What do primary care providers want to know when caring for patients living with frailty? An analysis of eConsult communications between primary care providers and specialists.

BACKGROUND: Frailty is a complex condition that primary care providers (PCPs) are managing in increasing numbers, yet there is no clear guidance or training for frailty care. OBJECTIVES: The present study examined eConsult questions PCPs asked specialists about patients with frailty, the specialists' responses, and the impact of eConsult on the care of these patients. DESIGN: Cross-sectional observational study. SETTING: ChamplainBASE™ eConsult located in Eastern Ontario, Canada. PARTICIPANTS: Sixty one eConsult cases closed by PCPs in 2019 that use the terms "frail" or "frailty" to describe patients 65 years of age or older. MEASUREMENTS: The Taxonomy of Generic Clinical Questions (TGCQ) was used to classify PCP questions and the International Classification for Primary Care 3 (ICPC-3) was used to classify the clinical content of each eConsult. The impact of eConsult on patient care was measured by PCP responses to a mandatory survey. RESULTS: PCPs most frequently directed their questions to cardiology (n = 7; 11%), gastroenterology (n = 7; 11%), and endocrinology (n = 6; 10%). Specialist answers most often pertained to medications (n = 63, 46%), recommendations for clinical investigation (n = 24, 17%), and diagnoses (n = 22, 16%). Specialist responses resulted in PCPs avoiding referral in 57% (n = 35) of cases whereas referrals were still required in 15% (n = 9) of cases. Specialists responded to eConsults in a median 1.11 days (IQR = 0.3-4.7), and 95% (n = 58) of cases received a response within 7 days. Specialists recorded a median of 15 min to respond (IQR = 10-20), with a median cost of $50.00 CAD (IQR = 33.33 - 66.66) per eConsult. CONCLUSIONS: Through the analysis of questions and responses submitted to eConsult, this study provides novel information on PCP knowledge gaps and approaches to care for patients living with frailty. Furthermore, these analyses provide evidence that eConsult is a feasible and valuable tool for improving care for patients with frailty in primary care settings.

Attenuated sensing of SHH by Ptch1 underlies evolution of bovine limbs.

The large spectrum of limb morphologies reflects the wide evolutionary diversification of the basic pentadactyl pattern in tetrapods. In even-toed ungulates (artiodactyls, including cattle), limbs are adapted for running as a consequence of progressive reduction of their distal skeleton to symmetrical and elongated middle digits with hoofed phalanges. Here we analyse bovine embryos to establish that polarized gene expression is progressively lost during limb development in comparison to the mouse. Notably, the transcriptional upregulation of the Ptch1 gene, which encodes a Sonic hedgehog (SHH) receptor, is disrupted specifically in the bovine limb bud mesenchyme. This is due to evolutionary alteration of a Ptch1 cis-regulatory module, which no longer responds to graded SHH signalling during bovine handplate development. Our study provides a molecular explanation for the loss of digit asymmetry in bovine limb buds and suggests that modifications affecting the Ptch1 cis-regulatory landscape have contributed to evolutionary diversification of artiodactyl limbs.

Establishing an integrated model of subacute care for the frail elderly.

The current health system in Ontario is not designed to meet the needs of frail older adults. This is particularly true for older adults hospitalized due to exacerbation of chronic illness or medical crisis. This article describes the Subacute Care Unit for the Frail Elderly (SAFE) program, one which is designed to serve frail older patients who are at risk of deconditioning or disability associated with prolonged hospitalization but who may safely return home or to a retirement home following up to 4 weeks of subacute care in a restorative environment. The program centres on an intense restorative and integrated care delivery model. The patient population is medically complex, requiring medical supervision and regular adjustment to the care plan to optimize medical status. Individuals are no longer acutely ill and are considered stable or stabilizing. Care and services are designed to improve outcomes for hospitalized frail older adults by proactively addressing the conditions that contribute to alternate level of care before the deconditioning associated with prolonged hospitalization is experienced.

Differential Water Thermodynamics Determine PI3K-Beta/Delta Selectivity for Solvent-Exposed Ligand Modifications.

