Geometric control of myogenic cell fate.

This work combines expertise in stem cell biology and bioengineering to define the system for geometric control of proliferation and differentiation of myogenic progenitor cells. We have created an artificial niche of myogenic progenitor cells, namely, modified extracellular matrix (ECM) substrates with spatially embedded growth or differentiation factors (GF, DF) that predictably direct muscle cell fate in a geometric pattern. Embedded GF and DF signal progenitor cells from specifically defined areas on the ECM successfully competed against culture media for myogenic cell fate determination at a clearly defined boundary. Differentiation of myoblasts into myotubes is induced in growth-promoting medium, myotube formation is delayed in differentiation-promoting medium, and myogenic cells, at different stages of proliferation and differentiation, can be induced to coexist adjacently in identical culture media. This method can be used to identify molecular interactions between cells in different stages of myogenic differentiation, which are likely to be important determinants of tissue repair. The designed ECM niches can be further developed into a vehicle for transplantation of myogenic progenitor cells maintaining their regenerative potential. Additionally, this work may also serve as a general model to engineer synthetic cellular niches to harness the regenerative potential of organ stem cells

Measuring decision quality: psychometric evaluation of a new instrument for breast cancer chemotherapy

Background: Women diagnosed with early stage (I or II) breast cancer face a highly challenging decision – whether or not to undergo adjuvant chemotherapy. We developed a decision quality instrument for chemotherapy for early stage breast cancer and sought to evaluate its performance. Methods: Cross-sectional, mailed survey of recent breast cancer survivors, providers, and healthy controls and a retest survey of survivors. The decision quality instrument includes questions on knowledge and personal goals. It results in a knowledge score and concordance score, which reflects the percentage of patients who received treatments that match their goals. Hypotheses related to acceptability, feasibility, validity, and reliability of the survey instrument were examined. Results: Responses were received from 352 patients, 89 providers and 35 healthy controls. The decision quality instrument was feasible to implement with few missing data. The knowledge scores had good retest reliability (intraclass correlation coefficient (ICC) =0.75). Knowledge scores discriminated between providers and patients (mean difference 31.1%, 95% CI 26.9, 35.3) and between patients and healthy controls (mean difference 11.2, 95% CI 5.4, 17.1). Most providers reported that the knowledge items covered essential content. Two of the five goal items had a ceiling effect, and one goal had low content validity. The goal items had moderate retest reliability (ICC’s 0.57 to 0.78). In the multivariable model of treatment, none of the patient goals was associated with receipt of chemotherapy. Age and hormone receptor status were the only variables independently associated with chemotherapy. Most patients (77.6%) had treatment concordant with that predicted by the model. Patients who had concordant treatment had similar levels of confidence and regret as those who did not. Conclusions: The Decision Quality Instrument is a reliable and valid measure of patient knowledge about chemotherapy, but its ability to measure concordance with patient goals is limited. In this sample, patient goals were not associated with treatment, and most patients reported they were not asked their preference, suggesting that goals were not adequately considered in decision making

Direct Observation of the Superfluid Phase Transition in Ultracold Fermi Gases

Water freezes into ice, atomic spins spontaneously align in a magnet, liquid helium becomes superfluid: Phase transitions are dramatic phenomena. However, despite the drastic change in the system's behaviour, observing the transition can sometimes be subtle. The hallmark of Bose-Einstein condensation (BEC) and superfluidity in trapped, weakly interacting Bose gases is the sudden appearance of a dense central core inside a thermal cloud. In strongly interacting gases, such as the recently observed fermionic superfluids, this clear separation between the superfluid and the normal parts of the cloud is no longer given. Condensates of fermion pairs could be detected only using magnetic field sweeps into the weakly interacting regime. The quantitative description of these sweeps presents a major theoretical challenge. Here we demonstrate that the superfluid phase transition can be directly observed by sudden changes in the shape of the clouds, in complete analogy to the case of weakly interacting Bose gases. By preparing unequal mixtures of the two spin components involved in the pairing, we greatly enhance the contrast between the superfluid core and the normal component. Furthermore, the non-interacting wings of excess atoms serve as a direct and reliable thermometer. Even in the normal state, strong interactions significantly deform the density profile of the majority spin component. We show that it is these interactions which drive the normal-to-superfluid transition at the critical population imbalance of 70(5)%.Comment: 16 pages (incl. Supplemental Material), 5 figure

Adherence to adjuvant endocrine therapy among breast cancer survivors: a systematic review and meta-synthesis of the qualitative literature using grounded theory

Purpose: Numerous studies have examined non-adherence to adjuvant endocrine therapy in women recovering from breast cancer, but none provide a comprehensive theory to explain the challenges of long-term medication-taking and resilience needed to continue. The aim of this study was to source, appraise, and synthesise data from existing qualitative studies to develop an in-depth explanatory model of non-adherence and discontinuation of hormonal medication among breast cancer survivors. Methods: A comprehensive search of databases and the literature identified 24 eligible qualitative studies published 2010-2019. Quotations (n= 801) listed within these papers and the original author interpretations were synthesised using NVivo, and grounded theory methodology. Results: At the beginning, knowledge about adjuvant endocrine therapy, trust in doctors, and worries and expectations, mean agreeing to medication is the only viable option, akin to a Hobson’s choice. Thereafter, women’s ability to deal with medication side-effects, knowledge, and support received affect their decision to continue, akin to a horned dilemma where giving up the medication risks cancer recurrence, and continuing means reduced contentment. Women stopping medication altogether question treatment necessity, search for normalcy, and prioritise quality of life. Conclusion: Shared experiences and understandings were uncovered by examining commonalities in existing publications. The core category explained the difficulties women face with the initial decision to accept long-term endocrine therapy and then the everyday challenges of continuing or deciding to stop treatment early. An educational tool to inform survivors and health professionals about these challenges could potentially improve women’s experience on treatment and in turn their adherence

