A critical appraisal of Monro's erroneous description of the cerebral interventricular foramina: Age-related magnetic resonance imaging spatial morphometry and a proposed new terminology.

Anatomic connections between the cerebral lateral and third ventricles have been mischaracterized since Monro's original erroneous description of his eponymous foramina (FoMs) as being only one T-shaped passage. Accurate knowledge of the in vivo three-dimensional (3D) configuration of FoM has important clinical neuroendoscopic, neurosurgical, and neuroimaging implications. We retrospectively analyzed volumetric high-resolution brain magnetic resonance imaging of 100 normal individuals to characterize the normal spatial anatomy and morphometry for each FoM. We measured the true anatomical 3D angulations of FoMs relative to standard neuroimaging orthogonal planes, and their minimum width, depth, and distance between the medial borders of bilateral FoMs. The right and left FoMs were separate, distinct, and in a V-shaped configuration. Each FoM was a round, oval, or crescent-shaped canal-like passage with well-defined borders formed by the semicircular concavity of the ipsilateral forniceal column. The plane of FoM was angled on average 56.8° ± 9.1° superiorly from the axial plane, 22.5° ± 10.7° laterally, and 37.0° ± 6.9° anteriorly from the midsagittal plane; all these angles changing significantly with increasing age. The mean narrowest diameter of FoM was 2.8 ± 1.2 mm, and its depth was 2.5 ± 0.2 mm. Thus, the true size and orientation of FoM differs from that depicted on standard neuroimaging. Notably, in young subjects, FoM has a diameter smaller than its depth, a configuration akin to a short, small canal. We propose that the eponym "Monro" no longer be associated with this structure, and the term "foramen" be abandoned. Instead, FoM should be more appropriately renamed as the "interventricular canaliculus," or IVC, for short.

Play Within the Pre-registration Children's Nursing Curriculum Within the United Kingdom: A Content Analysis of Programme Specifications.

PURPOSE: To determine the number of programme specifications which cite play within the curriculum and in what context. Play is an essential part of childhood. Therefore we might expect nurses caring for children to be trained in how to facilitate play within their clinical areas. Programme specifications provide information on course aims, the intended learning outcomes and what the learner is expected to achieve. DESIGN AND METHOD: Inductive qualitative content analysis. RESULTS: Only 13% (seven out of 54) programme specifications published by Higher Education Institutions cite play. Where play is mentioned there is a clear link made to use play as a communication tool. Also distraction figured prominently within the same sentence as play, despite these two terms being quite distinct. The availability of the programme specifications was also noted with 49% (28 out of 57) were easily accessible from the university web sites. A further 16% (9 out of 57) provided web links when access was requested. 35% were not publicly accessible without requesting access. Three Universities declined to be involved. CONCLUSION: It is clear that even if play is embedded within the child field nursing curriculum, it is not clearly stated as a priority within 87% of universities programme specifications which make no mention of it. PRACTICE IMPLICATIONS: If play is not part of programme specifications its importance could be lost to educators already delivering a full curriculum. Nurses could be qualifying with little or no knowledge around their role in facilitating play for their patients.

The LEAP™ Gesture Interface Device and Take-Home Laparoscopic Simulators: A Study of Construct and Concurrent Validity.

AIM: To assess the potential of the LEAP™ infrared motion tracking device to map laparoscopic instrument movement in a simulated environment. Simulator training is optimized when augmented by objective performance feedback. We explore the potential LEAP has to provide this in a way compatible with affordable take-home simulators. METHOD: LEAP and the previously validated InsTrac visual tracking tool mapped expert and novice performances of a standardized simulated laparoscopic task. Ability to distinguish between the 2 groups (construct validity) and correlation between techniques (concurrent validity) were the primary outcome measures. RESULTS: Forty-three expert and 38 novice performances demonstrated significant differences in LEAP-derived metrics for instrument path distance (P < .001), speed (P = .002), acceleration (P < .001), motion smoothness (P < .001), and distance between the instruments (P = .019). Only instrument path distance demonstrated a correlation between LEAP and InsTrac tracking methods (novices: r = .663, P < .001; experts: r = .536, P < .001). Consistency of LEAP tracking was poor (average % time hands not tracked: 31.9%). CONCLUSION: The LEAP motion device is able to track the movement of hands using instruments in a laparoscopic box simulator. Construct validity is demonstrated by its ability to distinguish novice from expert performances. Only time and instrument path distance demonstrated concurrent validity with an existing tracking method however. A number of limitations to the tracking method used by LEAP have been identified. These need to be addressed before it can be considered an alternative to visual tracking for the delivery of objective performance metrics in take-home laparoscopic simulators.

