Spin States Matter─from Fundamentals toward Synthetic Methodology Development and Drug Discovery.

ConspectusThe potent reactivity of carbenes and nitrenes has been traditionally harnessed by the employment of a transition-metal catalyst in which the reactivity of the metal carbene/nitrene intermediates can be controlled via the judicious tuning of the metal catalyst. In recent years, progress made in this research area has unveiled novel strategies to directly access free carbenes or nitrenes under visible-light-mediated conditions without the necessity of a metal catalyst for stabilization of the carbene/nitrene intermediate. Such photochemical approaches present new opportunities to leverage orthogonal reactions with classic metal-catalyzed transformations.In this Account, we describe the major contributions from our group over the past years pushing the boundaries of light-mediated carbene and nitrene transfer reactions. In the first section, the development from purely singlet carbene chemistry toward methods that allow access to triplet carbene intermediates will be dissected. We describe how the triplet spin state of reagents provides a rich array of novel synthetic methods that build on the fundamentals of spin conservation. We lay out the different strategies in accessing the triplet spin state of carbenes (i.e., via electronic stabilization, via triplet sensitization with suitable photocatalysts, or via exploitation of geometric features of these intermediates), followed by an analysis of how the triplet spin state can be employed to leverage reactions distinct to the classic singlet carbene chemistry.The second part focuses on free nitrene intermediates, whereby both photochemical and photocatalytic strategies are analyzed and compared. We initiate with a discussion of the reactivity of iminoiodinanes as nitrene precursors in the presence of a photocatalyst or under photochemical conditions and how these two approaches result in fundamentally distinct nitrogen-based intermediates. While a nitrene radical anion is formed under photocatalytic conditions, triplet nitrene is generated under photochemical conditions. We commence with an outline of the basic reactivity of nitrene transfer reactions under both conditions, with a focus on the reaction with substrates containing double bonds. Finally, the latest developments in advanced cycloaddition chemistry beyond classic aziridination reactions are examined, with a special emphasis on the relay of the triplet nitrene reactivity to enable a Pauson-Khand-like (2 + 2 + 1) cycloaddition reaction that offers convenient access to high value bioisosteres in drug discovery.The work from our group on spin-dependent reactivities offers insight into important fundamentals in synthesis, where the spin state of the reactive intermediate will dictate the reaction outcome. We hope this may inspire others to widen the scope of applications of light-mediated carbene and/or nitrene transfer reactions, and furthermore, we anticipate that these understandings may also enable the development of advanced catalytic systems featuring triplet metal carbene/nitrene intermediates.

On the glow of cremated remains: long-lived green photo-luminescence of heat-treated human bones.

The long-lived green luminescence of human bone (that has been heated to 600 °C for a short duration) is attributed to a carbon quantum dot material (derived from collagen) encapsulated and protected by an inorganic matrix (derived from bone apatite) and is more intense in dense rigid and crystalline parts of (healthy) human bones. The strong collagen-apatite interaction results (upon decomposition) in a protective inorganic environment of the luminescent centers allowing long-lived triplet-based emission of a carbon (quantum) dot-like material at room temperature, as well as resilience against oxidation between 550 and 650 °C. The graphitic black phase (obtained upon heating around 400 °C) is a precursor to the luminescent carbon-based material, that is strongly interacting with the crystalline inorganic matrix. Human bone samples that have been heated to 600 °C were subjected to steady-state and time-resolved spectroscopy. Excitation-emission matrix (EEM) luminescence spectroscopy revealed a broad range of excitation and emission wavelengths, indicating a heterogeneous system with a broad density of emissive states. The effect of low temperature on the heat-treated bone was studied with Cryogenic Steady State Luminescence Spectroscopy. Cooling the bone to 80 K leads to a slight increase in total emission intensity as well as an intensity increase towards to red part of the spectrum, incompatible with a defect state model displaying luminescent charge recombination in the inorganic matrix. Time-resolved spectroscopy with an Optical Multichannel Analyzer (OMA) and Time Correlated Single Photon Counting (TCSPC) of these samples showed that the decay could be fitted with a multi-exponential decay model as well as with second-order decay kinetics. Confocal Microscopy revealed distinct (plywood type) structures in the bone and high intensity-fast decay areas as well as a spatially heterogeneous distribution of green and (fewer) red emissive species. The use of the ATTO 565 dye aided in bone-structure visualization by chemical adsorption. Conceptually our data interpretation corresponds to previous reports from the material science field on luminescent powders.

