A novel missense variant in HIKESHI: Clinical phenotype, in vitro functional testing, and potential for gene therapy.

A 7-month-old boy presented to our clinic with developmental delay, Magnetic Resonance Imaging (MRI) features of delayed myelination and diffusion restriction, and a homozygous variant of uncertain significance (c.4T>G, p.Phe2Val) in HIKESHI, a gene associated with autosomal-recessive hypomyelinating leukodystrophy 13. We hypothesized that the variant is disease-causing and aimed to rescue the cellular phenotype with vector-mediated gene replacement. HIKESHI mediates heat-induced nuclear accumulation of heat-shock proteins, including HSP70, to protect cells from stress. We generated skin fibroblasts from the proband and proband's mother (heterozygous) to compare protein expression and subcellular localization of HSP70 under heat stress conditions, and the effect of vector-mediated overexpression of HIKESHI in the proband's cells under the same heat stress conditions. Western blot analysis revealed absent HIKESHI protein from proband fibroblasts, contrasted with ample expression in parental cells. Under heat stress conditions, while the mother's cells displayed appropriate nuclear localization of HSP70, the proband's cells displayed impaired nuclear translocalization. When patient fibroblasts were provided exogenous HIKESHI, the transfected proband's cells showed restored heat-induced nuclear translocalization of HSP70 under conditions of heat stress. These functional data establish that the patient's variant is a pathogenic loss-of-function mutation, thus confirming a diagnosis of hypomyelinating leukodystrophy 13 and that vector-mediated gene replacement may be an effective treatment approach for patients with this disorder.

Identifying clusters of objective functional impairment in patients with degenerative lumbar spinal disease using unsupervised learning.

OBJECTIVES: The five-repetition sit-to-stand (5R-STS) test was designed to capture objective functional impairment (OFI), and thus provides an adjunctive dimension in patient assessment. It is conceivable that there are different subsets of patients with OFI and degenerative lumbar disease. We aim to identify clusters of objectively functionally impaired individuals based on 5R-STS and unsupervised machine learning (ML). METHODS: Data from two prospective cohort studies on patients with surgery for degenerative lumbar disease and 5R-STS times of ≥ 10.5 s-indicating presence of OFI. K-means clustering-an unsupervised ML algorithm-was applied to identify clusters of OFI. Cluster hallmarks were then identified using descriptive and inferential statistical analyses. RESULTS: We included 173 patients (mean age [standard deviation]: 46.7 [12.7] years, 45% male) and identified three types of OFI. OFI Type 1 (57 pts., 32.9%), Type 2 (81 pts., 46.8%), and Type 3 (35 pts., 20.2%) exhibited mean 5R-STS test times of 14.0 (3.2), 14.5 (3.3), and 27.1 (4.4) seconds, respectively. The grades of OFI according to the validated baseline severity stratification of the 5R-STS increased significantly with each OFI type, as did extreme anxiety and depression symptoms, issues with mobility and daily activities. Types 1 and 2 are characterized by mild to moderate OFI-with female gender, lower body mass index, and less smokers as Type I hallmarks. CONCLUSIONS: Unsupervised learning techniques identified three distinct clusters of patients with OFI that may represent a more holistic clinical classification of patients with OFI than test-time stratifications alone, by accounting for individual patient characteristics.

FASCIA Method in the Assessment of Lymphocyte Mitogen Responses in the Laboratory Diagnostics of Primary Immunodeficiencies.

Lymphocyte responses to mitogens constitute a key part of the diagnostics of combined immunodeficiency (CID). Currently, mostly radioactive thymidine incorporation and carboxyfluorescein diacetate succinimidyl ester (CFSE) dilution methods are used. Flow-cytometric assay for specific cell-mediated immune-response in activated whole blood (FASCIA) has been put forth as an easy-to-perform option for the measurement of lymphocyte responses with the advantage of recognizing different lymphocyte subtypes and avoiding the use of radioactive reagents. Our aim was to analyze retrospectively the usefulness of FASCIA in the diagnostics of CID. We included all lymphocyte stimulation tests done with FASCIA in HUSLAB (Helsinki, Finland) between February 2015 and September 2018 in our analysis. The cohort was divided into two groups according to the patients' final diagnoses: CID (n = 30) or non-CID (n = 159). We evaluated the stimulation responses with a combined FASCIA score (the average of all mitogen responses). The FASCIA score was significantly lower among the CID group compared to the other patients (p = 0.002), and in the ROC analysis, the AUC was 0.75 (p < 0.001) for the FASCIA score. When the three mitogens were analyzed separately, phytohemagglutinin (PHA) was best in separating patients with CID from non-CID (in the ROC analysis AUC 0.71, p = 0.001). Immunosuppressive medication affected the FASCIA result significantly and needs to be considered when evaluating the results. In conclusion, FASCIA can reliably detect the CID patients in the absence of immunosuppressive medication. It emerges as a method with many benefits compared to tests requiring radioactive reagents or the complicated CFSE staining.

