Minimally invasive Dorsal cheilectomy and Hallux metatarsophalangeal joint arthroscopy for the treatment of Hallux Rigidus.

BACKGROUND: Minimally invasive dorsal cheilectomy (MIDC) has become a popular alternative to an open approach for treating Hallux Rigidus (HR). To reduce some of the complications related to the MIDC approach, a first metatarsophalangeal (MTP) joint arthroscopy can be performed in addition to address the intra-articular pathology associated with Hallux Rigidus. This study aims to examine the effectiveness of MIDC with first MTP arthroscopy in patients with HR with a minimum 1-year follow-up. METHODS: This was a multicenter retrospective review for adult patients with Coughlin and Shurnass Grade 0-3 who were treated with MIDC and first MTP arthroscopy between 3/1/2020 and 8/1/2022, with at least one year of follow-up data. Demographic information, first MTP range of motion (ROM), visual analog scale (VAS), Manchester-Oxford Foot Questionnaire (MOXFQ), and EQ-5D-5 L scores were collected. Continuous data was expressed as a mean and standard deviation, categorical data was expressed as a percentage. Wilcoxon Rank Sum test was used to compare continuous variables. All P < 0.05 was considered significant. RESULTS: A total of 31 patients were included in the study. Average follow-up time was 16.5 months (range: 12 to 26.2). There was 1 (3.2%) undersurface EHL tendon tear, 2 (6.5%) conversions to an MTP fusion, and 1 (3.2%) revision cheilectomy and capsular release for MTP joint contracture. There was a significant improvement in patient's ROM in dorsiflexion (50 vs 89.6 degrees, P = 0.002), postoperative VAS pain scores (6.4 vs 2.1, P < 0.001), MOXFQ pain scores (58.1 vs 30.7, P = 0.001), MOXFQ Walking/Standing scores (56.6 vs 20.6, P = 0.001), MOXFQ Social Interaction scores (47.3 vs 19.36, P = 0.002), and MOXFQ Index scores (54.7 vs 22.4, P < 0.001). CONCLUSION: We found that MIDC with first MTP arthroscopy was effective at improving patient-reported outcomes at one year with low complication and revision rates. These results suggest that MIDC with first MTP arthroscopy is an effective treatment for early-stage HR. LEVEL OF EVIDENCE: IV.

Hippocampal place cells have goal-oriented vector fields during navigation.

The hippocampal cognitive map supports navigation towards, or away from, salient locations in familiar environments1. Although much is known about how the hippocampus encodes location in world-centred coordinates, how it supports flexible navigation is less well understood. We recorded CA1 place cells while rats navigated to a goal on the honeycomb maze2. The maze tests navigation via direct and indirect paths to the goal and allows the directionality of place cells to be assessed at each choice point. Place fields showed strong directional polarization characterized by vector fields that converged to sinks distributed throughout the environment. The distribution of these 'convergence sinks' (ConSinks) was centred near the goal location and the population vector field converged on the goal, providing a strong navigational signal. Changing the goal location led to movement of ConSinks and vector fields towards the new goal. The honeycomb maze allows independent assessment of spatial representation and spatial action in place cell activity and shows how the latter relates to the former. The results suggest that the hippocampus creates a vector-based model to support flexible navigation, allowing animals to select optimal paths to destinations from any location in the environment.

Representation of ethological events by basolateral amygdala neurons.

The accurate interpretation of ethologically relevant stimuli is crucial for survival. While basolateral amygdala (BLA) neuronal responses during fear conditioning are well studied, little is known about how BLA neurons respond during naturalistic events. We recorded from the rat BLA during interaction with ethological stimuli: male or female rats, a moving toy, and rice. Forty-two percent of the cells reliably respond to at least one stimulus, with over half of these exclusively identifying one of the four stimulus classes. In addition to activation during interaction with their preferred stimulus, these cells signal micro-behavioral interactions like social contact. After stimulus removal, firing activity persists in 30% of responsive cells for several minutes. At the micro-circuit level, information flows from highly tuned event-specific neurons to less specific neurons, and connection strength increases after the event. We propose that individual BLA neurons identify specific ethological events, with event-specific neurons driving circuit-wide activity during and after salient events.

Frequent callers to UK ambulance services in the COVID-19 pandemic: managing mental health, social isolation and loneliness.

