Non-vitamin K oral anticoagulants versus warfarin for left atrial appendage thrombus resolution in nonvalvular atrial fibrillation or flutter.

BACKGROUND: Non-vitamin K oral anticoagulants (NOACs) have emerged as alternatives to vitamin K antagonists in select situations. For left atrial (LA) appendage thrombus in nonvalvular atrial fibrillation (AF) or flutter, guidelines recommend oral anticoagulation (OAC) for at least 3 weeks prior to reassessment. Data comparing NOACs to warfarin in this scenario are scarce. METHODS: A retrospective study identified subjects with nonvalvular AF or flutter who were: a) noted to have LA thrombus detected on transesophageal echocardiography (TEE), b) previously not receiving long-term OAC; and c) evaluated for resolution of LA thrombus by follow-up TEE between 3 weeks to less than 1 year of the initial TEE. RESULTS: The study included 45 subjects with mean age 63.2 years, 69% male, 78% white race/ethnicity, 42% paroxysmal, and mean CHA2 DS2 -VASc score 3.4 ± 1.7. All LA thrombi were confined to the appendage. OAC received included apixaban (3), dabigatran (13), rivaroxaban (6), and warfarin (23), The median follow-up time to repeat TEE was 67 (interquartile range, 49-96) days. LA appendage thrombus resolution rates were 76% for the entire cohort, 77% for NOACs, and 74% for warfarin. In univariable logistic regression analysis, LA appendage thrombus resolution was similar for NOACs when compared to warfarin (odds ratio, 1.20; 95% confidence interval, 0.31-4.69; P = .79). CONCLUSIONS: In patients nonvalvular AF or flutter who were OAC naïve at the time of diagnosis with LA appendage thrombus, complete resolution was similar between NOACs and warfarin.

A visual motion detection circuit suggested by Drosophila connectomics.

Animal behaviour arises from computations in neuronal circuits, but our understanding of these computations has been frustrated by the lack of detailed synaptic connection maps, or connectomes. For example, despite intensive investigations over half a century, the neuronal implementation of local motion detection in the insect visual system remains elusive. Here we develop a semi-automated pipeline using electron microscopy to reconstruct a connectome, containing 379 neurons and 8,637 chemical synaptic contacts, within the Drosophila optic medulla. By matching reconstructed neurons to examples from light microscopy, we assigned neurons to cell types and assembled a connectome of the repeating module of the medulla. Within this module, we identified cell types constituting a motion detection circuit, and showed that the connections onto individual motion-sensitive neurons in this circuit were consistent with their direction selectivity. Our results identify cellular targets for future functional investigations, and demonstrate that connectomes can provide key insights into neuronal computations.

The association of imaging equipment age with other quality metrics and successful laboratory accreditation by the Intersocietal Accreditation Commission.

BACKGROUND: Intersocietal Accreditation Commission (IAC) accreditation is granted or delayed depending on the fulfillment of several quality metrics. Investing in up-to-date equipment might reflect a commitment to quality. METHODS: Data from echocardiography (n = 3079) and nuclear cardiology (n = 1835) accreditation applications submitted between 2012 and 2014 were evaluated to determine the mean age of laboratory equipment. Laboratory quality was assessed by the number of missing quality metrics, and a composite quality score was calculated as the sum of missing quality metrics. A lower score thus represented better laboratory quality. The relationship between equipment age and quality was explored as an interaction term between equipment age and the composite quality score and was incorporated into regression models for prediction of accreditation status. RESULTS: During the study period, 49% of echocardiography and 42% of nuclear laboratories were granted accreditation without delay. For both echocardiography and nuclear laboratories, there was a statistically significant trend toward an increasing number of missing quality metrics with increasing quartiles of equipment age. The interaction between equipment age and the composite quality score was a significant predictor of delay of accreditation for both echocardiography and nuclear cardiology laboratories, with a stronger association for 1st-time applicants. Among sites applying for accreditation in both modalities simultaneously, accreditation in one modality predicted the accreditation decision for the other. CONCLUSIONS: Laboratory quality is an important determinant of IAC accreditation, and equipment age is an effect modifier of this relationship. Contemporary equipment likely reflects a commitment to quality, for both echocardiography and nuclear laboratories.

Recognition of emotional prosody by Mandarin-speaking adults with cochlear implants.

