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Emotion recognition and the resulting responses are important for survival and social functioning. However, how socially derived information is processed for reliable emotion recognition is incompletely understood. Here, we reveal an evolutionarily conserved long-range inhibitory/excitatory brain network mediating these socio-cognitive processes. Anatomical tracing in mice revealed the existence of a subpopulation of somatostatin (SOM) GABAergic neurons projecting from the medial prefrontal cortex (mPFC) to the retrosplenial cortex (RSC). Through optogenetic manipulations and Ca2+imaging fiber photometry in mice and functional imaging in humans, we demonstrate the specific participation of these long-range SOM projections from the mPFC to the RSC, and an excitatory feedback loop from the RSC to the mPFC, in emotion recognition. Notably, we show that mPFC-to-RSC SOM projections are dysfunctional in mouse models relevant to psychiatric vulnerability and can be targeted to rescue emotion recognition deficits in these mice. Our findings demonstrate a cortico-cortical circuit underlying emotion recognition.

Study Design Basic science (finite element analysis).Objectives Pedicle subtraction osteotomy (PSO) at L5 is an effective treatment for sagittal imbalance, especially in select cases of patients showing kyphosis with the apex at L4-L5 but has been scarcely investigated. The aim of this study was to simulate various “high-demand” instrumentation approaches, including varying numbers of rods and sacropelvic implants, for the stabilization of a PSO at L5.Methods A finite element model of T10-pelvis was modified to simulate posterior fixation with pedicle screws and rods from T10 to S1, alone or in combination with an L5 PSO. Five additional configurations were then created by employing rods and novel porous fusion/fixation implants across the sacroiliac joints, in varying numbers. All models were loaded using pure moments of 7.5 Nm in flexion-extension, lateral bending, and axial rotation.Results The osteotomy resulted in a general increase in motion and stresses in posterior rods and S1 pedicle screws. When the number of rods was varied, three- and four-rod configurations were effective in limiting the maximal rod stresses; values approached those of posterior fixation with no osteotomy. Maximum stresses in the accessory rods were similar to or less than those observed in the primary rods. Multiple sacropelvic implants were effective in reducing range of motion, particularly of the SIJ.Conclusions Multi-rod constructs and sacropelvic fixation generally reduced maximal implant stresses and motion in comparison with standard posterior fixation, suggesting a reduced risk of rod breakage and increased joint stability, respectively, when a high-demand construct is utilized for the correction of sagittal imbalance.

Purpose: Large language models (LLM) have the potential to bridge knowledge gaps in patient education and enrich patient-surgeon interactions. This study evaluated three chatbots for delivering empathetic and precise adolescent idiopathic scoliosis (AIS) related information and management advice. Specifically, we assessed the accuracy, clarity, and relevance of the information provided, aiming to determine the effectiveness of LLMs in addressing common patient queries and enhancing their understanding of AIS. Methods: We sourced 20 webpages for the top frequently asked questions (FAQs) about AIS and formulated 10 critical questions based on them. Three advanced LLMs—ChatGPT 3.5, ChatGPT 4.0, and Google Bard—were selected to answer these questions, with responses limited to 200 words. The LLMs’ responses were evaluated by a blinded group of experienced deformity surgeons (members of the European Spine Study Group) from seven European spine centers. A pre-established 4-level rating system from excellent to unsatisfactory was used with a further rating for clarity, comprehensiveness, and empathy on the 5-point Likert scale. If not rated 'excellent', the raters were asked to report the reasons for their decision for each question. Lastly, raters were asked for their opinion towards AI in healthcare in general in six questions. Results: The responses among all LLMs were ‘excellent’ in 26% of responses, with ChatGPT-4.0 leading (39%), followed by Bard (17%). ChatGPT-4.0 was rated superior to Bard and ChatGPT 3.5 (p= 0.003). Discrepancies among raters were significant (p< 0.0001), questioning inter-rater reliability. No substantial differences were noted in answer distribution by question (p= 0.43). The answers on diagnosis (Q2) and causes (Q4) of AIS were top-rated. The most dissatisfaction was seen in the answers regarding definitions (Q1) and long-term results (Q7). Exhaustiveness, clarity, empathy, and length of the answers were positively rated (> 3.0 on 5.0) and did not demonstrate any differences among LLMs. However, GPT-3.5 struggled with language suitability and empathy, while Bard’s responses were overly detailed and less empathetic. Overall, raters found that 9% of answers were off-topic and 22% contained clear mistakes. Conclusion: Our study offers crucial insights into the strengths and weaknesses of current LLMs in AIS patient and parent education, highlighting the promise of advancements like ChatGPT-4.o and Gemini alongside the need for continuous improvement in empathy, contextual understanding, and language appropriateness.