Remote Perimetry in a Virtual Reality Metaverse Environment for Out-of-Hospital Functional Eye Screening Compared Against the Gold Standard Humphrey Visual Fields Perimeter: Proof-of-Concept Pilot Study.

BACKGROUND: The growing global burden of visual impairment necessitates better population eye screening for early detection of eye diseases. However, accessibility to testing is often limited and centralized at in-hospital settings. Furthermore, many eye screening programs were disrupted by the COVID-19 pandemic, presenting an urgent need for out-of-hospital solutions. OBJECTIVE: This study investigates the performance of a novel remote perimetry application designed in a virtual reality metaverse environment to enable functional testing in community-based and primary care settings. METHODS: This was a prospective observational study investigating the performance of a novel remote perimetry solution in comparison with the gold standard Humphrey visual field (HVF) perimeter. Subjects received a comprehensive ophthalmologic assessment, HVF perimetry, and remote perimetry testing. The primary outcome measure was the agreement in the classification of overall perimetry result normality by the HVF (Swedish interactive threshold algorithm-fast) and testing with the novel algorithm. Secondary outcome measures included concordance of individual testing points and perimetry topographic maps. RESULTS: We recruited 10 subjects with an average age of 59.6 (range 28-81) years. Of these, 7 (70%) were male and 3 (30%) were female. The agreement in the classification of overall perimetry results was high (9/10, 90%). The pointwise concordance in the automated classification of individual test points was 83.3% (8.2%; range 75%-100%). In addition, there was good perimetry topographic concordance with the HVF in all subjects. CONCLUSIONS: Remote perimetry in a metaverse environment had good concordance with gold standard perimetry using the HVF and could potentially avail functional eye screening in out-of-hospital settings.

Full-Field Electroretinography Changes Associated with Age-Related Macular Degeneration: A Systematic Review with Meta-Analyses.

BACKGROUND: The aim of this study was to systematically review the literature and to perform meta-analyses on full-field electroretinography (ffERG) between healthy controls and age-related macular degeneration (AMD) to map the extent of retinal dysfunction. SUMMARY: We systematically searched 11 databases on 3 March 2021. Eligible studies had to measure retinal function using ffERG in eyes with AMD and in healthy controls. We extracted data on a-wave and b-wave function in dark- and light-adapted ffERG and calculated summary estimates on differences between eyes with AMD and controls using weighted mean differences (WMD). Subgroup analyses were made for early and late AMD. Six studies (n = 481 eyes) were eligible for review (301 with any AMD, 180 controls). For dark-adapted data, any AMD was associated with reduced a-wave amplitude (WMD: -17.16 µV; 95% CI: -31.79 to -2.52 µV; p = 0.02) and b-wave amplitude (WMD: -28.70 µV; 95% CI: -51.40 to -6.01 µV; p = 0.01). For light-adapted data, any AMD was associated with longer a-wave implicit time (WMD: 0.92 ms; 95% CI: 0.12-1.72 ms; p = 0.02), reduced b-wave amplitude (WMD: -13.26 µV; 95% CI: -18.64 to -7.88 µV; p < 0.0001), and longer b-wave implicit time (WMD: 0.69 ms; 95% CI: 0.30-1.08 ms; p = 0.0006). Subgroup analyses found that these changes were only statistically significant in eyes with late AMD, not early AMD. KEY MESSAGES: Reduced retinal function on ffERG is present in eyes with AMD, in particular those with late AMD. These findings suggest that AMD is a pan-retinal disease with AMD-associated photoreceptor dysfunction beyond the macula.

Validation of the Circular Tandem Walk Test and Optimal Cutoff Score to Determine the Risk of Falls in Active Community-Dwelling Older Adults.