To understand how cochlear implant processing affects emotional prosody recognition in tonal languages, how normal-hearing (NH) and cochlear-implanted (CI) adults identify four emotions ("angry," "happy," "sad," and "neutral") in short, semantically neutral, Mandarin sentences are compared. Depending on hearing status (CI, NH), adults heard natural speech and/or noise-vocoded speech conditions (4-, 8-, and 16-spectral channels). Results suggest that Mandarin-speaking adults with CIs recognize emotions with similar accuracy as NH listeners attending to spectrally degraded (4-channel) vocoded speech. The accuracy noted for Mandarin appears to be lower than that described in previous studies of English.

Oral anticoagulation and left atrial thrombi resolution in nonrheumatic atrial fibrillation or flutter: A systematic review and meta-analysis.

BACKGROUND: Oral anticoagulation (OAC) is prescribed for left atrial thrombi (LAT) in nonrheumatic atrial fibrillation (AF) and/or atrial flutter (AFL). The study objective was to review the existing evidence regarding LAT resolution in nonrheumatic AF and/or AFL with OAC agents. METHODS: Data sources included PubMed, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) between January 1, 1991 and February 10, 2017. English-language studies that assessed LAT resolution with OAC agents in subjects with nonrheumatic AF and/or AFL, by serial transesophageal echocardiography, and with follow-up times ≥ 3 weeks and < 1 year, were selected. Study quality was assessed using recommendations adapted from the Agency for Healthcare Research and Quality. Pooled LAT resolution rates were evaluated for vitamin K antagonist (VKA) studies and low risk of bias warfarin studies. RESULTS: The pooled LAT resolution rate of 619 subjects from 16 VKA studies was 63.7% (95% confidence interval [CI], 53.3%-72.9%). The pooled LAT resolution rate of 94 subjects from four studies that specified warfarin use, exclusion of prior long-term therapeutic OAC, and target international normalized ratio (INR) ≥ 2.0 and/or average achieved INR ≥ 2.0 was 79.3% (95% CI, 69.8%-86.4%). Two studies in direct-acting oral anticoagulants (DOACs) reported LAT resolution rates of 89.5% (17 of 19) for dabigatran and 41.5% (22 of 53) for rivaroxaban. CONCLUSIONS: Warfarin is the most studied initial OAC agent for treating LAT in nonrheumatic AF and/or AFL with a resolution rate of nearly 80%. Further studies in DOACs are warranted.

Synaptic circuits and their variations within different columns in the visual system of Drosophila.

We reconstructed the synaptic circuits of seven columns in the second neuropil or medulla behind the fly's compound eye. These neurons embody some of the most stereotyped circuits in one of the most miniaturized of animal brains. The reconstructions allow us, for the first time to our knowledge, to study variations between circuits in the medulla's neighboring columns. This variation in the number of synapses and the types of their synaptic partners has previously been little addressed because methods that visualize multiple circuits have not resolved detailed connections, and existing connectomic studies, which can see such connections, have not so far examined multiple reconstructions of the same circuit. Here, we address the omission by comparing the circuits common to all seven columns to assess variation in their connection strengths and the resultant rates of several different and distinct types of connection error. Error rates reveal that, overall, <1% of contacts are not part of a consensus circuit, and we classify those contacts that supplement (E+) or are missing from it (E-). Autapses, in which the same cell is both presynaptic and postsynaptic at the same synapse, are occasionally seen; two cells in particular, Dm9 and Mi1, form ≥ 20-fold more autapses than do other neurons. These results delimit the accuracy of developmental events that establish and normally maintain synaptic circuits with such precision, and thereby address the operation of such circuits. They also establish a precedent for error rates that will be required in the new science of connectomics.

Using electromagnetic articulography with a tongue lateral sensor to discriminate manner of articulation.

This study examined the contributions of the tongue tip (TT), tongue body (TB), and tongue lateral (TL) sensors in the electromagnetic articulography (EMA) measurement of American English alveolar consonants. Thirteen adults produced /ɹ/, /l/, /z/, and /d/ in /ɑCɑ/ syllables while being recorded with an EMA system. According to statistical analysis of sensor movement and the results of a machine classification experiment, the TT sensor contributed most to consonant differences, followed by TB. The TL sensor played a complementary role, particularly for distinguishing /z/.

