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Neurotypically developing children who toe walk usually spontaneously resolve by school age, those who do not are considered to have Persistent Idiopathic Toe Walking (ITWp) and may develop ankle contractures and foot skeletal deformities. Alvarez et al. proposed a classification scheme in 2006. When it was applied to our cohort, it failed to classify many subjects due to ambiguity in the classification scheme definitions

It has been noted that tripping and falling are the greatest source of accidental injury in children with motor disabilities[1]. Tripping most commonly occurs due to a decrease in foot clearance or ineffective limb shortening during the swing phase of gait. Moosabhoy and Gard developed equations based on a planar model of the leg to look directly at joint contributions to foot clearance in the adult population (Fig. 1)[2]. We modified and applied the analytical techniques used by Moosabhoy and Gard to analyze a new population of patients.

By the age of 3, most children develop a mature gait pattern, defined as plantigrade use of the foot with weightbearing through both the heel and metatarsal heads.Children with idiopathic toewalking (ITW) are otherwise neurologically normal but preferentially walk on their tiptoes. ITW resolves in most cases by 6 years of age.Children with persistent ITW (ITWp) may develop ankle contractures and foot skeletal deformities.The Alvarez criteria was established in 2006 and has since been the standard classification for ITWp based

ObjectivesTo characterize the goals and approaches of clinicians with experience discussing long-term prognostic information with older adults.DesignWe used a semistructured interview guide containing 2 domains of perceived benefits and strategies to explore why and how clinicians choose to discuss long-term prognosis, defined as life expectancy on the scale of years, with patients.SettingClinicians from home-based primary care practices, community-based clinics, and academic medical centers across San Francisco.ParticipantsFourteen physicians, including 11 geriatricians and 1 geriatric nurse practitioner, with a mean age of 40 and a mean 9 years in practice.MeasurementsClinician responses were analyzed qualitatively using the constant comparisons approach.ResultsPerceived benefits of discussing long-term prognosis included establishing realistic expectations for patients, encouraging conversations about future planning, and promoting shared decision-making through understanding of patient goals of care. Communication strategies included adapting discussions to individual patient preferences and engaging in multiple conversations over time. Clinicians preferred to communicate prognosis in words and with a visual aid, although most did not know of a suitable visual aid.ConclusionEngaging in customized longitudinal discussions of long-term prognosis aids clinicians in anchoring conversations about future planning and preparing patients for the end of life. J Am Geriatr Soc 66:2367-2371, 2018.

STUDY QUESTION: Does a man (patient 1) with a previously described deficiency in principle cation channel of sperm (CatSper) function have a mutation in the CatSper-epsilon (CATSPERE) and/or CatSper-zeta (CATSPERZ) gene? SUMMARY ANSWER: Patient 1 has a homozygous in-frame 6-bp deletion in exon 18 (c.2393_2398delCTATGG, rs761237686) of CATSPERE. WHAT IS KNOWN ALREADY: CatSper is the principal calcium channel of mammalian spermatozoa. Spermatozoa from patient 1 had a specific loss of CatSper function and were unable to fertilize at IVF. Loss of CatSper function could not be attributed to genetic abnormalities in coding regions of seven CatSper subunits. Two additional subunits (CatSper-epsilon (CATPSERE) and CatSper-zeta (CATSPERZ)) were recently identified, and are now proposed to contribute to the formation of the mature channel complex. STUDY DESIGN, SIZE, DURATION: This was a basic medical research study analysing genomic data from a single patient (patient 1) for defects in CATSPERE and CATSPERZ. PARTICIPANTS/MATERIALS, SETTING, METHODS: The original exome sequencing data for patient 1 were analysed for mutations in CATSPERE and CATSPERZ. Sanger sequencing was conducted to confirm the presence of a rare variant. MAIN RESULTS AND THE ROLE OF CHANCE: Patient 1 is homozygous for an in-frame 6-bp deletion in exon 18 (c.2393_2398delCTATGG, rs761237686) of CATSPERE that is predicted to be highly deleterious. LIMITATIONS, REASONS FOR CAUTION: The nature of the molecular deficit caused by the rs761237686 variant and whether it is exclusively responsible for the loss of CatSper function remain to be elucidated. WIDER IMPLICATIONS OF THE FINDINGS: Population genetics are available for a significant number of predicted deleterious variants of CatSper subunits. The consequence of homozygous and compound heterozygous forms on sperm fertilization potential could be significant. Selective targeting of CatSper subunit expression maybe a feasible strategy for the development of novel contraceptives. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by project grants from the MRC (MR/K013343/1 and MR/012492/1), Chief Scientist Office/NHS research Scotland. This work was also supported by NIH R01GM111802, Pew Biomedical Scholars Award 00028642 and Packer Wentz Endowment Will to P.V.L. C.L.R.B is the editor-in-chief of Molecular Human Reproduction, has received lecturing fees from Merck and Ferring, and is on the Scientific Advisory Panel for Ohana BioSciences. C.L.R.B was chair of the World Health Organization Expert Synthesis Group on Diagnosis of Male infertility (2012-2016).

