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Due to the successful implementation of measles and rubella elimination strategies, Mexico announced the interruption of endemic transmission of measles in 1996 and that of rubella in 2008. After a verification process, the region of the Americas was declared free of rubella and congenital rubella syndrome in 2015 and of measles in 2016. In order to maintain the elimination status in Mexico, it is essential to continue laboratory surveillance within the framework of the Global Measles and Rubella Laboratory Network. The Institute of Epidemiological Diagnosis and Reference, through the National Network of Public Health Laboratories, guarantees timely and reliable results in view of the possible reintroduction of these and other emerging pathogens.

OBJECTIVE: Adolescent depression is prevalent and is associated with significant morbidity and mortality. Although intravenous ketamine has shown efficacy in adult treatment-resistant depression, its efficacy in pediatric populations is unknown. The authors conducted an active-placebo-controlled study of ketamine’s safety and efficacy in adolescents. METHODS: In this proof-of-concept randomized, double-blind, single-dose crossover clinical trial, 17 adolescents (ages 13–17) with a diagnosis of major depressive disorder received a single intravenous infusion of either ketamine (0.5 mg/kg over 40 minutes) or midazolam (0.045 mg/kg over 40 minutes), and the alternate compound 2 weeks later. All participants had previously tried at least one antidepressant medication and met the severity criterion of a score >40 on the Children’s Depression Rating Scale–Revised. The primary outcome measure was score on the Montgomery-Åsberg Depression Rating Scale (MADRS) 24 hours after treatment. RESULTS: A single ketamine infusion significantly reduced depressive symptoms 24 hours after infusion compared with midazolam (MADRS score: midazolam, mean=24.13, SD=12.08, 95% CI=18.21, 30.04; ketamine, mean=15.44, SD=10.07, 95% CI=10.51, 20.37; mean difference=−8.69, SD=15.08, 95% CI=−16.72, −0.65, df=15; effect size=0.78). In secondary analyses, the treatment gains associated with ketamine appeared to remain 14 days after treatment, the latest time point assessed, as measured by the MADRS (but not as measured by the Children’s Depression Rating Scale–Revised). A significantly greater proportion of participants experienced a response to ketamine during the first 3 days following infusion as compared with midazolam (76% and 35%, respectively). Ketamine was associated with transient, self-limited dissociative symptoms that affected participant blinding, but there were no serious adverse events. CONCLUSIONS: In this first randomized placebo-controlled clinical trial of intravenous ketamine in adolescents with depression, the findings suggest that it is well tolerated acutely and has significant short-term (2-week) efficacy in reducing depressive symptoms compared with an active placebo. Reprinted from Am J Psychiatry 2021; 178:352–362 with permission from American Psychiatric Association Publishing.

The spread of early-stage (T1 and T2) adenocarcinomas to locoregional lymph nodes is a key event in disease progression of colorectal cancer (CRC). The cellular mechanisms behind this event are not completely understood and existing predictive biomarkers are imperfect. Here, we used an end-to-end deep learning algorithm to identify risk factors for lymph node metastasis (LNM) status in digitized histopathology slides of the primary CRC and its surrounding tissue. In two large population-based cohorts, we show that this system can predict the presence of more than one LNM in pT2 CRC patients with an area under the receiver operating curve (AUROC) of 0.733 (0.67-0.758) and patients with any LNM with an AUROC of 0.711 (0.597-0.797). Similarly, in pT1 CRC patients, the presence of more than one LNM or any LNM was predictable with an AUROC of 0.733 (0.644-0.778) and 0.567 (0.542-0.597), respectively. Based on these findings, we used the deep learning system to guide human pathology experts towards highly predictive regions for LNM in the whole slide images. This hybrid human observer and deep learning approach identified inflamed adipose tissue as the highest predictive feature for LNM presence. Our study is a first proof of concept that artificial intelligence (AI) systems may be able to discover potentially new biological mechanisms in cancer progression. Our deep learning algorithm is publicly available and can be used for biomarker discovery in any disease setting. © 2021 The Pathological Society of Great Britain and Ireland. Published by John WileySons, Ltd.

Background: Spinal Muscular Atrophy (SMA) is the most common neurodegenerative disease in childhood. New therapeutic interventions have been developed to interrupt rapid motor deterioration. The current standard of clinical evaluation for severely weak infants is the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND), originally developed for SMA type 1. This test however, remains subjective and requires extensive training to be performed reliably. Objective: Proof of principle of the motion tracking method for capturing complex movement patterns in ten children with SMA. Methods: We have developed a system for tracking full-body motion in infants (KineMAT) using a commercially available, low-cost RGB-depth sensor. Ten patients with SMA (2–46 months of age; CHOP INTEND score 10–50) were recorded for 2 minutes during unperturbed spontaneous whole-body activity. Five predefined motion parameters representing 56 degrees of freedom of upper, lower extremities and trunk joints were correlated with CHOP INTEND scores using Pearson product momentum correlation (r). Test-retest analysis in two patients used descriptive statistics. Results: 4/5 preselected motion parameters highly correlated with CHOP INTEND: 1. Standard deviation of joint angles (r = 0.959, test-retest range 1.3–1.9%), 2. Standard deviation of joint position (r = 0.933, test-retest range 2.9%), 3. Absolute distance of hand/foot travelled (r = 0.937, test-retest range 6–10.5%), 4. Absolute distance of hand/foot travelled against gravity (r = 0.923; test-retest range 4.8–8.5%). Conclusions: Markerless whole-body motion capture using the KineMAT proved to objectively capture motor performance in infants and children with SMA across different severity and ages.

Introduction Trochleoplasty is a surgical procedure used to treat patellar instability by modifying the trochlear groove. Analysis of the groove with a handheld scanner would enable accurate real-time planning and facilitate tailormade correction. We aimed to measure trochlear depth, sulcus angle, trochlear facet ratio, trochlear angle and lateral trochlear inclination angle and to establish inter- and intra-rater reliability for knee models to determine reliability and repeatability. Methods The trochlear grooves of three knee models were scanned by two investigators. Three-dimensional reference models were created and surface-matched. Custom software was used to determine the desired parameters. The intraclass correlation coefficient (ICC) was used to determine test–retest reliability and the parameter results for each model that showed best reproducibility. Results There was good interobserver reliability (trochlear depth, 1.0mm; sulcus angle, 2.7°; trochlear angle, 4.0°; lateral trochlear inclination angle, 4.0°), except in the trochlear facet ratio (32.0%) of one knee model. With outliers removed, the ICC was moderate to excellent in 73.34% of measurements, with trochlear depth showing the best reproducibility. Discussion This feasibility study showed a handheld scanner in conjunction with supporting software can measure trochlear parameters with good to excellent inter- and intra-observer reliability.

Structured Summary Background To prevent transmission of and infection with meticillin-resistant Staphylococcus aureus (MRSA), eradication treatment of colonized individuals is recommended. Throat colonization is a well-known risk factor for eradication failure. Staphylococcus aureus throat colonization is associated with colonization of the rhinopharynx, but in the currently recommended Danish MRSA eradication strategies, rhinopharynx colonization is not directly targeted. Rhinopharynx colonization could therefore be an important risk factor for prolonged MRSA throat carriage. Aim To determine if irrigation and wash of the rhinopharynx and mouth with dissolved mupirocin is a feasible and potentially efficacious supplementary strategy against treatment resistant MRSA throat carriage. Methods The patient study was an open, non-blinded, trial including 20 treatment resistant MRSA throat carriers. In the study, the patients received a supplementary treatment besides the standard treatment according to the Danish MRSA eradication strategy. The supplementary treatment consisted of rhinopharyngeal irrigation and mouth gurgling twice a day for 14 days with a mupirocin ointment (22 g 2% ointment per liter of isotonic sterile saline solution) in a 37oC solution. Findings Eighteen patients (90%) complied with the treatment protocol and none experienced any major adverse events. Out of the 18 patients who finished the study per protocol, 15 (83%) and 7 (39%) patients had negative MRSA sampling results one and six months after end of treatment, respectively. Conclusions This study demonstrates the feasibility and clinical potential of also targeting the rhinopharynx and oropharynx in non-systemic throat MRSA eradication strategies.

The lancet / Digital health 4(1), e18-e26 (2022). doi:10.1016/S2589-7500(21)00211-9, Published by The Lancet, London

Introduction: Nephrometric scores play an interesting role in nephron sparring surgery (NSS) planning. The aim of this study is to evaluate if R.E.N.A.L. score (RS) is capable to predict the occurrence of adverse events in laparoscopic NSS. Materials and Methods: We prospectively studied 150 laparoscopic NSS between 2015 and 2018 to evaluate the relationship between RS and incidence of adverse events. Clavien 3 or superior complications, warm ischemia time (WIT) over 30 minutes, tumor violation, positive surgical margins (PSM) and necessity of amplification of renal parenchyma during the resection of the masses to obtain free margins were considered as adverse events. We compared each item of the RS isolated and divided the patients between low risk and high risk. Results: Adverse results occurred in 48 cases (32%). Amplification of the margin of resection was observed in 28 cases (19%). WIT exceeded 30 minutes in 9 cases (6.1%), complications Clavien 3 or superior occurred in 13 cases (9%) and PSM were detected en 6 cases (4%). Comparing the patients with adverse outcomes and each item of the RS we did not find any statistical difference, but when divided into high risk and low risk, we found that patients in the high risk group had a higher tendency to present ad-verse results - 25.84% vs. 44.26% (p=0.03). Conclusions: RS system is a good way to predict adverse outcomes in NSS, especially in cases over 7. Further studies should focus on robotic approach and patient's characteristics other than the masses’ aspects.

