In vivo selection in non-human primates identifies AAV capsids for on-target CSF delivery to spinal cord.

Systemic administration of adeno-associated virus (AAV) vectors for spinal cord gene therapy has challenges including toxicity at high doses and pre-existing immunity that reduces efficacy. Intrathecal (IT) delivery of AAV vectors into cerebral spinal fluid can avoid many issues, although distribution of the vector throughout the spinal cord is limited, and vector entry to the periphery sometimes initiates hepatotoxicity. Here we performed biopanning in non-human primates (NHPs) with an IT injected AAV9 peptide display library. We identified top candidates by sequencing inserts of AAV DNA isolated from whole tissue, nuclei, or nuclei from transgene-expressing cells. These barcoded candidates were pooled with AAV9 and compared for biodistribution and transgene expression in spinal cord and liver of IT injected NHPs. Most candidates displayed increased retention in spinal cord compared with AAV9. Greater spread from the lumbar to the thoracic and cervical regions was observed for several capsids. Furthermore, several capsids displayed decreased biodistribution to the liver compared with AAV9, providing a high on-target/low off-target biodistribution. Finally, we tested top candidates in human spinal cord organoids and found them to outperform AAV9 in efficiency of transgene expression in neurons and astrocytes. These capsids have potential to serve as leading-edge delivery vehicles for spinal cord-directed gene therapies.

Diagnosis and management of cryptococcal meningitis in HIV-infected adults.

Cryptococcal meningitis is a leading cause of morbidity and mortality globally, especially in people with advanced HIV disease. Cryptococcal meningitis is responsible for nearly 20% of all deaths related to advanced HIV disease, with the burden of disease predominantly experienced by people in resource-limited countries. Major advancements in diagnostics have introduced low-cost, easy-to-use antigen tests with remarkably high sensitivity and specificity. These tests have led to improved diagnostic accuracy and are essential for screening campaigns to reduce the burden of cryptococcosis. In the last 5 years, several high-quality, multisite clinical trials have led to innovations in therapeutics that have allowed for simplified regimens, which are better tolerated and result in less intensive monitoring and management of medication adverse effects. One trial found that a shorter, 7-day course of deoxycholate amphotericin B is as effective as the longer 14-day course and that flucytosine is an essential partner drug for reducing mortality in the acute phase of disease. Single-dose liposomal amphotericin B has also been found to be as effective as a 7-day course of deoxycholate amphotericin B. These findings have allowed for simpler and safer treatment regimens that also reduce the burden on the healthcare system. This review provides a detailed discussion of the latest evidence guiding the clinical management and special circumstances that make cryptococcal meningitis uniquely difficult to treat.

Excitatory and Inhibitory Descending Commissural Interneurons Differentially Integrate Supraspinal and Segmental Sensory Signals.

The limited information about how descending inputs from the brain and sensory inputs from the periphery use spinal cord interneurons (INs) is a major barrier to understanding how these inputs may contribute to motor functions under normal and pathologic conditions. Commissural interneurons (CINs) are a heterogeneous population of spinal INs that has been implicated in crossed motor responses and bilateral motor coordination (ability to use the right and left side of the body in a coordinated manner) and, therefore, are likely involved in many types of movement (e.g., dynamic posture stabilization, jumping, kicking, walking). In this study, we incorporate mouse genetics, anatomy, electrophysiology, and single-cell calcium imaging to investigate how a subset of CINs, those with descending axons called dCINs, are recruited by descending reticulospinal and segmental sensory signals independently and in combination. We focus on two groups of dCINs set apart by their principal neurotransmitter (glutamate and GABA) and identified as VGluT2+ dCINs and GAD2+ dCINs. We show that VGluT2+ and GAD2+ dCINs are both extensively recruited by reticulospinal and sensory input alone but that VGluT2+ and GAD2+ dCINs integrate these inputs differently. Critically, we find that when recruitment depends on the combined action of reticulospinal and sensory inputs (subthreshold inputs), VGluT2+ dCINs, but not GAD2+ dCINs, are recruited. This difference in the integrative capacity of VGluT2+ and GAD2+ dCINs represents a circuit mechanism that the reticulospinal and segmental sensory systems may avail themselves of to regulate motor behaviors both normally and after injury.SIGNIFICANCE STATEMENT The way supraspinal and peripheral sensory inputs use spinal cord interneurons is fundamental to defining how motor functions are supported both in health and disease. This study, which focuses on dCINs, a heterogeneous population of spinal interneurons critical for crossed motor responses and bilateral motor coordination, shows that both glutamatergic (excitatory) and GABAergic (inhibitory) dCINs can be recruited by supraspinal (reticulospinal) or peripheral sensory inputs. Additionally, the study demonstrates that in conditions where the recruitment of dCINs depends on the combined action of reticulospinal and sensory inputs, only excitatory dCINs are recruited. The study uncovers a circuit mechanism that the reticulospinal and segmental sensory systems may avail themselves of to regulate motor behaviors both normally and after injury.