Phosphoinositide 3-kinases (PI3Ks) are involved in important cellular functions and represent desirable targets for drug discovery efforts, especially related to oncology; however, the four PI3K subtypes (α, ß, γ, and δ) have highly similar binding sites, making the design of selective inhibitors challenging. A series of inhibitors with selectivity toward the ß subtype over δ resulted in compound 3(S), which has entered a phase I/Ib clinical trial for patients with advanced PTEN-deficient cancer. Interestingly, X-ray crystallography revealed that the modifications making inhibitor 3(S) and related compounds selective toward the ß-isoform do not interact directly with either PI3Kß or PI3Kδ, thereby confounding rationalization of the SAR. Here, we apply explicit solvent molecular dynamics and solvent thermodynamic analysis using WaterMap in an effort to understand the unusual affinity and selectivity trends. We find that differences in solvent energetics and water networks, which are modulated upon binding of different ligands, explain the experimental affinity and selectivity trends. This study highlights the critical role of water molecules in molecular recognition and the importance of considering water networks in drug discovery efforts to rationalize and improve selectivity.

Msx1CreERT2 knock-In allele: A useful tool to target embryonic and adult cardiac valves.

Heart valve development begins with the endothelial-to-mesenchymal transition (EMT) of endocardial cells. Although lineage studies have demonstrated contributions from cardiac neural crest and epicardium to semilunar and atrioventricular (AV) valve formation, respectively, most valve mesenchyme derives from the endocardial EMT. Specific Cre mouse lines for fate-mapping analyses of valve endocardial cells are limited. Msx1 displayed expression in AV canal endocardium and cushion mesenchyme between E9.5 and E11.5, when EMT is underway. Additionally, previous studies have demonstrated that deletion of Msx1 and its paralog Msx2 results in hypoplastic AV cushions and impaired endocardial signaling. A knock-in tamoxifen-inducible Cre line was recently generated (Msx1CreERT2) and characterized during embryonic development and after birth, and was shown to recapitulate the endogenous Msx1 expression pattern. Here, we further analyze this knock-in allele and track the Msx1-expressing cells and their descendants during cardiac development with a particular focus on their contribution to the valves and their precursors. Thus, Msx1CreERT2 mice represent a useful model for lineage tracing and conditional gene manipulation of endocardial and mesenchymal cushion cells essential to understand mechanisms of valve development and remodeling.

Msx genes define a population of mural cell precursors required for head blood vessel maturation.

Vessels are primarily formed from an inner endothelial layer that is secondarily covered by mural cells, namely vascular smooth muscle cells (VSMCs) in arteries and veins and pericytes in capillaries and veinules. We previously showed that, in the mouse embryo, Msx1(lacZ) and Msx2(lacZ) are expressed in mural cells and in a few endothelial cells. To unravel the role of Msx genes in vascular development, we have inactivated the two Msx genes specifically in mural cells by combining the Msx1(lacZ), Msx2(lox) and Sm22α-Cre alleles. Optical projection tomography demonstrated abnormal branching of the cephalic vessels in E11.5 mutant embryos. The carotid and vertebral arteries showed an increase in caliber that was related to reduced vascular smooth muscle coverage. Taking advantage of a newly constructed Msx1(CreERT2) allele, we demonstrated by lineage tracing that the primary defect lies in a population of VSMC precursors. The abnormal phenotype that ensues is a consequence of impaired BMP signaling in the VSMC precursors that leads to downregulation of the metalloprotease 2 (Mmp2) and Mmp9 genes, which are essential for cell migration and integration into the mural layer. Improper coverage by VSMCs secondarily leads to incomplete maturation of the endothelial layer. Our results demonstrate that both Msx1 and Msx2 are required for the recruitment of a population of neural crest-derived VSMCs.

Msx1 and Msx2 promote meiosis initiation.

