a week. <h3>Main Outcome Measures</h3> Number of referring therapists Average number of hours per day of subluxation stimulation <h3>Clinician survey results</h3> barriers, satisfaction, relevance. <h3>Results</h3> Nineteen patients received long duration subluxation stimulation over the course of this year, 13 patients during phase 1 and 7 during phase 2. Phase 1 consisted of 10 months of providing a goal of 3.5 hours of subluxation stimulation for no more than 2 patients per day facilitated by supervised rehabilitation technician. Phase 2 consisted of 2 months of providing a goal of 6 hours for up to 8 patients per day. Data collection during phase 2 shows an average of 4.36 actual stimulation hours per day. Eight of nine occupational therapists who received training (didactic and experiential) on this protocol referred at least 1 patient to this service. After 12 months of participation, all survey respondents reported that they were 'very satisfied' with this protocol and that they 'strongly agree' that this protocol has a positive effect on patient outcomes and is relevant to persons with stroke during inpatient rehabilitation. <h3>Conclusions</h3> Occupational therapists at an inpatient facility demonstrate adoption of a long duration subluxation stimulation protocol when facilitated by a supervised rehabilitation technician. Knowledge translation efforts and innovative service provision techniques have led to increased duration of stimulation and reduced clinician's perceived barriers of conflicting treatment demands and time limitations. <h3>Author(s) Disclosures</h3> None.

Building on Community Research Partnerships and Training Students in a Multi-Phase Community-Based Participatory Research Study With Young Women of Cambodian Heritage in Massachusetts.

Refugees bring significant economic and cultural benefits to communities and yet face elevated risk of chronic disease and barriers to good health in the U.S. Community-based participatory research (CBPR) can benefit refugee communities and provide training/mentoring opportunities for students. The Cambodian Women's Health Study was a four-phase, multi-year CBPR university-community collaboration with the Massachusetts Cambodian community that focused on health, nutrition, pregnancy, and food security among primarily young women of Cambodian heritage ages 15-30 years old. Phase 1 was a focus group discussion (FGD, n = 4) and cross-sectional survey (n = 56) with pregnant women. Phase 2 was a cross-sectional survey (n = 107) with nonpregnant women. Phase 3 was a series of FGD (seven FGD, n = 38) with women. Phase 4 was a student-led translational nutrition intervention (three classes) with women (n = 11) and men (n = 10). The study design included compensation and support for the community partner and included structured mentoring of students (six graduates, eight undergraduates) in CBPR methods, adult learning, and cultural humility. Benefits to the community agency included enhanced research capacity, including supervising student research assistants, and robust compensation. Benefits to students included intensive mentoring and training. Successes included cost-effectiveness and strong recruitment and experiences with participants. Challenges included issues with student-led recruitment and organization that required additional mentoring and reflection. To work toward socially just and equitable research and interventions, CBPR collaborative efforts should include intentional meaningful compensation and community capacity-building as well as structured mentoring and training for student researchers and should build on existing work and relationships within communities.

Engaging and sustaining people with intellectual disabilities in physical activity: a narrative review of existing evidence

Background: People with intellectual disabilities (ID) experience many health and social inequalities. Increasing physical activity is a proven intervention to address such inequalities, yet the physical activity rates of this population are substantially lower than the general population. Aim: Research has been growing to understand why this is and how to intervene to increase the physical activity levels of people with ID. Method: Using a behavioural epidemiological framework, the research in this area from barriers and facilitators of physical activity to translational research testing interventions within natural settings is reviewed. Findings from a total of 14 reviews and eight empirical studies and protocols were included. Results: Whilst there are multiple investigations into what promotes or enhances physical activity for people with ID, findings from intervention studies show few successful outcomes. Gaps within the existing research are identified and recommendations about how intervention efficacy might be improved are provided to inform future research and practice. Conclusion: Findings from previous research on barriers and facilitators can be further capitalised on and intervention studies should be underpinned by better links to theory and more systemic approaches.

Protocol for iSISTAQUIT: Implementation phase of the supporting indigenous smokers to assist quitting project.