ImportanceLong-term prognosis informs clinical and personal decisions for older adults with late-life disability. However, many clinicians worry that telling patients their prognosis may cause harm.ObjectiveTo explore the safety of and reactions to prognosis communication in late-life disability.DesignParticipants estimated their own life expectancy and were then presented their calculated life expectancy using a validated prognostic index. We used a semi-structured interview guide to ask for their reactions. Qualitative data were analyzed using constant comparative analysis. Potential psychological and behavioral outcomes in response to receiving one's calculated prognosis were recorded and re-assessed 2-4 weeks later.SettingCommunity-dwelling older adults age 70+ residing in the San Francisco Bay Area.ParticipantsThirty five older adults with a median age of 80 requiring assistance with ≥1 Activity of Daily Living.ResultsSelf-estimates of life expectancy were similar to calculated results for 16 participants. 15 estimated their life expectancy to be longer than their calculated life expectancy by >2 years, while 4 shorter by >2 years. An overarching theme of, "fitting life expectancy into one's narrative" emerged from qualitative analysis. Discussing life expectancy led participants to express how they could alter their life expectancy (subtheme "locus of control"), how they saw their present health (subtheme "perceived health"), and their hopes and fears for the remaining years of their lives (subtheme "outlook on remaining years"). Feelings of anxiety and sadness in reaction to receiving calculated prognosis were rare.Conclusions and relevanceAbout half of the disabled older adults' self-estimates of prognosis were similar to calculated estimates. Evidence of sadness or anxiety was rare. These data suggest that in most cases, clinicians may offer to discuss prognosis.

To help students develop into confident and effective laboratory scientists it is necessary to facilitate their understanding and ability to participate effectively in all processes involved in experimental design and implementation in an engaging and realistic manner. Our challenge was to develop a 20-credit, ordinary degree (without honours) level, practical skills-based module for Biomedical Science students who are not on a National Health Service placement that encompasses elements of professionalism. We describe the design of a module that utilises Inquiry-based learning (IBL) and Quality by Design (QbD) principles and discuss staff experience and reflections following analysis of six years of anonymised module feedback data which includes quantitative and qualitative data. Key positive themes from the qualitative analysis were satisfaction at being able to make evidenced based decisions for changes in experimental factors and development of personal skills which was perceived as helpful for their preparation for their honours year project. The level of challenge that the format of the module presented was perceived negatively. We conclude that this mode of learning is challenging to implement and monitor for academics and challenges students intellectual and professional development, but that the benefits are worth the investment. [ABSTRACT FROM AUTHOR]