The mechanisms regulating germ line sex determination and meiosis initiation are poorly understood. Here, we provide evidence for the involvement of homeobox Msx transcription factors in foetal meiosis initiation in mammalian germ cells. Upon meiosis initiation, Msx1 and Msx2 genes are strongly expressed in the foetal ovary, possibly stimulated by soluble factors found there: bone morphogenetic proteins Bmp2 and Bmp4, and retinoic acid. Analysis of Msx1/Msx2 double mutant embryos revealed a majority of undifferentiated germ cells remaining in the ovary and, importantly, a decrease in the number of meiotic cells. In vivo, the Msx1/Msx2 double-null mutation prevented full activation of Stra8, a gene required for meiosis. In F9 cells, Msx1 can bind to Stra8 regulatory sequences and Msx1 overexpression stimulates Stra8 transcription. Collectively, our data demonstrate for the first time that some homeobox genes are required for meiosis initiation in the female germ line.

Mouse digit tip regeneration is mediated by fate-restricted progenitor cells.

Regeneration of appendages is frequent among invertebrates as well as some vertebrates. However, in mammals this has been largely relegated to digit tip regeneration, as found in mice and humans. The regenerated structures are formed from a mound of undifferentiated cells called a blastema, found just below the site of amputation. The blastema ultimately gives rise to all of the tissues in the regenerate, excluding the epidermis, and has classically been thought of as a homogenous pool of pluripotent stem cells derived by dedifferentiation of stump tissue, although this has never been directly tested in the context of mammalian digit tip regeneration. Successful digit tip regeneration requires that the level of amputation be within the nail bed and depends on expression of Msx1. Because Msx1 is strongly expressed in the nail bed mesenchyme, it has been proposed that the Msx1-expressing cells represent a pluripotent cell population for the regenerating digit. In this report, we show that Msx1 is dynamically expressed during digit tip regeneration, and it does not mark a pluripotent stem cell population. Moreover, we show that both the ectoderm and mesoderm contain fate-restricted progenitor populations that work in concert to regenerate their own lineages within the digit tip, supporting the hypothesis that the blastema is a heterogeneous pool of progenitor cells.

[François Gros: a leading figure, a secretive man]. / François Gros : Une personnalité de premier plan, un homme secret.

I joined François Gros' laboratory in 1975, to study mechanisms of gene expression in eukaryotes. Despite the lack of powerful tools, that would be brought later by genetic engineering, I obtained publishable results and was allowed to defend a third cycle thesis. Thereafter, I joined Margaret Buckingham's group, which was empowering within François' laboratory. I maintained regular meetings with François, a leading figure but a secretive man, who did not readily open up. It was my privilege, over the more than 45 years I have been around him, to have glimpses over what had been really significant to him. This has been a rich and very precious experience.

J'ai rejoint le laboratoire de François Gros en 1975, pour étudier les mécanismes de l'expression génétique chez les eucaryotes. Malgré la carence en outils performants, qu'allait apporter le génie génétique, j'ai obtenu des résultats publiables et pu soutenir une thèse de 3 e cycle. Après cela, j'ai rejoint le groupe de Margaret Buckingham, qui s'autonomisait dans le laboratoire de François. J'ai continué à avoir des rencontres régulières avec François, personnalité de premier plan mais homme secret, qui ne se livrait pas volontiers. J'ai eu le privilège, au cours des 45 ans et plus où je l'ai côtoyé, d'avoir quelques aperçus de ce qui l'avait marqué, l'avait formé, lui importait vraiment. Ça été une expérience riche et très précieuse.

Focusing on Provider Quality Measurement: Continued Consensus and Feasibility Testing of Practice-Based Quality Measures for Primary Care Providers in Long-Term Care.

