An integrated mechanical degradation model to explore the mechanical response of a bioresorbable polymeric scaffold.

Simulation of bioresorbable medical devices is hindered by the limitations of current material models. Useful simulations require that both the short- and long-term response must be considered; existing models are not physically-based and provide limited insight to guide performance improvements. This study presents an integrated degradation framework which couples a physically-based degradation model, which predicts changes in both crystallinity (Xc) and molecular weight (Mn), with the results of a micromechanical model, which predicts the effective properties of the semicrystalline polymer. This degradation framework is used to simulate the deployment of a bioresorbable PLLA (Poly (L-lactide) stent into a mock vessel and the subsequent mechanical response during degradation under different diffusion boundary conditions representing neointimal growth. A workflow is established in a commercial finite element code that couples both the immediate and long-term responses. Clinically relevant lumen loss is reported and used to compare different responses and the effect of neo-intimal tissue regrowth post-implantation on degradation and on the mechanical response is assessed. In addition, the effects of possible changes in Xc, which could occur during processing and stent deployment, are explored.

Ultra-high throughput mapping of genetic design space.

Massively parallel genetic screens have been used to map sequence-to-function relationships for a variety of genetic elements. However, because these approaches only interrogate short sequences, it remains challenging to perform high throughput (HT) assays on constructs containing combinations of sequence elements arranged across multi-kb length scales. Overcoming this barrier could accelerate synthetic biology; by screening diverse gene circuit designs, "composition-to-function" mappings could be created that reveal genetic part composability rules and enable rapid identification of behavior-optimized variants. Here, we introduce CLASSIC, a generalizable genetic screening platform that combines long- and short-read next-generation sequencing (NGS) modalities to quantitatively assess pooled libraries of DNA constructs of arbitrary length. We show that CLASSIC can measure expression profiles of >10 5 drug-inducible gene circuit designs (ranging from 6-9 kb) in a single experiment in human cells. Using statistical inference and machine learning (ML) approaches, we demonstrate that data obtained with CLASSIC enables predictive modeling of an entire circuit design landscape, offering critical insight into underlying design principles. Our work shows that by expanding the throughput and understanding gained with each design-build-test-learn (DBTL) cycle, CLASSIC dramatically augments the pace and scale of synthetic biology and establishes an experimental basis for data-driven design of complex genetic systems.

The effect of opioids on the efficacy of immunotherapy in recurrent/metastatic squamous cell carcinoma of the head and neck.

OBJECTIVES: Head and neck squamous cell carcinoma (HNSCC) causes severe pain and opioids, the mainstay of pain management, may have immunomodulatory effects. We evaluated the effect of opioids on immunotherapy efficacy in recurrent/metastatic (R/M) HNSCC patients. MATERIALS AND METHODS: In a retrospective study of 66 R/M HNSCC patients from 2015 to 2020, opioid dosage, calculated as mean morphine milligram equivalent per day, was assessed on the day of anti-PD-1 monoclonal antibody (mAb) treatment and most recent prior visit. Intratumoral T cells were evaluated by single cell RNAseq and immunohistochemistry prior to treatment. Univariable and multivariable Cox proportional hazards and logistic regression models were used to estimate the association between opioid usage, progression-free survival (PFS), overall survival (OS), disease control rate. RESULTS: Patients were 79% male, 35% oropharynx, 35% oral cavity, 40% locoregional recurrence, and 56% platinum failure. Higher opioid dosage by continuous variable was significantly associated with lower PFS (p = 0.016) and OS (p < 0.001). In multivariable analysis, including platinum failure status and PD-L1, higher opioids were associated with lower OS. Opioid usage by categorical variable was associated with significantly lower intratumoral CD8+ T cells. Opioid receptor, OPRM1, expression was identified in intratumoral and circulating T cells. CONCLUSIONS: In our study cohort of anti-PD-1 mAb treatment in R/M HNSCC patients, higher opioids were associated with significantly lower PFS and OS and lower CD8+ T cells in the tumor microenvironment. To our knowledge, this is the first analysis in R/M HNSCC patients and further research into the clinical and biologic effect of opioids is warranted.

Immunotherapy in Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck.

