Oral versus intravenous empirical antibiotics in children and adolescents with uncomplicated bone and joint infections: a nationwide, randomised, controlled, non-inferiority trial in Denmark.

BACKGROUND: Bone and joint infections (BJIs) are treated with intravenous antibiotics, which are burdensome and costly. No randomised controlled studies have compared if initial oral antibiotics are as effective as intravenous therapy. We aimed to investigate the efficacy and safety of initial oral antibiotics compared with initial intravenous antibiotics followed by oral antibiotics in children and adolescents with uncomplicated BJIs. METHODS: From Sept 15, 2020, to June 30, 2023, this nationwide, randomised, non-inferiority trial included patients aged 3 months to 17 years with BJIs who presented to one of the 18 paediatric hospital departments in Denmark. Exclusion criteria were severe infection (ie, septic shock, the need for acute surgery, or substantial soft tissue involvement), prosthetic material, comorbidity, previous BJIs, or antibiotic therapy for longer than 24 h before inclusion. Patients were randomly assigned (1:1), stratified by C-reactive protein concentration (<35 mg/L vs ≥35 mg/L), to initially receive either high-dose oral antibiotics or intravenous ceftriaxone (100 mg/kg per day in one dose). High-dose oral antibiotics were coformulated amoxicillin (100 mg/kg per day) and clavulanic acid (12·5 mg/kg per day) in three doses for patients younger than 5 years or dicloxacillin (200 mg/kg per day) in four doses for patients aged 5 years or older. After a minimum of 3 days, and upon clinical improvement and decrease in C-reactive protein, patients in both groups received oral antibiotics in standard doses. The primary outcome was sequelae after 6 months in patients with BJIs, defined as any atypical mobility or function of the affected bone or joint, assessed blindly, in all randomised patients who were not terminated early due to an alternative diagnosis (ie, not BJI) and who attended the primary outcome assessment. A risk difference in sequelae after 6 months of less than 5% implied non-inferiority of the oral treatment. Safety outcomes were serious complications, the need for surgery after initiation of antibiotics, and treatment-related adverse events in the as-randomised population. This trial was registered with ClinicalTrials.gov, NCT04563325. FINDINGS: 248 children and adolescents with suspected BJIs were randomly assigned to initial oral antibiotics (n=123) or initial intravenous antibiotics (n=125). After exclusion of patients without BJIs (n=54) or consent withdrawal (n=2), 101 patients randomised to oral treatment and 91 patients randomised to intravenous treatment were included. Ten patients did not attend the primary outcome evaluation. Sequelae after 6 months occurred in none of 98 patients with BJIs in the oral group and none of 84 patients with BJIs in the intravenous group (risk difference 0, one-sided 97·5% CI 0·0 to 3·8, pnon-inferiority=0·012). Surgery after randomisation was done in 12 (9·8%) of 123 patients in the oral group compared with seven (5·6%) of 125 patients in the intravenous group (risk difference 4·2%, 95% CI -2·7 to 11·5). We observed no serious complications. Rates of adverse events were similar across both treatment groups. INTERPRETATION: In children and adolescents with uncomplicated BJIs, initial oral antibiotic treatment was non-inferior to initial intravenous antibiotics followed by oral therapy. The results are promising for oral treatment of uncomplicated BJIs, precluding the need for intravenous catheters and aligning with the principles of antimicrobial stewardship. FUNDING: Innovation Fund Denmark and Rigshospitalets Forskningsfond.

Low-Dose CT-derived Bronchial Parameters in Individuals with Healthy Lungs.