The Value of Preoperative Rigid Tracheobronchoscopy for the Diagnosis of Tracheomalacia in Oesophageal Atresia Patients.

BACKGROUND: Oesophageal atresia (OA) is often accompanied by tracheomalacia (TM). The aim of this study was to evaluate its presence in OA patients during routine rigid tracheobronchoscopy (TBS) before primary correction and compare this to postoperative TBS and clinical signs of TM. METHODS: This retrospective cohort study included patients born with OA between June 2013 and December 2022 who had received a TBS before OA correction and had been followed for at least twelve months. Definite TM was postoperatively diagnosed through TBS, and probable TM was defined as having symptoms of TM. RESULTS: We analysed data from 79 patients, of whom 87% with OA type C. Preoperatively, TM was observed in 33 patients (42% of all patients), seven of whom had severe TM. Definite TM was observed in 21 patients (27%), of whom 15 had severe TM. Forty-one patients (52% of all patients) had developed symptoms of TM within twelve months, including harsh barking cough (n = 15), stridor and/or wheezing (n = 20), recurrent respiratory insufficiency (n = 11), or needing airway surgery (n = 7). The sensitivity of preoperative TBS for the presence of postoperative (definite and probable combined) TM is 50.0%, 95% CI [35.2-64.8], and the specificity 67.6%, 95% CI [51.7-81.1]. Clinical characteristics did not differ between the patients with or without postoperative TM. CONCLUSIONS: More than half of the studied patients with OA experienced symptoms of TM. While preoperative TBS is routinely performed prior to surgical OA correction, its predictive value for the presence of postoperative TM remains limited. LEVEL OF EVIDENCE: Level II. TYPE OF STUDY: Study of Diagnostics Test.

Postnatal chest X-ray in children with asymptomatic congenital lung malformations.

OBJECTIVE: The clinical implications of a postnatal chest X-ray (CXR) in asymptomatic children with a prenatally diagnosed congenital lung malformation (CLM) are uncertain. We assessed the justification for the postnatal use of CXR in these children. METHODS: We included patients with CLM confirmed through chest computed tomography angiography or histopathological analysis who were asymptomatic at birth, underwent routine postnatal CXR, and participated in our standard of care prospective structured longitudinal follow-up program. Children with major associated morbidities were excluded. Primary outcomes were the positive and negative predictive values (PPV and NPV) of CXR findings for symptom development at 4 weeks and 6 months of age. Secondarily, we sought to establish whether CXR findings were associated with undergoing additional diagnostics during the initial observational hospital stay or prolonged postnatal hospital admission. RESULTS: Among 121 included patients, CXR showed no abnormalities in 35 (29%), nonspecific abnormalities in 23 (19%), and probable CLM in 63 (52%). The PPV of CXR in relation to symptom development at 4 weeks and 6 months was 0.05 and 0.25, respectively. Corresponding NPVs were 0.96 and 0.91. An association was identified between CXR findings and undergoing further diagnostics during the initial observational hospital stay (p = .047). Additional diagnostic findings did not influence clinical management. CXR findings were not associated with prolonged initial hospital stay (p = .40). CONCLUSION: The routine practice of postnatal CXR in asymptomatic patients with prenatally diagnosed CLM can be omitted, as CXR findings do not influence subsequent clinical management.

Presentation and outcomes of Lassa fever in children in Nigeria: a prospective cohort study (LASCOPE).