Head and neck cancer is the 6th most common cancer worldwide with the most common histology being squamous cell carcinoma (HNSCC). While the majority of patients present at a stage where curative intent therapy is possible, when patients recur and/or develop metastatic disease, outcomes are generally poor, especially with systemic therapy alone, and they lag behind other solid tumors. Over the last decade immunotherapy has revolutionized the field of oncology, and anti-PD-1-based therapy has changed the standard of care in recurrent/metastatic (R/M) HNSCC as well. With these gains have come new questions to continue to move the field forward. In this review, we discuss the tumor immune microenvironment and predictive biomarkers and current status and future directions for immunotherapy in recurrent/metastatic head and neck cancer.

A hepatitis C elimination model in healthcare for the homeless organization: A novel reflexive laboratory algorithm and equity assessment.

BACKGROUND: Reaching World Health Organization hepatitis C (HCV) elimination targets requires diagnosis and treatment of people who use drugs (PWUD) with direct acting antivirals (DAAs). PWUD experience challenges engaging in HCV treatment, including needing multiple provider and laboratory appointments. Women, minoritized racial communities, and homeless individuals are less likely to complete treatment. METHODS: We implemented a streamlined opt-out HCV screening and linkage-to-care program in two healthcare for the homeless clinics and a medically supported withdrawal center. Front-line staff initiated a single-order reflex laboratory bundle combining screening, confirmation, and pre-treatment laboratory evaluation from a single blood draw. Multinomial logistic regression models identified characteristics influencing movement through each stage of the HCV treatment cascade. Multiple logistic regression models identified patient characteristics associated with HCV care cascade progression and Cox proportional hazards models assessed time to initiation of DAAs. RESULTS: Of 11,035 clients engaged in services between May 2017 and March 2020, 3,607 (32.7%) were screened. Of those screened, 1,020 (28.3%) were HCV PCR positive. Of those with detectable RNA, 712 (69.8%) initiated treatment and 670 (94.1%) completed treatment. Of those initiating treatment, 407 (57.2%) achieved SVR12. There were eight treatment failures and six reinfections. In the unadjusted model, the bundle intervention was associated with increased care cascade progression, and in the survival analysis, decreased time to initiation; these differences were attenuated in the adjusted model. Women were less likely to complete treatment and SVR12 labs than men. Homelessness increased likelihood of screening and diagnosis but was negatively associated with completing SVR12 labs. Presence of opioid and stimulant use disorder diagnoses predicted increased care cascade progression. CONCLUSIONS: The laboratory bundle and referral pathways improved treatment initiation, time to initiation, and movement across the cascade. Despite overall population improvements, women and homeless individuals experienced important gaps across the HCV care cascade.

Lifelong Aspirin for All in the Secondary Prevention of Chronic Coronary Syndrome: Still Sacrosanct or Is Reappraisal Warranted?

Four decades have passed since the first trial suggesting the efficacy of aspirin in the secondary prevention of myocardial infarction. Further trials, collectively summarized by the Antithrombotic Trialists' Collaboration, solidified the historical role of aspirin in secondary prevention. Although the benefit of aspirin in the immediate phase after a myocardial infarction remains incontrovertible, a number of emerging lines of evidence, discussed in this narrative review, raise some uncertainty as to the primacy of aspirin for the lifelong management of all patients with chronic coronary syndrome (CCS). For example, data challenging the previously unquestioned role of aspirin in CCS have come from recent trials where aspirin was discontinued in specific clinical scenarios, including early discontinuation of the aspirin component of dual antiplatelet therapy after percutaneous coronary intervention and the withholding of aspirin among patients with both CCS and atrial fibrillation who require anticoagulation. Recent primary prevention trials have also failed to consistently demonstrate net benefit for aspirin in patients treated to optimal contemporary cardiovascular risk factor targets, indicating that the efficacy of aspirin for secondary prevention of CCS may similarly have changed with the addition of more modern secondary prevention therapies. The totality of recent evidence supports further study of the universal need for lifelong aspirin in secondary prevention for all adults with CCS, particularly in stable older patients who are at highest risk for aspirin-induced bleeding.

Late Erosion of Percutaneous ASD Occlusion Device.

Percutaneous closure of atrial septal defects (ASDs) is an ever more common treatment modality in selected patients. Device erosion is a rare but often fatal complication of this therapy, which usually presents early in the post-procedure course. We describe the case of a patient presenting with chest pain and shock in whom early recognition and intervention prevented a negative outcome. Awareness of this potentially lethal complication is important as the population of patients undergoing percutaneous procedures for structural heart disease continues to grow. LEARNING POINTS: As the number of patients undergoing percutaneous atrial septal defect closure increases, so too will the volume presenting with late complications.Early recognition and intervention in cases of device erosion is critical to prevent death.