Background CT-derived bronchial parameters have been linked to chronic obstructive pulmonary disease and asthma severity, but little is known about these parameters in healthy individuals. Purpose To investigate the distribution of bronchial parameters at low-dose CT in individuals with healthy lungs from a Dutch general population. Materials and Methods In this prospective study, low-dose chest CT performed between May 2017 and October 2022 were obtained from participants who had completed the second-round assessment of the prospective, longitudinal Imaging in Lifelines study. Participants were aged at least 45 years, and those with abnormal spirometry, self-reported respiratory disease, or signs of lung disease at CT were excluded. Airway lumens and walls were segmented automatically. The square root of the bronchial wall area of a hypothetical airway with an internal perimeter of 10 mm (Pi10), luminal area (LA), wall thickness (WT), and wall area percentage were calculated. Associations between sex, age, height, weight, smoking status, and bronchial parameters were assessed using univariable and multivariable analyses. Results The study sample was composed of 8869 participants with healthy lungs (mean age, 60.9 years ± 10.4 [SD]; 4841 [54.6%] female participants), including 3672 (41.4%) never-smokers and 1197 (13.5%) individuals who currently smoke. Bronchial parameters for male participants were higher than those for female participants (Pi10, slope [ß] range = 3.49-3.66 mm; LA, ß range = 25.40-29.76 mm2; WT, ß range = 0.98-1.03 mm; all P < .001). Increasing age correlated with higher Pi10, LA, and WT (r2 range = 0.06-0.09, 0.02-0.01, and 0.02-0.07, respectively; all P < .001). Never-smoking individuals had the lowest Pi10 followed by formerly smoking and currently smoking individuals (3.62 mm ± 0.13, 3.68 mm ± 0.14, and 3.70 mm ± 0.14, respectively; all P < .001). In multivariable regression models, age, sex, height, weight, and smoking history explained up to 46% of the variation in bronchial parameters. Conclusion In healthy individuals, bronchial parameters differed by sex, height, weight, and smoking history; male sex and increasing age were associated with wider lumens and thicker walls. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Emrich and Varga-Szemes in this issue.

The Anterior Branch of the Medial Femoral Cutaneous Nerve Innervates Cutaneous and Deep Surgical Incisions in Total Knee Arthroplasty.

Background/Objectives: The intermediate femoral cutaneous nerve (IFCN), the saphenous nerve, and the medial femoral cutaneous nerve (MFCN) innervate the skin of the anteromedial knee region. However, it is unknown whether the MFCN has a deeper innervation. This would be relevant for total knee arthroplasty (TKA) that intersects deeper anteromedial genicular tissue layers. Primary aim: to investigate deeper innervation of the anterior and posterior MFCN branches (MFCN-A and MFCN-P). Secondary aim: to investigate MFCN innervation of the skin covering the anteromedial knee area and medial parapatellar arthrotomy used for TKA. Methods: This study consists of (1) a dissection study and (2) unpublished data and post hoc analysis from a randomized controlled double-blinded volunteer trial (EudraCT number: 2020-004942-12). All volunteers received bilateral active IFCN blocks (nerve block round 1) and saphenous nerve blocks (nerve block round 2). In nerve block round 3, all volunteers were allocated to a selective MFCN-A block. Results: (1) The MFCN-A consistently innervated deeper structures in the anteromedial knee region in all dissected specimens. No deep innervation from the MFCN-P was observed. (2) Sixteen out of nineteen volunteers had an unanesthetized skin gap in the anteromedial knee area and eleven out of the nineteen volunteers had an unanesthetized gap on the skin covering the medial parapatellar arthrotomy before the active MFCN-A block. The anteromedial knee area and medial parapatellar arthrotomy was completely anesthetized after the MFCN-A block in 75% and 82% of cases, respectively. Conclusions: The MFCN-A shows consistent deep innervation in the anteromedial knee region and the area of MFCN-A innervation overlaps the skin area covering the medial parapatellar arthrotomy. Further trials are mandated to investigate whether an MFCN-A block translates into a clinical effect on postoperative pain after total knee arthroplasty or can be used for diagnosis and interventional pain management for chronic neuropathic pain due to damage to the MFCN-A during surgery.

Paracetamol overdose in Danish children and adolescents during the Covid-19 restrictions.

INTRODUCTION: To assess the effect of long-term isolation on the mental state of Danish youth. This study aimed to investigate trends in paracetamol overdoses among people under 18 years of age in Denmark during Covid-19 restrictions as an indicator of mental health. METHODS: All patients under the age of 18 years presenting with paracetamol overdose at one of the 18 paediatric departments in Denmark from 2016 to 2021 were included. They were identified in all Danish hospital databases using specific diagnostic codes. RESULTS: From 2016 to 2021, a total of 3,217 people under 18 years of age were admitted for paracetamol overdose. Among these, 86% (n = 2,755) were girls and 14% (n = 462) were boys. During 2020, a slight (7%) decrease in admissions was observed among both boys and girls compared with the preceding four-year mean value. In 2021, the number of overdoses among girls exceeded by 35% the former all-time high from 2016. Furthermore, the number of overdoses among girls exceeded the pre-four-year period mean value by 43%. Among boys, an 8% increase was seen from the highest ever previous value recorded in 2019 and a 23% increase compared with the previous four-year mean value. CONCLUSIONS: During the first year of restrictions, a slight decrease in paracetamol overdoses was observed, possibly associated with limited accessibility. The second year showed a considerable increase in paracetamol overdoses, which may imply an affected mental state among youth during the prolonged lockdown restrictions as seen in previous epidemics. Therefore, further studies are warranted to develop a pandemic preparedness plan to protect general mental health. FUNDING: None. TRIAL REGISTRATION: Not relevant.