OBJECTIVES: Patients who frequently call ambulance services are a vulnerable yet heterogeneous population with unmet multiple and complex physical health, mental health and/or social care needs. In this article, we report the challenges that the COVID-19 pandemic has introduced for ambulance services across the UK when managing frequent callers, and reflect on how existing systems and practices are adapting to support changing patient needs. METHODS: Data reported in this article comprise reflections from the frequent caller leads in each ambulance service in the UK. All data were provided between 23 April 2020 and 1 May 2020, shortly after the peak of the outbreak in the UK. A single anonymised case study is also reported to illustrate how the pandemic is affecting people's circumstances and contributing to frequent caller behaviour. RESULTS: Ambulance services are observing changes to the frequent caller population, with many new frequent callers due to health anxiety caused or exacerbated by the pandemic. Management of frequent callers is also changing, with multidisciplinary and multi-agency working becoming more challenging due to decreased access to external services, whether in social care or the community and voluntary sector, and the redeployment of ambulance service staff. There is also decreased face-to-face contact with frequent callers, meaning that opportunities to deliver person-centred care are reduced. However, the introduction or increased use of tele/video conferencing with other organisations has mitigated some of these challenges, and in some cases has improved engagement among external organisations. CONCLUSIONS: Health anxieties, lack of access to other health, social and community and voluntary sector services and exacerbations of social isolation and/or loneliness have reportedly contributed to changing behaviour among frequent callers. The COVID-19 pandemic has also affected how ambulance services have been able to manage frequent callers. Ambulance services should continue to engage with external organisations to aid the delivery of person-centred care, particularly organisations with experience in multiple complex needs such as mental health, social isolation and/or loneliness. Future research should examine the consequences of the pandemic for frequent users of ambulance services, and how these impact on the wider health and care community.

Neuropixels 2.0: A miniaturized high-density probe for stable, long-term brain recordings.

Measuring the dynamics of neural processing across time scales requires following the spiking of thousands of individual neurons over milliseconds and months. To address this need, we introduce the Neuropixels 2.0 probe together with newly designed analysis algorithms. The probe has more than 5000 sites and is miniaturized to facilitate chronic implants in small mammals and recording during unrestrained behavior. High-quality recordings over long time scales were reliably obtained in mice and rats in six laboratories. Improved site density and arrangement combined with newly created data processing methods enable automatic post hoc correction for brain movements, allowing recording from the same neurons for more than 2 months. These probes and algorithms enable stable recordings from thousands of sites during free behavior, even in small animals such as mice.

Do hippocampal pyramidal cells respond to nonspatial stimuli?

There are currently a number of theories of rodent hippocampal function. They fall into two major groups that differ in the role they impute to space in hippocampal information processing. On one hand, the cognitive map theory sees space as crucial and central, with other types of nonspatial information embedded in a primary spatial framework. On the other hand, most other theories see the function of the hippocampal formation as broader, treating all types of information as equivalent and concentrating on the processes carried out irrespective of the specific material being represented, stored, and manipulated. One crucial difference, therefore, is the extent to which theories see hippocampal pyramidal cells as representing nonspatial information independently of a spatial framework. Studies have reported the existence of single hippocampal unit responses to nonspatial stimuli, both to simple sensory inputs as well as to more complex stimuli such as objects, conspecifics, rewards, and time, and these findings been interpreted as evidence in favor of a broader hippocampal function. Alternatively, these nonspatial responses might actually be feature-in-place signals where the spatial nature of the response has been masked by the fact that the objects or features were only presented in one location or one spatial context. In this article, we argue that when tested in multiple locations, the hippocampal response to nonspatial stimuli is almost invariably dependent on the animal's location. Looked at collectively, the data provide strong support for the cognitive map theory.

Increased flexor hallucis longus tension decreases ankle dorsiflexion.

BACKGROUND: Restricted excursion of the flexor hallucis longus (FHL) is associated with several clinical problems. An FHL excursion measurement device (EMD) was used to objectively assess differences between patients with clinically normal or tight FHL tendons. METHODS: 188 patients (356 feet) were enrolled. The EMD measured maximum ankle dorsiflexion with the great toe in 15°, 30°, and 45° of dorsiflexion. All had clinical assessment of FHL tightness by their provider independently of the EMD measurement. RESULTS: Increased hallux DF always caused decreased ankle DF. Patients with clinically tight FHLs demonstrated decreased ankle DF compared to normal subjects at all hallux positions (p<0.01). The EMD measurement was not sensitive enough for detection of FHL tightness in individuals. A clinically tight FHL was seen in almost 50% of feet. CONCLUSIONS: Tension in the FHL can limit ankle DF. Clinical tightness of the FHL is likely more common than currently recognized.

Author Correction: The honeycomb maze provides a novel test to study hippocampal-dependent spatial navigation.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Prolonged fasting drives a program of metabolic inflammation in human adipose tissue.