BACKGROUND: Data on the presentation, management and outcomes of Lassa fever (LF) in children are limited. METHODS: Description of the clinical and biological features, treatment and outcomes of RT-PCR-confirmed LF in children aged under 15, enrolled in the LASCOPE prospective cohort study in Nigeria between April 2018 and February 2023. RESULTS: 124 children (aged under 12 months: 19; over 12 months: 105) were hospitalized with RT-PCR-confirmed LF. All received intravenous ribavirin. During follow-up, 99/124 (80%) had fever; 71/124 (57%) had digestive symptoms, vomiting (n = 56/122, 46%) and abdominal pain (n = 34/78 aged ≥ 5 years, 44%) more often than diarrhea (n = 19/124, 15%); 17/124 (14%) had hemorrhagic signs; 44/112 (39%) had a hematocrit lower than 25%, of whom 32/44 (73%) received transfusions; 44/88 (50%) developed hypotension; 18/112 (16.1%) developed KDIGO ≥ 2 acute kidney injury; 10/112 (8.9%) had KDIGO 3 acute kidney failure; 4/124 (3.2%) underwent renal replacement therapy. 7 children died, including 4 aged under 12 months (case fatality rate: under 12 months - 22%, 95% CI 7 - 48%; over 12 months - 2.9%, 95% CI 0.7 - 8.7%). In univariable analysis, age (p=0.003), impaired consciousness (p=0.026), and Lassa RT-PCR Ct value (p=0.006) were associated to Day 30 mortality. CONCLUSIONS: The fatality rate for children over 12 months hospitalized with LF was lower than that previously reported for adults. Hypotension and acute kidney injury were the most frequent organ dysfunctions. Bleeding was relatively infrequent. Anemia and the need for transfusion were common, the relative contribution of ribavirin-induced hemolysis being unknown.

Photochemical α-amination of carbonyl groups with iodinanes.

We report on a photochemical reaction of silyl enol ethers with iminoiodinanes. This aza Rubottom reaction provides a direct access towards α-amino carbonyl compounds under catalyst free reaction conditions with light as the sole source of energy. Control experiments suggest the participation of triplet nitrene intermediates.

Trends in Surgical and Nonsurgical Aesthetic Procedures: A 14-Year Analysis of the International Society of Aesthetic Plastic Surgery-ISAPS.