Discovery and Characterization of a Bicyclic Peptide (Bicycle) Binder to Thymic Stromal Lymphopoietin.

Thymic stromal lymphopoietin (TSLP) is an epithelial-derived pro-inflammatory cytokine involved in the development of asthma and other atopic diseases. We used Bicycle Therapeutics' proprietary phage display platform to identify bicyclic peptides (Bicycles) with high affinity for TSLP, a target that is difficult to drug with conventional small molecules due to the extended protein-protein interactions it forms with both receptors. The hit series was shown to bind to TSLP in a hotspot, that is also used by IL-7Rα. Guided by the first X-ray crystal structure of a small peptide binding to TSLP and the identification of key metabolites, we were able to improve the proteolytic stability of this series in lung S9 fractions without sacrificing binding affinity. This resulted in the potent Bicycle 46 with nanomolar affinity to TSLP (KD = 13 nM), low plasma clearance of 6.4 mL/min/kg, and an effective half-life of 46 min after intravenous dosing to rats.

HORTENSIA, a program package for the simulation of nonadiabatic autoionization dynamics in molecules.

We present a program package for the simulation of ultrafast vibration-induced autoionization dynamics in molecular anions in the manifold of the adiabatic anionic states and the discretized ionization continuum. This program, called HORTENSIA (Hopping Real-time Trajectories for Electron-ejection by Nonadiabatic Self-Ionization in Anions), is based on the nonadiabatic surface-hopping methodology, wherein nuclei are propagated as an ensemble along classical trajectories in the quantum-mechanical potential created by the electronic density of the molecular system. The electronic Schrödinger equation is numerically integrated along the trajectory, providing the time evolution of electronic state coefficients, from which switching probabilities into discrete electronic states are determined. In the case of a discretized continuum state, this hopping event is interpreted as the ejection on an electron. The derived diabatic and nonadiabatic couplings in the time-dependent electronic Schrödinger equation are calculated from anionic and neutral wavefunctions obtained from quantum-chemical calculations with commercially available program packages interfaced with our program. Based on this methodology, we demonstrate the simulation of autoionization electron kinetic energy spectra that are both time- and angle-resolved. In addition, the program yields data that can be interpreted easily with respect to geometric characteristics, such as bonding distances and angles, which facilitate the detection of molecular configurations important for the autoionization process. Furthermore, several useful extensions are included, namely, tools for the generation of initial conditions and input files as well as for the evaluation of output files, all of this both through console commands and a graphical user interface.

Chiroptical Properties of Planar Benzobisthiazole-Bridged Squaraine Dimers.

Five chiral squaraine dimers were synthesized by fusing chiral indolenine semisquaraines with three different benzobisthiazole bridges. The thereby created squaraine dimers show a strong splitting of the lowest energy absorption bands caused by exciton coupling. The intensities of the two exciton transitions and the energetic splitting depend on the angle of the two squaraine moieties within the chromophore dimer. The electric circular dichroism spectra of the dimers show intense Cotton effects whose sign depends on the used squaraine chromophores. Sizable anisotropies gabs of up to 2.6 × 10-3 could be obtained. TD-DFT calculations were used to partition the rotational strength into the three Rosenfeld terms where the electric-magnetic coupling turned out to be the dominant contribution while the exciton chirality term is much smaller. This is because the chromophore dimers are essentially planar but the angle between the electric transition dipole moment of one squaraine and the magnetic transition dipole moment of the other squaraine strongly deviates from 90°, which makes the dot product between the two moment vectors and, thus, the rotational strength substantial.

Symptomatic malaria enhances protection from reinfection with homologous Plasmodium falciparum parasites.