This study was to develop and validate the circular tandem walk test (CTWT) by deriving an optimal cutoff score to indicate the fall risk in 89 active community-dwelling older individuals. The participants aged 65 years and older were assessed for their demographic data, fear of fall variables, and history of falls in the past 6 months. Subsequently, participants were randomized for the sequence of tests between the tandem walk test and the CTWT. The outcomes of CTWT showed the highest significant correlation with all the fall variables (ranging from .631 to .827, p < .001). Moreover, the time to perform the CTWT ≥ 14.6 s and ≥ two error scores had excellent and acceptable diagnostic accuracy to determine the risk of falls in the older individuals, respectively. The CTWT can be used as alternative screening tests for assessing the fall risk in active older adults in community settings.

The Concept of Acceleration and Deceleration in Isokinetics and Its Relation to 3 Hop Tests.

CONTEXT: Both isokinetic testing and functional tests are often used during patient rehabilitation programs. Most researchers have assessed the relationship of isokinetic testing and functional tests in parameters such as peak moment, work, or power. However, little information exists regarding the acceleration and deceleration parameters and their relationship to function. DESIGN: The purpose of the study was to investigate the concept of acceleration and deceleration of the knee flexor and extensor muscle groups during isokinetic testing and its relationship to function. METHODS: Twenty-six healthy individuals (14 men and 12 women) participated in the study. Isokinetic bilateral concentric knee flexion and extension muscular performance was assessed isokinetically at the angular velocities of 60°/s, 180°/s, and 300°/s. Functional performance was also assessed using (1) single hop for distance, (2) triple hop for distance, and (3) single timed hop. Functional data were normalized to body weight. A P value <.05 was considered to be significant. RESULTS: Fair and moderate to good correlations (r = .396, P = .045 to r = .705, P = .001) were discovered between flexors' and extensors' acceleration/deceleration variables and the normalized to body weight functional tests. CONCLUSIONS: Appropriate understanding of isokinetic parameters as described in this study, including acceleration/deceleration values, may provide useful information about the functional ability of the lower limb muscular system.

Functional Assays Are Essential for Interpretation of Missense Variants Associated with Variable Expressivity.

Missense DNA variants have variable effects upon protein function. Consequently, interpreting their pathogenicity is challenging, especially when they are associated with disease variability. To determine the degree to which functional assays inform interpretation, we analyzed 48 CFTR missense variants associated with variable expressivity of cystic fibrosis (CF). We assessed function in a native isogenic context by evaluating CFTR mutants that were stably expressed in the genome of a human airway cell line devoid of endogenous CFTR expression. 21 of 29 variants associated with full expressivity of the CF phenotype generated <10% wild-type CFTR (WT-CFTR) function, a conservative threshold for the development of life-limiting CF lung disease, and five variants had moderately decreased function (10% to ∼25% WT-CFTR). The remaining three variants in this group unexpectedly had >25% WT-CFTR function; two were higher than 75% WT-CFTR. As expected, 14 of 19 variants associated with partial expressivity of CF had >25% WT-CFTR function; however, four had minimal to no effect on CFTR function (>75% WT-CFTR). Thus, 6 of 48 (13%) missense variants believed to be disease causing did not alter CFTR function. Functional studies substantially refined pathogenicity assignment with expert annotation and criteria from the American College of Medical Genetics and Genomics and Association for Molecular Pathology. However, four algorithms (CADD, REVEL, SIFT, and PolyPhen-2) could not differentiate between variants that caused severe, moderate, or minimal reduction in function. In the setting of variable expressivity, these results indicate that functional assays are essential for accurate interpretation of missense variants and that current prediction tools should be used with caution.

Fecobionics assessment of the effect of position on defecatory efficacy in normal subjects.