INTRODUCTION: As part of the International Society of Aesthetic Plastic Surgery, we present an analysis of our global aesthetic statistics, fulfilling the role of a worldwide organization of plastic surgeons with a clear mission to disseminate aesthetic education worldwide, promote patient safety, protect high ethical standards, and communicate. MATERIAL AND METHODS: A retrospective analysis of the ISAPS Global Aesthetic Statistics was conducted annually from 2010 to 2023. The design and analysis of each survey was carefully developed and validated by Industry Insights, Inc. prior to distribution. Participants were recruited using an anonymous online questionnaire that focused primarily on the number of surgical and nonsurgical procedures performed in the previous year, as well as questions related to surgeon demographics and the prevalence of medical tourism. ISAPS invited all physicians in their data base who were board-certified plastic surgeons or equivalent and suggested National Societies to encourage their members to participate. RESULTS: The latest survey reported a global increase in 3.4%, including 34.9 million surgical and nonsurgical aesthetic procedures performed by plastic surgeons in 2023. More than 15.8 million surgical procedures and more than 19.1 million nonsurgical procedures were performed worldwide. During the past decade, a steady increase in aesthetic procedures has been observed, which has been more pronounced since 2021. In the last 4 years, the overall increase in procedures was 40%. SURGICAL PROCEDURES: The top five surgical procedures were liposuction, breast augmentation, eyelid surgery, abdominoplasty, and rhinoplasty. This trend has been stable for 14 years, with the exception of 2022, when breast lift surgery temporarily replaced rhinoplasty. FACE AND HEAD PROCEDURES: These procedures continue to be the most popular. This group included brow lift, ear surgery, eyelid surgery, facelift, facial bone contouring, facial fat grafting, lip augmentation or frontal surgery, neck lift, and rhinoplasty. BODY AND EXTREMITIES PROCEDURES: This group included abdominoplasty, buttock augmentation, buttock lift, liposuction, lower body lift, thigh lift, arm lift, upper body lift, labiaplasty, and vaginal rejuvenation. Over the past 14 years, body and extremity procedures have increased, with more than 5.1 million procedures in 2023 compared to 2.6 million in 2009. NONSURGICAL PROCEDURES: The five most popular nonsurgical procedures are botulinum toxin, hyaluronic acid, hair removal, chemical peels, and nonsurgical fat reduction. In 2022, chemical peels will replace nonsurgical skin tightening in the top five. MALE AESTHETIC SURGERY: Procedures performed on men continue to grow, with minimally invasive procedures dominating. The most recent survey reported that they represented 14.5% of the total. The top five surgical procedures were eyelid surgery, gynecomastia, liposuction, rhinoplasty, and facial fat grafting. The most popular nonsurgical procedures for men were botulinum toxin, hyaluronic acid, hair removal, nonsurgical skin tightening, and nonsurgical fat reduction. This trend has held steady for more than a decade. DISCUSSION: This study analyzes the most recent data and experience of board-certified aesthetic plastic surgeons in surgical and nonsurgical procedures worldwide over 14 years and provides insight into future trends. More than 60 years have passed since the introduction of liposuction, being one of the most performed aesthetic procedures worldwide over the past 14 years and currently number one procedure performed by plastic surgeons. New trends and technologies have evolved over the years, however, plastic surgeons must be cautious, as history has shown that risks increase when new technologies are introduced. With the popularity of liposuction, other body contouring procedures began to gain interest, and in 2015, gluteal lipoinjections were added to the ISAPS global aesthetic statistics and with them complications arise. In 2018 and 2019, the major patient safety societies, ISAPS, ASERF, ASPS, and ASAPS, began a systematic educational campaign to inform their members about the inherent risks of performing gluteal fat transfer surgery and what techniques or equipment can be used to minimize risks. Another procedure added to the ISAPS statistics in 2010 was vaginal aesthetic surgery. With the new trend of vaginal aesthetics, many believed that they were just changing the appearance of the area, but today it is clear that they are here for much more, to truly empower women with their sexuality. Breast augmentation showed a decline for the first-time last year. However, breast augmentation and liposuction have been the most performed procedures by plastic surgeons worldwide for more than a decade. On the other hand, implant removal has been the fastest growing procedure since 2015, with an overall increase in 46.3% over the past 5 years. In relation to male aesthetic surgery, the number of men undergoing aesthetic procedures has remained stable in recent years at around 14%. Male aesthetics is certainly a growing trend, and our practices should be more inclusive. Another prominent field is regenerative medicine. In relation to plastic surgery, regenerative surgery strategies often involve adipose tissue with stem cells and preadipocytes, alone or in combination with scaffolds. In terms of prevention, regenerative medicine aims to improve the quality of the skin by improving our outcomes and would make it possible to avoid the need for facelifts in the future. Finally, given the increasing popularity of medical procedures abroad ("medical tourism") and the fact that safety regulations and guidelines vary widely from place to place, we encourage patients to choose a board-certified, specialized, trained and experienced plastic surgeon for their procedure and an accredited surgical facility to ensure the procedure in done under the highest patient safety standards. CONCLUSIONS: Despite the obvious cultural and social differences from country to country that make certain procedures more desirable in some geographic areas and less so in other parts of the world, the results of this study show a significant overall increase in all surgical and nonsurgical procedures aimed at improving the aesthetic appearance of the body during14 years. As plastic surgeons, we are open to new possibilities in aesthetic procedures and are responsible for patient safety protocols and procedures. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Navigating the spectrum of pediatric sialorrhea management: A narrative review.