A signature remains elusive of naturally-acquired immunity against Plasmodium falciparum. We identified P. falciparum in a 14-month cohort of 239 people in Kenya, genotyped at immunogenic parasite targets expressed in the pre-erythrocytic (circumsporozoite protein, CSP) and blood (apical membrane antigen 1, AMA-1) stages, and classified into epitope type based on variants in the DV10, Th2R, and Th3R epitopes in CSP and the c1L region of AMA-1. Compared to asymptomatic index infections, symptomatic malaria was associated with reduced reinfection by parasites bearing homologous CSP-Th2R (adjusted hazard ratio [aHR]:0.63; 95% CI:0.45-0.89; p = 0.008) CSP-Th3R (aHR:0.71; 95% CI:0.52-0.97; p = 0.033), and AMA-1 c1L (aHR:0.63; 95% CI:0.43-0.94; p = 0.022) epitope types. The association of symptomatic malaria with reduced hazard of homologous reinfection was strongest for rare epitope types. Symptomatic malaria provides more durable protection against reinfection with parasites bearing homologous epitope types. The phenotype represents a legible molecular epidemiologic signature of naturally-acquired immunity by which to identify new antigen targets.

Impact of COVID-19 Restrictions on Acute Gastroenteritis in Children: A Regional, Danish, Register-Based Study.

This study aimed to evaluate the impact of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) restrictions such as social distancing on the occurrence of acute gastroenteritis (AGE) among children. This study is a register-based study, including every child seen in the departments of paediatrics with the initial diagnosis of AGE in three neighbouring hospitals in Denmark, from March 2018 through February 2021. The study also included every positive stool sample for AGE-causing pathogens analysed in these three hospitals from children during the same period. The Wilcoxon rank-sum test was used to determine differences between the period during the SARS-CoV-2 restrictions and before. In all, 222,157 children were seen in the three paediatric departments during this period. Of these, 3917 children were diagnosed with AGE. We found a decrease of 46.6% in AGE-related visits per month after the SARS-CoV-2 restrictions were introduced compared to before (p-value < 0.001). Positive stool samples decreased by 38.2% (p-value = 0.008) during the restrictions. This study found that cases of paediatric AGE decreased significantly the during COVID-19 restrictions, suggesting that studies should be conducted to determine whether this reduction was a result of good hand hygiene and social distancing or just a result of altered health-seeking behaviour among children.

Reproducibility of a combined artificial intelligence and optimal-surface graph-cut method to automate bronchial parameter extraction.

OBJECTIVES: Computed tomography (CT)-based bronchial parameters correlate with disease status. Segmentation and measurement of the bronchial lumen and walls usually require significant manpower. We evaluate the reproducibility of a deep learning and optimal-surface graph-cut method to automatically segment the airway lumen and wall, and calculate bronchial parameters. METHODS: A deep-learning airway segmentation model was newly trained on 24 Imaging in Lifelines (ImaLife) low-dose chest CT scans. This model was combined with an optimal-surface graph-cut for airway wall segmentation. These tools were used to calculate bronchial parameters in CT scans of 188 ImaLife participants with two scans an average of 3 months apart. Bronchial parameters were compared for reproducibility assessment, assuming no change between scans. RESULTS: Of 376 CT scans, 374 (99%) were successfully measured. Segmented airway trees contained a mean of 10 generations and 250 branches. The coefficient of determination (R2) for the luminal area (LA) ranged from 0.93 at the trachea to 0.68 at the 6th generation, decreasing to 0.51 at the 8th generation. Corresponding values for Wall Area Percentage (WAP) were 0.86, 0.67, and 0.42, respectively. Bland-Altman analysis of LA and WAP per generation demonstrated mean differences close to 0; limits of agreement (LoA) were narrow for WAP and Pi10 (± 3.7% of mean) and wider for LA (± 16.4-22.8% for 2-6th generations). From the 7th generation onwards, there was a sharp decrease in reproducibility and a widening LoA. CONCLUSION: The outlined approach for automatic bronchial parameter measurement on low-dose chest CT scans is a reliable way to assess the airway tree down to the 6th generation. STATEMENT ON CLINICAL RELEVANCE: This reliable and fully automatic pipeline for bronchial parameter measurement on low-dose CT scans has potential applications in screening for early disease and clinical tasks such as virtual bronchoscopy or surgical planning, while also enabling the exploration of bronchial parameters in large datasets. KEY POINTS: • Deep learning combined with optimal-surface graph-cut provides accurate airway lumen and wall segmentations on low-dose CT scans. • Analysis of repeat scans showed that the automated tools had moderate-to-good reproducibility of bronchial measurements down to the 6th generation airway. • Automated measurement of bronchial parameters enables the assessment of large datasets with less man-hours.