UK endoscopy trainer survey: perspectives on current endoscopy training delivery, experience, barriers and opportunities.

Objective: UK endoscopy training is delivered by trainers possessing well developed endoscopy and teaching skills to help learners perform high-quality endoscopy. Train The Trainer (TTT) courses are effective, but additional trainer support is variable with little formal quality assurance. We performed a survey to map UK endoscopy training, assess trainer perspectives on training delivery and identify factors that would enhance training. Design/Method: An online survey was designed by trainer representatives, in collaboration with the JAG training committee, and collected responses from trainers registered on JAG endoscopy training system e-portfolio from April to June 2022. Results: There were 1024 responses from all trainer disciplines, with 813 (79%) completing TTT courses and 584 (57%) having job planned dedicated training lists (DTLs). Clinical endoscopists most frequently had job-planned DTLs (71%), and DTLs occurring at least weekly (58%). 293 (29%) respondents participated as course faculty. Trainers reported high levels of pre-procedure preparation, effective dialogue and frequent feedback. The DOPS forms were 'always/often' completed by 81% of clinical endoscopists, 73% of gastroenterologist and 58% of surgeons. 435 (42%) trainers never had peer feedback. Responses suggested training could improve by protecting training time, attending courses, participating as faculty and receiving feedback from experienced trainers. Conclusion: This survey demonstrates substantial proportions of highly motivated UK trainers who value time spent teaching and learning how to teach. Skills taught on the TTT courses are often actively used in everyday training. Improved trainer course access, protected training time and formal use of existing feedback tools by peers were highlighted as measures that could support trainers' development.

Pain and cognitive performance in adults with multiple sclerosis: A systematic review.

INTRODUCTION: Pain and cognitive dysfunction are separately known to be important manifestations of multiple sclerosis (MS). Although pain is a complex subjective phenomenon with affective and cognitive aspects, it is not known if people with MS reporting pain are at greater risk of reduced performance in objective tests of cognition. The presence or direction of any association remains to be clarified, as do the roles of confounders such as fatigue, medication and mood. METHODS: We conducted a systematic review of studies examining the relationship between pain and objectively measured cognition in adults with confirmed MS, according to a pre-registered protocol (PROSPERO 42,020,171,469). We carried out searches in MEDLINE, Embase and PsychInfo. Studies of adults with any subtype of MS, with chronic pain and in which cognitive evaluation was conducted by validated instruments were included. We evaluated the role of potential confounders (medication, depression, anxiety, fatigue and sleep) and described findings by eight pre-specified cognitive domains. Risk of bias was assessed using the Newcastle-Ottawa Scale. RESULTS: 11 studies (n = 3714 participants, range 16 to 1890 per study) were included in the review. Four studies included longitudinal data. Nine studies identified a relationship between pain and objectively measured cognitive performance. In seven of these studies, higher pain scores were associated with poorer cognitive performance. However, no evidence was available for some cognitive domains. Heterogeneous study methodology precluded meta-analysis. Studies infrequently controlled for the specified confounders. Most studies were judged to be at risk of bias. DISCUSSION: Several studies, but not all, identified a negative relationship between pain severity and objectively measured cognitive performance. Our ability to further characterise this relationship is limited by study design and lack of evidence in many cognitive domains. Future studies should better establish this relationship and delineate the neurological substrate underpinning it.

Systematic, comprehensive, evidence-based approach to identify neuroprotective interventions for motor neuron disease: using systematic reviews to inform expert consensus.