BACKGROUND: Defecation is a complex process and up to 25% of the population suffer from symptoms of defecatory dysfunction. For functional testing, diagnostics, and therapy of anorectal disorders, it is important to know the optimal defecation position. is The aim of this study was to evaluate defecation pressure patterns in side lying, seated and squatting defecation positions in normal subjects using a simulated stool device called Fecobionics. METHODS: The Fecobionics expulsion parameters were assessed in an interventional study design conducted from May 29 to December 9 2019. Subjects were invited to participate in the study through advertisement at The Chinese University of Hong Kong. The Fecobionics device consisted of a core containing pressure sensors at the front (caudal end) and rear (cranial end) and a polyester-urethane bag spanning most of the core length which also contained sensors. The Fecobionics bag was distended to 50 ml in the rectum of normal subjects (no present and past symptoms of defecatory disorders, no prior abdominal surgery, medication or chronic diseases). Studies were done in side lying (left lateral recumbent position), seated (hip flexed 90°) and squatting position (hip flexed 25°). Pressure endpoints including the rear-front pressure diagram and defecation indices were compared between positions. RESULTS: Twelve subjects (6 females/6 males, mean age 26.3 ± 2.6 [19.0-48.0] years) were included and underwent the planned procedures. The resting anal pressure for side lying and seated positions were 33.1 ± 4.1 cmH2O and 37.1 ± 4.0 cmH2O (p > 0.3). The anal squeeze pressure for side lying and seated positions were 98.4 ± 6.9 cmH2O and 142.3 ± 16.4 cmH2O (p < 0.05). The expulsion duration for the side lying, seated and squatting positions were 108.9 ± 8.3 s, 15.0 ± 2.1 s and 16.1 ± 2.9 s, respectively (p < 0.01 between lying and the two other positions). The maximum evacuation pressure for seated and squatting were 130.1 ± 12.4 cmH2O and 134.0 ± 11.1 cmH2O (p > 0.5). Rear-front pressure diagrams and distensibility indices demonstrated distinct differences in pressure patterns between the side lying position group and the other positions. CONCLUSIONS: The delay in expelling the Fecobionics device in the lying position was associated with dyssynergic pressure patterns on the device. Quantitative differences were not found between the seated and squatting position. Trial Registration http://www.clinicaltrials.gov Identifier: NCT03317938.

Criteria-based return-to-sport testing is associated with lower recurrence rates following arthroscopic Bankart repair.

HYPOTHESIS AND BACKGROUND: This study aimed to analyze the impact of a criteria-based return-to-sport (CBRTS) testing protocol on recurrent instability following arthroscopic Bankart repair. We hypothesized that patients who underwent an objective CBRTS testing protocol to guide their clearance to return to sports would have less recurrent instability than those who did not undergo testing. METHODS: Thirty-six consecutive patients who underwent arthroscopic Bankart repair from 2016 to 2018, had a minimum of 1 year of follow-up, and completed functional and strength testing to evaluate readiness to return to sports were included in this retrospective case-control study. Patients with critical glenoid bone loss > 13.5%, multidirectional instability, and off-track Hill-Sachs lesions necessitating a remplissage or bone augmentation procedure were excluded from the study. Recurrence was defined as dislocation or subluxation symptoms requiring revision surgery. Statistical analysis included analysis of variance and the independent t test. RESULTS: There was no difference between the study and control groups regarding age (P = .15), sex (P = .11), hand dominance (P = .56), or participation in contact sports (P = .78). Patients who underwent the CBRTS testing protocol had a reduced rate of recurrent shoulder instability (5% vs. 22%; odds ratio, 4.85; P < .001). There was no difference in the time from surgery to recurrence between the groups (12 months vs. 13.6 months, P = .43). CONCLUSION: Athletes who underwent an objective CBRTS testing protocol to guide their clearance to return to sports had a lower rate of recurrent instability following arthroscopic Bankart repair than those cleared to return based on the time from surgery. Athletes who did not undergo CBRTS testing after arthroscopic shoulder stabilization had a 4.85 times increased likelihood of recurrent instability development after return to sports.

SCN1A variants from bench to bedside-improved clinical prediction from functional characterization.

Variants in the SCN1A gene are associated with a wide range of disorders including genetic epilepsy with febrile seizures plus (GEFS+), familial hemiplegic migraine (FHM), and the severe childhood epilepsy Dravet syndrome (DS). Predicting disease outcomes based on variant type remains challenging. Despite thousands of SCN1A variants being reported, only a minority has been functionally assessed. We review the functional SCN1A work performed to date, critically appraise electrophysiological measurements, compare this to in silico predictions, and relate our findings to the clinical phenotype. Our results show, regardless of the underlying phenotype, that conventional in silico software correctly predicted benign from pathogenic variants in nearly 90%, however was unable to differentiate within the disease spectrum (DS vs. GEFS+ vs. FHM). In contrast, patch-clamp data from mammalian expression systems revealed functional differences among missense variants allowing discrimination between disease severities. Those presenting with milder phenotypes retained a degree of channel function measured as residual whole-cell current, whereas those without any whole-cell current were often associated with DS (p = .024). These findings demonstrate that electrophysiological data from mammalian expression systems can serve as useful disease biomarker when evaluating SCN1A variants, particularly in view of new and emerging treatment options in DS.