Conditioned Media from Head and Neck Cancer Cell Lines and Serum Samples from Head and Neck Cancer Patients Drive Catabolic Pathways in Cultured Muscle Cells.

BACKGROUND: The role of secreted factors from the tumor cells in driving cancer cachexia and especially muscle loss is unknown. We wanted to study both the action of secreted factors from head and neck cancer (HNC) cell lines and circulating factors in HNC patients on skeletal muscle protein catabolism. METHODS: Conditioned media (CM) made from head and neck cancer cell lines and mix of sera from head and neck cancer (HNC) patients were incubated for 48 h with human myotubes. The atrophy and the catabolic pathway were monitored in myotubes. The patients were classified regarding their skeletal muscle loss observed at the outset of management. RESULTS: Tumor CM (TCM) was able to produce atrophy on myotubes as compared with control CM (CCM). However, a mix of sera from HNC patients was not able to produce atrophy in myotubes. Despite this discrepancy on atrophy, we observed a similar regulation of the catabolic pathways by the tumor-conditioned media and mix of sera from cancer patients. The catabolic response after incubation with the mix of sera seemed to depend on the muscle loss seen in patients. CONCLUSION: This study found evidence that the atrophy observed in HNC patients cannot be solely explained by a deficit in food intake.

Time-resolved photoelectron spectroscopy of 4-(dimethylamino)benzethyne - an experimental and computational study.

We investigated the excited-state dynamics of 4-(dimethylamino)benzethyne (4-DMABE) in a combined theoretical and experimental study using surface-hopping simulations and time-resolved ionisation experiments. The simulations predict a decay of the initially excited S2 state into the S1 state in only a few femtoseconds, inducing a subsequent partial twist of the dimethylamino group within ∼100 fs. This leads to drastically reduced Franck-Condon factors for the ionisation transition to the cationic ground state, thus inhibiting the effective ionisation of the molecule, which leads to a vanishing photoelectron signal on a similar timescale as observed in our time-resolved photoelectron spectra. From the phototoelectron spectra, an adiabatic ionisation energy of 7.17 ± 0.02 eV was determined. The experimental decays match the theoretical predictions very well and the combination of both reveals the electronic characteristics of the molecule, namely the role of intramolecular charge transfer (ICT) states in the deactivation pathway of electronically excited 4-DMABE.

European coastal monitoring programmes may fail to identify impacts on benthic macrofauna caused by bottom trawling.

Bottom trawling (hereafter trawling) is the dominant human pressure impacting continental shelves globally. However, due to ongoing data deficiencies for smaller coastal vessels, the effects of trawling on nearshore seabed ecosystems are poorly understood. In Europe, the Water Framework Directive (WFD) provides a framework for the protection and improvement of coastal water bodies. It requires member states to track the status of 'biological quality elements' (including benthic macrofauna) using WFD-specific ecological indicators. While many of these metrics are sensitive to coastal pressures such as nutrient enrichment, little is known about their ability to detect trawling impacts. Here, we analysed a comprehensive data set of 5885 nearshore benthic samples - spatiotemporally matched to high-resolution trawling and environmental data - to examine how these pressures affect coastal benthos. In addition, we investigated the ability of 8 widely-used benthic monitoring metrics to detect impacts on benthic biological quality. We found that abundance (N) and species richness (S) were strongly impacted by bottom trawling. A clear response to trawling was also observed for the WFD-specific Benthic Quality Index (BQI). Relationships between N and S, and trawling were particularly consistent across the study area, indicating sensitivity across varying environmental conditions. In contrast, WFD indices such as AZTIs Marine Biotic Index (AMBI), multivariate AMBI (M-AMBI), and the Danish Quality Index (DKI), were unresponsive to trawling. In fact, some of the most heavily trawled areas examined were classified as being of 'high/good ecological status' by these indices. A likely explanation for this is that the indices are calculated using species sensitivity scores, based on expected species response to eutrophication and chemical pollution. While the BQI also uses species sensitivity scores, these are based on observed responses to disturbance gradients comprising a range of coastal pressures. Given the prominent use of AMBI and DKI throughout Europe, our results highlight the considerable risk that the metrics used to assess Good Ecological Status (GES) under the WFD may fail to identify trawling impacts. As trawling represents a widespread source of coastal disturbance, fishing impacts on benthic macrofauna may be underestimated, or go undetected, in many coastal monitoring programmes around Europe.