OBJECTIVE: The human adaptive fasting response enables survival during periods of caloric deprivation. A crucial component of the fasting response is the shift from glucose metabolism to utilization of lipids, underscoring the importance of adipose tissue as the central lipid-storing organ. The objective of this study was to investigate the response of adipose tissue to a prolonged fast in humans. METHODS: We performed RNA sequencing of subcutaneous adipose tissue samples longitudinally collected during a 10-day, 0-calorie fast in humans. We further investigated observed transcriptional signatures utilizing cultured human monocytes and Thp1 cells. We examined the cellularity of adipose tissue biopsies with transmission electron microscopy and tested for associated changes in relevant inflammatory mediators in the systemic circulation by ELISA assays of longitudinally collected blood samples. RESULTS: Coincident with the expected shift away from glucose utilization and lipid storage, we demonstrated downregulation of pathways related to glycolysis, oxidative phosphorylation, and lipogenesis. The canonical lipolysis pathway was also downregulated, whereas fasting drove alternative lysosomal paths to lipid digestion. Unexpectedly, the dominant induced pathways were associated with immunity and inflammation, although this only became evident at the 10-day time point. Among the most augmented transcripts were those associated with macrophage identity and function, such as members of the erythroblast transformation-specific (ETS) transcription factor family. Key components of the macrophage transcriptional signal in fasting adipose tissue were recapitulated with induced expression of two of the ETS transcription factors via cultured macrophages, SPIC and SPI1. The inflammatory signal was further reflected by an increase in systemic inflammatory mediators. CONCLUSIONS: Collectively, this study demonstrates an unexpected role of metabolic inflammation in the human adaptive fasting response.

Two Distinct Types of Eye-Head Coupling in Freely Moving Mice.

Animals actively interact with their environment to gather sensory information. There is conflicting evidence about how mice use vision to sample their environment. During head restraint, mice make rapid eye movements coupled between the eyes, similar to conjugate saccadic eye movements in humans. However, when mice are free to move their heads, eye movements are more complex and often non-conjugate, with the eyes moving in opposite directions. We combined head and eye tracking in freely moving mice and found both observations are explained by two eye-head coupling types, associated with vestibular mechanisms. The first type comprised non-conjugate eye movements, which compensate for head tilt changes to maintain a similar visual field relative to the horizontal ground plane. The second type of eye movements was conjugate and coupled to head yaw rotation to produce a "saccade and fixate" gaze pattern. During head-initiated saccades, the eyes moved together in the head direction but during subsequent fixation moved in the opposite direction to the head to compensate for head rotation. This saccade and fixate pattern is similar to humans who use eye movements (with or without head movement) to rapidly shift gaze but in mice relies on combined head and eye movements. Both couplings were maintained during social interactions and visually guided object tracking. Even in head-restrained mice, eye movements were invariably associated with attempted head motion. Our results reveal that mice combine head and eye movements to sample their environment and highlight similarities and differences between eye movements in mice and humans.

Combined task activation display as an effective method to teach introductory fMRI users.

RATIONALE AND OBJECTIVES: Interpreting functional magnetic resonance imaging (fMRI) can be an overwhelming and challenging task for trainees, particularly when post processing, synthesizing and interpreting data from multiple language paradigms. Currently, there is no established best method for teaching fMRI interpretation to new trainees. The purpose of our study is to compare the use of combined task activation display (CTAD) and conventional display of fMRI language paradigms as an effective method to teach fMRI to the introductory learner. MATERIALS AND METHODS: Following IRB approval, 43 unique cases (with 10 repeat cases to assess intra-reader variability) were identified based on the inclusion/exclusion criteria. Eight radiology trainees, without prior exposure to fMRI, were asked to determine language lateralization based on activation of Wernicke's area, Broca's area, and the pre-supplementary motor area. Prior to trainee interpretation, a 15-minute training session was conducted to describe the expected anatomic locations of the language centers. Trainees were asked to determine language dominance using either the CTAD or conventional methods. Following a 6-week washout period, the same eight trainees were asked to interpret the cases using the opposite interpretation approach. RESULTS: Interpreting fMRI with the CTAD method significantly increased trainee accuracy (85.4% vs 70.9% p < 0.001) and trainee confidence (4.3 vs 3.6 p < 0.001), while decreasing time to interpretation (mean difference of 29 min), and intra-reader variability when compared to the conventional approach. CONCLUSION: Combined task activation display is an effective method to teach fMRI to introductory learners.

A Head-Mounted Camera System Integrates Detailed Behavioral Monitoring with Multichannel Electrophysiology in Freely Moving Mice.