OBJECTIVE: This study aims to generate a reproducible and generalizable Workflow model of ICG-angiography integrating Standardization and Quantification (WISQ) that can be applied uniformly within the surgical innovation realm independent of the user.SUMMARY BACKGROUND DATA: Tissue perfusion based on indocyanine green (ICG)-angiography is a rapidly growing application in surgical innovation. Interpretation of have been subjective and error-prone due to the lack of a standardized and quantitative ICG-workflow and analytical methodology. There is a clinical need for a more generic, reproducible, and quantitative ICG perfusion model for objective assessment of tissue perfusion.METHODS: In this multicenter, proof-of-concept study, we present a generic and reproducible ICG-workflow integrating standardization and quantification for perfusion assessment. To evaluate our model's clinical feasibility and reproducibility, we assessed the viability of parathyroid glands after performing thyroidectomy. Biochemical hypoparathyroidism was used as the postoperative endpoint and its correlation with ICG quantification intraoperatively. Parathyroid gland are an ideal model as parathyroid function post-surgery is only affected by perfusion.RESULTS: We show that visual -subjective- interpretation of ICG-angiography by experienced surgeons on parathyroid perfusion cannot reliably predict organ function impairment postoperatively, emphasizing the importance of an ICG quantification model. WISQ was able to standardize and quantify ICG-angiography and provided a robust and reproducible perfusion curve analysis. A low ingress slope of the perfusion curve combined with a compromised egress slope was indicative for parathyroid organ dysfunction in 100% of the cases.CONCLUSION: WISQ needs prospective validation in larger series and may eventually support clinical decision-making to predict and prevent postoperative organ function impairment in a large and varied surgical population.

Purpose The purpose of this study was to assess the feasibility and efficacy of docetaxel-loaded bead chemoembolization in spontaneous prostate cancer in a canine model. Materials and methods Five pet dogs with histopathologically proven prostate cancer were referred for prostate artery chemoembolization (PACE). After PACE, all animals were followed, including pharmacokinetic study and clinical and biological evolution, until death. Pelvic contrast-enhanced computed tomography examination was performed at one and two months. Animals were subjected to pathological examination after death. Results Both prostate arteries were successfully chemoembolized in all dogs. A median dose of 18 mg (Q1, Q3; 11.8, 20 mg) docetaxel loaded in 3 mL of 50–100 µm super absorbent polymer beads was injected into each dog. At one month, four of the five dogs were still alive and the median prostate volume was 51% lower (prePACE median prostate volume, 18.4 mL [Q1, Q3; 12, 32.1 mL] vs. postPACE median prostate volume, 6.2 mL [Q1, Q3; 6.2, 11 mL]). At two months, three dogs died because of disease progression. The two remaining dogs showed a 70% median decrease in prostate volume. Prostate pathological examination showed 73% of necrosis. No worsening of urinary symptoms was observed. Pharmacokinetic analysis showed limited systemic passage of docetaxel. All dogs died of metastatic spread at nine months. Conclusion This study suggests that PACE is feasible and safe for the treatment of spontaneous prostate cancer in a canine model and may provide a new approach to treat selected patients with prostate cancer.

Background Familial partial lipodystrophy (FPLD) is a rare disease characterized by selective loss of peripheral subcutaneous fat, associated with dyslipidemia and diabetes mellitus. Reductions in circulating levels of ANGPTL3 are associated with lower triglyceride and other atherogenic lipids, making it an attractive target for treatment of FPLD patients. This proof-of-concept study was conducted to assess the efficacy and safety of targeting ANGPTL3 with vupanorsen in patients with FPLD. Methods This was an open-label study. Four patients with FPLD (two with pathogenic variants in LMNA gene, and two with no causative genetic variant), diabetes (HbA1c ≥ 7.0 % and ≤ 12 %), hypertriglyceridemia (≥ 500 mg/dL), and hepatic steatosis (hepatic fat fraction, HFF ≥ 6.4 %) were included. Patients received vupanorsen subcutaneously at a dose of 20 mg weekly for 26 weeks. The primary endpoint was the percent change from baseline in fasting triglycerides at Week 27. Other endpoints analyzed at the same time point included changes in ANGPTL3, fasting lipids and lipoproteins, insulin secretion/sensitivity, postprandial lipids, and glycemic changes in response to a mixed meal test, HFF measured by MRI, and body composition measured by dual-energy absorptiometry (DEXA). Results Baseline mean ± SD fasting triglyceride level was 9.24 ± 4.9 mmol/L (817.8 ± 431.9 mg/dL). Treatment resulted in reduction in fasting levels of triglycerides by 59.9 %, ANGPTL3 by 54.7 %, and in several other lipoproteins/lipids, including very low-density lipoprotein cholesterol by 53.5 %, non-high-density lipoprotein cholesterol by 20.9 %, and free fatty acids (FFA) by 41.7 %. The area under the curve for postprandial triglycerides, FFA, and glucose was reduced by 60 %, 32 %, and 14 %, respectively. Treatment with vupanorsen also resulted in 55 % reduction in adipose tissue insulin resistance index, while other insulin sensitivity indices and HbA1c levels were not changed. Additional investigations into HFF and DEXA parameters suggested dynamic changes in fat partitioning during treatment. Adverse events observed were related to common serious complications associated with diabetes and FPLD. Vupanorsen was well tolerated, and there was no effect on platelet count. Conclusions Although limited, these results suggest that targeting ANGPTL3 with vupanorsen could address several metabolic abnormalities in patients with FPLD.

Background: Repeated neuromuscular electrical stimulation in type 1 Myotonic Dystrophy (DM1) has previously been shown to cause an increase in strength and a decrease in hyperexcitability of the tibialis anterior muscle. Objective: In this proof-of-principle study our objective was to test the hypothesis that noninvasive repetitive transcranial magnetic stimulation of the primary motor cortex (M1) with a new portable wearable multifocal stimulator causes improvement in muscle function in DM1 patients. Methods: We performed repetitive stimulation of M1, localized by magnetic resonance imaging, with a newly developed Transcranial Rotating Permanent Magnet Stimulator (TRPMS). Using a randomized within-patient placebo-controlled double-blind TRPMS protocol, we performed unilateral active stimulation along with contralateral sham stimulation every weekday for two weeks in 6 adults. Methods for evaluation of muscle function involved electromyography (EMG), hand dynamometry and clinical assessment using the Medical Research Council scale. Results: All participants tolerated the treatment well. While there were no significant changes clinically, EMG showed significant improvement in nerve stimulus-evoked compound muscle action potential amplitude of the first dorsal interosseous muscle and a similar but non-significant trend in the trapezius muscle, after a short exercise test, with active but not sham stimulation. Conclusions: We conclude that two-week repeated multifocal cortical stimulation with a new wearable transcranial magnetic stimulator can be safely conducted in DM1 patients to investigate potential improvement of muscle strength and activity. The results obtained, if confirmed and extended by future safety and efficacy trials with larger patient samples, could offer a potential supportive TRPMS treatment in DM1.

Background Sellar masses (SM) frequently present with insidious hormonal dysfunction. We previously showed that, by utilizing a combined reflex/reflecting approach involving a laboratory clinician (LC) on common endocrine test results requested by non-specialists, and subsequently adding further warranted tests, previously undiagnosed pituitary disorders can be identified. However, manually employing these strategies by an LC is not feasible for wider screening of pituitary disorders. Objective The aim of this study was to compare the accuracy and financial impact of an Artificial Intelligence (AI) based, fully computerized reflex protocol with manual reflex/reflective intervention protocol led by an LC. Methods We developed a proof-of-concept AI-based framework to fully computerize multi-stage reflex testing protocols for pituitary dysfunction using automated reasoning methods. We compared the efficacy of this AI-based protocol with a reflex/reflective protocol based on manually curated retrospective data in identifying pituitary dysfunction based on 12 months of laboratory testing. Results The AI-based reflex protocol, as compared with the manual protocol, would have identified laboratory tests for add-on that either directly matched or included all manual add-on tests in 92% of cases, and recommended a similar specialist referral in 90% of the cases. The AI-based protocol would have issued 2.8 times the total number of manual add-on laboratory tests at an 85% lower operation cost than the manual protocol when considering marginal test costs, technical staff and specialist salary. Conclusion/Discussion Our AI-based reflex protocol can successfully identify patients with pituitary dysfunction, with lower estimated laboratory cost. Future research will focus on enhancing the protocol’s accuracy and incorporating the AI-based reflex protocol into institutional laboratory and hospital information systems for the detection of undiagnosed pituitary disorders.