Prevalence and Burden of Migraine in Switzerland: Cross-Sectional Study in ten Specialised Headache Centres from the BECOME Study.

INTRODUCTION: There is limited real-world evidence on the burden of migraine among patients with prior preventive treatment failure (PPTF). In the BECOME Swiss subanalysis, we aimed to assess current prevalence of PPTF in patients with migraine seen at specialised headache centres in Switzerland and burden of migraine in these patients. Furthermore, we assessed this burden in subgroups stratified by monthly migraine days (MMDs) and number of PPTFs. METHODS: BECOME was a prospective, multicentre, non-interventional two-part study conducted in 17 countries across Europe and Israel. This subanalysis includes patients visiting ten headache specialist centres in Switzerland. In part 1, patients visiting the centres over 3 months were screened by physicians for frequency of PPTF, MMD and other migraine characteristics. Patients with ≥ 1 PPTF and ≥ 4 MMDs were invited to take part in part 2. The primary endpoint was the proportion of patients with ≥ 1 PPTF (part 1). Other endpoints included proportion of patients specified by number of PPTF and MMD (part 1, part 2), and impact of migraine on patient-reported outcomes (PROs; part 2). RESULTS: Patients (1677) from ten Swiss centres were included in part 1, of which 855 (51.0%) reported ≥ 1 PPTF. One hundred fifty-five patients were included in part 2: 6.5% reported ≥ 4 PPTFs and 43.2% reported ≥ 15 MMDs. Mean EuroQoL 5 and EuroQoL visual analogue scale (EQ-VAS) were 0.8 ± 0.2 and 69.6 ± 20.2, respectively, suggesting a mild level of impairment in the daily functioning and self-reported health of the patients. Mean six-item Headache Impact Test (HIT-6) and modified Migraine Disability Assessment (mMIDAS) scores were 63.3 ± 6.5 and 22.7 ± 21.8, respectively, corresponding to severe migraine burden. Patients also reported impairment in work-related productivity and general activities (48.6 ± 22.8) but no associations of anxiety (7.2 ± 4.4) or depression (6.0 ± 4.4) with migraine were noted. Burden of migraine increased with increasing frequency of PPTF and MMD. CONCLUSIONS: Migraine-related quality of life, as well as work productivity are significantly affected in Swiss patients with migraine. Increasing migraine burden is associated with increasing migraine frequency and prior treatment failures.

The anterior branch of the medial femoral cutaneous nerve innervates the anterior knee: a randomized volunteer trial.

BACKGROUND: The midline skin incision for total knee arthroplasty may be an important generator of chronic neuropathic pain. The incision is innervated by the medial femoral cutaneous nerve (MFCN), the intermediate femoral cutaneous nerves (IFCN) and the infrapatellar branch from the saphenous nerve. The MFCN divides into an anterior (MFCN-A) and a posterior branch (MFCN-P). The primary aim was to compare the areas anesthesized by MFCN-A versus MFCN-P block for coverage of the incision. METHODS: Nineteen healthy volunteers had IFCN and saphenous nerve blocks. The subgroup of volunteers with a non-anesthetized gap between the areas anesthetized by the saphenous and the IFCN blocks was defined as the study group for the primary outcome. Subsequently selective MFCN-A block and MFCN block (MFCN-A + MFCN-P) were performed to investigate the contributions from MFCN-A and MFCN-P to the innervation of the midline incision. All assessments were performed blinded. RESULTS: Ten out of 19 volunteers had a non-anesthetized gap. Nine out of these 10 volunteers had coverage of the non-anesthetized gap after selective anesthesia of the MFCN-A, whereas anesthesia of the MFCN-P did not contribute to coverage of the gap in any of the 10 volunteers. CONCLUSIONS: In half of the cases, a gap of non-anesthetized skin was present on the surgical midline incision after anesthesia of the saphenous nerve and the IFCN. This gap was covered by selective anesthesia of the MFCN-A without contribution from MFCN-P. The selective MFCN-A block may be relevant for diagnosis and interventional management of neuropathic pain due to injury of MFCN-A.