Etiologies of Extreme Thrombocytosis: A Contemporary Series.

OBJECTIVE: To describe the multifactorial etiologies of extreme thrombocytosis (EXT) in different care settings and the frequency of finding an occult malignancy. PATIENTS AND METHODS: We conducted a retrospective chart review at Mayo Clinic from January 1, 2011, through December 31, 2016. Adult patients who had at least 2 readings of platelet counts greater than 1000×109/L within 30 days of each other were included. We determined the causes of EXT on the basis of preset definitions of precipitating factors and identified the dominant causes on the basis of the trend of platelet counts. RESULTS: A total of 44,490 patients had thrombocytosis, and 305 patients (0.7%) had EXT. In 242 patients (79.3%), EXT was multifactorial. Surgical complications (54.1%) and hematologic malignancies (27.9%) were the 2 most dominant causes. Thirty-eight patients (12.5%) had new diagnoses of malignancies, mostly myeloproliferative neoplasms. In inpatients, surgical complications (71.9%), concurrent/previous splenectomy (50.5%), and infections (44.9%) were the most common causes, whereas hematologic malignancies (56.9%), iron deficiency (36.7%), and previous splenectomy (28.4%) were the most common causes in outpatients. Hematologic malignancy was 3.4 times more likely to be the cause of EXT in outpatients than in inpatients (56.9% vs 16.8%), and a new diagnosis of hematologic malignancy was 1.9 times more likely to be made in outpatients (15.6% vs 8.2%). Eighty-four percent of patients had resolution of EXT within 30 days. One patient died during the period of EXT. Nonsurgical patients with hematologic malignancies had the most prolonged period of EXT. CONCLUSION: Extreme thrombocytosis is a multifactorial hematologic condition, and its etiology differs substantially between inpatients and outpatients. Occult hematologic malignancies are uncommon in EXT when other major causes are present.

Characteristics of long-term survivors with multiple myeloma: A National Cancer Data Base analysis.

BACKGROUND: There exist insufficient data characterizing patients with multiple myeloma (MM) who experienced prolonged survival. A population-based analysis of long-term survivors was conducted to investigate the roles of sociodemographic factors and upfront stem cell transplantation (SCT). METHODS: The National Cancer Data Base is a US cancer database of approximately 34 million patients from >1500 cancer centers. Patients with MM were identified using the International Classification of Diseases for Oncology (ICD-O) code 9732 from January 2004 to December 2006 and were divided into 4 groups based on overall survival (OS). Sociodemographic characteristics, treatment facility, and use of SCT were recorded. The univariate and multivariate analyses were performed using multiple logistic regression and Pearson chi-square tests. RESULTS: A total of 26,986 patients with MM were identified. The median OS was 2.74 years. The majority of patients were male (54%), white (77%), insured (93%) and otherwise healthy (78%), lived in a metropolitan area (82%), were of high income (66%) and educational (58%) levels, and received treatment at nonacademic facilities (63%). Upfront SCT was used in 10% of patients. One in 6 patients (16%) were long-term survivors (group 4). When comparing group 4 (OS of ≥8.22 years) with the other groups (OS of <8.22 years), young age, female sex, high income and educational levels, residence in a rural area, insured status, no comorbidity, receipt of upfront SCT, and treatment at high-volume facilities were associated with long-term survival. CONCLUSIONS: Key differences in sociodemographic characteristics, patient volume at treatment facilities, and upfront SCT were associated with long-term survival. Improvements in health care access and health literacy, upfront SCT, and treatment at high-volume facilities might prolong patient survival.

Short-course versus long-course antibiotics in prosthetic joint infections: a systematic review and meta-analysis of one randomized controlled trial plus nine observational studies.