Sporadic late-onset nemaline myopathy (SLONM) is an enigmatic, supposedly very rare, putatively immune-mediated late-onset myopathy, typically presenting with subacutely progressive limb-girdle muscular weakness, yet slowly progressing cases have been described too. We systematically studied (para)clinical and histopathological findings in a cohort of 18 isolated yet suspected inherited myopathy patients, showing late-onset, slowly progressive limb-girdle muscle weakness, remaining unsolved after whole-exome sequencing. The presence of a monoclonal gammopathy of unknown significance (MGUS) and anti-HMGCR antibodies was determined. Biopsies were systematically re-evaluated and systematic immunohistochemical and electron microscopy studies were performed to particularly evaluate the presence of rods and/or inflammatory features. Ten patients showed rods as core feature on muscle biopsy on re-evaluation, four of these had an IgG κ MGUS in blood. As such, these ten patients represented suspected slowly progressing SLONM patients, with auxiliary data supporting this diagnosis: 1) additional muscle biopsy features pointing towards Z-disk and myofibrillar pathology; 2) a common selective pattern of muscle involvement on MRI; 3) inflammatory features on muscle biopsy. Findings in this proof-of-concept study highlight difficulties in reliably diagnosing slowly progressing SLONM and the probably underestimated prevalence of this entity in cohorts of whole exome sequencing negative myopathy patients, initially considered having an inherited myopathy.

Background Early-stage symptomology of necrotizing enterocolitis (NEC) is similar in presentation to non-NEC sepsis, though the treatment plans differ based on antibiotic administration and withholding of feeds. Improved diagnostics for NEC differentiation would allow clinicians to more rapidly set individual patients on a targeted treatment path. Extracellular vesicle-derived miRNAs, have previously demonstrated efficacy as disease biomarkers. To determine if these miRNAs are differentially-expressed in NEC infants, we performed transcriptomic analysis of urine-derived extracellular vesicle-derived miRNAs. Methods Urine was non-invasively obtained from infants in one of four groups (n ≥ 8) (Medical NEC, Surgical NEC, non-NEC sepsis, and healthy age-matched controls). EV-derived miRNAs were isolated and transcriptomic analysis was performed. Results Multiple miRNAs, including miR-376a, miR-518a-3p and miR-604, were significantly altered when comparing NEC to non-NEC sepsis and healthy controls, and could potentially be used as specific NEC biomarkers. Additionally, Ingenuity Pathway Analysis demonstrated that miRs differentially-expressed in NEC were associated with inflammatory disease and intestinal disease. Signal transduction molecules associated with NEC including TP53 and RPS15, which were also reduced transcriptionally in a rat model of NEC. Conclusion These data indicate that there is a pool of potential urine EV-derived miRNAs that may be validated as NEC biomarkers in the differentiation of NEC from non-NEC sepsis and from age-matched controls. Additionally, signal transduction molecules associated with miRNAs differentially-expressed in human NEC are altered in a murine model of NEC, suggesting potential crossover between murine models of the disease and actual human presentation. Level of Evidence Level III Study of Diagnostic Test.

Background Endoscopic transnasal transclival intradural surgery is limited by a high postoperative cerebrospinal fluid leak rate. The aim of this study was to investigate the role of three-dimensional printing to create a personalized, rigid scaffold for clival reconstruction. Methods Two different types of clivectomy were performed in 5 specimens with the aid of neuronavigation, and 11 clival reconstructions were simulated. They were repaired with polylactide, three-dimensional–printed scaffolds that were manually designed in a computer-aided environment based either on the real or on the predicted defect. Scaffolds were printed with a fused filament fabrication technique and different offsets. They were positioned and fixed either following the gasket seal technique or with screws. Postdissection radiological evaluation of scaffold position was performed in all cases. In 3 specimens, the cerebrospinal fluid leak pressure point was measured immediately after reconstruction. Results The production process took approximately 30 hours. The designed scaffolds were satisfactory when no offset was added. Wings were added during the design to allow for screw positioning, but broke in 30% of cases. Radiological assessment documented maximal accuracy of scaffold positioning when the scaffold was created on the real defect; accuracy was satisfactory when the predicted clivectomy was performed under neuronavigation guidance. The cerebrospinal fluid leak pressure point was significantly higher when the scaffold was fixed with screws compared with the gasket technique. Conclusions In this preclinical setting, additive manufacturing allows the creation of customized scaffolds that are effective in reconstructing even large and geometrically complex clival defects.

Background The breath print is a quantitative measurement of molecules in exhaled breath and represents a new frontier for biomarker identification. It is unknown whether this state-of-the-art, noninvasive method can detect malnutrition. We hypothesize that individuals with malnutrition will present with a distinguishable breath print. Methods We conducted a retrospective chart review on patients with previously analyzed breath samples to identify malnutrition. Breath was analyzed by selected-ion flow-tube mass spectrometry. Registered dietitians conducted a retrospective chart review to collect malnutrition diagnosis and nutritional status indicators. Patients were categorized into one of four groups: pulmonary arterial hypertension (PAH), PAH with malnutrition (PAH-Mal), Control, and Control with malnutrition, based on malnutrition diagnosis present in the patient's chart. Principle component analysis was conducted to characterize the breath print. A logistic regression model with forward selection was used to detect the best breath predictor combination of malnutrition. Results 74 subjects met inclusion criteria (PAH:52; PAH-Mal:10; Control:10; Control-Mal:2). 1-octene (PAH-Mal 5.1±1.2, PAH 12.5±11.2; p = 0.005) and ammonia (PAH-Mal 14.6±15.8, PAH 56.2±64.2; p = 0.013) were reduced in PAH-Mal compared to PAH. The combination of 1-octene (p = 0.010) and 3-methylhexane (p = 0.045) distinguished malnutrition in PAH (ROC AUC: 0.8549). Conclusions This proof-of-concept study provides the first evidence that the breath print is altered in malnutrition. Larger, prospective studies are needed to validate these results and establish whether breath analysis may be a useful tool to screen for malnutrition in the clinical setting. Clinical relevancy statement Early identification and intervention combats malnutrition. However, malnutrition screening practices are hindered by a lack of a malnutrition biomarker. The breath print describes the molecules released in the exhaled breath and is a novel "tissue" to identify biomarkers of disease. This report identifies that the breath print is altered in patients with malnutrition and implicates potential for its use as a malnutrition screening biomarker. This article is protected by copyright. All rights reserved.

Objective This proof-of-principle-study evaluated the extent to which spontaneous activity (SA) of the muscle can be detected via non-invasive magnetomyography (MMG) with optically pumped magnetometers (OPM). Methods Five patients, who together exhibited all forms of SA (fibrillations, positive sharp waves, fasciculations, myotonic discharges, complex-repetitive discharges) with conventional needle electromyography (EMG), were studied by OPM-MMG and simultaneous surface EMG (sEMG) while at rest, during light muscle activation, and when a muscle stretch reflex was elicited. Three healthy subjects were measured as controls. SA was considered apparent in the OPM-MMG if a signal could be visually detected that corresponded in shape and frequency to the SA in the respective needle EMG. Results SA in the context of fasciculations could be detected in 2 of 5 patients by simultaneous OPM-MMG/sEMG. Other forms of SA could not be detected at rest, during light muscle activation, or after provocation of a muscle stretch reflex. Conclusions This proof-of-principle study shows that fasciculations could be detected non-invasively via a new method (OPM). Significance We show that other forms of SA are not detectable with current OPM and propose necessary technical solutions to overcome this circumstance. Our results motivate to pursue OPM-MMG as a new clinical neurophysiological diagnostic.

Introduction ND0612 is a continuous, subcutaneous levodopa/carbidopa delivery system under development for patients with Parkinson's disease (PD) and motor fluctuations. Methods This was a randomized, placebo-controlled, double-blind, 2-period study evaluating the safety and pharmacokinetics of ND0612 in PD patients on an optimized oral levodopa regimen and experiencing ≥2 h/day of OFF time. During Period-1, patients received their current standard of care (SoC) levodopa/carbidopa and were randomized (2:1) to 14 days treatment with adjunct ND0612 (daily levodopa/carbidopa dose of 270/63 mg) or placebo infusion +SoC. During Period-2, 16 patients were randomized to receive 7 days treatment with ND0612 or ND0612 plus oral entacapone. Reduction in OFF time was analyzed as an exploratory measure using a futility design with a predefined margin of 1.6 h. Results ND0612 was well-tolerated; most patients experienced infusion site nodules (95% vs. 56% with placebo), which all resolved without sequelae. Patients treated with adjunct ND0612 during Period-1 avoided deep troughs in levodopa plasma levels and had a decreased fluctuation index versus placebo (1.6 ± 0.5 vs 3.1 ± 1.6 at end of Period-1, respectively). In Period-2, the coadministration of entacapone with continuous ND0612 SC infusion translated to an increase in mean levodopa AUC0–10h compared to baseline. Exploratory efficacy analysis of Period 1 showed mean ± SD OFF time reductions of −2.13 ± 2.24 [90%CI: -2.8, ∞] hours (p = 0.84 using H0 of μ0 ≤-1.6). Conclusion Levodopa/carbidopa infusion with ND0612 was generally well-tolerated and resulted in reduced fluctuations in plasma levodopa concentrations when given with SoC oral levodopa. ND0612 met the efficacy endpoint for the futility design.