Functional screening of GATOR1 complex variants reveals a role for mTORC1 deregulation in FCD and focal epilepsy.

Mutations in the GAP activity toward RAGs 1 (GATOR1) complex genes (DEPDC5, NPRL2 and NPRL3) have been associated with focal epilepsy and focal cortical dysplasia (FCD). GATOR1 functions as an inhibitor of the mTORC1 signalling pathway, indicating that the downstream effects of mTORC1 deregulation underpin the disease. However, the vast majority of putative disease-causing variants have not been functionally assessed for mTORC1 repression activity. Here, we develop a novel in vitro functional assay that enables rapid assessment of GATOR1-gene variants. Surprisingly, of the 17 variants tested, we show that only six showed significantly impaired mTORC1 inhibition. To further investigate variant function in vivo, we generated a conditional Depdc5 mouse which modelled a 'second-hit' mechanism of disease. Generation of Depdc5 null 'clones' in the embryonic brain resulted in mTORC1 hyperactivity and modelled epilepsy and FCD symptoms including large dysmorphic neurons, defective migration and lower seizure thresholds. Using this model, we validated DEPDC5 variant F164del to be loss-of-function. We also show that Q542P is not functionally compromised in vivo, consistent with our in vitro findings. Overall, our data show that mTORC1 deregulation is the central pathological mechanism for GATOR1 variants and also indicates that a significant proportion of putative disease variants are pathologically inert, highlighting the importance of GATOR1 variant functional assessment.

Simulated stool for assessment of anorectal physiology.

Fecal continence is maintained by several mechanisms including anatomical factors, anorectal sensation, rectal compliance, stool consistency, anal muscle strength, mobility, and psychological factors. The homeostatic balance is easily disturbed, resulting in symptoms including fecal incontinence and constipation. Current technologies for assessment of anorectal function have limitations. Overlap exist between data obtained in different patient groups, and there is lack of correlation between measurements and symptoms. This review describes a novel technology named Fecobionics for assessment of anorectal physiology. Fecobionics is a simulated stool, capable of dynamic measurements of a variety of variables during defecation in a single examination. The data facilitate novel analysis of defecatory function as well as providing the foundation for modeling studies of anorectal behavior. The advanced analysis can enhance our physiological understanding of defecation and future interdisciplinary research for unraveling defecatory function, anorectal sensory-motor disorders, and symptoms. This is a step in the direction of improved diagnosis of anorectal diseases.

A multi-dimensional analysis of genotype-phenotype discordance in malignant hyperthermia susceptibility.

BACKGROUND: Malignant hyperthermia (MH) susceptibility is an inherited condition, diagnosed either by the presence of a pathogenic genetic variant or by in vitro caffeine-halothane contracture testing. Through a multi-dimensional approach, we describe the implications of discordance between genetic and in vitro test results in a patient with a family history of possible MH. METHODS: The patient, whose brother had a possible MH reaction, underwent the caffeine-halothane contracture test (CHCT) according to the North American MH Group protocol. Screening of the complete RYR1 and CACNA1S transcripts was done using Sanger sequencing. Additional functional analyses included skinned myofibre calcium-induced calcium release sensitivity, calcium signalling assays in cultured myotubes, and in silico evaluation of the effect of any genetic variants on their chemical environment. RESULTS: The patient's CHCT result was negative but she carried an RYR1 variant c.1209C>G, p.Ile403Met, that is listed as pathogenic by the European Malignant Hyperthermia Group. Functional tests indicated a gain-of-function effect with a weak impact, and the variant was predicted to affect the folding stability of the 3D structure of the RyR1 protein. Based on American College of Medical Genetics and Genomics/Association of Molecular Pathology guidelines, this variant would be characterised as a variant of uncertain significance. CONCLUSIONS: Available data do not confirm or exclude an increased risk of MH for this patient. Further research is needed to correlate RyR1 functional assays, including the current gold standard testing for MH susceptibility, with clinical phenotypes. The pathogenicity of genetic variants associated with MH susceptibility should be re-evaluated.