About 44% of Aboriginal and/or Torres Strait Islander women smoke during pregnancy compared to 12% of their general population counterparts. Evidence-based quit smoking advice received from health care professionals (HCPs) can increase smoking cessation rates. However, HCPs lack culturally appropriate smoking cessation training, which is a major barrier to provision of smoking cessation care for this population. iSISTAQUIT is a multicentre, single arm study aiming to implement and evaluate the evidence-based, culturally competent iSISTAQUIT smoking cessation training among health practitioners who provide support and assistance to pregnant, Aboriginal and Torres Strait Islander women in Australia. This project will implement the iSISTAQUIT intervention in Aboriginal Medical Services and Mainstream Health Services. The proposed sample size is 10 of each of these services (total N = 20), however if the demand is higher, we will aim to accommodate up to 30 services for the training. Participating sites and their HCPs will have the option to choose one of the two iSISTAQUIT packages available: a) Evaluation- research package b) Training package (with or without continued professional development points). Training will be provided via an online eLearning platform that includes videos, text, interactive elements and a treatment manual. A social media campaign will be conducted from December 2021 to September 2022 to raise brand and issue awareness about smoking cessation for Aboriginal and Torres Strait Islander women in pregnancy. This national campaign will consist of systematic advertising and promotion of iSISTAQUIT and video messages through various social media platforms. We will use the RE-AIM framework (Reach, Effectiveness, Adoption, Implementation and Maintenance) to plan, evaluate and report the intervention impact of iSISTAQUIT. Effectiveness of social media campaign will be assessed via social media metrics, cross-sectional surveys, and interviews. This innovative research, using a multi-component intervention, aims to practically apply and integrate a highly translatable smoking cessation intervention in real-world primary care settings in Aboriginal Medical Services and Mainstream services. The research benefits Aboriginal women, babies and their family and community members through improved support for smoking cessation during pregnancy. The intervention is based on accepted Australian and international smoking cessation guidelines, developed and delivered in a culturally appropriate approach for Aboriginal communities.

Lifelong docosahexaenoic acid intervention ameliorates aging in the telomere-DNA-mitochondria axis in telomerase-deficient mice

The health benefits of n-3 polyunsaturated fatty acids (PUFAs) in multiple age-related diseases are associated with telomere length. Telomerase is intimately related to inflammation and oxidative stress, but whether the underlying function of n-3 PUFAs on telomere maintenance is based on telomerase activation or related mechanisms remains unclear. Herein, we utilized late-generation (G4) telomerase-deficient (Terc−/−) mice to perform a lifelong docosahexaenoic acid (DHA) intervention to determine the potential of DHA in telomere maintenance and health promotion. Unfortunately, DHA failed to prolong mouse longevity in either intrinsic or premature aging. However, intriguingly, lifelong dietary DHA intervention slowed the aging phenotypes and profoundly attenuated telomere attrition in blood leukocytes and multiple tissues, consistent with decreased β-galactosidase activity and other senescence hallmarks with no observed sex differences. Notably, DHA intervention alleviated telomere attrition-induced γ-H2AX accumulation dependent on poly (ADP-ribose) polymerase 1 (PARP1) recruitment, and further regulated mitochondrial dysfunction critically involved in the DNA damage response. Together with the improvement of mitochondria function, the blocked reactive oxygen species (ROS) accumulation and suppression of the nuclear factor-κB (NF-κB)/nucleotide-binding domain-like receptor protein 3 (NLRP3)/caspase-1 pathways partially indicated anti-oxidative and anti-inflammatory effects of DHA. These data revealed a regulatory paradigm involving DHA in the telomere-DNA-mitochondria feedback loop mediated by DNA damage response and inflammation in alleviating senescence, which may hold potential as a translatable intervention in telomere-related diseases during aging.

Antibiotic-disrupted ribosome biogenesis facilitates tumor chemokine superinduction

Upon exposure to internal or external stressors, ribosomes stand sentinel via modulation of ribosome assembly and protein translation. Ribosome-dependent cellular dysfunctions have been associated with pathophysiological processes during inflammation and tumorigenesis. In the present study, ribosome biogenesis was assessed to determine its effects on tumor chemokines, potentially contributing to cancer cell malignant features. In particular, ribosome biogenesis inhibition by antibiotic actinomycin D (ActD) enhanced the expression of chemokines in intestinal cancer cells under endoplasmic reticulum stress that governs multiple pro-tumoral reprogramming. Mechanistically, ribosome biogenesis inhibition superinduced proinflammatory chemokines via transcriptional and post-transcriptional regulation. Moreover, ribosomal stress-responsive p53 and its target macrophage inhibitory cytokine 1 (MIC-1) mediated chemokine superinduction by activating TGF-β–activated kinase 1 (TAK-1) and nuclear factor-kappa B (NF-κB) in intestinal cancer cells. Cancer cell-based regulation of chemokine induction via MIC-1 signaling was verified using clinical transcriptome datasets. Clinical tumor tissue-derived MIC-1 was a positive regulator of chemokines and genes involved in the ribosome biogenesis pathway, supporting the in vitro assessments. Moreover, MIC-1-correlated chemokine expressions predicted poor prognoses in patients with colorectal cancer. Ribosome-based chemokine regulation via MIC-1 signaling would provide novel insights into translational interventions against malignant inflammatory insults.

Knowledge translation interventions for facilitating evidence-informed decision-making amongst health policymakers

Objectives This is a protocol for a Cochrane Review (intervention). The objectives are as follows: The aim of this review is to determine the effectiveness of knowledge translation interventions for facilitating evidence‐informed decision‐making amongst health policymakers.

Cellular Senescence and Periodontitis: Mechanisms and Therapeutics.