Purpose: Our objective was to analysis the barycentremetry, obtained from the external envelope reconstruction of biplanar radiographs, in adolescent idiopathic scoliosis (AIS) and to determine whether assessing would help predict the distinction between progressive and stable AIS at the early stage. Methods: A retrospective study with a multicentre cohort of 205 AIS was conducted. All AIS underwent a biplanar X-ray between 2013 and 2020. Inclusion criteria were Cobb angle between 10° and 25°; Risser sign lower than 3; age higher than 10 years; and no previous treatment. A 3D spine reconstruction was performed, and the barycentremetry parameters were computed, i.e., the center of mass position at the apex and the axial torque at the apex, the upper and lower junction. A severity index, helping to distinguish stable and progressive AIS, was computed on the first radiograph, and weighted according to these parameters. A clinical and radiographic monitoring determined if AIS were classified such a stable or progressive scoliosis. Results: One hundred and sixty-two AIS were included (i.e., 87 were classified as stable and 75 as progressive). The apex center of mass position was different between the stable and progressive AIS groups (6 mm, SD = 4 mm for the whole cohort; 5 mm, SD = 4 mm for stable AIS versus 7 mm, SD = 4 mm for progressive AIS; p= 0.02). In AIS thoracic, the specificity and positive predictive value of the severity index increased by 19% and 16%, respectively, by adding the apex vertebral axial torque. Conclusion: Early assessment of the external envelope from biplanar X-ray reconstruction of idiopathic scoliosis showed that the apex centre of mass position was significantly different between progressive and stable scoliosis. The inclusion of the axial torque of the apex vertebra in the severity index is promising to help the clinician distinguish between stable and progressive thoracic AIS at an early stage. Level of evidence: II - Prognostic studies

Ti-5Al-5V-5Mo-3Cr (Ti-5553) alloy is increasingly used in structural airplane components, such as landing gear and fuselage, thanks to its high strength, good ductility, and low density. These components are consistently subjected to sub-zero temperatures during the flight. In this study, pulsed laser powder bed fusion (L-PBF) parameters were firstly optimized to fabricate highly dense (>99%) parts, and their effect on microstructure and microhardness was analyzed. Finally, tensile properties were evaluated under sub-zero temperature conditions and compared to the standard room ones to validate the feasibility of using Ti5553 under low-temperature environments.

Next-generation fiber laser sources can dynamically combine Gaussian beams with ring distributions within the source. The irradiance manipulation may add flexibility to the Laser Powder Bed Fusion process, for instance to control microstructure or surface roughness. However, their use is limited by a lack of studies revealing how beam shaping can be exploited in a reproducible manner. Accordingly, this work shows the use of novel beam profiles provided by a multi-core fiber laser source in the LPBF of AlSi7Mg0.6. Irradiance profiles were characterized, then large experiments were conducted to investigate their effect on surface roughness and microstructure of produced parts.

Electromobility applications require several welded connections using demanding materials often in dissimilar combinations. Copper, aluminium, or steel alloys are laser welded for energy storage and traction related components. On the one hand, high power fiber laser sources provide in-source beam shaping solutions able to modify the irradiance profile towards ring-shaped beams. On the other hand, research focused on the effect of the beam shapes on the melting mechanisms and process quality is still in progress. This work studies the effect of different beam profiles on AISI301LN, AA6082 and pure Cu with a 5 kW fiber laser. Linear trends of power over penetration depth as a function of speed confirms the validity of employing the lumped heat capacity model for ring-shaped beams. Moreover, the specific melting fluence is observed to exhibit an exponential decaying trend with the proportion of power allocated in the fiber core, irrespective of tested material.

Study Design: Retrospective study.Objectives: Huge amounts of images and medical reports are being generated in radiology departments. While these datasets can potentially be employed to train artificial intelligence tools to detect findings on radiological images, the unstructured nature of the reports limits the accessibility of information. In this study, we tested if natural language processing (NLP) can be useful to generate training data for deep learning models analyzing planar radiographs of the lumbar spine.Methods: NLP classifiers based on the Bidirectional Encoder Representations from Transformers (BERT) model able to extract structured information from radiological reports were developed and used to generate annotations for a large set of radiographic images of the lumbar spine (N = 10 287). Deep learning (ResNet-18) models aimed at detecting radiological findings directly from the images were then trained and tested on a set of 204 human-annotated images.Results: The NLP models had accuracies between 0.88 and 0.98 and specificities between 0.84 and 0.99; 7 out of 12 radiological findings had sensitivity >0.90. The ResNet-18 models showed performances dependent on the specific radiological findings with sensitivities and specificities between 0.53 and 0.93.Conclusions: NLP generates valuable data to train deep learning models able to detect radiological findings in spine images. Despite the noisy nature of reports and NLP predictions, this approach effectively mitigates the difficulties associated with the manual annotation of large quantities of data and opens the way to the era of big datafor artificial intelligence in musculoskeletal radiology.