The interrater reliability of dynamic leap and balance test in healthy and chronic ankle instability.

The primary aim of this study was to assess the interrater reliability of the Dynamic Leap and Balance Test (DLBT) in chronic ankle instability (CAI) and healthy groups. The secondary aim was to assess the differences in errors and time taken to complete the DLBT between the two groups for both raters and to identify cutoff scores to distinguish between patients with CAI and healthy controls. This was a controlled laboratory reliability analysis study. Fourteen healthy college-aged subjects (9 women 5 men; weight = 62.10 ± 8.03; height = 168.35 ± 6.0) and sixteen with a history of CAI (9 women, 7 men; weight = 68.01 ± 10.74; height = 172.08 ± 11.37) participated. Interrater reliability was determined by independent raters for both total time taken to complete the task and errors made. The most optimal score to discriminate between two groups was determined by receiver operator curve analysis. Total time taken and errors made were also documented for group differences as secondary analysis. A strong agreement was found between the two raters for time and errors with intraclass correlation coefficient >0.80. Significantly (P < .05) higher number of errors were made and greater time taken by the CAI subjects when compared with healthy for both raters. The most optimal score to discriminate between CAI and healthy control was 43.28s and 4 errors. Excellent interrater reliability substantiates that it can be used confidently by different clinicians for testing dynamic balance. CAI group took more time and made more errors to complete the DLBT.

Association of maximum back and leg pain severity with objective functional impairment as assessed by five-repetition sit-to-stand testing: analysis of two prospective studies.

The five-repetition sit-to-stand (5R-STS) test was designed to capture objective functional impairment (OFI), and provides a new adjunctive dimension in patient assessment. Its interpretability and confounders remain poorly understood. We quantify the association among maximum patient-reported back (MBP) or leg pain (MLP) and OFI as measured by the 5R-STS using data from two prospective studies. Patients performed the 5R-STS test and completed visual analogue scales (VAS) for back and leg pain severity. Maximum pain severity was defined as VAS scores of 9 or 10. The association of MBP and MLP with 5R-STS test times as well as with the presence of OFI (> 10.5 s) and severe OFI (> 22.0 s) as determined by the 5R-STS baseline severity stratification was quantified by use of crude and adjusted regression models. A total of 258 patients were included. MBP and MLP were reported by 27 (10.5%) and 76 (29.5%) patients, respectively. Rates of OFI differed among patients with (92.6%) and without (55.0%) MBP (p < 0.001), while presence of MLP did not influence OFI (61.8% vs. 57.7%, p = 0.632). Similarly, severe OFI was more common among patients with MBP (33.3% vs. 9.1%, p < 0.001), but not among patients with MLP (17.1% vs. 9.3%, p = 0.119). In the adjusted logistic analysis, the influence of MBP on OFI persisted (odds ratio [OR] 10.08, confidence interval [CI] 2.73-65.74, p = 0.003), while MLP demonstrated no association (OR 0.91, CI 0.49-1.72, p = 0.780). These associations were consistent with findings pertaining to raw 5R-STS test times and in discectomy patients alone. There is a strong association of maximum back pain severity on VAS with the degree of OFI determined by 5R-STS testing. Radiculopathy with maximally strong back pain, however, does not seem to relevantly influence 5R-STS performance.Trial registration ClinicalTrials.gov : NCT03321357 & NCT03303300.

Initial classification of low back and leg pain based on objective functional testing: a pilot study of machine learning applied to diagnostics.