Background The incorporation of genetic variables into risk scores for predicting venous thromboembolic events (VTE) could improve their capacity to identify those patients for whom thromboprophylaxis would be most beneficial. Proof‐of‐concept of this is provided by the TiC‐ONCO score for predicting the risk of VTE in patients with solid tumours. Our aim was to develop a similarly improved tool—the TiC‐LYMPHO score—for predicting VTE in patients with lymphoma. Methods In a retrospective observational study of 208 patients with lymphoma, 31 (14.9%) were found to have experienced an episode of VTE either at the time of diagnosis or over the next 6 months. Clinical variables associated with VTE, determined via logistic regression analysis, plus the same genetic variables included in the TiC‐ONCO score, were used to build the TiC‐LYMPHO score algorithm. The sensitivity, specificity, predictive values and AUC of the TiC‐LYMPHO, the Khorana and ThroLy scores were compared in the same population. Results The TiC‐LYMPHO score showed a significantly higher AUC, sensitivity and NPV (0.783, 95.35% and 97.98% respectively) than the other scores. The ThroLy score showed a significantly higher specificity (96.43% vs. 54.49%; p, This is a single‐centre observational study that analyses the utility of combining genetic and clinical variables in a thromboembolism risk score in patients with lymphoma. The TiC‐LYMPHO score showed a significantly higher AUC, sensitivity and NPV (0.783%, 95.35% and 97.98%, respectively) than the other scores. These results show that by incorporating genetic and clinical data into VTE risk assessment, the TiC‐LYMPHO score can categorize patients with lymphoma better in terms of their risk of VTE and allow individualized thromboprophylaxis to be prescribed.

Background Neurosurgeons have limited tools in their armamentarium to visualize critical brain networks during surgical planning. Quicktome was designed using machine-learning to generate robust visualization of important brain networks that can be used with standard neuronavigation to minimize those deficits. We sought to see whether Quicktome could help localize important cerebral networks and tracts during intracerebral surgery. Methods We report on all patients who underwent keyhole intracranial surgery with available Quicktome-enabled neuronavigation. We retrospectively analyzed the locations of the lesions and determined functional networks at risks, including chief executive network, default mode network, salience, corticospinal/sensorimotor, language, neglect, and visual networks. We report on the postoperative neurologic outcomes of the patients and retrospectively determined whether the outcomes could be explained by Quicktome’s functional localizations. Results Fifteen high-risk patients underwent craniotomies for intra-axial tumors, with the exception of one meningioma and one case of leukoencephalopathy. Eight patients were male. The median age was 49.6 years. Quicktome was readily integrated in our existing navigation system in every case. New postoperative neurologic deficits occurred in 8 patients. All new deficits, except for one resulting from a postoperative stroke, were expected and could be explained by preoperative findings by Quicktome. In addition, in those who did not have new neurologic deficits, Quicktome offered explanations for their outcomes. Conclusions Quicktome helps to visualize complex functional connectomic networks and tracts by seamlessly integrating into existing neuronavigation platforms. The added information may assist in reducing neurological deficits and offer explanations for postsurgical outcomes.

Pressure-based immunoassays have been studied for point-of-care testing for which increasing the sensitivity is still a challenge. In this study, we described an enhanced pressure-based immunoassay with a versatile electronic sensor for the sensitive biological analysis. The versatile electronic sensor had multifunctional sensing capabilities with temperature and pressure recording. Magnetic bead-modified capture antibody and platinum nanoparticle-labeled detection antibody were used as the biorecognition element of the target carcinoembryonic antigen (CEA) (as a model analyte) and would form a sandwich-type immune complex with CEA. After simple magnetic separation, this complex was transferred into the detection chamber, which contained both hydrogen peroxide (H2O2) and 3,3',5,5'-tetramethylbenzidine (TMB). With the catalytic ability of PtNPs, the "H2O2-TMB-PtNPs" system was catalyzed to generate a large amount of oxygen (O2) and photothermal agent of oxidizer TMB (ox-TMB). Meanwhile, in a sealed chamber, further irradiation with an 808 nm near-infrared laser led to a triple-step signal amplification strategy of pressure increase, temperature increase, and gas thermal expansion to receive a strong electrical signal through the electronic sensor in real time. Thus, the amplified electrical signal from the electronic sensor could reveal the target concentration. In addition, we also verified that the synergistic system with two physical quantities had a lower limit of detection and a wider detection range compared to the detection system with a single physical quantity. In general, this immunoassay not only helped in exploring an effective signal amplification pathway but also offered an opportunity for the development of versatile electronic sensors in point-of-care settings.

BACKGROUND Timely recognition of sepsis and identification of pathogens can improve outcomes in critical care patients but microbial cultures have low accuracy and long turnaround times. In this proof-of-principle study, we describe metagenomic sequencing and analysis of nonhuman DNA in plasma. We hypothesized that quantitative analysis of bacterial DNA (bDNA) levels in plasma can enable detection and monitoring of pathogens. METHODS We enrolled 30 patients suspected of sepsis in the surgical trauma intensive care unit and collected plasma samples at the time of diagnostic workup for sepsis (baseline), and 7 days and 14 days later. We performed metagenomic sequencing of plasma DNA and used computational classification of sequencing reads to detect and quantify total and pathogen-specific bDNA fraction. To improve assay sensitivity, we developed an enrichment method for bDNA based on size selection for shorter fragment lengths. Differences in bDNA fractions between samples were evaluated using t test and linear mixed-effects model, following log transformation. RESULTS We analyzed 72 plasma samples from 30 patients. Twenty-seven samples (37.5%) were collected at the time of infection. Median total bDNA fraction was 1.6 times higher in these samples compared with samples with no infection (0.011% and 0.0068%, respectively, p < 0.001). In 17 patients who had active infection at enrollment and at least one follow-up sample collected, total bDNA fractions were higher at baseline compared with the next sample (p < 0.001). Following enrichment, bDNA fractions increased in paired samples by a mean of 16.9-fold. Of 17 samples collected at the time when bacterial pathogens were identified, we detected pathogen-specific DNA in 13 plasma samples (76.5%). CONCLUSION Bacterial DNA levels in plasma are elevated in critically ill patients with active infection. Pathogen-specific DNA is detectable in plasma, particularly after enrichment using selection for shorter fragments. Serial changes in bDNA levels may be informative of treatment response. LEVEL OF EVIDENCE Epidemiologic/Prognostic, Level V.

Non-alcoholic steatohepatitis is frequently associated with diabetes and may cause progressive liver disease. Current treatment options are limited. Here we report on a prospective, randomised, double-blind, placebo-controlled trial of two doses of HTD1801 (berberine ursodeoxycholate, an ionic salt of berberine and ursodeoxycholic acid), versus placebo that was conducted in 100 subjects with fatty liver disease and diabetes (NCT03656744). Treatment was for 18 weeks with a primary endpoint of reduction in liver fat content measured by magnetic resonance imaging proton density fat fraction. Key secondary endpoints included improvement in glycemic control, liver-associated enzymes and safety. The pre-specified primary endpoint was met. Thus, subjects receiving 1000 mg twice a day of berberine ursodeoxycholate had significantly greater reduction in liver fat content than in placebo recipients (mean absolute decrease −4.8% vs. −2.0% (p = 0.011). Compared to placebo, subjects receiving this dose also experienced significant improvement in glycemic control as well as reductions in liver-associated enzymes and significant weight loss. Diarrhea and abdominal discomfort were the most frequently reported adverse events. We conclude that berberine ursodeoxycholate has a broad spectrum of metabolic activity in patients with presumed NASH and diabetes. It is relatively well tolerated and merits further development as a treatment for NASH with diabetes., Berberine ursodeoxycholate has been studied for its serum lipid and lipoprotein lowering effects. Here the authors report an 18-week phase 2, randomised, double-blind, placebo-controlled clinical trial that tested the effect of berberine ursodeoxycholate in patients with fatty liver disease and diabetes, and showed that the group taking the higher dose of the drug had reduced liver fat content.

Objectives (1) To investigate the remote check test battery, designed for self-administration by cochlear implant (CI) recipients, parents/caregivers, to determine if the results give adequate information for clinicians to decide the necessity of an appointment and to capture suggestions for improvement. (2) To gauge acceptance of remote monitoring by CI-recipients and their parents/caregivers. Design Prospective, multicentre, un-blinded, non-randomized, single-subject, repeated-measures evaluation. The test battery includes an implant-site photograph, impedance measurements, datalogs, questionnaires, speech perception and aided threshold tests. Clinicians reviewed test battery results, followed by a clinical appointment with each CI-recipient, and reported if the battery identified all the issues. Study sample: n = 93 CI-recipients (73 adults, 20 children) and 28 clinicians. Results The test battery identified 94% (615/656) of all issues. The test battery and clinician observations agreed in 99% (92/93) of cases on the need for a clinic visit. For 68% (63/93) of cases, the test battery identified all clinician observed issues. The majority (77%, 72/93) of recipients would be satisfied if clinic visits were based on their test battery results. A significantly high proportion agreed that remote monitoring was more convenient than clinic visits and could result in travel, time and cost reductions. Conclusion This is the first comprehensive test battery designed for CI-recipient remote monitoring.