Increasing inter-pedal distance (Q-Factor: QF) in cycling increases peak internal knee abduction moments (KAbM). The effect of smaller and normalized changes in QF has not been investigated. The purposes of this study were to examine changes in KAbM with small and normalized increases and whether static knee alignment accounts for any changes in knee biomechanics in cycling. Fifteen healthy participants were included (age: 22.7 ± 2.5 years, BMI: 23.95 ± 3.21 kg/m2). Motion capture and instrumented pedals collected kinematic and pedal reaction force (PRF) data, respectively, while participants cycled at five different QFs. Each participant's mechanical axis angle (MAA) was estimated using motion capture. Each participant's QFs were normalized by starting at 160 mm and increasing by 2% of the participant's leg length (L), where the five QF conditions were as follows: QF1 (160), QF2 (160 + 0.02 × L), QF3 (160 + 0.04 × L), QF4 (160 + 0.06 × L), and QF5 (160 + 0.08 × L). A linear mixed model was performed to detect differences between QF conditions. KAbM increased by more than 30% in QF5 from QF1, QF2, QF3, and QF4. Medial PRF increased by at least 20% in QF5 from QF1, QF2, and QF3. MAA had varying degrees of correlation with the variables of interest. These results suggest that KAbM is more sensitive to changes in QF at greater QF increases. [ABSTRACT FROM AUTHOR]

Study questionAre significant abnormalities in outward (K(+)) conductance and resting membrane potential (Vm) present in the spermatozoa of patients undertaking IVF and ICSI and if so, what is their functional effect on fertilization success?Summary answerNegligible outward conductance (≈5% of patients) or an enhanced inward conductance (≈4% of patients), both of which caused depolarization of Vm, were associated with a low rate of fertilization following IVF.What is known alreadySperm-specific potassium channel knockout mice are infertile with defects in sperm function, suggesting that these channels are essential for fertility. These observations suggest that malfunction of K(+) channels in human spermatozoa might contribute significantly to the occurrence of subfertility in men. However, remarkably little is known of the nature of K(+) channels in human spermatozoa or the incidence and functional consequences of K(+) channel defects.Study design, size and durationSpermatozoa were obtained from healthy volunteer research donors and subfertile IVF and ICSI patients attending a hospital assisted reproductive techniques clinic between May 2013 and December 2015. In total, 40 IVF patients, 41 ICSI patients and 26 normozoospermic donors took part in the study.Participants/materials, setting, methodsSamples were examined using electrophysiology (whole-cell patch clamping). Where abnormal electrophysiological characteristics were identified, spermatozoa were further examined for Ca(2+) influx induced by progesterone and penetration into viscous media if sufficient sample was available. Full exome sequencing was performed to specifically evaluate potassium calcium-activated channel subfamily M α 1 (KCNMA1), potassium calcium-activated channel subfamily U member 1 (KCNU1) and leucine-rich repeat containing 52 (LRRC52) genes and others associated with K(+) signalling. In IVF patients, comparison with fertilization rates was done to assess the functional significance of the electrophysiological abnormalities.Main results and the role of chancePatch clamp electrophysiology was used to assess outward (K(+)) conductance and resting membrane potential (Vm) and signalling/motility assays were used to assess functional characteristics of sperm from IVF and ICSI patient samples. The mean Vm and outward membrane conductance in sperm from IVF and ICSI patients were not significantly different from those of control (donor) sperm prepared under the same conditions, but variation between individuals was significantly greater (P< 0.02) with a large number of outliers (>25%). In particular, in ≈10% of patients (7/81), we observed either a negligible outward conductance (4 patients) or an enhanced inward current (3 patients), both of which caused depolarization of Vm. Analysis of clinical data from the IVF patients showed significant association of depolarized Vm (≥0 mV) with low fertilization rate (P= 0.012). Spermatozoa with electrophysiological abnormities (conductance and Vm) responded normally to progesterone with elevation of [Ca(2+)]i and penetration of viscous medium, indicating retention of cation channel of sperm (CatSper) channel function.Limitations, reasons for cautionFor practical, technical, ethical and logistical reasons, we could not obtain sufficient additional semen samples from men with conductance abnormalities to establish the cause of the conductance defects. Full exome sequencing was only available in two men with conductance defects.Wider implications of the findingsThese data add significantly to the understanding of the role of ion channels in human sperm function and its impact on male fertility. Impaired potassium channel conductance (Gm) and/or Vm regulation is both common and complex in human spermatozoa and importantly is associated with impaired fertilization capacity when the Vm of cells is completely depolarized.Study funding/competing interestsThe majority of the data were obtained using funding from MRC project grants (#MR/K013343/1, MR/012492/1). Additional funding was provided by NHS Tayside, TENOVUS, Chief Scientist Office NRS Fellowship and University of Abertay. The authors declare that there is no conflict of interest.Trial registration numberNot applicable.