OBJECTIVE: This review summarizes the approaches to pediatric sialorrhea management from least-to-most invasive: non-pharmacological management, anticholinergic medications, botulinum neurotoxin, non-invasive surgery, and invasive surgical intervention. REVIEW METHODS: An electronic literature review identified English-language articles on sialorrhea management in pediatric patients. Publications between 1982 and 2022 were used, with a focus on articles published from 2012 to 2022. Additional augmentation of pharmacologic information was obtained from the latest editions of medical textbooks supplemented with official package inserts of investigated medications. CONCLUSIONS: Sialorrhea is abnormal in patients greater than four years of age. Severe cases warrant intervention to improve patient quality of life and reduce caregiver burden. Management starts with conservative approaches. Viable candidates begin with non-pharmacological management options. Anticholinergic medications can decrease saliva production, but adverse side effects may outweigh benefits. Botulinum neurotoxin injection of the salivary glands decreases salivary flow rate; however, relief is transient and thus multiple treatments are required. Non-invasive sclerotherapy is an emerging treatment option showing promising results for sialorrhea. In contrast, surgical intervention is reserved as a last-resort treatment for patients with severe symptoms, due to its higher risk for adverse consequences. IMPLICATIONS FOR PRACTICE: Physicians should be familiar with the different pediatric sialorrhea management options, including advantages and disadvantages, to adequately facilitate shared decision making with caretakers of pediatric patients who require treatment.

Clinical impact of novel CMR technology on patients with congenital heart disease. A scientific statement of the Association for European Pediatric and Congenital Cardiology (AEPC) and the European Association of Cardiovascular Imaging (EACVI) of the ESC.

Cardiovascular magnetic resonance (CMR) imaging is recommended in patients with congenital heart disease (CHD) in clinical practice guidelines as the imaging standard for a large variety of diseases. As CMR is evolving, novel techniques are becoming available. Some of them are already used clinically, whereas others still need further evaluation. In this statement the authors give an overview of relevant new CMR techniques for the assessment of CHD. Studies with reference values for these new techniques are listed in the supplement.

Denitrogenative dismantling of heteroaromatics by nucleophilic substitution reactions with diazomethyl compounds.

Nucleophiles from deprotonation of diazomethyl compounds having diverse electron withdrawing groups react with 4-carboxylato-1,2,3-triazines at the 6-position to extrude dinitrogen and produce diazovinylketoesters compounds with five or six linear contiguous sp2-hybridized carbons, whereas these same nucleophiles react with 4-carboxylato-1,2,3-triazine 1-oxides, also at the 6-position, to form pyrazolines with the expulsion of nitrous oxide and cyanocarboxylate. This disparity is due to the significant difference in reactivity of the nucleophilic addition products.

Prevalence of Gastroesophageal Reflux Disease in Congenital Diaphragmatic Hernia Survivors From Infancy to Adulthood.

BACKGROUND: Gastroesophageal reflux disease (GERD) is a common comorbidity associated with congenital diaphragmatic hernia (CDH), with reported cases of Barrett's esophagus (BE) and esophageal adenocarcinoma before the age of 25. The prevalence and natural course of GERD in CDH survivors remain uncertain due to variations in diagnostic methods. We aimed to analyse the GERD prevalence from infancy through young adulthood. METHODS: We retrospectively analyzed pH-impedance measurements and endoscopic findings in 96 CDH survivors evaluated as routine care using well established clinical protocols. GERD was defined as an abnormal acid exposure time for pH-MII measurements and as presence of reflux esophagitis or BE at upper endoscopy. Clinical data including symptoms at time of follow-up and use of antireflux medication were collected. RESULTS: GERD prevalence remained consistently low (≤10%) across all age groups, yet many patients experienced GER symptoms. Histological abnormalities were observed in 80% of adolescents and young adults, including microscopic esophagitis in 50%. BE was diagnosed in 7% before the age of 18, all had GER symptoms. CDH severity, anatomy at the time of CDH correction, alcohol usage, and smoking did not emerge as significant risk factors for GERD. CONCLUSIONS: Given the low GERD prevalence in CDH survivors, a symptom-driven approach to diagnosis and follow-up is warranted. We advise long-term follow-up for all adult patients due to the early onset of BE and the limited evidence available. The longitudinal course and impact of GERD on other long-term CDH-related comorbidities should be explored in larger cohorts. LEVEL OF EVIDENCE: Not applicable.

Simultaneous 3D T 1 $$ {\mathrm{T}}_1 $$ , T 2 $$ {\mathrm{T}}_2 $$ , and fat-signal-fraction mapping with respiratory-motion correction for comprehensive liver tissue characterization at 0.55 T.