Medical providers in long-term care (LTC) use a unique skillset in delivering comprehensive resident care. Publicly reported quality measures (QMs) do not directly emphasize medical provider competency and their role in care. The impact of providers is understudied and to a large extent, unknown. Our objective was to define, test, and validate QMs to pragmatically measure the practice-based quality of medical providers in a pilot study. We included 7 North American LTC homes with data from practicing medical providers for LTC residents. We engaged in a 4-phased approach. In phase 1, experts rated 95 candidate QMs using 5 pragmatic-focused criteria in a RAND-modified Delphi process. Phase 2 involved specifying 37 QMs for collection (4 QMs were dropped during pilot testing). We created an abstraction manual and data collection tool for all QMs. Phase 3 involved a retrospective chart review in 7 LTC homes on 33 QMs with trained data abstractors. Data were sufficient to analyze performance for 26 QMs. Lastly, in phase 4 results and psychometric properties were reviewed with an expert panel. They ranked the tested measures for validity and feasibility for use by a nonphysician auditor to evaluate medical provider performance based on medical record review. In total, we examined data from 343 resident charts from 7 LTC homes and 49 providers. Our process yielded 10 QMs as being specified for measurement, feasible to collect, and had good test performance. This is the only study to systematically identify a subset of QMs for feasible collection from the medical record by various data collectors. This pragmatic approach to measuring practice-based quality and quantifying select medical provider competencies allows for the evaluation of individual and facility-level performance and facilitates quality improvement initiatives. Future work should perform broader testing and validate and refine operationalized QMs.

What Do We Know About Nurse Practitioner/Physician Care Models in Long-Term Care: Results of a Scoping Review.

OBJECTIVES: Due to the rise of the nurse practitioner (NP) role in long-term care settings, it is important to understand the underlying structures and processes that influence NP and physician care models. This scoping review aims to answer the question, "What are the structures, processes, and outcomes of care models involving NPs and physicians in long-term care (LTC) homes?" A secondary aim was to describe the structural enablers and barriers across care models. RESEARCH DESIGN AND METHODS: Seven databases were searched. Studies that described NPs and physicians working in LTC were identified and included in the review. We stratified the findings by care model and synthesized using the Donabedian model, which evaluates health care quality based on 3 dimensions: structure, process, and outcome. We then categorized macro, meso, and micro structural enablers and barriers. RESULTS: Sixty papers were included in the review. The main structural influencers within 5 care models included policies on scope of practice, clarity of role description, and workload. A limited number of papers referred to the process of enabling the development of a working relationship. Thirty-five (49%) studies described resident, staff, and health system outcomes. CONCLUSIONS AND IMPLICATIONS: Although structural characteristics of NP and physician care models are described in-depth, there is less detail on the processes that occur within the NP and physician care models. We highlight structural barriers and enablers within the care models, allowing for recognition of the importance of organizational influence on the NP and physician relationship. Future work should focus on the processes of the relationships in the models by identifying the drivers and initiators of collaboration between NPs and physicians and how these relationships influence outcomes.

Palliative End-of-Life Medication Prescribing Rates in Long-Term Care: A Retrospective Cohort Study.

BACKGROUND: Medications are often needed to manage distressing end-of-life symptoms (eg, pain, agitation). OBJECTIVES: In this study, we describe the variation in prescribing rates of symptom relief medications at the end of life among long-term care (LTC) decedents. We evaluate the extent these medications are prescribed in LTC homes and whether prescribing rates of end-of-life symptom management can be used as an indicator of quality end-of-life care. DESIGN: Retrospective cohort study using administrative health data. SETTING AND PARTICIPANTS: LTC decedents in all 626 publicly funded LTC homes in Ontario, Canada, between January 1, 2017, and March 17, 2020. METHODS: For each LTC home, we measured the percent of decedents who received 1+ prescription(s) for a subcutaneous end-of-life symptom management medication ("end-of-life medication") in their last 14 days of life. We then ranked LTC homes into quintiles based on prescribing rates. RESULTS: We identified 55,916 LTC residents who died in LTC. On average, two-thirds of decedents (64.7%) in LTC homes were prescribed at least 1 subcutaneous end-of-life medication in the last 2 weeks of life. Opioids were the most common prescribed medication (overall average prescribing rate of 62.7%). LTC homes in the lowest prescribing quintile had a mean of 37.3% of decedents prescribed an end-of-life medication, and the highest quintile mean was 82.5%. In addition, across these quintiles, the lowest prescribing quintile had a high average (30.3%) of LTC residents transferred out of LTC in the 14 days compared with the highest prescribing quintile (12.7%). CONCLUSIONS AND IMPLICATIONS: Across Ontario's LTC homes, there are large differences in prescribing rates for subcutaneous end-of-life symptom relief medications. Although future work may elucidate why the variability exists, this study provides evidence that administrative data can provide valuable insight into the systemic delivery of end-of-life care.