IMPORTANCE: There is a lack of validated biomarkers for disability progression independent of relapse activity (PIRA) in multiple sclerosis (MS). OBJECTIVE: To determine how serum glial fibrillary acidic protein (sGFAP) and serum neurofilament light chain (sNfL) correlate with features of disease progression vs acute focal inflammation in MS and how they can prognosticate disease progression. DESIGN, SETTING, AND PARTICIPANTS: Data were acquired in the longitudinal Swiss MS cohort (SMSC; a consortium of tertiary referral hospitals) from January 1, 2012, to October 20, 2022. The SMSC is a prospective, multicenter study performed in 8 centers in Switzerland. For this nested study, participants had to meet the following inclusion criteria: cohort 1, patients with MS and either stable or worsening disability and similar baseline Expanded Disability Status Scale scores with no relapses during the entire follow-up; and cohort 2, all SMSC study patients who had initiated and continued B-cell–depleting treatment (ie, ocrelizumab or rituximab). EXPOSURES: Patients received standard immunotherapies or were untreated. MAIN OUTCOMES AND MEASURES: In cohort 1, sGFAP and sNfL levels were measured longitudinally using Simoa assays. Healthy control samples served as the reference. In cohort 2, sGFAP and sNfL levels were determined cross-sectionally. RESULTS: This study included a total of 355 patients (103 [29.0%] in cohort 1: median [IQR] age, 42.1 [33.2-47.6] years; 73 female patients [70.9%]; and 252 [71.0%] in cohort 2: median [IQR] age, 44.3 [33.3-54.7] years; 156 female patients [61.9%]) and 259 healthy controls with a median [IQR] age of 44.3 [36.3-52.3] years and 177 female individuals (68.3%). sGFAP levels in controls increased as a function of age (1.5% per year; P < .001), were inversely correlated with BMI (−1.1% per BMI unit; P = .01), and were 14.9% higher in women than in men (P = .004). In cohort 1, patients with worsening progressive MS showed 50.9% higher sGFAP levels compared with those with stable MS after additional sNfL adjustment, whereas the 25% increase of sNfL disappeared after additional sGFAP adjustment. Higher sGFAP at baseline was associated with accelerated gray matter brain volume loss (per doubling: 0.24% per year; P < .001) but not white matter loss. sGFAP levels remained unchanged during disease exacerbations vs remission phases. In cohort 2, median (IQR) sGFAP z scores were higher in patients developing future confirmed disability worsening compared with those with stable disability (1.94 [0.36-2.23] vs 0.71 [−0.13 to 1.73]; P = .002); this was not significant for sNfL. However, the combined elevation of z scores of both biomarkers resulted in a 4- to 5-fold increased risk of confirmed disability worsening (hazard ratio [HR], 4.09; 95% CI, 2.04-8.18; P < .001) and PIRA (HR, 4.71; 95% CI, 2.05-9.77; P < .001). CONCLUSIONS AND RELEVANCE: Results of this cohort study suggest that sGFAP is a prognostic biomarker for future PIRA and revealed its complementary potential next to sNfL. sGFAP may serve as a useful biomarker for disease progression in MS in individual patient management and drug development.

New generation of multi-core fiber laser sources provide in-source dynamic beam shaping. Such sources can switch between Gaussian and ring beams, providing new irradiance profiles. The new irradiance profiles add up to the process flexibility for controlling the temperature fields generated in the laser powder bed fusion (LPBF) process. On the other hand, they bring further complexity as new process parameters should be defined and their influence on the mechanical properties unveiled. Accordingly, this work studies the use of seven different beam shapes provided by a multi-core industrial fiber laser source with beam diameters varying between 47 μm to 144 μm during the LPBF of AlSi7Mg0.6 alloy. The beam spatial profiles were measured and descriptive irradiance parameters were defined. The Al-alloy constituted a challenging material type due to its high reflectivity and low melting point, hence, more prone to lack-of-fusion and keyhole defects. LPBF experiments were conducted at fixed energy density and peak irradiance levels investigating the influence of the beam shapes on the melt pool geometry in prismatic samples. The results showed that the peak irradiance and the ring intensity had a direct impact on the melt pool aspect ratio (AR) and melt pool depth to layer thickness ratio (h/z). With all the conditions providing adequately dense parts (>99.5 %), the mechanical properties were found to be correlated to the melt pool geometry. The results confirm that the beam shape can be tuned between the central peak and the ring to further manipulate the material properties in LPBF.

Study design: Biomechanical finite-element study. Objective: To directly compare the biomechanical effects of two different techniques for sagittal plane correction of adult spine deformity based on the anterior longitudinal ligament (ALL) resection and use of hyperlordotic cages, namely, the anterior column realignment (ACR) in L3–4, and ALIF in L5–S1 in terms of primary stability and rod stresses using finite-element models. Methods: A finite-element model of the thoracolumbar spine was used to perform the analysis. Starting from this "intact” model, three further models were constructed through the insertion of spinal instrumentation, i.e., pedicle screws, rods and cages: Results: All models presented a significant reduced ROM when compared to the intact model; the ROM reduction was higher both at L3–4 in the ACR model and at L5–S1 in the ALIF model. At L3–4, the ACR model had, in all cases, the lowest maximum values of Von Mises stresses on the rods, especially in flexion–extension. At L4–5, the ALIF model had the lowest stresses during flexion–extension and axial rotation, while the ACR model had the lowest stresses during lateral bending. At L5–S1, the ALIF model had, in all cases, the lowest stresses on the rods. Conclusions: This finite-element study showed how both ACR at L3–4 and ALIF–ACR at L5–S1 are effective in restoring lumbar lordosis (LL), stabilizing the spine and reducing stress on posterior rods at the index level when compared to a simple fixation model. Interestingly, ALIF–ACR reduces rod stress even at L4–5 in flexion–extension and axial rotation, possibly due to a better distribution of LL, especially on the lower arch, while ACR reduces the stress at L4–5 in lateral bending, possibly thanks to the larger footprint of the cage that increases the area of contact with the lateral side of the endplates.