Phycobiliproteins are a class of light-harvesting fluorescent proteins existing in cyanobacteria and microalgae, which harvest light and convert it into electricity. Owing to recent demands on environmental-friendly and renewable apparatuses, phycobiliproteins have attracted substantial interest in bioenergy and sustainable devices. However, converting energy from biological materials remains challenging to date. Herein, we report a novel scheme to enhance biological light-harvesting through light-matter interactions at the biointerface of whispering-gallery modes (WGMs), where phycobiliproteins were employed as the active gain material. By exploiting microdroplets as a carrier for light-harvesting biomaterials, strong local electric field enhancement and photon confinement at the cavity interface resulted in significantly enhanced bio-photoelectricity. A threshold-like behavior was discovered in photocurrent enhancement and the WGM modulated fluorescence. Systematic studies of biologically produced photoelectricity and optical mode resonance were carried out to illustrate the impact of the cavity quality factor, structural geometry, and refractive indices. Finally, a biomimetic system was investigated by exploiting cascade energy transfer in phycobiliprotein assembly composed of three light-harvesting proteins. The key findings not only highlight the critical role of optical cavity in light-harvesting but also offer deep insights into light energy coupling in biomaterials. Ministry of Education (MOE) Nanyang Technological University This research is supported by the Ministry of Education Singapore (Tier 1-RG 158/19(S)). We would like to thank Internal Grant NAP SUG -M4082308.040 from NTU.

Body composition measures derived from already available electronic medical records (computed tomography [CT] scans) can have significant value, but automation of measurements is needed for clinical implementation. We sought to use artificial intelligence to develop an automated method to measure body composition and test the algorithm on a clinical cohort to predict mortality. We constructed a deep learning algorithm using Google’s DeepLabv3+ on a cohort of de‐identified CT scans (n = 12,067). To test for the accuracy and clinical usefulness of the algorithm, we used a unique cohort of prospectively followed patients with cirrhosis (n = 238) who had CT scans performed. To assess model performance, we used the confusion matrix and calculated the mean accuracy of 0.977 ± 0.02 (0.975 ± 0.018 for the training and test sets, respectively). To assess for spatial overlap, we measured the mean intersection over union and mean boundary contour scores and found excellent overlap between the manual and automated methods with mean scores of 0.954 ± 0.030, 0.987 ± 0.009, and 0.948 ± 0.039 (0.983 ± 0.013 for the training and test set, respectively). Using these automated measurements, we found that body composition features were predictive of mortality in patients with cirrhosis. On multivariate analysis, the addition of body composition measures significantly improved prediction of mortality for patients with cirrhosis over Model for End‐Stage Liver Disease alone (P

Few studies have identified the intrahemispheric functional connectivity between the ipsilateral dorsal premotor cortex (PMd) and the primary motor hand area (M1hand) due to technical limitations. In this proof-of-concept study, a novel neuronavigated dsTMS set-up was employed, combining stimulation over left PMd and left M1hand using the edge of a butterfly coil and a small cooled-coil. This arrangement was warranted because coil (over)heating and inter coil distance are limiting factors when investigating connectivity between stimulation targets in close proximity and over a longer duration. The proposed set-up was designed to deal with these limitations. Specifically, the effect of four dual-site transcranial magnetic stimulation (dsTMS) protocols on twenty-eight right-handed participants (12 males) was evaluated. These protocols differed in stimulus order, interstimulus interval and current direction induced in PMd. A structural scan with electric (E-)field modeling was obtained from seven participants prior to dsTMS, demonstrating that PMd and M1hand were effectively stimulated. Results indicate that one protocol, in which a latero-medial current was induced in PMd 2.8 ms prior to stimulation over M1hand, induced a sex-mediated effect. In males, significant inhibition of motor-evoked potentials was identified, whereas females demonstrated a facilitatory effect that did not survive correction for multiple comparisons. E-field simulations revealed that the E-field induced by the coil targeting PMd was maximal in PMd, with weaker E-field strengths extending to regions beyond PMd. Summarizing, the current dsTMS set-up enabled stimulating at an inter-target distance of 35 mm without any indications of coil-overheating.

Background: Medical imaging methods such as PET and MRI aid clinical assessment of Alzheimer’s disease (AD). Less expensive, less technically demanding, and more widely deployable technologies are needed to expand objective screening for diagnosis, treatment, and research. We previously reported brain tissue near-infrared optical spectroscopy (NIR) in vitro indicating the potential to meet this need. Objective: To determine whether completely non-invasive, clinical, NIR in vivo can distinguish AD patients from age-matched controls and to show the potential of NIR as a clinical screen and monitor of therapeutic efficacy. Methods: NIR spectra were acquired in vivo. Three groups were studied: autopsy-confirmed AD, control and mild cognitive impairment (MCI). A feature selection approach using the first derivative of the intensity normalized spectra was used to discover spectral regions that best distinguished “AD-alone” (i.e., without other significant neuropathology) from controls. The approach was then applied to other autopsy-confirmed AD cases and to clinically diagnosed MCI cases. Results: Two regions about 860 and 895 nm completely separate AD patients from controls and differentiate MCI subjects according to the degree of impairment. The 895 nm feature is more important in separating MCI subjects from controls (ratio-of-weights: 1.3); the 860 nm feature is more important for distinguishing MCI from AD (ratio-of-weights: 8.2). Conclusion: These results form a proof of the concept that near-infrared spectroscopy can detect and classify diseased and normal human brain in vivo. A clinical trial is needed to determine whether the two features can track disease progression and monitor potential therapeutic interventions.

BackgroundResting state functional connectivity (rsFC) offers promise for individualizing stimulation targets for transcranial magnetic stimulation (TMS) treatments. However current targeting approaches do not account for non-focal TMS effects or large-scale connectivity patterns. To overcome these limitations, we propose a novel targeting optimization approach that combines whole-brain rsFC and electric-field (e-field) modelling to identify single-subject, symptom-specific TMS targets.MethodsIn this proof of concept study, we recruited 91 anxious misery (AM) patients and 25 controls. We measured depression symptoms (MADRS/HAMD) and recorded rsFC. We used a PCA regression to predict symptoms from rsFC and estimate the parameter vector, for input into our e-field augmented model. We modeled 17 left dlPFC and 7 M1 sites using 24 equally spaced coil orientations. We computed single-subject predicted ΔMADRS/HAMD scores for each site/orientation using the e-field augmented model, which comprises a linear combination of the following elementwise products 1) the estimated connectivity/symptom coefficients, 2) a vectorized e-field model for site/orientation, 3) the pre-treatment rsFC matrix, scaled by a proportionality constant.ResultsIn AM patients, our pre-stimulation connectivity-based model predicted a significant decrease depression for sites near BA46, but not M1 for coil orientations perpendicular to the cortical gyrus. In control subjects, no site/orientation combination showed a significant predicted change.DiscussionThese results corroborate previous work suggesting the efficacy of left dlPFC stimulation for depression treatment, and predict better outcomes with individualized targeting. They also suggest that our novel connectivity-based e-field modelling approach may effectively identify potential TMS treatment responders and individualize TMS targeting to maximize the therapeutic impact.

Background Although Alzheimer’s disease affects around 800,000 people in the UK and costs almost £23 billion per year, currently licenced treatments only offer modest benefit at best. Seizures, which are more common in patients with Alzheimer’s disease than age matched controls, may contribute to the loss of nerve cells and abnormal brain discharges can disrupt cognition. This aberrant electrical activity may therefore present potentially important drug targets. The anti-seizure medication levetiracetam can reduce abnormal cortical discharges and reverse memory deficits in a mouse model of Alzheimer’s disease. Levetiracetam has also been shown to improve memory difficulties in patients with mild cognitive impairment, a precursor to Alzheimer’s disease. Clinical use of levetiracetam is well-established in treatment of epilepsy and extensive safety data are available. Levetiracetam thus has the potential to provide safe and efficacious treatment to help with memory difficulties in Alzheimer’s disease. Methods The proposed project is a proof of concept study to test whether levetiracetam can help cognitive function in people with dementia. We plan to recruit thirty patients with mild to moderate Alzheimer’s disease with no history of previous seizures or other significant co-morbidity. Participants will be allocated to a double-blind placebo-controlled crossover trial that tests levetiracetam against placebo. Standardised scales to assess cognition and a computer-based touchscreen test that we have developed to better detect subtle improvements in hippocampal function will be used to measure changes in memory. All participants will have an electroencephalogram (EEG) at baseline. The primary outcome measure is a change in the computer-based touchscreen cognitive task while secondary outcomes include the effect of levetiracetam on mood, quality of life and modelling of the EEG, including time series measures and feature-based analysis to see whether the effect of levetiracetam can be predicted. The effect of levetiracetam and placebo will be compared within a given patient using the paired t-test and the analysis of covariance adjusting for baseline values. Discussion This is the first study to evaluate if an anti-seizure medication can offer meaningful benefit to patients with Alzheimer’s disease. If this study demonstrates at least stabilisation of memory function and/or good tolerability, the next step will be to rapidly progress to a larger study to establish whether levetiracetam may be a useful and cost-effective treatment for patients with Alzheimer’s disease. Trial registration ClinicalTrials.govNCT03489044. Registered on April 5, 2018.