Changes in End-of-Life Symptom Management Prescribing among Long-Term Care Residents during COVID-19.

OBJECTIVE: To examine changes in the prescribing of end-of-life symptom management medications in long-term care (LTC) homes during the COVID-19 pandemic. DESIGN: Retrospective cohort study using routinely collected health administrative data in Ontario, Canada. SETTING AND PARTICIPANTS: We included all individuals who died in LTC homes between January 1, 2017, and March 31, 2021. We separated the study into 2 periods: before COVID-19 (January 1, 2017, to March 17, 2020) and during COVID-19 (March 18, 2020, to March 31, 2021). METHODS: For each LTC home, we measured the percentage of residents who died before and during COVID-19 who had a subcutaneous symptom management medication prescription in their last 14 days of life. We grouped LTC homes into quintiles based on their mean prescribing rates before COVID-19, and examined changes in prescribing during COVID-19 and COVID-19 outcomes across quintiles. RESULTS: We captured 75,438 LTC residents who died in Ontario's 626 LTC homes during the entire study period, with 19,522 (25.9%) dying during COVID-19. The mean prescribing rate during COVID-19 ranged from 46.9% to 79.4% between the lowest and highest prescribing quintiles. During COVID-19, the mean prescribing rate in the lowest prescribing quintile increased by 9.6% compared to before COVID-19. Compared to LTC homes in the highest prescribing quintile, homes in the lowest prescribing quintile experienced the highest proportion of COVID-19 outbreaks (73.4% vs 50.0%), the largest mean outbreak intensity (0.27 vs 0.09 cases/bed), the highest mean total days with a COVID-19 outbreak (72.7 vs 24.2 days), and the greatest proportion of decedents who were transferred and died outside of LTC (22.1% vs 8.6%). CONCLUSIONS AND IMPLICATIONS: LTC homes in Ontario had wide variations in the prescribing rates of end-of-life symptom management medications before and during COVID-19. Homes in the lower prescribing quintiles had more COVID-19 cases per bed and days spent in an outbreak.

Generation and characterization of a tamoxifen inducible Msx1(CreERT2) knock-in allele.

Msx1, a member of the Msx gene family, encodes a homeodomain transcription factor and plays critical roles during mouse development in numerous organs. By homologous recombination, we generated a new Msx1 allele (Msx1(CreERT2) ) in which the CreERT2 fusion protein is produced in place of the endogenous Msx1 protein. Using different reporter mouse strains and appropriate tamoxifen treatments, we show that, in mice bearing the Msx1(CrERT2) allele, CreERT2 is capable to induce loxP genomic recombination specifically in Msx1-expressing cells and that this can be obtained during embryonic development as well as after birth. These results show that this new mouse line can be used for lineage tracing of Msx1-expressing cells and their descendants and, combined with Cre-inducible Msx null alleles, for the analysis of Msx1 and/or Msx2 functions in the Msx1-expressing organs, in a time-dependant manner.

Characterization of Pax3-expressing cells from adult blood vessels.

We report expression of Pax3, an important regulator of skeletal muscle stem cell behaviour, in the brachial and femoral arteries of adult mice. In these contractile arteries of the limb, but not in the elastic arteries of the trunk, bands of GFP-positive cells were observed in Pax3(GFP/+) mice. Histological and biochemical examination of the vessels, together with clonal analysis after purification of Pax3-GFP-positive cells by flow cytometry, established their vascular smooth muscle identity. These blood-vessel-derived cells do not respond to inducers of other mesodermal cell types, such as bone, however, they can contribute to muscle fibre formation when co-cultured with skeletal muscle cells. This myogenic conversion depends on the expression of Pax3, but is rare and non-cell autonomous as it requires cell fusion. Myocardin, which promotes acquisition of a mature smooth muscle phenotype in these Pax3-GFP-positive cells, antagonises their potential for skeletal muscle differentiation. Genetic manipulation shows that myocardin is, however, positively regulated by Pax3, unlike genes for other myocardin-related factors, MRTFA, MRTFB or SRF. Expression of Pax3 overlaps with that reported for Msx2, which is required for smooth muscle differentiation of blood vessel-derived multipotent mesoangioblasts. These observations are discussed with respect to the origin and function of Pax3-expressing cells in blood vessels, and more general questions of cell fate determination and adult cell plasticity and reprogramming.