QT interval prolongation in end-stage liver disease cannot be explained by nonhepatic factors.

INTRODUCTION: QT interval prolongation in patients with end-stage liver disease (ESLD) is common. However, electrolyte abnormalities, renal insufficiency, treatment with QT-prolonging drugs, and other factors known to prolong QT interval independently of liver disease occur frequently in ESLD. Moreover, elevated heart rate may be present in ESLD and result in spurious QTc prolongation if the Bazett formula is used for rate correction. It thus remains unclear whether QT prolongation in ESLD is directly caused by liver failure, or indirectly by these confounding factors. METHODS: Medical records of all patients (n = 437) who received orthotopic liver transplantation (OLTx) at our institution between 2008 and 2011 were reviewed. Data from 51 patients with available pre-OLTx dobutamine stress echo (DSE), post-OLTx ECG and without nonhepatic factors affecting QT interval duration were analyzed. For each patient, QT versus RR regression line was calculated from ECG tracings obtained during DSE. The QT interval on post-OLTx ECG was compared with the pre-OLTx QT predicted by the regression line for the same RR interval. RESULTS: QT interval shortened significantly post-OLTx (from 394 ± 47 to 364 ± 45 ms at RR interval 750 ± 144 ms; P < 0.002) when compared using the regression method. Corrected QT intervals calculated by Bazett and Fridericia formulas also shortened. Patients with prolonged QT pre-OLTx had significantly higher INR and lower serum albumin. CONCLUSION: ESLD impairs ventricular repolarization even in the absence of other known factors affecting repolarization. QT prolongation in ESLD is associated with impaired synthetic liver function.

Echocardiographic sizing of the left atrium of the transplanted heart.

BACKGROUND: The left atrium (LA) in the transplanted heart (TH) is a surgically created chamber from variable portions of donor and recipient LA. The American Society of Echocardiography (ASE) recommends measuring LA size in native hearts using biplane LA volume index (LAVI) as a more accurate measurement than LA anterior-posterior diameter (LA-APD). We hypothesized that LA-APD underestimates LA size when compared with LAVI in the TH. METHODS: Patients with a TH from 1/05 to 1/10 who had a transthoracic echocardiogram within 24 months of transplant were studied. Patients were excluded if they had an ejection fraction <50%, left ventricular hypertrophy, >mild aortic or mitral regurgitation, or poor image quality. Echocardiograms were analyzed for LA-APD and LAVI. LA size was classified as normal, mild, moderate, or severely enlarged based on age and sex specific cutoffs per the ASE. RESULTS: Of 297 patients evaluated, 160 met inclusion criteria. Mean age was 57 ± 13 years and 79% were males. Mean LA-APD and LAVI were 4.3 ± 0.6 cm and 36 ± 14 mL/m(2), respectively. LAVI correlated with LA-APD (r = 0.43, R(2) = 0.18, P < 0.0001). By LA-APD measurement, 20 (13%) LA were classified as having moderate or severe LA enlargement versus 80 (50%) by LAVI, P = 0.001. LA size was underclassified by ≥ 2 classes in 44 (28%) by LA-APD versus LAVI. CONCLUSIONS: In the setting of cardiac transplant, the LA size classified by LA-APD is commonly less than that classified by LAVI.

Right Ventricular Strain Improves the Echocardiographic Diagnosis and Risk Stratification of Transthyretin Cardiac Amyloidosis Among Other Phenotypes of Left Ventricular Hypertrophy.