We call a hemiparetic hand with paralyzed finger extensors and volitional but spastic flexors a "spastic combination hand." Anecdotally, patients report hand-as-a-holder function with objects like pill bottles, motivating us to formally study spastic combination hand holding capacity using cylinders with different diameters. Nine participants with spastic hemiparesis and spastic combination hand more than 24 mos performed a standardized motor task with 10 cylinder diameters ranging between 1.3 and 9.5 cm and weighing 0.8 and 8.4 oz. Using the unaffected hand, participants attempted to insert a given cylinder into their spastic combination hand, holding it independently for 5 secs. Successful holds were counted during two sessions before and one session after botulinum toxin intervention of Ashworth 3 hand muscles. Findings revealed that a median capacity of six different cylinder diameters was successfully inserted into spastic combination hand at least once before block and a median capacity of 10 cylinders was inserted after block. A mixed-effect statistical model using fixed effects of cylinder diameter and session revealed that total number of successful holds was 43% higher after botulinum. We conclude that this proof-of-concept study does support the idea that spastic combination hand has holding capacity for cylindrical objects of specified diameter and weight and that botulinum neurotoxin offers potential for enlarging spastic combination hand capacity.

PURPOSE: Preclinical radiation replicating clinical intensity modulated radiation therapy (IMRT) techniques can provide data translatable to clinical practice. For this work, treatment plans were created for oxygen-guided dose-painting in small animals using inverse-planned IMRT. Spatially varying beam intensities were achieved using 3-dimensional (3D)-printed compensators. METHODS AND MATERIALS: Optimized beam fluence from arbitrary gantry angles was determined using a verified model of the XRAD225Cx treatment beam. Compensators were 3D-printed with varied thickness to provide desired attenuation using copper/polylactic-acid. Spatial resolution capabilities were investigated using printed test-patterns. Following American Association of Physicists in Medicine TG119, a 5-beam IMRT plan was created for a miniaturized (~1/8th scale) C-shape target. Electron paramagnetic resonance imaging of murine tumor oxygenation guided simultaneous integrated boost (SIB) plans conformally treating tumor to a base dose (Rx(1)) with boost (Rx(2)) based on tumor oxygenation. The 3D-printed compensator intensity modulation accuracy and precision was evaluated by individually delivering each field to a phantom containing radiochromic film and subsequent per-field gamma analysis. The methodology was validated end-to-end with composite delivery (incorporating 3D-printed tungsten/polylactic-acid beam trimmers to reduce out-of-field leakage) of the oxygen-guided SIB plan to a phantom containing film and subsequent gamma analysis. RESULTS: Resolution test-patterns demonstrate practical printer resolution of ~0.7 mm, corresponding to 1.0 mm bixels at the isocenter. The miniaturized C-shape plan provides planning target volume coverage (V(95%) = 95%) with organ sparing (organs at risk D(max) < 50%). The SIB plan to hypoxic tumor demonstrates the utility of this approach (hypoxic tumor V(95%,Rx2) = 91.6%, normoxic tumor V(95%,Rx1) = 95.7%, normal tissue V(100%,Rx1) = 7.1%). The more challenging SIB plan to boost the normoxic tumor rim achieved normoxic tumor V(95%,Rx2) = 90.9%, hypoxic tumor V(95%,Rx1) = 62.7%, and normal tissue V(100%,Rx2) = 5.3%. Average per-field gamma passing rates using 3%/1.0 mm, 3%/0.7 mm, and 3%/0.5 mm criteria were 98.8% ± 2.8%, 96.6% ± 4.1%, and 90.6% ± 5.9%, respectively. Composite delivery of the hypoxia boost plan and gamma analysis (3%/1 mm) gave passing results of 95.3% and 98.1% for the 2 measured orthogonal dose planes. CONCLUSIONS: This simple and cost-effective approach using 3D-printed compensators for small-animal IMRT provides a methodology enabling preclinical studies that can be readily translated into the clinic. The presented oxygen-guided dose-painting demonstrates that this methodology will facilitate studies driving much needed biologic personalization of radiation therapy for improvements in patient outcomes.

Beta-blockers are well known to reduce myocardial oxygen consumption (MVO2) and improve the prognosis of heart failure (HF) patients. However, its negative chronotropic and inotropic effects limit their use in the acute phase of HF due to the risk of circulatory collapse. In this study, as a first step for a safe β-blocker administration strategy, we aimed to develop and evaluate the feasibility of an automated β-blocker administration system. We developed a system to monitor arterial pressure (AP), left atrial pressure (PLA), right atrial pressure, and cardiac output. Using negative feedback of hemodynamics, the system controls AP and PLA by administering landiolol (an ultra-short-acting β-blocker), dextran, and furosemide. We applied the system for 60 min to 6 mongrel dogs with rapid pacing-induced HF. In all dogs, the system automatically adjusted the doses of the drugs. Mean AP and mean PLA were controlled within the acceptable ranges (AP within 5 mmHg below target; PLA within 2 mmHg above target) more than 95% of the time. Median absolute performance error was small for AP [median (interquartile range), 3.1% (2.2–3.8)] and PLA [3.6% (2.2–5.7)]. The system decreased MVO2 and PLA significantly. We demonstrated the feasibility of an automated β-blocker administration system in a canine model of acute HF. The system controlled AP and PLA to avoid circulatory collapse, and reduced MVO2 significantly. As the system can help the management of patients with HF, further validations in larger samples and development for clinical applications are warranted.

Background CT colonography does not enable definite differentiation between benign and premalignant colorectal polyps. Purpose To perform machine learning-based differentiation of benign and premalignant colorectal polyps detected with CT colonography in an average-risk asymptomatic colorectal cancer screening sample with external validation using radiomics. Materials and Methods In this secondary analysis of a prospective trial, colorectal polyps of all size categories and morphologies were manually segmented on CT colonographic images and were classified as benign (hyperplastic polyp or regular mucosa) or premalignant (adenoma) according to the histopathologic reference standard. Quantitative image features characterizing shape (n = 14), gray level histogram statistics (n = 18), and image texture (n = 68) were extracted from segmentations after applying 22 image filters, resulting in 1906 feature-filter combinations. Based on these features, a random forest classification algorithm was trained to predict the individual polyp character. Diagnostic performance was validated in an external test set. Results The random forest model was fitted using a training set consisting of 107 colorectal polyps in 63 patients (mean age, 63 years ± 8 [standard deviation]; 40 men) comprising 169 segmentations on CT colonographic images. The external test set included 77 polyps in 59 patients comprising 118 segmentations. Random forest analysis yielded an area under the receiver operating characteristic curve of 0.91 (95% CI: 0.85, 0.96), a sensitivity of 82% (65 of 79) (95% CI: 74%, 91%), and a specificity of 85% (33 of 39) (95% CI: 72%, 95%) in the external test set. In two subgroup analyses of the external test set, the area under the receiver operating characteristic curve was 0.87 in the size category of 6-9 mm and 0.90 in the size category of 10 mm or larger. The most important image feature for decision making (relative importance of 3.7%) was quantifying first-order gray level histogram statistics. Conclusion In this proof-of-concept study, machine learning-based image analysis enabled noninvasive differentiation of benign and premalignant colorectal polyps with CT colonography. © RSNA, 2021 Online supplemental material is available for this article.

The spread of multidrug resistant organisms (MDRO) is a global healthcare challenge. Nosocomial outbreaks caused by MDRO are an important contributor to this threat. Computer-based applications facilitating outbreak detection can be essential to address this issue. To allow application reusability across institutions, the various heterogeneous microbiology data representations needs to be transformed into standardised, unambiguous data models. In this work, we present a multi-centric standardisation approach by using openEHR as modelling standard. Data models have been consented in a multicentre and international approach. Participating sites integrated microbiology reports from primary source systems into an openEHR-based data platform. For evaluation, we implemented a prototypical application, compared the transformed data with original reports and conducted automated data quality checks. We were able to develop standardised and interoperable microbiology data models. The publicly available data models can be used across institutions to transform real-life microbiology reports into standardised representations. The implementation of a proof-of-principle and quality control application demonstrated that the new formats as well as the integration processes are feasible. Holistic transformation of microbiological data into standardised openEHR based formats is feasible in a real-life multicentre setting and lays the foundation for developing cross-institutional, automated outbreak detection systems.