Aging of sensorimotor processes: a systematic study in Fitts' task.

Though age-related decrease in information-processing capacities is hypothesized to be a prominent cause of behavioral slowing, it has been scarcely systematically studied in goal-directed motor tasks. The present study investigated how the decrease in information processing affects the sensorimotor processes underlying the control of a discrete Fitts' task. The index of difficulty (ID) of the task was manipulated using changes in either target distance (D) or target width (W). In each manipulation, movement (MTs), acceleration (ATs) and deceleration times (DTs) of young and older participants were compared across eight ID levels. They were analyzed with efficiency functions, state traces and Brinley plots. Our results showed that older participants were always slower. However, in both age groups, MTs were longer in D manipulation, which resulted from a slowing of both ATs and DTs, while W manipulation affected mainly DTs. In D manipulation, equivalent age-related slowing ratios were observed for AT and DT (1.3). In W manipulation, ATs of older participants were additively slower than those of young participants. Conversely, DTs presented a multiplicative slowing ratio of 1.3. These findings showed that ID manipulations differentially loaded information processing in the nervous system and that age-related slowing of multisensory control processes was independent of the manipulated dimension. Nevertheless, ID manipulations revealed different age-related adaptations to task constraints, suggesting that D and W manipulations are complementary means to assess age-related slowing of the processes involved in target-directed rapid-aiming tasks, with D scaling being more specific to capture the slowing of force-impulse control.

The cost-effectiveness of a nursing home-based transitional care unit for increasing the potential for independent living in the community among hospitalized older adults.

OBJECTIVE: In Canada, a persistent barrier to achieving healthcare system efficiency has been patient days accumulated by individuals with an alternate level of care (ALC) designation. Transitional care units (TCUs) may address the capacity pressures associated with ALC. We sought to assess the cost-effectiveness of a nursing home (NH) based TCU leveraging existing infrastructure to support a hospitalized older adult's transition to independent living at home. METHODS: This case-control study included frail, older adults who received care within a function-focused TCU following a hospitalization between 1 March 2018 and 30 June 2019. TCU patients were propensity score matched to hospitalized ALC patients ("usual care"). The primary outcome was days without requiring institutional care six months following discharge, defined as institutional-free days. This was calculated by excluding all days in hospitals, rehabilitation facilities, complex continuing care facilities and NHs. Using the total direct cost of care up to discharge from TCU or hospital, the incremental cost-effectiveness ratio was calculated. RESULTS: TCU patients spent, on average, 162.0 days institution-free (95% CI: 156.3-167.6d) within six months days post-discharge, while usual care patients spent 140.6 days institution-free (95% CI: 132.3-148.8d). TCU recipients had a lower total cost of care, by CAN$1,106 (95% CI: $-6,129-$10,319), due to the reduced hospital length of stay (mean [SD] 15.6d [13.3d] for TCU patients and 28.6d [67.4d] days for usual care). TCU was deemed the more cost-effective model of care. LIMITATIONS: The main limitation was the potential inclusion of patients not eligible for SAFE in our usual group. To minimize this selection bias, we expanded the geographical pool of ALC patients to patients with SAFE admission potential in other area hospitals. CONCLUSIONS: Through rehabilitative and restorative care, TCUs can reduce hospital length of stay, increase potential for independent living, and reduce risk for subsequent institutionalization.