AIMS: Cardiac amyloidosis is a diffuse disease affecting all cardiac chambers. The value of right ventricular free-wall strain is uncertain as an echocardiographic red flag. We hypothesized that right ventricular free-wall strain is of added value for diagnostic and prognostic purposes in patients with transthyretin cardiac amyloidosis (ATTR-CA). METHOD: A diagnosis of ATTR-CA required positive Tc-99m pyrophosphate scintigraphy and negative serum clonal dyscrasia. Patients with left ventricular (LV) hypertrophy (LVH; interventricular septal thickness ≥1.2 cm) by echocardiography and negative pyrophosphate scintigraphy served as controls after exclusion of amyloid light-chain cardiac amyloidosis. Longitudinal strain was computed with speckle-tracking echocardiography. RESULTS: We studied 108 subjects with ATTR-CA and 106 controls with LVH, retrospectively. Right ventricular free-wall strain was independently associated with the diagnosis of ATTR-CA after adjusting for classical echocardiographic parameters, namely, relative apical sparing (RAS), e', and E/e'. Right ventricular free-wall strain ≥ -16% was incremental to LV RAS in the overall group and in the subgroup without extreme wall thickness (≤1.4 cm; Harrell's C, net reclassification improvement = 0.213, P < .001; and net reclassification improvement = 0.463, P = .015, respectively). Major adverse cardiovascular and cerebrovascular events (heart failure hospitalization, stroke, death) occurred in 47 ATTR-CA patients, during follow-up (median, 38; range, 6-60 months). Right ventricular free-wall strain ≥-16% was associated with 3-fold increased risk of MACCE in ATTR-CA patients independently of age, comorbidities, B-type natriuretic peptide, and tafamidis treatment. Right ventricular free-wall strain was additive to LV ejection fraction for risk stratification (chi square = 10.2; P = .017). CONCLUSIONS: Right ventricular free-wall strain >-16% has incremental value to LV RAS for the differential diagnosis of ATTR-CA among LVH phenotypes and is associated with poor prognosis.

Connectome-driven neural inventory of a complete visual system.

Vision provides animals with detailed information about their surroundings, conveying diverse features such as color, form, and movement across the visual scene. Computing these parallel spatial features requires a large and diverse network of neurons, such that in animals as distant as flies and humans, visual regions comprise half the brain's volume. These visual brain regions often reveal remarkable structure-function relationships, with neurons organized along spatial maps with shapes that directly relate to their roles in visual processing. To unravel the stunning diversity of a complex visual system, a careful mapping of the neural architecture matched to tools for targeted exploration of that circuitry is essential. Here, we report a new connectome of the right optic lobe from a male Drosophila central nervous system FIB-SEM volume and a comprehensive inventory of the fly's visual neurons. We developed a computational framework to quantify the anatomy of visual neurons, establishing a basis for interpreting how their shapes relate to spatial vision. By integrating this analysis with connectivity information, neurotransmitter identity, and expert curation, we classified the ~53,000 neurons into 727 types, about half of which are systematically described and named for the first time. Finally, we share an extensive collection of split-GAL4 lines matched to our neuron type catalog. Together, this comprehensive set of tools and data unlock new possibilities for systematic investigations of vision in Drosophila, a foundation for a deeper understanding of sensory processing.

Morbid obesity: obscuring the diagnosis of aortic stenosis in a patient with cardiogenic wheezing.

We report the case of a morbidly obese 65-year-old female who presented with repeated hypotensive episodes following dialysis. She was misdiagnosed as suffering from asthma, and eventually was found to have severe aortic stenosis. Obesity has become a common and formidable obstacle to gathering important diagnostic information in patients. Modern diagnostic lab tests and imaging modalities such as transthoracic echocardiography (TTE) can provide spurious data in the morbidly obese population, which can ultimately lead to misdiagnosis. In this clinical vignette, we discuss the relationship between the basic pathophysiologic mechanisms underlying aortic stenosis and patient clinical presentation. We also review the relevant literature and discuss the impact of obesity on the diagnosis of this condition.

Speaking Rate, Immediate Memory, and Grammatical Processing in Prelingual Cochlear Implant Recipients.

PURPOSE: This study examined the extent to which prelingual cochlear implant (CI) users show a slowed speaking rate compared with typical-hearing (TH) talkers when repeating various speech stimuli and whether the slowed speech of CI users relates to their immediate verbal memory. METHOD: Participants included 10 prelingually deaf teenagers who received CIs before the age of 5 years and 10 age-matched TH teenagers. Participants repeated nonword syllable strings, word strings, and center-embedded sentences, with conditions balanced for syllable length and metrical structure. Participants' digit span forward and backward scores were collected to measure immediate verbal memory. Speaking rate data were analyzed using a mixed-design, repeated-measures analysis of variance, and the relationships between speaking rate and digit spans were evaluated by Pearson correlation. RESULTS: Participants with CIs spoke more slowly than their TH peers during the sentence repetition task but not in the nonword string and word string repetition tasks. For the CI group, significant correlations emerged between speaking rate and digit span scores (both forward and backward) for the sentence repetition task but not for the nonword string or word string repetition task. For the TH group, no significant correlations were found. CONCLUSIONS: The findings indicate a relation between slowed speech production, reduced immediate verbal memory, and diminished language capabilities of prelingual CI users, particularly for syntactic processing. These results support theories claiming that immediate memory, including components of a central executive, influences the speaking rate of these talkers. Implications for therapies designed to increase speech fluency in CI recipients are discussed. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.21644795.