BACKGROUND: Prosthetic joint infections (PJIs) often require long-course antibiotic therapy. However, recent studies argue against the current practice and raise concerns such as the development of antibiotic resistance, side effects of medications and medical costs. OBJECTIVES: To review and compare the outcomes of short-course and long-course antibiotics in PJIs. METHODS: We conducted a systemic review and meta-analysis using a predefined search term in PubMed and EMBASE databases. Studies that met the inclusion criteria from inception to June 2018 were included. The quality of the included studies was assessed. RESULTS: A total of 10 articles and 856 patients were analysed, comprising 9 observational studies and 1 randomized controlled trial. Our meta-analysis showed no significant difference between short-course and long-course antibiotics (relative risk = 0.87, 95% CI = 0.62-1.22). Additionally, the older the studied group was, the more short-course antibiotics were favoured. CONCLUSIONS: When treating PJI patients following debridement, antibiotics and implant retention, an 8 week course of antibiotic therapy for total hip arthroplasty and a 75 day course for total knee arthroplasty may be a safe approach. For two-stage exchange, a shorter duration of antibiotic treatment during implant-free periods is also generally safe with the usage of antibiotic-loaded cement spacers.

The Least Mating Pathway: Synthetically Refactoring a Familiar Signaling System for New Applications.

Synthetic refactoring makes naturally occurring regulatory systems more amenable to manipulation by removing or recoding their natural genetic complexity. Shaw et al. apply this technique to the yeast mating response pathway, creating a simplified, highly engineerable signaling module that can be used to construct precisely optimized, application-specific GPCR biosensors.

Short- versus long-course antibiotics in osteomyelitis: A systematic review and meta-analysis.

Current practice of long-term antibiotic use in patients with osteomyelitis is controversial. Recent studies showed short-term antibiotic use to be non-inferior to long-term use, but the results of these studies have been inconsistent. In this review, the PubMed and Embase databases were searched from inception through to June 2018 for randomised controlled trials (RCTs), cohort studies or case-control studies comparing two different durations of antibiotic use. Short antibiotic courses were defined as antibiotics administered for a shorter period than the recommended 4-6 weeks. A random-effects model was used to calculate summary odds ratios (ORs) of treatment failure in patients treated with short-course antibiotics compared with long-course antibiotics. A total of 15 articles (5 RCTs and 10 observational studies) and 3598 patients were included. The overall OR of treatment failure in patients receiving short-course antibiotics was 1.50 [95% confidence interval (CI) 0.97-2.34]. Subgroup analysis revealed that a short course of antibiotic treatment was associated with an increased treatment failure rate in vertebral osteomyelitis (OR = 2.06, 95% CI 1.18-3.57) while having a similar rate to a long antibiotic course in acute osteomyelitis of childhood (OR = 1.86, 95% CI 0.75-4.64). Meta-regression found a higher proportion of Staphylococcus aureus infection was related to a higher risk of treatment failure in patients with vertebral osteomyelitis (Coef. = 4.996; P = 0.032). Short-course antibiotics are safe and effective in children with acute osteomyelitis. Long-course antibiotics may still be preferred in vertebral osteomyelitis, especially in patients with S. aureus infection.

Physical activity and mental health in an Irish population.

BACKGROUND: Physical activity represents a modifiable behaviour which may be associated with increased likelihood of experiencing positive mental health. AIMS: The aim of this study was to examine the association between self-rated physical activity and subjective indicators of both positive and negative mental health in an Irish adult population. METHODS: Based on data from a population-based, observational, cross-sectional study, participants were categorised using the International Physical Activity Questionnaire (IPAQ) into those who reported that they did and did not meet recommended physical activity requirements. Self-reported positive and negative mental health indicators were assessed using the Energy and Vitality Index (EVI) and the Mental Health Index-5 (MHI-5) from the SF-36 Health Survey Instrument, respectively. Binary logistic regression was used to identify variables independently associated with self-reported positive and negative mental health. RESULTS: A total of 7539 respondents were included in analysis. Overall, 32% reported that they met recommended minimal physical activity requirements. Self-reported positive and negative mental health were reported by 16 and 9% of respondents, respectively. Compared with those who reported meeting-recommended physical activity requirements, those performing no physical activity were three times less likely to report positive mental health (adjusted odds ratio (OR) 0.39, 95% confidence interval (CI) 0.28-0.55) and three times more likely to report negative mental health (OR 3.27, 95% CI 2.38-4.50). CONCLUSION: Compared with those who do not, those who report meeting-recommended physical activity requirements are more and less likely to report experiencing positive and negative mental health, respectively. Future policy development around physical activity should take cognisance of the impact of this activity on both physical and mental health outcomes.

A systematic review of the clinical effectiveness of emergency endovascular therapy using mechanical thrombectomy in acute ischaemic stroke: implications for service delivery.