Polysomnography (PSG) is the current gold standard for the diagnosis of sleep disorders. However, this multi-parametric sleep monitoring tool also has some drawbacks, e.g. it limits the patient's mobility during the night and it requires the patient to come to a specialized sleep clinic or hospital to attach the sensors. Unobtrusive techniques for the detection of sleep disorders such as sleep apnea are therefore gaining increasing interest. Remote photoplethysmography using video is a technique which enables contactless detection of hemodynamic information. Promising results in near-infrared have been reported for the monitoring of sleep-relevant physiological parameters pulse rate, respiration and blood oxygen saturation. In this study we validate a contactless monitoring system on eight patients with a high likelihood of relevant obstructive sleep apnea, which are enrolled for a sleep study at a specialized sleep center. The dataset includes 46.5 hours of video recordings, full polysomnography and metadata. The camera can detect pulse and respiratory rate within 2 beats/breaths per minute accuracy 92% and 91% of the time, respectively. Estimated blood oxygen values are within 4 percentage points of the finger-oximeter 89% of the time. These results demonstrate the potential of a camera as a convenient diagnostic tool for sleep apnea, and sleep disorders in general.

Chronic activation of NF-κB is a key driver of muscle degeneration and suppression of muscle regeneration in Duchenne muscular dystrophy. Edasalonexent (CAT-1004) is an orally-administered novel small molecule that covalently links two bioactive compounds (salicylic acid and docosahexaenoic acid) that inhibit NF-κB. This placebo-controlled, proof-of-concept phase 2 study with open-label extension in boys ≥4-8 years old with any dystrophin mutation examined the effect of edasalonexent (67 or 100 mg/kg/day) compared to placebo or off-treatment control. Endpoints were safety/tolerability, change from baseline in MRI T

Objective To assess the clinical safety and effectiveness of coronary revascularization in patients who underwent coronary artery bypass grafting (CABG) based exclusively on coronary computed tomography angiography (CCTA) results. Methods 53 patients (62.3±7.1 years) underwent CCTA before a CABG surgery without prior invasive coronary angiography (ICA). Primary endpoints were all-cause mortality and major adverse cardiovascular events (MACE). The secondary endpoint was quality of life (QoL) assessed with the Minnesota Living with Heart Failure Questionnaire (MLHFQ). All were collected one year after the surgery. Results CCTA revealed multivessel coronary artery disease (CAD) in 52 patients. Indication for bypass surgery was made exclusively based on CCTA results. 136 distal anastomoses were performed. Assessment at 1 year (13.3±1.4 months) was completed in 98.1% of the patients. MACE and mortality rates were 0%. The MLHFQ total score was 21.8±8.7, and active lifestyle was maintained in all patients. Conclusions In this proof of concept prospective pilot study, we observed that non-invasive coronary angiography may provide adequate anatomic detail to guide CABG surgery. Further study of this concept is warranted.

Objectives Juvenile nasopharyngeal angiofibroma (JNA) expresses prostate-specific membrane antigen (PSMA), and PSMA PET/CT scan may be used for its imaging. Also, the precise diagnosis of residual/recurrent JNA after surgical treatment remains difficult with conventional contrast MRI and/or CT; functional imaging with PSMA PET/CT promises greater accuracy in the detection or exclusion of recurrent/residual JNA. Patients and methods In this prospective study, 22 postoperative JNA patients who underwent a PSMA PET/CT scan both preoperatively and postoperatively from January 2018 to September 2020 were included. All patients underwent a low-dose head and neck spot PET/CT imaging. Abnormal postcontrast enhancement of a definite lesion was considered residual/recurrent tumor in contrast-enhanced MRI (CEMRI). In PSMA PET/CT, any abnormal uptake apart from physiological sites in the head and neck was considered as residual lesions. Radiological results were categorized as negative, suspicious for residual lesions, or definite residual/recurrent tumors. PSMA PET/CT findings were considered as the radiological standard, and patients were managed accordingly. The sensitivity, specificity, positive predictive value, and negative predictive value were separately calculated for CEMRI and PSMA PET/CT for diagnosing residual lesions. Results On postoperative CEMRI evaluation, 12 patients had residual tumors, 2 had normal suspicious scans, and 8 had normal postoperative scans. On PSMA PET/CT, only 7 patients had residual tumors and 15 had normal postoperative scans. In 1 patient with a residual tumor on both scans, a discrepancy was noted concerning tumor extent, and PSMA PET/CT accurately mapped the tumor. The sensitivity, specificity, positive predictive value, and negative predictive value of CEMRI were 100%, 53.33%, 41.67%, and 100%, respectively. The sensitivity, specificity, positive predictive value, and negative predictive value of PSMA PET/CT were 100% for all parameters. Conclusions Because CEMRI is oversensitive and less specific compared with PSMA PET/CT, Postoperative Angiofibroma Radionuclide Imaging Study (PARIS) protocol should be used always. In residual tumors, PSMA PET/CT has an outright advantage over CEMRI in the diagnosis, tumor mapping, decision making, planning stereotactic radiation, and aiding in future follow-ups.

While the applications of deep learning are considered revolutionary within several medical specialties, forensic applications have been scarce despite the visual nature of the field. For example, a forensic pathologist may benefit from deep learning-based tools in gunshot wound interpretation. This proof-of-concept study aimed to test the hypothesis that trained neural network architectures have potential to predict shooting distance class on the basis of a simple photograph of the gunshot wound. A dataset of 204 gunshot wound images (60 negative controls, 50 contact shots, 49 close-range shots, and 45 distant shots) was constructed on the basis of nineteen piglet carcasses fired with a .22 Long Rifle pistol. The dataset was used to train, validate, and test the ability of neural net architectures to correctly classify images on the basis of shooting distance. Deep learning was performed using the AIDeveloper open-source software. Of the explored neural network architectures, a trained multilayer perceptron based model (MLP_24_16_24) reached the highest testing accuracy of 98%. Of the testing set, the trained model was able to correctly classify all negative controls, contact shots, and close-range shots, whereas one distant shot was misclassified. Our study clearly demonstrated that in the future, forensic pathologists may benefit from deep learning-based tools in gunshot wound interpretation. With these data, we seek to provide an initial impetus for larger-scale research on deep learning approaches in forensic wound interpretation. Supplementary Information The online version contains supplementary material available at 10.1007/s00414-021-02566-3.

Introduction Surgeons in practice have limited opportunities to learn new techniques and procedures. Traditionally, in-person hands-on courses have been the most common means for surgeons to gain exposure to new techniques and procedures. The COVID19 pandemic caused a cessation in these courses and left surgeons with limited opportunities to continue their professional development. Thus, SAGES elected to create an innovative hands-on course that could be completed at home in order to provide surgeons with opportunities to learn new procedures during the pandemic. Methods This course was initially planned to be taught as an in-person hands-on course utilizing the Acquisition of Data for Outcomes and Procedure Transfer(ADOPT) method 1. We identified a virtual telementoring platform, Proximie Ltd(London, UK), and a company that could create a model of an abdominal wall in order to perform a Transversus Abdominis Release, KindHeart™(Chapel Hill, NC, USA). The course consisted of pre-course lectures and videos to be reviewed by participants, a pre-course call to set learning goals, the hands-on telementoring session from home, and monthly webinars for a year. Results The ADOPT hands-on hernia course at home was successfully completed on October 23rd of 2020. All participants and faculty were successfully able to set up their model and utilize the telementoring platform, but 15% required assistance. Post course-surveys showed that participants felt that the course was successful in meeting their educational goals and felt similar to prior in-person courses. Conclusions SAGES was successfully able to transition and in-person hands-on course to a virtual at-home format. This innovative approach to continuing professional development will be necessary during the times of the COVID19 pandemic, but may be a helpful option for rural surgeons and others with travel restrictions in the future to continue their professional development without the need to travel away from their practice.

New therapies to treat pancreatic cancer are direly needed. However, efficacious interventions lack a strong preclinical model that can recapitulate patients’ anatomy and physiology. Likewise, the availability of human primary malignant tissue for ex vivo studies is limited. These are significant limitations in the biomedical device field. We have developed RAG2/IL2RG deficient pigs using CRISPR/Cas9 as a large animal model with the novel application of cancer xenograft studies of human pancreatic adenocarcinoma. In this proof-of-concept study, these pigs were successfully generated using on-demand genetic modifications in embryos, circumventing the need for breeding and husbandry. Human Panc01 cells injected subcutaneously into the ears of RAG2/IL2RG deficient pigs demonstrated 100% engraftment with growth rates similar to those typically observed in mouse models. Histopathology revealed no immune cell infiltration and tumor morphology was highly consistent with the mouse models. The electrical properties and response to irreversible electroporation of the tumor tissue were found to be similar to excised human pancreatic cancer tumors. The ample tumor tissue produced enabled improved accuracy and modeling of the electrical properties of tumor tissue. Together, this suggests that this model will be useful and capable of bridging the gap of translating therapies from the bench to clinical application.