Effect of bisphosphonates on the progression of degenerative aortic stenosis.

Bisphosphonates appear to regulate mineralization in both bone and vasculature. Degenerative aortic stenosis (AS) is thought to be due to vascular calcification. We studied the effect of bisphosphonates on the progression of degenerative AS. A retrospective study was performed on patients >70 years, who had transthoracic echocardiograms (TTE) >1 year apart and an initial aortic valve area (AVA) of 0.6-2.0 cm². Patients were excluded if they had an ejection fraction <40%, other significant valvular or congenital heart disease, end-stage renal disease or heart transplant. The cohort was divided depending on the use of bisphosphonates. Data were obtained by review of the TTE reports. AVA, peak and mean aortic valve gradient (AVG), and the change between the studies were calculated. Of 4,270 patients screened for AS, 76 patients fit study criteria with 8 in the bisphosphonate group and 68 in the nonbisphosphonate group. The period between the TTEs was 23 ± 5 months in both the groups. AVA in the nonbisphosphonate group worsened by 0.2 cm² and in the bisphosphonate group it improved by 0.1 cm² (P = 0.001 vs. nonbisphosphonate). The changes in peak and mean AVG between groups and compared to baseline were not significant. Bisphosphonates show promise for slowing the progression of degenerative AS.

The Role of Visibility in Silent Speech Tongue Movements: A Kinematic Study of Consonants.

Purpose To better understand the role of tongue visibility in speech, this study compared the spatiotemporal patterns of silent versus audible speech for lingual consonants of American English. Kinematic data were obtained for articulatory features assumed to be visually salient, including tongue movement (anterior displacement and midsagittal area), lip aperture, and consonant duration. Method Electromagnetic articulography was used to measure 11 native speakers' productions of five consonants (/É¡/, /w/, /ɹ/, /l/, and /ð/), selected to represent a continuum of tongue visibility. Nonword consonant-vowel syllables were elicited during a procedure designed to convey a dyadic communication environment. A method of kinematic-based consonant segmentation was developed for data processing, and results were analyzed with repeated-measures analysis of variance. Results Findings indicated increased consonant duration and lip aperture in the silent condition (vs. audible) for all five consonants. Tongue forward displacement was slightly greater in the silent condition, compared to audible, for all consonants except /É¡/, the only consonant without a visible tongue component. In addition, the extent of tongue forwarding in silent speech corresponded with the degree of tongue visibility. Conclusion During silent speech, talkers increased their lip aperture and consonant duration and tended to shift their tongues forward for the most visible lingual consonants, suggesting that talkers may be aware at some level of the need to increase articulatory visibility of the tongue in the presence of an interlocutor during adverse speech conditions.

Impact of Pre-Existing Mitral Regurgitation Following Left Ventricular Assist Device Implant.

OBJECTIVES: Optimal management of significant mitral regurgitation (SMR) during left ventricular assist device (LVAD) placement remains uncertain. This study evaluates the effect of untreated preop SMR on outcomes following LVAD implant. METHODS: Adults undergoing primary LVAD placement from April 2004 to May 2017 were included. Most recent preop transthoracic echocardiogram (TTE) was used to divide patients into an SMR group with moderate or greater regurgitation, and a group without SMR. Patients underwent LVAD implant without correction of SMR. Primary endpoint was 3-year postoperative survival, with secondary endpoints of length of stay (LOS), resolution of SMR following LVAD on postdischarge (30 day) TTE, and 1-year TTE. RESULTS: LVAD placement was performed in 270 patients, 172 (63.7%) without SMR and 98 (36.3%) with SMR. There were no differences in comorbidities including diabetes, hypertension, and renal disease. Preop ejection fraction was similar, but a higher pulmonary vascular resistance was recorded in the SMR group (3.6 vs 3.0 Wood Units, P = 0.048). There was no difference in 3-year mortality between the 2 cohorts (log-rank P = 0.0.803). The SMR group had decreased LOS (median 19.5 vs 22 days, P = 0.009). Of the 98 SMR patients, 91 (92.9%) had resolution of SMR to less than moderate at 30 days. At 1 year, 15% of those with preoperative SMR had recurrent SMR. CONCLUSIONS: Patients undergoing LVAD placement with preop SMR experience no differences in mortality, and a majority experience resolution of MR after implant. Longer-term SMR recurrence and need for mitral intervention with LVAD implant warrant further investigation.