BACKGROUND: Twelve randomised controlled trials (RCTs) comparing mechanical thrombectomy against traditional treatment options for patients experiencing acute ischaemic stroke (AIS) have been published. AIMS: To evaluate whether this technology is more effective and/or safer than traditional treatment options and to assess the potential for implementation of this technology as a treatment strategy for acute ischaemic stroke in Ireland. METHODS: RCTs published up to February 2017 were included. Meta-analysis was performed for two primary (mortality at 90 days, mRS at 90 days) and four secondary outcomes. Cumulative meta-analysis was used to investigate the point at which a consistent treatment effect was observed for outcomes that had a statistically significant pooled effect. RESULTS: Mechanical thrombectomy was associated with higher likelihood of being independent (mRS, p < 0.01; Barthel index, p < 0.01) at 90 days post-AIS (p < 0.001). Cumulative meta-analysis demonstrated a consistent treatment effect in favour of mechanical thrombectomy after each trial was added to the analysis. There was no evidence of a difference in mortality rates (p = 0.21) or rates of SICH (p = 0.71) between patients randomised to intervention and control arms. Although the intervention appears to be associated with higher rates of any cerebral haemorrhage (p < 0.01) and recurrent ischaemic stroke (p = 0.03), considerable uncertainty remains as to these treatment effects. CONCLUSIONS: The trials published most recently have acted as a 'watershed' for mechanical thrombectomy, and while there are significant caveats, the data suggests that mechanical thrombectomy needs to be factored into the planning and delivery of services for the management of patients with acute ischaemic stroke in Ireland.

Acute ischaemic stroke: a systematic review of the cost-effectiveness of emergency endovascular therapy using mechanical thrombectomy.

PURPOSE: Although good evidence exists regarding the clinical effectiveness of mechanical thrombectomy for people with acute ischaemic stroke, cost-effectiveness should also be considered. The aim of this study was to systematically review the evidence of cost-effectiveness of emergency endovascular therapy using mechanical thrombectomy in the management of acute ischaemic stroke. METHODS: The search was carried out in PubMed, EMBASE, Cochrane Library, and a grey literature search. Studies were included if they compared the costs and consequences of mechanical thrombectomy added to usual medical care compared to usual care alone for people with acute ischaemic stroke in the anterior and/or posterior region. Study quality was assessed using two appraisal tools tailored to economic evaluations. FINDINGS: Thirteen studies were identified including twelve cost-utility analyses and one cost-benefit analysis. Studies could be dichotomised into those that evaluated first-generation (n = 4) and second-generation (n = 9) mechanical thrombectomy devices. Six studies had low applicability, six had moderate applicability, and one had high applicability to other settings. All cost-utility studies reported incremental cost-effectiveness ratios that would be considered cost-effective under typical willingness-to-pay thresholds. CONCLUSIONS: If the outcomes of the trials underpinning the evidence of clinical effectiveness can be replicated, then mechanical thrombectomy is likely to be cost-effective by typical willingness-to-pay thresholds. This finding holds under the assumption that no investment is required to develop stroke centres to the standard required to provide a safe emergency endovascular service and that additional expenditure on timely patient transport is not required.

Chemsex, risk behaviours and sexually transmitted infections among men who have sex with men in Dublin, Ireland.

BACKGROUND: Drug use for or during sex ('chemsex') among MSM has caused concern, because of the direct effects of the drugs themselves, and because of an increased risk of transmission of sexually transmitted infections (STIs). This study aimed to assess the prevalence of chemsex, associated behaviours and STIs among attendees at Ireland's only MSM-specific sexual health clinic in Dublin over a six week period in 2016. METHODS: The questionnaire collected demographic data, information on sexuality and sexual practice, self-reported history of treatment for STIs, and chemsex use. Key variables independently associated with treatment for STIs over the previous 12 months were identified using multivariable logistic regression. RESULTS: The response rate was 90% (510/568). One in four (27%) reported engaging in chemsex within the previous 12 months. Half had taken ≥2 drugs on his last chemsex occasion. One in five (23%) reported that they/their partners had lost consciousness as a result of chemsex. Those engaging in chemsex were more likely to have had more sexual partners(p<0.001), more partners for anal intercourse (p<0.001) and to have had condomless anal intercourse(p=0.041). They were also more likely to report having been treated for gonorrhoea over the previous 12 months (adjusted OR 2.03, 95% CI 1.19-3.46, p=0.009). One in four (25%) reported that chemsex was impacting negatively on their lives and almost one third (31%) reported that they would like help or advice about chemsex. CONCLUSION: These results support international evidence of a chemsex culture among a subset of MSM. They will be used to develop an effective response which simultaneously addresses addiction and sexual ill-health among MSM who experience harm/seek help as a consequence of engagement in chemsex.