IMPORTANCE: The mechanisms driving neurodegeneration and brain atrophy in relapsing multiple sclerosis (RMS) are not completely understood. OBJECTIVE: To determine whether disability progression independent of relapse activity (PIRA) in patients with RMS is associated with accelerated brain tissue loss. DESIGN, SETTING, AND PARTICIPANTS: In this observational, longitudinal cohort study with median (IQR) follow-up of 3.2 years (2.0-4.9), data were acquired from January 2012 to September 2019 in a consortium of tertiary university and nonuniversity referral hospitals. Patients were included if they had regular clinical follow-up and at least 2 brain magnetic resonance imaging (MRI) scans suitable for volumetric analysis. Data were analyzed between January 2020 and March 2021. EXPOSURES: According to the clinical evolution during the entire observation, patients were classified as those presenting (1) relapse activity only, (2) PIRA episodes only, (3) mixed activity, or (4) clinical stability. MAIN OUTCOMES AND MEASURES: Mean difference in annual percentage change (MD-APC) in brain volume/cortical thickness between groups, calculated after propensity score matching. Brain atrophy rates, and their association with the variables of interest, were explored with linear mixed-effect models. RESULTS: Included were 1904 brain MRI scans from 516 patients with RMS (67.4% female; mean [SD] age, 41.4 [11.1] years; median [IQR] Expanded Disability Status Scale score, 2.0 [1.5-3.0]). Scans with insufficient quality were excluded (n = 19). Radiological inflammatory activity was associated with increased atrophy rates in several brain compartments, while an increased annualized relapse rate was linked to accelerated deep gray matter (GM) volume loss. When compared with clinically stable patients, patients with PIRA had an increased rate of brain volume loss (MD-APC, −0.36; 95% CI, −0.60 to −0.12; P = .02), mainly driven by GM loss in the cerebral cortex. Patients who were relapsing presented increased whole brain atrophy (MD-APC, −0.18; 95% CI, −0.34 to −0.02; P = .04) with respect to clinically stable patients, with accelerated GM loss in both cerebral cortex and deep GM. No differences in brain atrophy rates were measured between patients with PIRA and those presenting relapse activity. CONCLUSIONS AND RELEVANCE: Our study shows that patients with RMS and PIRA exhibit accelerated brain atrophy, especially in the cerebral cortex. These results point to the need to recognize the insidious manifestations of PIRA in clinical practice and to further evaluate treatment strategies for patients with PIRA in clinical trials.

Study Design: Retrospective cohort study.Objectives: This study aimed to address the prevalence, distribution, and clinical significance of cervical high-intensity zones (HIZs) on magnetic resonance imaging (MRI) with respect to pain and other patient-reported outcomes in the setting of patients that will undergo an anterior cervical discectomy and fusion (ACDF) procedure.Methods: A retrospective cohort study of ACDF patients surgically treated at a single center from 2008 to 2015. Based on preoperative MRI, HIZ subtypes were identified as either traditional T2-hyperintense, T1-hypointense (“single-HIZs”), or combined T1- and T2-hyperintense (“dual-HIZs”), and their level-specific prevalence was assessed. Preoperative symptoms, patient-reported outcomes, and disc degeneration pathology were assessed in relation to HIZs and HIZ subtypes.Results: Of 861 patients, 58 demonstrated evidence of HIZs in the cervical spine (6.7%). Single-HIZs and dual-HIZs comprised 63.8% and 36.2% of the overall HIZs, respectively. HIZs found outside of the planned fusion segment reported better preoperative Neck Disability Index (NDI; P= .049) and Visual Analogue Scale (VAS) Arm (P= .014) scores relative to patients without HIZs. Furthermore, patients with single-HIZs found inside the planned fusion segment had worse VAS Neck (P= .045) and VAS Arm (P= .010) scores. In general, dual-HIZ patients showed no significant differences across all clinical outcomes.Conclusions: This is the first study to evaluate the clinical significance of HIZs in the cervical spine, noting level-specific and clinical outcome–specific variations. Single-HIZs were associated with significantly more pain when located inside the fusion segment, while dual-HIZs showed no associations with patient-reported outcomes. The presence of single-HIZs may correlate with concurrent spinal pathologies and should be more closely evaluated.