Acute In Vivo Functional Assessment of a Biodegradable Stentless Elastomeric Tricuspid Valve.

Degradable heart valves based on in situ tissue regeneration have been proposed as potentially durable and non-thrombogenic prosthetic alternatives. We evaluated the acute in vivo function, microstructure, mechanics, and thromboresistance of a stentless biodegradable tissue-engineered heart valve (TEHV) in the tricuspid position. Biomimetic stentless tricuspid valves were fabricated with poly(carbonate urethane)urea (PCUU) by double-component deposition (DCD) processing to mimic native valve mechanics and geometry. Five swine then underwent 24-h TEHV implantation in the tricuspid position. Echocardiography demonstrated good leaflet motion and no prolapse and trace to mild regurgitation in all but one animal. Histology revealed patches of proteinaceous deposits with no cellular uptake. SEM demonstrated retained scaffold microarchitecture with proteinaceous deposits but no platelet aggregation or thrombosis. Explanted PCUU leaflet thickness and mechanical anisotropy were comparable with native tricuspid leaflets. Bioinspired, elastomeric, stentless TEHVs fabricated by DCD were readily implantable and demonstrated good acute function in the tricuspid position.

A connectome and analysis of the adult Drosophila central brain.

The neural circuits responsible for animal behavior remain largely unknown. We summarize new methods and present the circuitry of a large fraction of the brain of the fruit fly Drosophila melanogaster. Improved methods include new procedures to prepare, image, align, segment, find synapses in, and proofread such large data sets. We define cell types, refine computational compartments, and provide an exhaustive atlas of cell examples and types, many of them novel. We provide detailed circuits consisting of neurons and their chemical synapses for most of the central brain. We make the data public and simplify access, reducing the effort needed to answer circuit questions, and provide procedures linking the neurons defined by our analysis with genetic reagents. Biologically, we examine distributions of connection strengths, neural motifs on different scales, electrical consequences of compartmentalization, and evidence that maximizing packing density is an important criterion in the evolution of the fly's brain.

Animal brains of all sizes, from the smallest to the largest, work in broadly similar ways. Studying the brain of any one animal in depth can thus reveal the general principles behind the workings of all brains. The fruit fly Drosophila is a popular choice for such research. With about 100,000 neurons ­ compared to some 86 billion in humans ­ the fly brain is small enough to study at the level of individual cells. But it nevertheless supports a range of complex behaviors, including navigation, courtship and learning. Thanks to decades of research, scientists now have a good understanding of which parts of the fruit fly brain support particular behaviors. But exactly how they do this is often unclear. This is because previous studies showing the connections between cells only covered small areas of the brain. This is like trying to understand a novel when all you can see is a few isolated paragraphs. To solve this problem, Scheffer, Xu, Januszewski, Lu, Takemura, Hayworth, Huang, Shinomiya et al. prepared the first complete map of the entire central region of the fruit fly brain. The central brain consists of approximately 25,000 neurons and around 20 million connections. To prepare the map ­ or connectome ­ the brain was cut into very thin 8nm slices and photographed with an electron microscope. A three-dimensional map of the neurons and connections in the brain was then reconstructed from these images using machine learning algorithms. Finally, Scheffer et al. used the new connectome to obtain further insights into the circuits that support specific fruit fly behaviors. The central brain connectome is freely available online for anyone to access. When used in combination with existing methods, the map will make it easier to understand how the fly brain works, and how and why it can fail to work correctly. Many of these findings will likely apply to larger brains, including our own. In the long run, studying the fly connectome may therefore lead to a better understanding of the human brain and its disorders. Performing a similar analysis on the brain of a small mammal, by scaling up the methods here, will be a likely next step along this path.