PURPOSE: To develop a framework for simultaneous three-dimensional (3D) mapping of T 1 $$ {\mathrm{T}}_1 $$ , T 2 $$ {\mathrm{T}}_2 $$ , and fat signal fraction in the liver at 0.55 T. METHODS: The proposed sequence acquires four interleaved 3D volumes with a two-echo Dixon readout. T 1 $$ {\mathrm{T}}_1 $$ and T 2 $$ {\mathrm{T}}_2 $$ are encoded into each volume via preparation modules, and dictionary matching allows simultaneous estimation of T 1 $$ {\mathrm{T}}_1 $$ , T 2 $$ {\mathrm{T}}_2 $$ , and M 0 $$ {M}_0 $$ for water and fat separately. 2D image navigators permit respiratory binning, and motion fields from nonrigid registration between bins are used in a nonrigid respiratory-motion-corrected reconstruction, enabling 100% scan efficiency from a free-breathing acquisition. The integrated nature of the framework ensures the resulting maps are always co-registered. RESULTS: T 1 $$ {\mathrm{T}}_1 $$ , T 2 $$ {\mathrm{T}}_2 $$ , and fat-signal-fraction measurements in phantoms correlated strongly (adjusted r 2 > 0 . 98 $$ {r}^2>0.98 $$ ) with reference measurements. Mean liver tissue parameter values in 10 healthy volunteers were 427 ± 22 $$ 427\pm 22 $$ , 47 . 7 ± 3 . 3 ms $$ 47.7\pm 3.3\;\mathrm{ms} $$ , and 7 ± 2 % $$ 7\pm 2\% $$ for T 1 $$ {\mathrm{T}}_1 $$ , T 2 $$ {\mathrm{T}}_2 $$ , and fat signal fraction, giving biases of 71 $$ 71 $$ , - 30 . 0 ms $$ -30.0\;\mathrm{ms} $$ , and - 5 $$ -5 $$ percentage points, respectively, when compared to conventional methods. CONCLUSION: A novel sequence for comprehensive characterization of liver tissue at 0.55 T was developed. The sequence provides co-registered 3D T 1 $$ {\mathrm{T}}_1 $$ , T 2 $$ {\mathrm{T}}_2 $$ , and fat-signal-fraction maps with full coverage of the liver, from a single nine-and-a-half-minute free-breathing scan. Further development is needed to achieve accurate proton-density fat fraction (PDFF) estimation in vivo.

Free-breathing 3D whole-heart joint T1/T2 mapping and water/fat imaging at 0.55 T.

PURPOSE: To develop and validate a highly efficient motion compensated free-breathing isotropic resolution 3D whole-heart joint T1/T2 mapping sequence with anatomical water/fat imaging at 0.55 T. METHODS: The proposed sequence takes advantage of shorter T1 at 0.55 T to acquire three interleaved water/fat volumes with inversion-recovery preparation, no preparation, and T2 preparation, respectively. Image navigators were used to facilitate nonrigid motion-compensated image reconstruction. T1 and T2 maps were jointly calculated by a dictionary matching method. Validations were performed with simulation, phantom, and in vivo experiments on 10 healthy volunteers and 1 patient. The performance of the proposed sequence was compared with conventional 2D mapping sequences including modified Look-Locker inversion recovery and T2-prepared balanced steady-SSFP sequence. RESULTS: The proposed sequence has a good T1 and T2 encoding sensitivity in simulation, and excellent agreement with spin-echo reference T1 and T2 values was observed in a standardized T1/T2 phantom (R2 = 0.99). In vivo experiments provided good-quality co-registered 3D whole-heart T1 and T2 maps with 2-mm isotropic resolution in a short scan time of about 7 min. For healthy volunteers, left-ventricle T1 mean and SD measured by the proposed sequence were both comparable with those of modified Look-Locker inversion recovery (640 ± 35 vs. 630 ± 25 ms [p = 0.44] and 49.9 ± 9.3 vs. 54.4 ± 20.5 ms [p = 0.42]), whereas left-ventricle T2 mean and SD measured by the proposed sequence were both slightly lower than those of T2-prepared balanced SSFP (53.8 ± 5.5 vs. 58.6 ± 3.3 ms [p < 0.01] and 5.2 ± 0.9 vs. 6.1 ± 0.8 ms [p = 0.03]). Myocardial T1 and T2 in the patient measured by the proposed sequence were in good agreement with conventional 2D sequences and late gadolinium enhancement. CONCLUSION: The proposed sequence simultaneously acquires 3D whole-heart T1 and T2 mapping with anatomical water/fat imaging at 0.55 T in a fast and efficient 7-min scan. Further investigation in patients with cardiovascular disease is now warranted.