Symptomatic malaria enhances protection from reinfection with homologous Plasmodium falciparum parasites.

A signature remains elusive of naturally-acquired immunity against Plasmodium falciparum . We identified P. falciparum in a 14-month cohort of 239 people in Kenya, genotyped at immunogenic parasite targets expressed in the pre-erythrocytic (circumsporozoite protein, CSP) and blood (apical membrane antigen 1, AMA-1) stages, and classified into epitope type based on variants in the DV10, Th2R, and Th3R epitopes in CSP and the c1L region of AMA-1. Compared to asymptomatic index infections, symptomatic malaria was associated with a reduced reinfection by parasites bearing homologous CSP-Th2R (adjusted hazard ratio [aHR]:0.63; 95% CI:0.45-0.89; p=0.008) CSP-Th3R (aHR:0.71; 95% CI:0.52-0.97; p=0.033), and AMA-1 c1L (aHR:0.63; 95% CI:0.43-0.94; p=0.022) epitope types. The association of symptomatic malaria with reduced risk of homologous reinfection was strongest for rare epitope types. Symptomatic malaria more effectively promotes functional immune responses. The phenotype represents a legible molecular epidemiologic signature of naturally-acquired immunity by which to identify new antigen targets.

Telestration with augmented reality improves surgical performance through gaze guidance.

BACKGROUND: In minimally invasive surgery (MIS), trainees need to learn how to interpret the operative field displayed on the laparoscopic screen. Experts currently guide trainees mainly verbally during laparoscopic procedures. A newly developed telestration system with augmented reality (iSurgeon) allows the instructor to display hand gestures in real-time on the laparoscopic screen in augmented reality to provide visual expert guidance (telestration). This study analysed the effect of telestration guided instructions on gaze behaviour during MIS training. METHODS: In a randomized-controlled crossover study, 40 MIS naive medical students performed 8 laparoscopic tasks with telestration or with verbal instructions only. Pupil Core eye-tracking glasses were used to capture the instructor's and trainees' gazes. Gaze behaviour measures for tasks 1-7 were gaze latency, gaze convergence and collaborative gaze convergence. Performance measures included the number of errors in tasks 1-7 and trainee's ratings in structured and standardized performance scores in task 8 (ex vivo porcine laparoscopic cholecystectomy). RESULTS: There was a significant improvement 1-7 on gaze latency [F(1,39) = 762.5, p < 0.01, ηp2 = 0.95], gaze convergence [F(1,39) = 482.8, p < 0.01, ηp2 = 0.93] and collaborative gaze convergence [F(1,39) = 408.4, p < 0.01, ηp2 = 0.91] upon instruction with iSurgeon. The number of errors was significantly lower in tasks 1-7 (0.18 ± 0.56 vs. 1.94 ± 1.80, p < 0.01) and the score ratings for laparoscopic cholecystectomy were significantly higher with telestration (global OSATS: 29 ± 2.5 vs. 25 ± 5.5, p < 0.01; task-specific OSATS: 60 ± 3 vs. 50 ± 6, p < 0.01). CONCLUSIONS: Telestration with augmented reality successfully improved surgical performance. The trainee's gaze behaviour was improved by reducing the time from instruction to fixation on targets and leading to a higher convergence of the instructor's and the trainee's gazes. Also, the convergence of trainee's gaze and target areas increased with telestration. This confirms augmented reality-based telestration works by means of gaze guidance in MIS and could be used to improve training outcomes.

Quantum-classical dynamics of vibration-induced autoionization in molecules.