OBJECTIVES: Motor neuron disease (MND) is an incurable progressive neurodegenerative disease with limited treatment options. There is a pressing need for innovation in identifying therapies to take to clinical trial. Here, we detail a systematic and structured evidence-based approach to inform consensus decision making to select the first two drugs for evaluation in Motor Neuron Disease-Systematic Multi-arm Adaptive Randomised Trial (MND-SMART: NCT04302870), an adaptive platform trial. We aim to identify and prioritise candidate drugs which have the best available evidence for efficacy, acceptable safety profiles and are feasible for evaluation within the trial protocol. METHODS: We conducted a two-stage systematic review to identify potential neuroprotective interventions. First, we reviewed clinical studies in MND, Alzheimer's disease, Huntington's disease, Parkinson's disease and multiple sclerosis, identifying drugs described in at least one MND publication or publications in two or more other diseases. We scored and ranked drugs using a metric evaluating safety, efficacy, study size and study quality. In stage two, we reviewed efficacy of drugs in MND animal models, multicellular eukaryotic models and human induced pluripotent stem cell (iPSC) studies. An expert panel reviewed candidate drugs over two shortlisting rounds and a final selection round, considering the systematic review findings, late breaking evidence, mechanistic plausibility, safety, tolerability and feasibility of evaluation in MND-SMART. RESULTS: From the clinical review, we identified 595 interventions. 66 drugs met our drug/disease logic. Of these, 22 drugs with supportive clinical and preclinical evidence were shortlisted at round 1. Seven drugs proceeded to round 2. The panel reached a consensus to evaluate memantine and trazodone as the first two arms of MND-SMART. DISCUSSION: For future drug selection, we will incorporate automation tools, text-mining and machine learning techniques to the systematic reviews and consider data generated from other domains, including high-throughput phenotypic screening of human iPSCs.

An improved racemase/acylase biotransformation for the preparation of enantiomerically pure amino acids.

Using directed evolution, a variant N-acetyl amino acid racemase (NAAAR G291D/F323Y) has been developed with up to 6-fold higher activity than the wild-type on a range of N-acetylated amino acids. The variant has been coupled with an enantiospecific acylase to give a preparative scale dynamic kinetic resolution which allows 98% conversion of N-acetyl-DL-allylglycine into D-allylglycine in 18 h at high substrate concentrations (50 g L(-1)). This is the first example of NAAAR operating under conditions which would allow it to be successfully used on an industrial scale for the production of enantiomerically pure α-amino acids. X-ray crystal analysis of the improved NAAAR variant allowed a comparison with the wild-type enzyme. We postulate that a network of novel interactions that result from the introduction of the two side chains is the source of improved catalytic performance.

Longitudinal retinal imaging study of newly diagnosed relapsing-remitting multiple sclerosis in Scottish population: baseline and 12 months follow-up profile of FutureMS retinal imaging cohort.

OBJECTIVE: Multiple sclerosis (MS) is an inflammatory degenerative condition of central nervous system. The disease course and presentation of MS is highly heterogeneous. Advanced retinal imaging techniques such as optic coherence tomography (OCT) can capture abnormalities of anterior visual pathway with high resolution, which may contribute greater insights into the pathophysiology of MS. METHODS: People with newly diagnosed relapsing-remitting MS were recruited for FutureMS retinal imaging study from two study centres in Scotland. The baseline visit was completed within 6 months of diagnosis with initial follow-up 12 months after the baseline visit. The assessments included in FutureMS retinal imaging study were visual acuity test, self-reported eye questionnaire and OCT scan. RESULTS: A total of 196 FutureMS participants completed the retinal imaging study of FutureMS with 185 participants at M0 and 155 at M12. A total of 144 participants completed both M0 and M12 visits. At the whole cohort level, the distribution of retinal measures is generally consistent between baseline and follow-up. CONCLUSION: The FutureMS retinal imaging study aims to demonstrate that patient with MS present with different extent of retinal abnormalities that can be captured by retinal imaging modalities such as OCT soon after diagnosis. These changes may sensitively mirror the brain atrophy or serve as predictors for disease activity. By developing sensitive, quantifiable and objective retinal biomarkers, FutureMS retinal imaging study will provide an opportunity to stratify patient with MS at an early stage and support future therapeutic strategies for a better outcome.

Active Arf6 recruits ARNO/cytohesin GEFs to the PM by binding their PH domains.