Breakthroughs in understanding the neural basis of natural behavior require neural recording and intervention to be paired with high-fidelity multimodal behavioral monitoring. An extensive genetic toolkit for neural circuit dissection, and well-developed neural recording technology, make the mouse a powerful model organism for systems neuroscience. However, most methods for high-bandwidth acquisition of behavioral data in mice rely upon fixed-position cameras and other off-animal devices, complicating the monitoring of animals freely engaged in natural behaviors. Here, we report the development of a lightweight head-mounted camera system combined with head-movement sensors to simultaneously monitor eye position, pupil dilation, whisking, and pinna movements along with head motion in unrestrained, freely behaving mice. The power of the combined technology is demonstrated by observations linking eye position to head orientation; whisking to non-tactile stimulation; and, in electrophysiological experiments, visual cortical activity to volitional head movements.

Targeting nuclear receptor NR4A1-dependent adipocyte progenitor quiescence promotes metabolic adaptation to obesity.

Adipocyte turnover in adulthood is low, suggesting that the cellular source of new adipocytes, the adipocyte progenitor (AP), resides in a state of relative quiescence. Yet the core transcriptional regulatory circuitry (CRC) responsible for establishing a quiescent state and the physiological significance of AP quiescence are incompletely understood. Here, we integrate transcriptomic data with maps of accessible chromatin in primary APs, implicating the orphan nuclear receptor NR4A1 in AP cell-state regulation. NR4A1 gain and loss of function in APs ex vivo decreased and enhanced adipogenesis, respectively. Adipose tissue of Nr4a1-/- mice demonstrated higher proliferative and adipogenic capacity compared with that of WT mice. Transplantation of Nr4a1-/- APs into the subcutaneous adipose tissue of WT obese recipients improved metrics of glucose homeostasis relative to administration of WT APs. Collectively, these data identify NR4A1 as a previously unrecognized constitutive regulator of AP quiescence and suggest that augmentation of adipose tissue plasticity may attenuate negative metabolic sequelae of obesity.

The circulating metabolome of human starvation.

The human adaptive starvation response allows for survival during long-term caloric deprivation. Whether the physiology of starvation is adaptive or maladaptive is context dependent: activation of pathways by caloric restriction may promote longevity, yet in the context of caloric excess, the same pathways may contribute to obesity. Here, we performed plasma metabolite profiling of longitudinally collected samples during a 10-day, 0-calorie fast in humans. We identify classical milestones in adaptive starvation, including the early consumption of gluconeogenic amino acids and the subsequent surge in plasma nonesterified fatty acids that marks the shift from carbohydrate to lipid metabolism, and demonstrate findings, including (a) the preferential release of unsaturated fatty acids and an associated shift in plasma lipid species with high degrees of unsaturation and (b) evidence that acute, starvation-mediated hypoleptinemia may be a driver of the transition from glucose to lipid metabolism in humans.

Local transformations of the hippocampal cognitive map.

Grid cells are neurons active in multiple fields arranged in a hexagonal lattice and are thought to represent the "universal metric for space." However, they become nonhomogeneously distorted in polarized enclosures, which challenges this view. We found that local changes to the configuration of the enclosure induce individual grid fields to shift in a manner inversely related to their distance from the reconfigured boundary. The grid remained primarily anchored to the unchanged stable walls and showed a nonuniform rescaling. Shifts in simultaneously recorded colocalized grid fields were strongly correlated, which suggests that the readout of the animal's position might still be intact. Similar field shifts were also observed in place and boundary cells-albeit of greater magnitude and more pronounced closer to the reconfigured boundary-which suggests that there is no simple one-to-one relationship between these three different cell types.

A "Seleno Effect" Differentiates the Roles of Redox Active Cysteine Residues in Plasmodium falciparum Thioredoxin Reductase.

Here, we introduce the concept of the "seleno effect" in the study of oxidoreductases that catalyze thiol/disulfide exchange reactions. In these reactions, selenium can replace sulfur as a nucleophile, electrophile, or leaving group, and the resulting change in rate (the seleno effect) is defined as kS/ kSe. In solution, selenium accelerates the rate of thiol/disulfide exchange regardless of its chemical role (e.g., nucleophile or electrophile). Here we show that this is not the case for enzyme catalyzed reactions and that the magnitude of the seleno effect can differentiate the role of each sulfur atom of a disulfide bond between that of an electrophile or leaving group. We used selenium for sulfur substitution to study the thiol/disulfide exchange step that occurs between the N-terminal redox center and the C-terminal disulfide-containing ß-hairpin motif of Plasmodium falciparum thioredoxin reductase (PfTrxR), which has the sequence Gly-Cys535-Gly-Gly-Gly-Lys-Cys540-Gly. We assayed a truncated PfTrxR enzyme missing this C-terminal tail for disulfide-reductase activity using synthetic peptide substrates in which either Cys535 or Cys540 was replaced with selenocysteine (Sec). The results show that substitution of Cys535 with Sec resulted in a nearly 9-fold decrease in the rate of reduction, while substitution of Cys540 resulted in a 1.5-fold increase in the rate of reduction. We also produced full-length, semisynthetic enzymes in which Sec replaced either of these two Cys residues and observed similar results using E. coli thioredoxin as the substrate. In this assay, the observed seleno effect ( kS/ kSe) for the C535U mutant was 7.4, and that for the C540U mutant was 0.2.