Negative phenotypic and genetic associations between copulation duration and longevity in male seed beetles

Reproduction can be costly and is predicted to trade-off against other characters. However, while these trade-offs are well documented for females, there has been less focus on aspects of male reproduction. Furthermore, those studies that have looked at males typically only investigate phenotypic associations, with the underlying genetics often ignored. Here, we report on phenotypic and genetic trade-offs in male reproductive effort in the seed beetle, Callosobruchus maculatus. We find that the duration of a male's first copulation is negatively associated with subsequent male survival, phenotypically and genetically. Our results are consistent with life-history theory and suggest that like females, males trade-off reproductive effort against longevity

Engaging in Health Behaviors to Lower Risk for Breast Cancer Recurrence

Purpose While post-treatment breast cancer survivors face up to twice the cancer risk of the general population, modifiable health behaviors may somewhat reduce this risk. We sought to better understand health behaviors that early stage breast cancer survivors engage in to reduce recurrence risk. Methods Data came from a cross-sectional multi-site survey of 186 early-stage breast cancer survivors who received genomic testing for breast cancer recurrence risk (Oncotype DX) during their clinical care. Study outcomes were meeting health behavior recommendations (daily fruit and vegetable intake, regular physical activity, and having a healthy body mass index (BMI)). Results Approximately three-quarters of survivors we surveyed believed the 3 behaviors might reduce their cancer risk but many did not engage in these behaviors for this purpose: 62% for BMI, 36% for fruit and vegetable consumption, and 37% for physical activity. Survivors with higher recurrence risk, as indicated by their genomic test results, were no more likely to meet any of the three health behavior recommendations. Adherence to health behavior recommendations was higher for women who were white, college-educated, and had higher incomes. Conclusions Many nonadherent breast cancer survivors wish to use these behavioral strategies to reduce their risk for recurrence, suggesting an important opportunity for intervention. Improving BMI, which has the largest association with cancer risk, is an especially promising target

Ideal timing to transfer from an acute care hospital to an interdisciplinary inpatient rehabilitation program following a stroke: an exploratory study

BACKGROUND: Timely accessibility to organized inpatient stroke rehabilitation services may become compromised since the demand for rehabilitation services following stroke is rapidly growing with no promise of additional resources. This often leads to prolonged lengths of stays in acute care facilities for individuals surviving a stroke. It is believed that this delay spent in acute care facilities may inhibit the crucial motor recovery process taking place shortly after a stroke. It is important to document the ideal timing to initiate intensive inpatient stroke rehabilitation after the neurological event. Therefore, the objective of this study was to examine the specific influence of short, moderate and long onset-admission intervals (OAI) on rehabilitation outcomes across homogeneous subgroups of patients who were admitted to a standardized interdisciplinary inpatient stroke rehabilitation program. METHODS: A total of 418 patients discharged from the inpatient neurological rehabilitation program at the Montreal Rehabilitation Hospital Network after a first stroke (79% of all cases reviewed) were included in this retrospective study. After conducting a matching procedure across these patients based on the degree of disability, gender, and age, a total of 40 homogeneous triads (n = 120) were formed according to the three OAI subgroups: short (less than 20 days), moderate (between 20 and 40 days) or long (over 40 days; maximum of 70 days) OAI subgroups. The rehabilitation outcomes (admission and discharge Functional Independence Measure scores (FIM), absolute and relative FIM gain scores, rehabilitation length of stay, efficiency scores) were evaluated to test for differences between the three OAI subgroups. RESULTS: Analysis revealed that the three OAI subgroups were comparable for all rehabilitation outcomes studied. No statistical difference was found for admission (P = 0.305–0.972) and discharge (P = 0.083–0.367) FIM scores, absolute (P = 0.533–0.647) and relative (P = 0.496–0.812) FIM gain scores, rehabilitation length of stay (P = 0.096), and efficiency scores (P = 0.103–0.674). CONCLUSION: OAI does not seem to affect significantly inpatient stroke rehabilitation outcomes of patients referred from acute care facilities where rehabilitation services are rapidly initiated after the onset of the stroke and offered throughout their stay. However, other studies considering factors such as the type and intensity of the rehabilitation are required to support those results

A homologue of the Parkinson's disease-associated protein LRRK2 undergoes a monomer-dimer transition during GTP turnover.

Mutations in LRRK2 are a common cause of genetic Parkinson's disease (PD). LRRK2 is a multi-domain Roco protein, harbouring kinase and GTPase activity. In analogy with a bacterial homologue, LRRK2 was proposed to act as a GTPase activated by dimerization (GAD), while recent reports suggest LRRK2 to exist under a monomeric and dimeric form in vivo. It is however unknown how LRRK2 oligomerization is regulated. Here, we show that oligomerization of a homologous bacterial Roco protein depends on the nucleotide load. The protein is mainly dimeric in the nucleotide-free and GDP-bound states, while it forms monomers upon GTP binding, leading to a monomer-dimer cycle during GTP hydrolysis. An analogue of a PD-associated mutation stabilizes the dimer and decreases the GTPase activity. This work thus provides insights into the conformational cycle of Roco proteins and suggests a link between oligomerization and disease-associated mutations in LRRK2