ARNO is a soluble guanine nucleotide exchange factor (GEF) for the Arf family of GTPases. Although in biochemical assays ARNO prefers Arf1 over Arf6 as a substrate, its localization in cells at the plasma membrane (PM) suggests an interaction with Arf6. In this study, we found that ARNO activated Arf1 in HeLa and COS-7 cells resulting in the recruitment of Arf1 on to dynamic PM ruffles. By contrast, Arf6 was activated less by ARNO than EFA6, a canonical Arf6 GEF. Remarkably, Arf6 in its GTP-bound form recruited ARNO to the PM and the two proteins could be immunoprecipitated. ARNO binding to Arf6 was not mediated through the catalytic Sec7 domain, but via the pleckstrin homology (PH) domain. Active Arf6 also bound the PH domain of Grp1, another ARNO family member. This interaction was direct and required both inositol phospholipids and GTP. We propose a model of sequential Arf activation at the PM whereby Arf6-GTP recruits ARNO family GEFs for further activation of other Arf isoforms.

Falls in Progressive Supranuclear Palsy.

BACKGROUND: Despite falls being an almost universal clinical feature and central to the presentation and diagnostic criteria of progressive supranuclear palsy, our understanding of falls is surprisingly limited and there are few effective treatment options. OBJECTIVES: To provide an overview of the topic of the impact, assessment, mechanism, and management of falls in progressive supranuclear palsy. METHODS: We performed a literature search for "falls" and "progressive supranuclear palsy" and included additional relevant literature known to us. We synthesized this literature with experience from clinical practice. RESULTS: We review current understanding of the pathophysiology of falls, highlighting the roles of the indirect pathway and the pedunculopontine nucleus. We go on to identify shortcomings in commonly used assessments to measure falls. We discuss medical and nonmedical fall prevention strategies, and finally we discuss balancing falls risk against promoting independence. CONCLUSION: Falls are central to progressive supranuclear palsy presentation and diagnosis. Indirect locomotor and pedunculopontine nucleus dysfunction are thought to be the neural substrate of falls in this condition. Attempts to measure and prevent falls, by medical and nonmedical means, are currently limited. A personalized approach is advocated in the management of falls.

Systematic review of prediction models in relapsing remitting multiple sclerosis.

The natural history of relapsing remitting multiple sclerosis (RRMS) is variable and prediction of individual prognosis challenging. The inability to reliably predict prognosis at diagnosis has important implications for informed decision making especially in relation to disease modifying therapies. We conducted a systematic review in order to collate, describe and assess the methodological quality of published prediction models in RRMS. We searched Medline, Embase and Web of Science. Two reviewers independently screened abstracts and full text for eligibility and assessed risk of bias. Studies reporting development or validation of prediction models for RRMS in adults were included. Data collection was guided by the checklist for critical appraisal and data extraction for systematic reviews (CHARMS) and applicability and methodological quality assessment by the prediction model risk of bias assessment tool (PROBAST). 30 studies were included in the review. Applicability was assessed as high risk of concern in 27 studies. Risk of bias was assessed as high for all studies. The single most frequently included predictor was baseline EDSS (n = 11). T2 Lesion volume or number and brain atrophy were each retained in seven studies. Five studies included external validation and none included impact analysis. Although a number of prediction models for RRMS have been reported, most are at high risk of bias and lack external validation and impact analysis, restricting their application to routine clinical practice.

An effector domain mutant of Arf6 implicates phospholipase D in endosomal membrane recycling.

In this study, we investigated the role of phospholipase D (PLD) in mediating Arf6 function in cells. Expression of Arf6 mutants that are defective in activating PLD, Arf6N48R and Arf6N48I, inhibited membrane recycling to the plasma membrane (PM), resulting in an accumulation of tubular endosomal membranes. Additionally, unlike wild-type Arf6, neither Arf6 mutant could generate protrusions or recruit the Arf6 GTPase activating protein (GAP) ACAP1 onto the endosome in the presence of aluminum fluoride. Remarkably, all of these phenotypes, including accumulated tubular endosomes, blocked recycling, and failure to make protrusions and recruit ACAP effectively, could be recreated in either untransfected cells or cells expressing wild-type Arf6 by treatment with 1-butanol to inhibit the formation of phosphatidic acid (PA), the product of PLD. Moreover, most of the defects present in cells expressing Arf6N48R or N48I could be reversed by treatment with agents expected to elevate PA levels in cells. Together, these observations provide compelling evidence that Arf6 stimulation of PLD is required for endosomal membrane recycling and GAP recruitment.

Diets with customary levels of fat from plant origin may reverse coronary artery disease.