Unrestrained activation of the complement system till the terminal products, C5a and C5b-9, plays a pathogenetic role in acute and chronic inflammatory diseases. In endothelial cells, complement hyperactivation may translate into cell dysfunction, favoring thrombus formation. The aim of this study was to investigate the role of the C5a/C5aR1 axis as opposed to C5b-9 in inducing endothelial dysfunction and loss of antithrombogenic properties. In vitro and ex vivo assays with serum from patients with atypical hemolytic uremic syndrome (aHUS), a prototype rare disease of complement-mediated microvascular thrombosis due to genetically determined alternative pathway dysregulation, and cultured microvascular endothelial cells, demonstrated that the C5a/C5aR1 axis is a key player in endothelial thromboresistance loss. C5a added to normal human serum fully recapitulated the prothrombotic effects of aHUS serum. Mechanistic studies showed that C5a caused RalA-mediated exocytosis of von Willebrand factor (vWF) and P-selectin from Weibel-Palade bodies, which favored further vWF binding on the endothelium and platelet adhesion and aggregation. In patients with severe COVID-19 who suffered from acute activation of complement triggered by severe acute respiratory syndrome coronavirus 2 infection, we found the same C5a-dependent pathogenic mechanisms. These results highlight C5a/C5aR1 as a common prothrombogenic effector spanning from genetic rare diseases to viral infections, and it may have clinical implications. Selective C5a/C5aR1 blockade could have advantages over C5 inhibition because the former preserves the formation of C5b-9, which is critical for controlling bacterial infections that often develop as comorbidities in severely ill patients. The ACCESS trial registered at www.clinicaltrials.govas #NCT02464891 accounts for the results related to aHUS patients treated with CCX168.

Unrestrained activation of the complement system till the terminal products, C5a and C5b-9, plays a pathogenetic role in acute and chronic inflammatory diseases. In endothelial cells, complement hyperactivation may translate into cell dysfunction, favoring thrombus formation. The aim of this study was to investigate the role of the C5a/C5aR1 axis as opposed to C5b-9 in inducing endothelial dysfunction and loss of antithrombogenic properties. In vitro and ex vivo assays with serum from patients with atypical hemolytic uremic syndrome (aHUS), a prototype rare disease of complement-mediated microvascular thrombosis due to genetically determined alternative pathway dysregulation, and cultured microvascular endothelial cells, demonstrated that the C5a/C5aR1 axis is a key player in endothelial thromboresistance loss. C5a added to normal human serum fully recapitulated the prothrombotic effects of aHUS serum. Mechanistic studies showed that C5a caused RalA-mediated exocytosis of von Willebrand factor (vWF) and P-selectin from Weibel-Palade bodies, which favored further vWF binding on the endothelium and platelet adhesion and aggregation. In patients with severe COVID-19 who suffered from acute activation of complement triggered by severe acute respiratory syndrome coronavirus 2 infection, we found the same C5a-dependent pathogenic mechanisms. These results highlight C5a/C5aR1 as a common prothrombogenic effector spanning from genetic rare diseases to viral infections, and it may have clinical implications. Selective C5a/C5aR1 blockade could have advantages over C5 inhibition because the former preserves the formation of C5b-9, which is critical for controlling bacterial infections that often develop as comorbidities in severely ill patients. The ACCESS trial registered at www.clinicaltrials.gov as #NCT02464891 accounts for the results related to aHUS patients treated with CCX168.

Autism Spectrum Disorder (ASD) is characterized by substantial, yet highly heterogeneous abnormalities in functional brain connectivity. However, the origin and significance of this phenomenon remain unclear. To unravel ASD connectopathy and relate it to underlying etiological heterogeneity, we carried out a bi-center cross-etiological investigation of fMRI-based connectivity in the mouse, in which specific ASD-relevant mutations can be isolated and modeled minimizing environmental contributions. By performing brain-wide connectivity mapping across 16 mouse mutants, we show that different ASD-associated etiologies cause a broad spectrum of connectional abnormalities in which diverse, often diverging, connectivity signatures are recognizable. Despite this heterogeneity, the identified connectivity alterations could be classified into four subtypes characterized by discrete signatures of network dysfunction. Our findings show that etiological variability is a key determinant of connectivity heterogeneity in ASD, hence reconciling conflicting findings in clinical populations. The identification of etiologically-relevant connectivity subtypes could improve diagnostic label accuracy in the non-syndromic ASD population and paves the way for personalized treatment approaches.

Cholinergic drugs acting at M1/M4 muscarinic receptors hold promise for the treatment of symptoms associated with brain disorders characterized by cognitive impairment, mood disturbances, or psychosis, such as Alzheimer’s disease or schizophrenia. However, the brain-wide functional substrates engaged by muscarinic agonists remain poorly understood. Here we used a combination of pharmacological fMRI (phMRI), resting-state fMRI (rsfMRI), and resting-state quantitative EEG (qEEG) to investigate the effects of a behaviorally active dose of the M1/M4-preferring muscarinic agonist xanomeline on brain functional activity in the rodent brain. We investigated both the effects of xanomeline per se and its modulatory effects on signals elicited by the NMDA-receptor antagonists phencyclidine (PCP) and ketamine. We found that xanomeline induces robust and widespread BOLD signal phMRI amplitude increases and decreased high-frequency qEEG spectral activity. rsfMRI mapping in the mouse revealed that xanomeline robustly decreased neocortical and striatal connectivity but induces focal increases in functional connectivity within the nucleus accumbens and basal forebrain. Notably, xanomeline pre-administration robustly attenuated both the cortico-limbic phMRI response and the fronto-hippocampal hyper-connectivity induced by PCP, enhanced PCP-modulated functional connectivity locally within the nucleus accumbens and basal forebrain, and reversed the gamma and high-frequency qEEG power increases induced by ketamine. Collectively, these results show that xanomeline robustly induces both cholinergic-like neocortical activation and desynchronization of functional networks in the mammalian brain. These effects could serve as a translatable biomarker for future clinical investigations of muscarinic agents, and bear mechanistic relevance for the putative therapeutic effect of these class of compounds in brain disorders.