OBJECTIVE: The five-repetition sit-to-stand (5R-STS) test was designed to capture objective functional impairment and thus provided an adjunctive dimension in patient assessment. The clinical interpretability and confounders of the 5R-STS remain poorly understood. In clinical use, it became apparent that 5R-STS performance may differ between patients with lumbar disk herniation (LDH), lumbar spinal stenosis (LSS) with or without low-grade spondylolisthesis, and chronic low back pain (CLBP). We seek to evaluate the extent of diagnostic information contained within 5R-STS testing. METHODS: Patients were classified into gold standard diagnostic categories based on history, physical examination, and imaging. Crude and adjusted comparisons of 5R-STS performance were carried out among the three diagnostic categories. Subsequently, a machine learning algorithm was trained to classify patients into the three categories using only 5R-STS test time and patient age, gender, height, and weight. RESULTS: From two prospective studies, 262 patients were included. Significant differences in crude and adjusted test times were observed among the three diagnostic categories. At internal validation, classification accuracy was 96.2% (95% CI 87.099.5%). Classification sensitivity was 95.7%, 100%, and 100% for LDH, LSS, and CLBP, respectively. Similarly, classification specificity was 100%, 95.7%, and 100% for the three diagnostic categories. CONCLUSION: 5R-STS performance differs according to the etiology of back and leg pain, even after adjustment for demographic covariates. In combination with machine learning algorithms, OFI can be used to infer the etiology of spinal back and leg pain with accuracy comparable to other diagnostic tests used in clinical examination. These slides can be retrieved under Electronic Supplementary Material.

After ISCHEMIA: is invasive physiology the only remaining gatekeeper for myocardial revascularization in chronic coronary syndromes?

The International Study of Comparative Health Effectiveness With Medical And Invasive Approaches (ISCHEMIA) has the potential to be a game changer in terms of the diagnostic and management approach to patients presenting with chronic coronary syndrome, suggesting that coronary revascularization may become almost like a "bail-out" strategy in the treatment of these patients. However, invasive perfusion assessment as a means of detecting the source of myocardial ischaemia at a lesion level, such as fractional flow reserve (FFR), has been validated in the past and established beyond doubt as a key diagnostic tool. The complementary role of the two approaches will be discussed here.

Should NICE guidelines be universally accepted for the evaluation of stable coronary disease? A debate.

The 2016 National Institute of Health and Care Excellence clinical guideline for the assessment and diagnosis of chest pain positions coronary computed tomography angiography as the first test for all stable chest pain patients without confirmed coronary artery disease and discards the previous emphasis on calculation of pre-test likelihood recommended in their 2012 edition of the guidelines. On the other hand, the American College of Cardiology Foundation/American Heart Association and the European Society of Cardiology guidelines continue to present the stress testing functional modalities as the tests of choice. The aim of this review is to present, in the form of a debate, the pros and cons of these paradigm changing recommendations, with an emphasis on literature review and projection of future needs, with conclusions to be drawn by the reader.

Return to sports bridge program improves outcomes, decreases ipsilateral knee re-injury and contralateral knee injury rates post-ACL reconstruction.

PURPOSE: To present the results of a return to sports bridge program designed to reduce knee injuries following ACL reconstruction and physical therapy. METHODS: One hundred and fifty (male = 83, female = 67) patients participated in a whole body neuromuscular control, progressive resistance strength and agility training program. Post-program testing included functional movement form, dynamic knee stability, lower extremity power, agility, and sports skill assessments. Participants completed the Knee Outcome Survey-Sports Activity Scale (KOS-SAS) before and after program initiation. Pre-participation scores were re-estimated following program completion. RESULTS: Global rating KOS-SAS score at program entry was 75 ± 13. Post-program global rating and calculated KOS-SAS were 91.0 ± 9.8 and 90.9 ± 9.7, respectively (p < 0.0001). Pre-participation KOS-SAS score re-estimates at program completion were 54.5 ± 23.3 and 57.3 ± 18.5, respectively. The approximately 20% lower pre-program KOS-SAS score re-estimates (p < 0.0001) observed at program completion suggests that subjects had inaccurately high sports readiness perceptions at program entry. Perceived overall sports activity knee function ratings improved from 2.9 ± 0.6 (abnormal) at program entry to 1.3 ± 0.5 (normal) at completion (p < 0.0001). Most subjects returned back to sports at or above their pre-injury performance skill/performance level (84%, 126/150). By 6.8 ± 3.2 years (range = 2-13 years) post-surgery, ten subjects had sustained an ipsilateral knee re-injury or contralateral knee injury (6.7%). The 2.7% non-contact contralateral and 1.3% non-contact ipsilateral knee injury rates observed were significantly lower than those cited in previous reports. CONCLUSION: Supplementing primary ACL reconstruction and standard physical therapy with a return to sports bridge program prior to release to unrestricted sports performance was effective at improving patient outcomes and decreasing ipsilateral knee re-injury and contralateral knee injury rates. LEVEL OF EVIDENCE: II.