We present a novel method for the simulation of the vibration-induced autoionization dynamics in molecular anions in the framework of the quantum-classical surface hopping approach. Classical trajectories starting from quantum initial conditions are propagated on a quantum-mechanical potential energy surface while allowing for autoionization through transitions into discretized continuum states. These transitions are induced by the couplings between the electronic states of the bound anionic system and the electron-detached system composed of the neutral molecule and the free electron. A discretization scheme for the detached system is introduced, and a set of formulas is derived that enable the approximate calculation of couplings between the bound and free-electron states. We demonstrate our method on the example of the anion of vinylidene, a high-energy isomer of acetylene, for which detailed experimental data are available. Our results provide information on the time scale of the autoionization process and give insight into the energetic and angular distribution of the ejected electrons, as well as the associated changes in the molecular geometry. We identify the formation of structures with reduced C-C bond lengths and T-like conformations through bending of the CH2 group with respect to the C-C axis and point out the role of autoionization as a driving process for the isomerization to acetylene.

Interfractional dose accumulation for MR-guided liver SBRT: Variation among algorithms is highly patient- and fraction-dependent.

BACKGROUND AND PURPOSE: Daily plan adaptations could take the dose delivered in previous fractions into account. Due to high dose delivered per fraction, low number of fractions, steep dose gradients, and large interfractional organ deformations, this might be particularly important for liver SBRT. This study investigates inter-algorithm variation of interfractional dose accumulation for MR-guided liver SBRT. MATERIALS AND METHODS: We assessed 27 consecutive MR-guided liver SBRT treatments of 67.5 Gy in three (n = 15) or 50 Gy in five fractions (n = 12), both prescribed to the GTV. We calculated fraction doses on daily patient anatomy, warped these doses to the simulation MRI using seven different algorithms, and accumulated the warped doses. Thus, we obtained differences in planned doses and warped or accumulated doses for each algorithm. This enabled us to calculate the inter-algorithm variations in warped doses per fraction and in accumulated doses per treatment course. RESULTS: The four intensity-based algorithms were more consistent with planned PTV dose than affine or contour-based algorithms. The mean (range) variation of the dose difference for PTV D95% due to dose warping by these intensity-based algorithms was 10.4 percentage points (0.3 to 43.7) between fractions and 8.6 (0.3 to 24.9) between accumulated treatment doses. As seen by these ranges, the variation was very dependent on the patient and the fraction being analyzed. Nevertheless, no correlations between patient or plan characteristics on the one hand and inter-algorithm dose warping variation on the other hand was found. CONCLUSION: Inter-algorithm dose accumulation variation is highly patient- and fraction-dependent for MR-guided liver SBRT. We advise against trusting a single algorithm for dose accumulation in liver SBRT.

Artificial intelligence (AI)-based decision support improves reproducibility of tumor response assessment in neuro-oncology: An international multi-reader study.

BACKGROUND: To assess whether artificial intelligence (AI)-based decision support allows more reproducible and standardized assessment of treatment response on MRI in neuro-oncology as compared to manual 2-dimensional measurements of tumor burden using the Response Assessment in Neuro-Oncology (RANO) criteria. METHODS: A series of 30 patients (15 lower-grade gliomas, 15 glioblastoma) with availability of consecutive MRI scans was selected. The time to progression (TTP) on MRI was separately evaluated for each patient by 15 investigators over two rounds. In the first round the TTP was evaluated based on the RANO criteria, whereas in the second round the TTP was evaluated by incorporating additional information from AI-enhanced MRI sequences depicting the longitudinal changes in tumor volumes. The agreement of the TTP measurements between investigators was evaluated using concordance correlation coefficients (CCC) with confidence intervals (CI) and P-values obtained using bootstrap resampling. RESULTS: The CCC of TTP-measurements between investigators was 0.77 (95% CI = 0.69,0.88) with RANO alone and increased to 0.91 (95% CI = 0.82,0.95) with AI-based decision support (P = .005). This effect was significantly greater (P = .008) for patients with lower-grade gliomas (CCC = 0.70 [95% CI = 0.56,0.85] without vs. 0.90 [95% CI = 0.76,0.95] with AI-based decision support) as compared to glioblastoma (CCC = 0.83 [95% CI = 0.75,0.92] without vs. 0.86 [95% CI = 0.78,0.93] with AI-based decision support). Investigators with less years of experience judged the AI-based decision as more helpful (P = .02). CONCLUSIONS: AI-based decision support has the potential to yield more reproducible and standardized assessment of treatment response in neuro-oncology as compared to manual 2-dimensional measurements of tumor burden, particularly in patients with lower-grade gliomas. A fully-functional version of this AI-based processing pipeline is provided as open-source (https://github.com/NeuroAI-HD/HD-GLIO-XNAT).