Unlocking catalytic potential: a rhodium(II)-based coordination polymer for efficient carbene transfer reactions with donor/acceptor diazoalkanes.

Herein, we report the use of a molecular-defined rhodium(II) coordination polymer (Rh-CP) as a heterogeneous, recyclable catalyst in carbene transfer reactions. We showcase the application of this heterogeneous catalyst in a range of carbene transfer reactions and conclude with the functionalization of natural products and drug molecules.

A multipurpose, adolescent idiopathic scoliosis-specific, short MRI protocol: A feasibility study in volunteers.

INTRODUCTION: Visualization of scoliosis typically requires ionizing radiation (radiography and CT) to visualize bony anatomy. MRI is often additionally performed to screen for neural axis abnormalities. We propose a 14-minutes radiation-free scoliosis-specific MRI protocol, which combines MRI and MRI-based synthetic CT images to visualize soft and osseous structures in one examination. We assess the ability of the protocol to visualize landmarks needed to detect 3D patho-anatomical changes, screen for neural axis abnormalities, and perform surgical planning and navigation. METHODS: 18 adult volunteers were scanned on 1.5 T MR-scanner using 3D T2-weighted and synthetic CT sequences. A predefined checklist of relevant landmarks was used for the parameter assessment by three readers. Parameters included Cobb angles, rotation, torsion, segmental height, area and centroids of Nucleus Pulposus and Intervertebral Disc. Precision, reliability and agreement between the readers measurements were evaluated. RESULTS: 91 % of Likert-based questions scored ≥ 4, indicating moderate to high confidence. Precision of 3D dot positioning was 1.0 mm. Precision of angle measurement was 0.6° (ICC 0.98). Precision of vertebral and IVD height measurements was 0.4 mm (ICC 0.99). Precision of area measurement for NP was 8 mm2 (ICC 0.55) and for IVD 18 mm2 (ICC 0.62) for IVD. Precision of centroid measurement for NP was 1.3 mm (ICC 0.88-0.92) and for IVD 1.1 mm (ICC 0.88-91). CONCLUSIONS: The proposed MRI protocol with synthetic CT reconstructions, has high precision, reliability and agreement between the readers for multiple scoliosis-specific measurements. It can be used to study scoliosis etiopathogenesis and to assess 3D spinal morphology.

Dual Functional Antibacterial-Antioxidant Core/Shell Alginate/Poly(ε-caprolactone) Nanofiber Membrane: A Potential Wound Dressing.

Core/shell nanofibers offer the advantage of encapsulating multiple drugs with different hydrophilicity in the core and shell, thus allowing for the controlled release of pharmaceutic agents. Specifically, the burst release of hydrophilic drugs from such fiber membranes causes an instantaneous high drug concentration, whereas a long and steady release is usually desired. Herein, we tackle the problem of the initial burst release by the generation of core/shell nanofibers with the hydrophilic antibiotic drug gentamycin loaded within a hydrophilic alginate core surrounded by a hydrophobic shell of poly(ε-caprolactone). Emulsion electrospinning was used as the nanofibrous mesh generation procedure. This process also allows for the loading of a hydrophobic compound, where we selected a natural antioxidant molecule, betulin (BTL), to detoxify the radicals. The resulting nanofibers exhibited a cylindrical shape with a core/shell structure. In vitro tests showed a controlled release of gentamicin from nanofibers via diffusion. The drug reached 93% release in an alginate hydrogel film but only 50% release in the nanofibers, suggesting its potential to minimize the initial burst release. Antibacterial tests revealed significant activity against both Gram-negative and Gram-positive bacteria. The antioxidant property of betulin was confirmed through the DPPH assay, where the incorporation of 20% BTL revealed 37.3% DPPH scavenging. The nanofibers also exhibited favorable biocompatibility in cell culture studies, and no harmful effects on cell viability were observed. Overall, this research offers a promising approach to producing core/shell nanofibrous mats with antibacterial and antioxidant properties, which could effectively address the requirements of wound dressings, including infection prevention and wound healing acceleration.