Introduction Atrial fibrillation (AF) is the most common arrhythmia diagnosed in clinical practice. Currently, 33.5 million people are affected by AF globally (Wann et al. 2011). As the global population [...], The number of patients diagnosed with atrial fibrillation (AF) has been rising due to increased incidence, enhanced detection methods, and greater survival rates following diagnosis. Due to this increase, AF is now the most commonly diagnosed arrhythmia in clinical practice. AF is characterized by irregular, high-frequency contractions of atrial myocytes that lead to turbulent blood flow and the potential for thrombus formation, stroke, or heart failure. These high-frequency contractions of the atrial myocytes cause an imbalance between metabolic supply and demand. Although advances have been made in understanding the pathophysiology of AF, the etiology and underlying pathogenic mechanism remain unknown. However, recent evidence suggests that cardiomyocyte metabolism involving 5&apos; AMP-activated protein kinase (AMPK) activation is altered in patients with AF. Here, we critically reviewed the current understanding of AMPK activation in AF and how it could affect structural, contractile, and electrophysiological cellular properties in the pathogenesis of AF. Key words: atrial fibrillation, cardiomyocyte metabolism, cardiomyocyte, cardiac metabolism, arrhythmias, AMPK. Le nombre de patient ayant recu un diagnostic de fibrillation atriale (FA) est a la hausse en raison d&apos;une augmentation de son incidence, de l&apos;amelioration des modes de detection et d&apos;une augmentation des taux de survie a la suite du diagnostic. En raison de cette augmentation, la FA est maintenant l&apos;arythmie la plus frequemment diagnostiquee en pratique clinique. La FA se caracterise par des contractions irregulieres a frequence elevee des myocytes atriaux, menant a un flux sanguin turbulent et a la possibilite de la formation d&apos;un thrombus ainsi que de l&apos;apparition d&apos;un AVC et d&apos;une insuffisance cardiaque. Ces contractions a haute frequence des myocytes atriaux entrainent un desequilibre entre l&apos;apport et la demande metaboliques. Bien que des avancees aient ete realisees dans la comprehension de la physiopathologie de la FA, son etiologie et les modes d&apos;action pathogenes sous-jacents demeurent inconnus. Cependant, des donnees recentes laissent entrevoir que le metabolisme des cardiomyocytes mettant en jeu l&apos;activation de la proteine kinase activee par le 5&apos; AMP (AMPK) serait altere chez les patients atteints de FA. Nous presentons ici une synthese critique de la litterature portant sur la comprehension actuelle du role de l&apos;activation de l&apos;AMPK dans la FA, et sur comment celle-la pourrait affecter les proprietes structurelles, contractiles et electrophysiologiques des cellules dans la pathogenese de la FA. [Traduit par la Redaction] Mots-cles : fibrillation atriale, metabolisme des cardiomyocytes, cardiomyocytes, metabolisme cardiaque, arythmies, AMPK.