The honeycomb maze provides a novel test to study hippocampal-dependent spatial navigation.

Here we describe the honeycomb maze, a behavioural paradigm for the study of spatial navigation in rats. The maze consists of 37 platforms that can be raised or lowered independently. Place navigation requires an animal to go to a goal platform from any of several start platforms via a series of sequential choices. For each, the animal is confined to a raised platform and allowed to choose between two of the six adjacent platforms, the correct one being the platform with the smallest angle to the goal-heading direction. Rats learn rapidly and their choices are influenced by three factors: the angle between the two choice platforms, the distance from the goal, and the angle between the correct platform and the direction of the goal. Rats with hippocampal damage are impaired in learning and their performance is affected by all three factors. The honeycomb maze represents a marked improvement over current spatial navigation tests, such as the Morris water maze, because it controls the choices of the animal at each point in the maze, provides the ability to assess knowledge of the goal direction from any location, enables the identification of factors influencing task performance and provides the possibility for concomitant single-cell recording.

Fully integrated silicon probes for high-density recording of neural activity.

Sensory, motor and cognitive operations involve the coordinated action of large neuronal populations across multiple brain regions in both superficial and deep structures. Existing extracellular probes record neural activity with excellent spatial and temporal (sub-millisecond) resolution, but from only a few dozen neurons per shank. Optical Ca2+ imaging offers more coverage but lacks the temporal resolution needed to distinguish individual spikes reliably and does not measure local field potentials. Until now, no technology compatible with use in unrestrained animals has combined high spatiotemporal resolution with large volume coverage. Here we design, fabricate and test a new silicon probe known as Neuropixels to meet this need. Each probe has 384 recording channels that can programmably address 960 complementary metal-oxide-semiconductor (CMOS) processing-compatible low-impedance TiN sites that tile a single 10-mm long, 70 × 20-µm cross-section shank. The 6 × 9-mm probe base is fabricated with the shank on a single chip. Voltage signals are filtered, amplified, multiplexed and digitized on the base, allowing the direct transmission of noise-free digital data from the probe. The combination of dense recording sites and high channel count yielded well-isolated spiking activity from hundreds of neurons per probe implanted in mice and rats. Using two probes, more than 700 well-isolated single neurons were recorded simultaneously from five brain structures in an awake mouse. The fully integrated functionality and small size of Neuropixels probes allowed large populations of neurons from several brain structures to be recorded in freely moving animals. This combination of high-performance electrode technology and scalable chip fabrication methods opens a path towards recording of brain-wide neural activity during behaviour.

Hippocampus at 25.

The journal Hippocampus has passed the milestone of 25 years of publications on the topic of a highly studied brain structure, and its closely associated brain areas. In a recent celebration of this event, a Boston memory group invited 16 speakers to address the question of progress in understanding the hippocampus that has been achieved. Here we present a summary of these talks organized as progress on four main themes: (1) Understanding the hippocampus in terms of its interactions with multiple cortical areas within the medial temporal lobe memory system, (2) understanding the relationship between memory and spatial information processing functions of the hippocampal region, (3) understanding the role of temporal organization in spatial and memory processing by the hippocampus, and (4) understanding how the hippocampus integrates related events into networks of memories. © 2016 Wiley Periodicals, Inc.

Framing the grid: effect of boundaries on grid cells and navigation.

Cells in the mammalian hippocampal formation subserve neuronal representations of environmental location and support navigation in familiar environments. Grid cells constitute one of the main cell types in the hippocampal formation and are widely believed to represent a universal metric of space independent of external stimuli. Recent evidence showing that grid symmetry is distorted in non-symmetrical environments suggests that a re-examination of this hypothesis is warranted. In this review we will discuss behavioural and physiological evidence for how environmental shape and in particular enclosure boundaries influence grid cell firing properties. We propose that grid cells encode the geometric layout of enclosures.