A persistent barrier to achieving efficiency within the Canadian healthcare system has been days accumulated by patients who no longer require the intensity of hospital care but are waiting to be discharged to more appropriate care settings. Prolonged hospital stays are known to expose patients to various health risks.Transitional care units are care settings designed to improve care continuation for patients moving between different locations or levels of care. They an opportunity to address the capacity pressures and health risks associated with prolonged hospital stays.Studies have demonstrated the effectiveness of transitional care units to improve outcomes among older adults, such as reducing hospital length of stay, nursing home placement, and falls, as well as improving functional status, quality of life, and likelihood of being discharged home. However, the financial implications of transitional care units, in terms of resources required to operate their services, and value for money are not well understood.This study found that a nursing home-based, function-focused transitional care unit reduced the length of stay in hospitals and the risk for subsequent institutionalization among frail, older adults. This was achieved at a lower total cost of care. Older adults who received transitional care were able to remain at home for three weeks longer without requiring institutional care compared to those who did not receive transitional care. Considering the growing investments in transitional care, this research provides evidence supporting nursing home-based transitional care programs.

Ring expansion of cyclic ß-amino alcohols induced by diethylaminosulfur trifluoride: synthesis of cyclic amines with a tertiary fluorine at C3.

As the replacement of a hydrogen atom by a fluorine atom in a compound can have an important impact on its biological properties, the development of methods allowing the introduction of a fluorine atom is of great importance. The scope and limitations of the ring expansion of cyclic 2-hydroxymethyl amines induced by diethylaminosulfur trifluoride (DAST) to produce cyclic ß-fluoro amines was studied as well as the enantioselectivity of the process.

Combining movement kinematics, efficiency functions, and Brinley plots to study age-related slowing of sensorimotor processes: insights from Fitts' task.

BACKGROUND: Measurement of changes in human information-processing capacities underlying slowing of sensorimotor processes is an important challenge for aging research. Methods exist to estimate the magnitude of slowing and variability coefficients, but attempts to apply them in motor tasks have been scarce. In the present experiment we combined movement kinematic analysis, efficiency functions and Brinley plot to assess age-related slowing and variability of sensorimotor processes in a discrete Fitts' aiming task. OBJECTIVES: (1) Quantifying slowing and variability for the different sensorimotor processes involved in aiming movements, and (2) determining whether changes occurred continuously over time by comparing different age groups. METHODS: 29 participants (24-90 years) divided into four age groups were tested. Target size manipulation resulted in three levels of difficulty. Total movement time, durations of the first and secondary movement phases and related variability were analyzed. Fitts and Brinley regression functions were calculated on the basis of the different movement variables. RESULTS: Only older participants were slower than the three younger age groups. For this group, age-difficulty effect was observed for total movement times, but analyses showed that only the secondary movement phase slowed multiplicatively. Additive and proportional increases in variability were also observed in older participants for the first and secondary movement phases, respectively. For the secondary movement phase, estimated slowing coefficients were comparable to those reported in cognitive literature. In addition, Brinley analyses showed that variability increased more than movement time in the secondary movement phase. DISCUSSION: Combination of the different methods of analysis allowed a precise assessment of the locus of slowing and variability of sensorimotor processes in the different movement phases. Results showed that significant changes in both slowing and variability of the different processes occurred late in life. Our findings also suggest that slowing could result from age-induced increase in noise produced by the neural system. Finally, the present results raise the question of whether age-related slowing and increase in variability observed in both cognitive and sensorimotor domains share common causes in the central nervous system.

Msx1 and Msx2 in limb mesenchyme modulate digit number and identity.

Msx1 and Msx2 encode homeodomain transcription factors that play a crucial role in limb development. However, the limb phenotype of the double Msx1(null/null) Msx2(null/null) mutant is difficult to analyze, particularly along the anteroposterior axis, because of the complex effects of the double mutation on both ectoderm- and mesoderm-derived structures. Namely, in the mutant, formation of the apical ectodermal ridge (AER) is impaired anteriorly and, consequently, the subjacent mesenchyme does not form. Using the Cre/loxP system, we investigated the respective roles of Msx genes in ectoderm and mesoderm by generating conditional mutant embryos with no Msx activity solely in the mesoderm. In these mutants, the integrity of the ectoderm-derived AER was maintained, allowing formation of the anterior mesenchyme. With this strategy, we demonstrate that mesenchymal expression of Msx1 and Msx2 is required for proper Shh and Bmp4 signaling to specify digit number and identity.