Disaster risk in the 21st century differs from the experience of past generations and is defined by its evolving systemic nature. The increased role of technological networks, societal interdependencies and climate change dynamics make crises more complex and unpredictable. Cascading and compounding dynamics are becoming the new “business as usual”, challenging emergency management to maintain operations in face of complex disruptions while requiring the development of good practices and strategy for facilitate the recovery process. Our special issue aimed to support the development of a paradigm shift in the understanding of complex events, utilizing a network-based, cross-disciplinary approach to resilience. This editorial introduces and summarizes 18 papers across four thematic areas: 1) Resilience Challenges; 2) Area Studies and the Sendai Framework for Disaster Risk Reduction; 3) Community and Health; 4) Enhancing New Methodologies. The conclusions highlight open research challenges for future exploration.

Although primary atypical hemolytic uremic syndrome (aHUS) is associated with abnormalities in complement genes and antibodies to complement factor H, the role of complement in secondary aHUS remains debatable. We evaluated the usefulness of an ex vivo test to: (1) detect complement activation within the endothelium in primary and secondary aHUS, (2) differentiate active disease from remission, (3) monitor the effectiveness of eculizumab therapy, and (4) identify relapses during eculizumab dosage tapering and after discontinuation of treatment.

Epimuscular fat (EF) has rarely been studied in the context of low back pain (LBP).

Study design Retrospective data analysis.Objectives This study aims to develop a deep learning model for the automatic calculation of some important spine parameters from lateral cervical radiographs.Methods We collected two datasets from two different institutions. The first dataset of 1498 images was used to train and optimize the model to find the best hyperparameters while the second dataset of 79 images was used as an external validation set to evaluate the robustness and generalizability of our model. The performance of the model was assessed by calculating the median absolute errors between the model prediction and the ground truth for the following parameters: T1 slope, C7 slope, C2-C7 angle, C2-C6 angle, Sagittal Vertical Axis (SVA), C0-C2, Redlund-Johnell distance (RJD), the cranial tilting (CT) and the craniocervical angle (CCA).Results Regarding the angles, we found median errors of 1.66° (SD 2.46°), 1.56° (1.95°), 2.46° (SD 2.55), 1.85° (SD 3.93°), 1.25° (SD 1.83°), .29° (SD .31°) and .67° (SD .77°) for T1 slope, C7 slope, C2-C7, C2-C6, C0-C2, CT, and CCA respectively. As concerns the distances, we found median errors of .55 mm (SD .47 mm) and .47 mm (.62 mm) for SVA and RJD respectively.Conclusions In this work, we developed a model that was able to accurately predict cervical spine parameters from lateral cervical radiographs. In particular, the performances on the external validation set demonstrate the robustness and the high degree of generalizability of our model on images acquired in a different institution.

Generative AI is revolutionizing patient education in healthcare, particularly through chatbots that offer personalized, clear medical information. Reliability and accuracy are vital in AI-driven patient education.

Active fibre lasers are widely used in the industry for different manufacturing applications ranging from cutting, to welding and additive manufacturing. The recent introduction of the multiple-core fibre lasers allows these sources to flexibly change the Power Density Distribution (PDD) from conventional Gaussian profiles towards ring shapes. While the advantages of the novel beam shapes over the conventional ones are still being explored, the need for modeling tools to define the PDD shapes becomes more evident. This work studies the analytical modeling of Gaussian to ring profiles with the aim to move towards standardized parameters referable to the manufacturing processes. The proposed models combine Gaussian and annular components to define the novel beam shapes. Among the different models assessed, the Torus and Multi-Gaussian approaches exhibited the best fitting quality thus enabling the definition of descriptive metrics of the PDD. The modeling framework developed was validated on an industrial Laser Powder Bed Fusion (LPBF) system with a double-core light source. The beam shape variation along the propagation axis was assessed to analyze the effect of defocusing using the developed beam parameters. Eventually, the best performing model was furtherly validated with a bead on plate experiment to explain how the model coefficients can be jointly exploited to predict the material response using a Gaussian or a ring beam profile.

Modic Changes (MCs) are MRI alterations in spine vertebrae's signal intensity. This study introduces an end-to-end model to automatically detect and classify MCs in lumbar MRIs. The model's two-step process involves locating intervertebral regions and then categorizing MC types (MC0, MC1, MC2) using paired T1-and T2-weighted images. This approach offers a promising solution for efficient and standardized MC assessment.