Study questionAre significant abnormalities of CatSper function present in IVF patients with normal sperm concentration and motility and if so what is their functional significance for fertilization success?Summary answerSperm with a near absence of CatSper current failed to respond to activation of CatSper by progesterone and there was fertilization failure at IVF.What is known alreadyIn human spermatozoa, Ca(2+) influx induced by progesterone is mediated by CatSper, a sperm-specific Ca(2+) channel. A suboptimal Ca(2+) influx is significantly associated with, and more prevalent in, men with abnormal semen parameters, and is associated with reduced fertilizing capacity. However, abnormalities in CatSper current can only be assessed directly using electrophysiology. There is only one report of a CatSper-deficient man who showed no progesterone potentiated CatSper current. A CatSper 2 genetic abnormality was present but there was no information on the [Ca(2+)]i response to CatSper activation by progesterone. Additionally, the semen samples had indicating significant abnormalities (oligoasthenoteratozoospermia) multiple suboptimal functional responses in the spermatozoon. As such it cannot be concluded that impaired CatSper function alone causes infertility or that CatSper blockade is a potential safe target for contraception.Study design, size, durationSpermatozoa were obtained from donors and subfertile IVF patients attending a hospital assisted reproductive techniques clinic between January 2013 and December 2014. In total 134 IVF patients, 28 normozoospermic donors and 10 patients recalled due to a history of failed/low fertilization at IVF took part in the study.Participants/materials, setting, methodsSamples were primarily screened using the Ca(2+) influx induced by progesterone and, if cell number was sufficient, samples were also assessed by hyperactivation and penetration into viscous media. A defective Ca(2+) response to progesterone was defined using the 99% confidence interval from the distribution of response amplitudes in normozoospermic donors. Samples showing a defective Ca(2+) response were further examined in order to characterize the potential CatSper abnormalities. In men where there was a consistent and robust failure of calcium signalling, a direct assessment of CatSper function was performed using electrophysiology (patch clamping), and a blood sample was obtained for genetic analysis.Main results and the role of chanceA total of 101/102 (99%) IVF patients and 22/23 (96%) donors exhibited a normal Ca(2+) response. The mean (± SD) normalized peak response did not differ between donors and IVF patients (2.57 ± 0.68 [n = 34 ejaculates from 23 different donors] versus 2.66 ± 0.68 [n = 102 IVF patients], P = 0.63). In recall patients, 9/10 (90%) showed a normal Ca(2+) response. Three men were initially identified with a defective Ca(2+) influx. However, only one (Patient 1) had a defective response in repeat semen samples. Electrophysiology experiments on sperm from Patient 1 showed a near absence of CatSper current and exon screening demonstrated no mutations in the coding regions of the CatSper complex. There was no increase in penetration of viscous media when the spermatozoa were stimulated with progesterone and importantly there was failed fertilization at IVF.Limitations, reasons for cautionA key limitation relates to working with a specific functional parameter (Ca(2+) influx induced by progesterone) in fresh sperm samples from donors and patients that have limited viability. Therefore, for practical, technical and logistical reasons, some men (∼ 22% of IVF patients) could not be screened. As such the incidence of significant Ca(2+) abnormalities induced by progesterone may be higher than the ∼ 1% observed here. Additionally, we used a strict definition of a defective Ca(2+) influx such that only substantial abnormalities were selected for further study. Furthermore, electrophysiology was only performed on one patient with a robust and repeatable defective calcium response. This man had negligible CatSper current but more subtle abnormalities (e.g. currents present but significantly smaller) may have been present in men with either normal or below normal Ca(2+) influx.Wider implications of the findingsThese data add significantly to the understanding of the role of CatSper in human sperm function and its impact on male fertility. Remarkably, these findings provide the first direct evidence that CatSper is a suitable and specific target for human male contraception.

Improving children's attendance is a high priority for Head Start and other early childhood education programs serving low-income children. We conducted a randomized control trial in a major northern city to evaluate the impact of a low-cost intervention designed to promote parents' social capital as a potential influence on children's attendance in Head Start centers. The intervention assigned children to treatment group classrooms based on (a) neighborhood of residence (geography condition) or (b) the geography condition plus the opportunity for parents to form partnerships in support of their children's attendance, or to control group classrooms according to Head Start guidelines only. We did not find impacts on average attendance throughout the year. However, the intervention did lead to increased attendance during the winter when average center attendance was lowest. There were no impacts on fall or spring attendance. Follow-up exploratory analyses of focus groups with parents and staff suggested that parents' level of connection and trust, self-generated partnership strategies, and commitment to their children's education may be factors by which parents' social capital expands and children's attendance improves.