Enhancement of STroke REhabilitation with Levodopa (ESTREL): Rationale and design of a randomized placebo-controlled, double blind superiority trial.

RATIONALE: Novel therapeutic approaches are needed in stroke recovery. Whether pharmacological therapies are beneficial for enhancing stroke recovery is unclear. Dopamine is a neurotransmitter involved in motor learning, reward, and brain plasticity. Its prodrug levodopa is a promising agent for stroke recovery. AIM AND HYPOTHESIS: To investigate the hypothesis that levodopa, in addition to standardized rehabilitation therapy based on active task training, results in an enhancement of functional recovery in acute ischemic or hemorrhagic stroke patients compared to placebo. DESIGN: ESTREL (Enhancement of Stroke REhabilitation with Levodopa) is a randomized (ratio 1:1), multicenter, placebo-controlled, double-blind, parallel-group superiority trial. PARTICIPANTS: 610 participants (according to sample size calculation) with a clinically meaningful hemiparesis will be enrolled ⩽7 days after stroke onset. Key eligibility criteria include (i) in-hospital-rehabilitation required, (ii) capability to participate in rehabilitation, (iii) previous independence in daily living. INTERVENTION: Levodopa 100 mg/carbidopa 25 mg three times daily, administered for 5 weeks in addition to standardized rehabilitation. The study intervention will be initiated within 7 days after stroke onset. COMPARISON: Matching placebo plus standardized rehabilitation. OUTCOMES: The primary outcome is the between-group difference of the Fugl-Meyer-Motor Assessment (FMMA) total score measured 3 months after randomization. Secondary outcomes include patient-reported health and wellbeing (PROMIS 10 and 29), patient-reported assessment of improvement, Rivermead Mobility Index, modified Rankin Scale, National Institutes of Health Stroke Scale (NIHSS), and as measures of harm: mortality, recurrent stroke, and serious adverse events. CONCLUSION: The ESTREL trial will provide evidence of whether the use of Levodopa in addition to standardized rehabilitation in stroke patients leads to better functional recovery compared to rehabilitation alone.

Maturation of the vertebral ring apophysis is delayed in girls with adolescent idiopathic scoliosis compared to the normal population.

PURPOSE: The ring apophysis is a secondary ossification center on both sides of each vertebral body, to which the annulus of the intervertebral disc inserts. Recently, its pattern of ossification and fusion to the vertebral body was described for the normal growing spine. The aim of the present study was to investigate the ossification and fusion of the ring apophysis in patients with adolescent idiopathic scoliosis (AIS) and compare it to the normal growing population. METHODS: Ring apophysis maturation along the entire thoracic and lumbar spine was analyzed on CT scans of 99 female, pre-operative AIS patients and compared to 134 CT scans of non-scoliotic girls, aged 12 to 20. RESULTS: The ring apophysis maturation in AIS patients was delayed at all spinal levels in AIS patients compared to non-scoliotic controls. Ossification starts at T4-T11 at age 12, followed by T1-T5 and L3-S1 at age 15. The fusion process in AIS patients continues longer in the midthoracic region as compared to the other regions and as compared to non-scoliotic controls, with many incomplete fusions still at age 20. CONCLUSION: The ring apophysis maturation in AIS is delayed compared to that in the normal population and lasts longer in the mid/low thoracic spine. Delayed maturation of the spine's most important stabilizer, while the body's dimensions continue to increase, could be part of the patho-mechanism of AIS.