AbstractThe diagnosis and treatment of spinal disorders often requires the measurements of anatomical parameters on radiographic projections, which is usually performed manually. Due to the non negligible degree of intra- and inter-observer variability of these measurements, a user-independent, automated method for the characterisation of the spinal anatomy is needed. Artificial neural networks are currently used for many automated tasks in which a robust, fault-tolerant performance is needed, and may prove to be useful for this task. In this paper, a novel method based on a neural network aimed to the automatic identification of vertebral landmarks is presented. A radiographic database of lumbar sagittal radiographic projections vertebrae of adult patients suffering from various spinal disorders was created. Vertebral landmarks at the projected corners of the vertebral endplates of L3 and L4 were manually identified in all images. The annotated images were used to train and test an artificial neural network in the automatic recognition of such landmarks. The values of clinically relevant anatomical parameters (disc and vertebral heights, disc wedging) were then geometrically calculated based on the predicted landmark coordinates and compared to manual measurements. The novel method proved to be able to identify vertebral landmarks, with errors and limitations which should be taken into account. Possible future applications of neural network-based methods include the automatic extraction of clinically relevant parameters from radiographic images of the lumbar spine.

Vertebral fractures associated with the loss of structural integrity of neoplastic vertebrae are common, and determined to the deterioration of the bone quality in the lesion area. The prediction of the fracture risk in metastatically involved spines can guide in deciding if preventive solutions, such as medical prophylaxis, bracing, or surgery are indicated for the patient. In this study, finite element models of 22 thoracolumbar vertebrae were built based on CT scans of three spines, covering a wide spectrum of possible clinical scenarios in terms of age, bone quality and degenerative features, taking into account the local material properties of bone tissue. Simulations were performed in order to investigate the effect of the size and location of the tumoral lesion, the bone quality and the vertebral level in determining the structural stability of the neoplastic vertebrae. Tumors with random size and positions were added to the models, for a total of 660 simulations in which a compressive load was simulated. Results highlighted the fundamental role of the tumor size, whereas the other parameters had a lower, but non-negligible impact on the axial collapse of the vertebra, the vertebral bulge in the transverse plane and the canal narrowing under the application of the load. All the considered parameters are radiologically measurable, and can therefore be translated in a straightforward way to the clinical practice to support decisions about preventive treatment of metastatic fractures.

Serotonin-producing neurons profusely innervate brain regions via long-range projections. However, it remains unclear whether and how endogenous serotonergic transmission specifically influences regional or global functional activity. We combined designed receptors exclusively activated by designed drugs (DREADD)-based chemogenetics and functional magnetic resonance imaging (fMRI), an approach we term “chemo-fMRI,” to causally probe the brain-wide substrates modulated by endogenous serotonergic activity. We describe the generation of a conditional knockin mouse line that, crossed with serotonin-specific Cre-recombinase mice, allowed us to remotely stimulate serotonergic neurons during fMRI scans. We show that endogenous stimulation of serotonin-producing neurons does not affect global brain activity but results in region-specific activation of a set of primary target regions encompassing corticohippocampal and ventrostriatal areas. By contrast, pharmacological boosting of serotonin levels produced widespread fMRI deactivation, plausibly reflecting the mixed contribution of central and perivascular constrictive effects. Our results identify the primary functional targets of endogenous serotonergic stimulation and establish causation between activation of serotonergic neurons and regional fMRI signals.

The neuropeptides oxytocin (OXT) and vasopressin (AVP) have been identified as modulators of emotional social behaviors and associated with neuropsychiatric disorders characterized by social dysfunction. Experimental and therapeutic use of OXT and AVP via the intranasal route is the subject of extensive clinical research. However, the large-scale functional substrates directly engaged by these peptides and their functional dynamics remain elusive. By using cerebral blood volume (CBV) weighted fMRI in the mouse, we show that intranasal administration of OXT rapidly elicits the transient activation of cortical regions and a sustained activation of hippocampal and forebrain areas characterized by high oxytocin receptor density. By contrast, intranasal administration of AVP produced a robust and sustained deactivation in cortico-parietal, thalamic and mesolimbic regions. Importantly, intravenous administration of OXT and AVP did not recapitulate the patterns of modulation produced by intranasal dosing, supporting a central origin of the observed functional changes. In keeping with this notion, hippocampal local field potential recordings revealed multi-band power increases upon intranasal OXT administration. We also show that the selective OXT-derivative TGOT reproduced the pattern of activation elicited by OXT and that the deletion of OXT receptors does not affect AVP-mediated deactivation. Collectively, our data document divergent modulation of brainwide neural systems by intranasal administration of OXT and AVP, an effect that involves key substrates of social and emotional behavior. The observed divergence calls for a deeper investigation of the systems-level mechanisms by which exogenous OXT and AVP modulate brain function and exert their putative therapeutic effects.

In both atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G) complement plays a primary role in disease pathogenesis. Herein we report the outcome of a 2015 Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference where key issues in the management of these 2 diseases were considered by a global panel of experts. Areas addressed included renal pathology, clinical phenotype and assessment, genetic drivers of disease, acquired drivers of disease, and treatment strategies. In order to help guide clinicians who are caring for such patients, recommendations for best treatment strategies were discussed at length, providing the evidence base underpinning current treatment options. Knowledge gaps were identified and a prioritized research agenda was proposed to resolve outstanding controversial issues.