Simple SummaryOral health is increasingly recognized as an important part of overall health. Tooth loss is a contributor to overall musculoskeletal frailty and is closely associated with increased morbidity in the elderly population. Limited intervention exists to alleviate tooth loss associated with periodontitis, other than antibiotics. Mounting evidence suggests that targeting cellular senescence could slow down the fundamental aging process, and thus alleviate a wide range of age-related tissue dysfunctions, likely including tooth loss. Therefore, we feel it might be valuable to review the current understanding of the role and potential mechanisms of senescent cells in oral health with aging.Periodontitis is a chronic inflammatory disease which increases in prevalence and severity in the older population. Aging is a leading risk factor for periodontitis, which exacerbates alveolar bone loss and results in tooth loss in the elderly. However, the mechanism by which aging affects periodontitis is not well understood. There is considerable evidence to suggest that targeting cellular senescence could slow down the fundamental aging process, and thus alleviate a series of age-related pathological conditions, likely including alveolar bone loss. Recently, it has been discovered that the senescent cells accumulate in the alveolar bone and promote a senescence-associated secretory phenotype (SASP). Senescent cells interacting with bacteria, together with secreted SASP components altering the local microenvironment and inducing paracrine effects in neighboring cells, exacerbate the chronic inflammation in periodontal tissue and lead to more alveolar bone loss. This review will probe into mechanisms underlying excessive alveolar bone loss in periodontitis with aging and discuss potential therapeutics for the treatment of alveolar bone loss targeting cellular senescence and the SASP. Inspecting the relationship between cellular senescence and periodontitis will lead to new avenues of research in this field and contribute to developing potential translatable clinical interventions to mitigate or even reverse the harmful effects of aging on oral health.

Epigenetic Mediation of Prenatal Tobacco and Alcohol Exposure and Infant Neurodevelopment in a South African Birth Cohort: A High-Dimensional Mediation Analysis

BACKGROUND AND AIMS Prenatal tobacco exposure (PTE) and prenatal alcohol exposure (PAE) have been associated with an increased risk of delayed neurodevelopment in children as well as differential newborn DNA methylation (DNAm). However, the biological mechanisms connecting PTE and PAE, DNAm, and neurodevelopment are largely unknown. Here we aim to determine whether differential DNAm in cord blood mediates the association between PTE and PAE and neurodevelopment in 113 children of 6 months of age from the South African Drakenstein Child Health Study. METHODS PTE and PAE were assessed antenatally using urine cotinine measurements and the ASSIST questionnaire, respectively. DNAm was measured from cord blood using the EPIC and 450K BeadChips. Neurodevelopment was measured at 6 months across five domains (cognitive, language, motor, adaptive behavior, socioemotional) using the Bayley Scale of Infant and Toddler Development, Third Edition. We conducted a high-dimensional mediation analysis using a novel approach called the divide-aggregate composite null test (DACT), followed by causal mediation analysis to estimate the average causal mediation effects (ACME) and total effect (TE). RESULTS In this population, 35% of mothers actively smoked and 23% of mothers consumed alcohol during pregnancy. We identified 31 CpG sites and 8 CpG sites to have a significant mediating effect (ACME and TE P &amp;#x3c;0.05) between PTE and cognitive and motor development, respectively. For PAE, 16 CpG sites and 1 CpG site had a significant mediating effect on motor and adaptive behavior development, respectively. CONCLUSIONS These findings suggest that changes in the methylome may in part explain the biological mechanisms underlying the relationship between PTE and PAE and infant neurodevelopment. The identification of significant CpG sites could provide novel insights for early detection of disease and potential prevention targets in translational research and community interventions in at-risk populations. KEYWORDS: epigenomics; mediation analysis; neurodevelopment; prenatal smoking; prenatal alcohol exposure

The impact of an integrated, interprofessional knowledge translation intervention on access to inpatient rehabilitation for persons with cognitive impairment.

Stroke rehabilitation teams' skills and knowledge in treating persons with cognitive impairment (CI) contribute to their reduced access to inpatient rehabilitation. This study examined stroke inpatient rehabilitation referral acceptance rates for persons with CI before and after the implementation of a multi-faceted integrated knowledge translation (KT) intervention aimed at improving clinicians' skills in a cognitive-strategy based approach, Cognitive Orientation to daily Occupational Performance (CO-OP), CO-OP KT. CO-OP KT was implemented at five inpatient rehabilitation centres, using an interrupted time series design and data from an electronic referral and database system called E-Stroke. CO-OP KT included a 2-day workshop, 4 months of implementation support, health system support, and a sustainability plan. A mixed effects model was used to model monthly acceptance rates for 12 months prior to the intervention and 6 months post. The dataset was comprised of 2604 pre-intervention referrals and 1354 post. In the mixed effects model, those with CI had a lower pre-intervention acceptance rate than those without. Post-intervention the model showed the acceptance rate for those with CI increased by 8.6% (p = 0.02), whereas those with no CI showed a non-significant increase of less than 1%. Proportionally more persons with CI gained access to inpatient stroke rehabilitation following an integrated KT intervention.