Public knowledge and understanding of dementia-evidence from a national survey in Ireland.

Background: there is growing consensus around the importance of population level approaches which seek to improve public knowledge and awareness of dementia. Aim: to assess knowledge of the relationship between dementia and ageing, and of the risk and protective factors associated with it, among the general public in Ireland. Design: cross-sectional survey. Participants selected using quota sampling based on Census data. Methods: the final sample of 1,217 respondents provided estimates of dementia knowledge in the Irish population. Logistic regression was used to assess the impact of potential predictor variables on knowledge of dementia. Results: a majority (52%) reported that they knew someone living with dementia. Just 39% were confident that they could tell the difference between the early signs of dementia and normal ageing. Less than half (46%) believed that there were things they could do to reduce their risk of developing dementia, and knowledge of risk and protective factors for dementia was very poor. Although significant differences were seen according to area of residence, social class and experience of dementia, even those groups with 'better' understanding demonstrated substantial knowledge deficits regarding risk and protective factors. Conclusions: the general public in Ireland are confused about the relationship between dementia and ageing, and knowledge of risk and protective factors for dementia is very poor. While not dissimilar to those reported internationally, the findings present a challenge to those tasked with promoting behaviour change and interventions to delay or prevent the onset of dementia.

Hyaluronan Hydrogels for a Biomimetic Spongiosa Layer of Tissue Engineered Heart Valve Scaffolds.

Advanced tissue engineered heart valves must be constructed from multiple materials to better mimic the heterogeneity found in the native valve. The trilayered structure of aortic valves provides the ability to open and close consistently over a full human lifetime, with each layer performing specific mechanical functions. The middle spongiosa layer consists primarily of proteoglycans and glycosaminoglycans, providing lubrication and dampening functions as the valve leaflet flexes open and closed. In this study, hyaluronan hydrogels were tuned to perform the mechanical functions of the spongiosa layer, provide a biomimetic scaffold in which valve cells were encapsulated in 3D for tissue engineering applications, and gain insight into how valve cells maintain hyaluronan homeostasis within heart valves. Expression of the HAS1 isoform of hyaluronan synthase was significantly higher in hyaluronan hydrogels compared to blank-slate poly(ethylene glycol) diacrylate (PEGDA) hydrogels. Hyaluronidase and matrix metalloproteinase enzyme activity was similar between hyaluronan and PEGDA hydrogels, even though these scaffold materials were each specifically susceptible to degradation by different enzyme types. KIAA1199 was expressed by valve cells and may play a role in the regulation of hyaluronan in heart valves. Cross-linked hyaluronan hydrogels maintained healthy phenotype of valve cells in 3D culture and were tuned to approximate the mechanical properties of the valve spongiosa layer. Therefore, hyaluronan can be used as an appropriate material for the spongiosa layer of a proposed laminate tissue engineered heart valve scaffold.

A thermodynamically motivated model for stress-fiber reorganization.

We present a model for stress-fiber reorganization and the associated contractility that includes both the kinetics of stress-fiber formation and dissociation as well as the kinetics of stress-fiber remodeling. These kinetics are motivated by considering the enthalpies of the actin/myosin functional units that constitute the stress fibers. The stress, strain and strain rate dependence of the stress-fiber dynamics are natural outcomes of the approach. The model is presented in a general 3D framework and includes the transport of the unbound stress-fiber proteins. Predictions of the model for a range of cyclic loadings are illustrated to rationalize hitherto apparently contrasting observations. These observations include: (1) For strain amplitudes around 10 % and cyclic frequencies of about 1 Hz, stress fibers align perpendicular to the straining direction in cells subjected to cyclic straining on a 2D substrate while the stress fibers align parallel with the straining direction in cells constrained in a 3D tissue. (2) At lower applied cyclic frequencies, stress fibers in cells on 2D substrates display no sensitivity to symmetric applied strain versus time waveforms but realign in response to applied loadings with a fast lengthening rate and slow shortening. (3) At very low applied cyclic frequencies (on the order of mHz) with symmetric strain versus time waveforms, cells on 2D substrates orient perpendicular to the direction of cyclic straining above a critical strain amplitude.