This paper deals with switched linear systems subject to time-varying delay. The main goal is to design state and output feedback switching strategies preserving closed-loop stability and a guaranteed H2or H∞performance. The switching strategies are based on a generalization of a recent extended version of the small gain theorem and do not require any assumption on the continuity of the delay and its time-variation rate. The key point to obtain the design conditions is the adoption of an equivalent switched linear system where the time-varying delay is modeled as a norm-bounded perturbation. Moreover, with this approach, it is possible to deal with sampled-data control systems. All conditions are formulated in terms of Lyapunov–Metzler inequalities, which allow the maximization of an upper bound on the time-delay preserving stability and guaranteed performance. Numerical examples are discussed in order to illustrate the effectiveness of the design approach.

Advances in MR imaging technologies, as well as the widening of their availability, boosted their use in the diagnosis of spinal disorders and in the preoperative planning of spine surgeries. However, the most consolidated approach to the assessment of adult patients with spinal disorders is based on the analysis of full standing radiographs (posteroanterior and laterolateral views). In this article, the radiographic spinal and pelvic parameters, which have relevance in the clinical management of adults with spinal disorders, are summarized.

A 12-year-old boy was hospitalized for hemolytic anemia, thrombocytopenia, acute kidney injury, and generalized seizures. The childhood onset, severely decreased kidney function, absence of prodromal diarrhea, negative test results for Shiga-like toxin-producing Escherichia coli, elevated plasma levels of the terminal complement complex sC5b-9, and ex vivo testing in endothelial cells showing serum-induced complement activation were all consistent with a diagnosis of complement-mediated atypical hemolytic uremic syndrome. Before plasma ADAMTS13 (von Willebrand factor protease) activity results were available, the patient was treated with the anti-C5 monoclonal antibody eculizumab, and treatment was followed by prompt disease remission. However, results of ADAMT13 activity level tests and gene screening revealed a severe deficiency associated with 2 heterozygous mutations in the ADAMTS13gene, fully consistent with a diagnosis of congenital thrombotic thrombocytopenic purpura. Screening for atypical hemolytic uremic syndrome–associated genes failed to show a mutation and an assay for plasma anti–factor H antibodies gave negative results both before and after eculizumab treatment initiation. The patient’s clinical evolution suggests that complement activation plays a role in the pathogenesis of thrombotic thrombocytopenic purpura and provides unexpected new insights into the treatment of this life-threatening disease.

Preclinical evaluation of spinal implants is a necessary step to ensure their reliability and safety before implantation. The American Society for Testing and Materials reapproved F1717 standard for the assessment of mechanical properties of posterior spinal fixators, which simulates a vertebrectomy model and recommends mimicking vertebral bodies using polyethylene blocks. This set-up should represent the clinical use, but available data in the literature are few. Anatomical parameters depending on the spinal level were compared to published data or measurements on biplanar stereoradiography on 13 patients. Other mechanical variables, describing implant design were considered, and all parameters were investigated using a numerical parametric finite element model. Stress values were calculated by considering either the combination of the average values for each parameter or their worst-case combination depending on the spinal level. The standard set-up represents quite well the anatomy of an instrumented average thoracolumbar segment. The stress on the pedicular screw is significantly influenced by the lever arm of the applied load, the unsupported screw length, the position of the centre of rotation of the functional spine unit and the pedicular inclination with respect to the sagittal plane. The worst-case combination of parameters demonstrates that devices implanted below T5 could potentially undergo higher stresses than those described in the standard suggestions (maximum increase of 22.2% at L1). We propose to revise F1717 in order to describe the anatomical worst case condition we found at L1 level: this will guarantee higher safety of the implant for a wider population of patients.

Atypical hemolytic-uremic syndrome (aHUS) is associated with genetic complement abnormalities/anti–complement factor H antibodies, which paved the way to treatment with eculizumab. We studied 44 aHUS patients and their relatives to (1) test new assays of complement activation, (2) verify whether such abnormality occurs also in unaffected mutation carriers, and (3) search for a tool for eculizumab titration. An abnormal circulating complement profile (low C3, high C5a, or SC5b-9) was found in 47% to 64% of patients, irrespective of disease phase. Acute aHUS serum, but not serum from remission, caused wider C3 and C5b-9 deposits than control serum on unstimulated human microvascular endothelial cells (HMEC-1). In adenosine 5′-diphosphate–activated HMEC-1, also sera from 84% and 100% of patients in remission, and from all unaffected mutation carriers, induced excessive C3 and C5b-9 deposits. At variance, in most patients with C3 glomerulopathies/immune complex-associated membranoproliferative glomerulonephritis, serum-induced endothelial C5b-9 deposits were normal. In 8 eculizumab-treated aHUS patients, C3/SC5b-9 circulating levels did not change posteculizumab, whereas serum-induced endothelial C5b-9 deposits normalized after treatment, paralleled or even preceded remission, and guided drug dosing and timing. These results point to efficient complement inhibition on endothelium for aHUS treatment. C5b-9 endothelial deposits might help monitor eculizumab effectiveness, avoid drug overexposure, and save money considering the extremely high cost of the drug.