Context Children with anorexia nervosa (AN) are at risk of adult height deficit due to prolonged low height velocity (HV). Objective To investigate the effects of human growth hormone (GH) injections on HV in children with AN and severe growth impairment. Design and participants In this prospective, randomized, double-blind, single-center, proof-of-concept trial, children with AN and low HV (≤2 cm/year) for at least 18 months, and a bone age ≤12 years for girls and ≤14 years for boys, were randomized to receive daily subcutaneous injections of human GH (0.050 mg/kg/day) or placebo for 12 months. Main outcome measures Change in HV after 12 months. Results In total, 8 patients were assigned to the GH group and 6 to the placebo group. Patients had a median (25th-75th percentile) HV of 1.0 (0.5;1.5) cm/year. The effect of GH treatment increased strongly after 6 months, with a height gain after 12 months of 9.65 (8.0;11.6) cm for the GH group vs 3.85 (1.7;7.3) cm for the placebo group, with an absolute median (2.5th-97.5th percentile) difference between the groups of 5.8 (−1.85;9.68) cm after bootstrapping. The percentage of patients with a HV > 5 cm/year during the study period was higher in the GH group than in the placebo group (100% vs 50%, P = 0.05). Adverse events occurred in similar numbers in the 2 groups, were mild or nonfatal, and did not lead to treatment being stopped. Conclusion GH administration to improve HV is a potentially valid option for increasing HV in children with AN and prolonged severe growth failure.

Objective This open-label 12-week study was conducted to evaluate the efficacy and safety of tofacitinib, a JAK inhibitor, in treatment-refractory active dermatomyositis (DM). Methods Tofacitinib in extended-release doses of 11 mg was administered daily to 10 subjects with DM. Prior to treatment, a complete washout of all steroid-sparing agents was performed. The primary outcome measure was assessment of disease activity improvement based on the International Myositis Assessment and Clinical Studies group definition of improvement. Response rate was measured as the total improvement score according to the 2016 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) myositis response criteria. Secondary outcome measures included Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) scores, chemokine levels, immunohistochemical analysis of STAT1 expression in the skin, RNA sequencing analysis, and safety. Results At 12 weeks, the primary outcome was met in all 10 subjects. Five (50%) of 10 subjects experienced moderate improvement in disease activity, and the other 50% experienced minimal improvement according to the 2016 ACR/EULAR myositis response criteria. The secondary outcome of the mean change in the CDASI activity score over 12 weeks was statistically significant (mean ± SD 28 ± 15.4 at baseline versus 9.5 ± 8.5 at 12 weeks) (P = 0.0005). Serum chemokine levels of CXCL9/CXCL10 showed a statistically significant change from baseline. A marked decrease in STAT1 signaling in association with suppression of interferon target gene expression was demonstrated in 3 of 9 skin biopsy samples from subjects with dermatomyositis. The mean ± SD level of creatine kinase in the 10 subjects at baseline was 82 ± 34.8 IU/liter, highlighting that disease activity was predominantly located in the skin. Conclusion This is the first prospective, open-label clinical trial of tofacitinib in DM that demonstrates strong clinical efficacy of a pan-JAK inhibitor, as measured by validated myositis response criteria. Future randomized controlled trials using JAK inhibitors should be considered for treating DM.

Catheter-based or surgical procedures in patients with long-standing persistent atrial fibrillation (LSPAF) remain a challenge. As a result, different approaches including hybrid (surgical and endocardial) ablation have been developed. Bachmann’s bundle (BB) is a mainly epicardial structure capable of sustaining arrhythmic reentry that could be involved in the development and perpetuation of atrial fibrillation. We investigated the efficacy and safety of an adjunctive BB ablation in LSPAF patients undergoing hybrid ablation. In a two-arm non-randomized study, consecutive LSPAF patients undergoing epicardial isolation of pulmonary veins with left atrial posterior wall (box lesion) with (n = 30, BB group) and without additional BB ablation (n = 30, CONV group) were enrolled in the study. All patients underwent an endocardial procedure within 6 weeks post-surgery to assess for potential lesion gaps and additional atrial substrate modification. The primary endpoint was freedom from AF through 12 months of follow-up. The two-staged hybrid ablation was successfully completed in all patients. One-year freedom from atrial arrhythmias recurrence rates was 96.6% in the BB group vs 76.6% in the CONV group (p = 0.025). At procedure completion, 30 (100%) and 17 (56%) patients had a spontaneous cardioversion in BB and CONV group, respectively (p < 0.001). No significant differences in quality of life or complication rates were observed. This initial experience shows, for the first time, that adjunctive BB ablation in the setting of hybrid ablation for LSPAF is a feasible and effective approach in increasing maintenance of sinus rhythm without increasing complication rates.

Background Sniffer dogs are able to detect certain chemical particles and are suggest to be capable of helping diagnose some medical conditions and complications, such as colorectal cancer, melanoma, bladder cancer, and even critical states such as hypoglycemia in diabetic patients. With the global spread of COVID-19 throughout the world and the need to have a real-time screening of the population, especially in crowded places, this study aimed to investigate the applicability of sniffer dogs to carry out such a task. Methods Firstly, three male and female dogs from German shepherd (Saray), German black (Kuzhi) and Labrador (Marco) breeds had been intensively trained throughout the classical conditioning method for 7 weeks. They were introduced to human specimens obtained from the throat and pharyngeal secretions of participants who were already reported positive or negative for SARS-COV-2 infection be RT-PCR. Each dog underwent the conditioning process for almost 1000 times. In the meantime another similar condition process was conducted on clothes and masks of COVID-19 patient using another three male and female dogs from Labrador (Lexi), Border gypsy (Sami), and Golden retriever (Zhico) breeds. In verification test for the first three dogs, 80 pharyngeal secretion samples consisting of 26 positive and 54 negative samples from different medical centers who underwent RT-PCR test were in a single-blind method. In the second verification test for the other three dogs, masks and clothes of 50 RT-PCR positive and 70 RT-PCR negative cases from different medical center were used. Results In verification test using pharyngeal secretion, the sniffer dogs’ detection capability was associated with a 65% of sensitivity and 89% of specificity and they amanged to identify 17 out of the 26 positive and 48 out of the 54 true negative samples. In the next verification test using patients’ face masks and clothes, 43 out of the 50 positive samples were correctly identified by the dogs. Moreover, out of the 70 negative samples, 65 samples were correctly found to be negative. The sensitivity of this test was as high as 86% and its specificity was 92.9%. In addition, the positive and negative predictive values were 89.6 and 90.3%, respectively. Conclusion Dogs are capable of being trained to identify COVID-19 cases by sniffing their odour, so they can be used as a reliable tool in limited screening.

Heart rhythm assessment is indispensable in diagnosis and management of many cardiac conditions and to study heart rate variability in healthy individuals. We present a proof-of-concept system for acquiring individual heart beats using smart speakers in a fully contact-free manner. Our algorithms transform the smart speaker into a short-range active sonar system and measure heart rate and inter-beat intervals (R-R intervals) for both regular and irregular rhythms. The smart speaker emits inaudible 18–22 kHz sound and receives echoes reflected from the human body that encode sub-mm displacements due to heart beats. We conducted a clinical study with both healthy participants and hospitalized cardiac patients with diverse structural and arrhythmic cardiac abnormalities including atrial fibrillation, flutter and congestive heart failure. Compared to electrocardiogram (ECG) data, our system computed R-R intervals for healthy participants with a median error of 28 ms over 12,280 heart beats and a correlation coefficient of 0.929. For hospitalized cardiac patients, the median error was 30 ms over 5639 heart beats with a correlation coefficient of 0.901. The increasing adoption of smart speakers in hospitals and homes may provide a means to realize the potential of our non-contact cardiac rhythm monitoring system for monitoring of contagious or quarantined patients, skin sensitive patients and in telemedicine settings., Anran Wang et al. present a contact-free method of monitoring individual heart beats by converting smart-speakers into active sonar systems. Their approach is capable of measuring heart rhythms with high accuracy in both healthy participants and hospitalized patients, and may be a useful healthcare tool for remote diagnosis or patient monitoring.

Premenstrual dysphoric disorder (PMDD) is a common mood disorder, characterized by distressing affective, behavioral, and somatic symptoms in the late luteal phase of the menstrual cycle. The authors investigated continuous treatment with a selective progesterone receptor modulator, ulipristal acetate (UPA), as a potential treatment for PMDD.The authors conducted an investigator-initiated, multicenter, double-blind, randomized, parallel-group clinical trial in which women with PMDD (N=95) were treated with either 5 mg/day of UPA or placebo during three 28-day treatment cycles. The primary outcome was the change in premenstrual total score on the Daily Record of Severity of Problems (DRSP) from baseline to end of treatment. DRSP scores were captured by daily ratings using a smartphone application and were analyzed with linear mixed models for repeated measures.The mean improvement in DRSP score after 3 months was 41% (SD=18) in the UPA group, compared with 22% (SD=27) in the placebo group (mean difference -18%; 95% CI=-29, -8). Treatment effects were also noted for the DRSP depressive symptom subscale (42% [SD=22] compared with 22% [SD=32]) and the DRSP anger/irritability subscale (47% [SD=21] compared with 23% [SD=35]), but not for the DRSP physical symptom subscale. Remission based on DRSP score was attained by 20 women in the UPA group (50.0%) and eight women in the placebo group (21.1%) (a statistically significant difference).If these results are replicated, UPA could be a useful treatment for PMDD, particularly for the psychological symptoms associated with the disorder.