The primary cause of death worldwide is heart disease and the most common type of heart disease is coronary artery disease. While coronary artery disease is treated with medications, it responds to lifestyle interventions. A low-fat plant-based diet was designed for reversing coronary artery disease and it is effective in reversing the disease. It has not been tested, however, as far as we know, whether diets with customary levels of fat can also reverse coronary artery disease. Nevertheless, evidence is accumulating to show that atherosclerosis and coronary artery disease are reversed with diets containing customary levels of fat. It has been known that fats of plant origin decrease the risk factors of cardiovascular disease. It is also known that vegans who consume diets with customary levels of fat have the lowest risk of cardiovascular disease. But recent and more specific data show that atherosclerosis was decreased when nuts that are rich in fat were added to a Mediterranean diet while atherosclerosis was increased in the controls. Also, two clinical cases show that coronary artery disease was reversed by low-fat plant-based diets that were supplemented with fat-rich foods of plant origin. These data, then, provide evidence that coronary artery disease may be reversed with a diet containing customary levels of fat from plant sources. We hypothesize that coronary artery disease may be reversed by diets with customary levels of fat of plant origin that are low in saturated fat content. This hypothesis needs to be tested by comparing a traditional low-fat plant-based diet with a plant-based diet containing customary levels of fat of plant origin in their effectiveness to reverse coronary artery disease.

Efficient Hydrogen-Dependent Carbon Dioxide Reduction by Escherichia coli.

Hydrogen-dependent reduction of carbon dioxide to formic acid offers a promising route to greenhouse gas sequestration, carbon abatement technologies, hydrogen transport and storage, and the sustainable generation of renewable chemical feedstocks [1]. The most common approach to performing direct hydrogenation of CO2 to formate is to use chemical catalysts in homogeneous or heterogeneous reactions [2]. An alternative approach is to use the ability of living organisms to perform this reaction biologically. However, although CO2 fixation pathways are widely distributed in nature, only a few enzymes have been described that have the ability to perform the direct hydrogenation of CO2 [3-5]. The formate hydrogenlyase (FHL) enzyme from Escherichia coli normally oxidizes formic acid to carbon dioxide and couples that reaction directly to the reduction of protons to molecular hydrogen [6]. In this work, the reverse reaction of FHL is unlocked. It is established that FHL can operate as a highly efficient hydrogen-dependent carbon dioxide reductase when gaseous CO2 and H2 are placed under pressure (up to 10 bar). Using intact whole cells, the pressurized system was observed to rapidly convert 100% of gaseous CO2 to formic acid, and >500 mM formate was observed to accumulate in solution. Harnessing the reverse reaction has the potential to allow the versatile E. coli system to be employed as an exciting new carbon capture technology or as a cell factory dedicated to formic acid production, which is a commodity in itself as well as a feedstock for the synthesis of other valued chemicals.

Transseptal course of anomalous left main coronary artery originating from single right coronary orifice presenting as unstable angina.

Transseptal course of coronary artery has often been described as a benign entity; however, this report and literature analysis provides growing evidence of high risk of serious cardiovascular events in this anomaly. We present a case of unstable angina in a patient with anomalous common origin of left and right coronary arteries from a single coronary ostium at the right sinus of Valsalva, with subsequent transseptal course of the left main artery, review of relevant literature, and discussion of possible management options.

Microwave-assisted ring opening of epoxides: a general route to the synthesis of 1-aminopropan-2-ols with anti malaria parasite activities.

A series of 1-aminopropan-2-ols were synthesized and evaluated against two strains of malaria, Plasmodium falciparum FCR3 (chloroquine-resistant) and 3D7 (chloroquine-sensitive). Microwave-assisted ring opening of epoxides (aryl and alkyl glycidyl ethers, glycidol, epichlorohydrin) with various amines without catalysts generated the desired library of beta-amino alcohols rapidly and efficiently. Most of the compounds showed micromolar potency against malaria, with seven of them having IC50 values between 1 and 10 microM against both Plasmodium falciparum strains.

Lumbar dural ectasia secondary to spinal fusion: a report of two cases.

Two cases of lumbar dural ectasia secondary to spinal fusion are presented. Background history of dural ectasia is discussed; computed tomography (CT) and MR imaging characteristics of dural ectasia are shown and possible causes are discussed.