Excitatory action of low frequency depolarizing GABA/glycine synaptic inputs is prevalent in prenatal spinal SOD1G93A motoneurons.

Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disease characterized by progressive motor neuron degeneration and muscle paralysis. Recent evidence suggests the dysfunction of inhibitory signalling in ALS motor neurons. We have shown that embryonic day (E)17.5 spinal motoneurons (MNs) of the SOD1G93A mouse model of ALS exhibit an altered chloride homeostasis. At this prenatal stage, inhibition of spinal motoneurons (MNs) is mediated by depolarizing GABAergic/glycinergic postsynaptic potentials (dGPSPs). Here, using an ex vivo preparation and patch clamp recording from MNs with a chloride equilibrium set below spike threshold, we report that low input resistance (Rin ) E17.5 MNs from the SOD1G93A ALS mouse model do not correctly integrate dGPSPs evoked by electrical stimulations of GABA/glycine inputs at different frequencies. Indeed, firing activity of most wild-type (WT) MNs with low Rin was inhibited by incoming dGPSPs, whereas low Rin SOD1G93A MNs were excited or exhibited a dual response (excited by low frequency dGPSPs and inhibited by high frequency dGPSPs). Simulation highlighted the importance of the GABA/glycine input density and showed that pure excitation could be obtained in SOD-like MNs by moving GABA/glycine input away from the cell body to dendrites. This was in agreement with confocal imaging showing a lack of peri-somatic inhibitory terminals in SOD1G93A MNs compared to WT littermates. Putative fast ALS-vulnerable MNs with low Rin are therefore lacking functional inhibition at the near-term prenatal stage. KEY POINTS: We analysed the integration of GABAergic/glycinergic synaptic events by embryonic spinal motoneurons (MNs) in a mouse model of the amyotrophic lateral sclerosis (ALS) neurodegenerative disease. We found that GABAergic/glycinergic synaptic events do not properly inhibit ALS MNs with low input resistance, most probably corresponding to future vulnerable MNs. We used a neuron model to highlight the importance of the GABA/glycine terminal location and density in the integration of the GABAergic/glycinergic synaptic events. Confocal imaging showed a lack of GABA/glycine terminals on the cell body of ALS MNs. The present study suggests that putative ALS vulnerable MNs with low Rin lack functional inhibition at the near-term stage.

Pain quality patterns in delayed onset muscle soreness of the lower back suggest sensitization of fascia rather than muscle afferents: a secondary analysis study.

Delayed onset muscle soreness (DOMS) of the lower back is considered a surrogate for acute low back pain (aLBP) in experimental studies. Of note, it is often unquestioningly assumed to be muscle pain. To date, there has not been a study analyzing lumbar DOMS in terms of its pain origin, which was the aim of this study. Sixteen healthy individuals (L-DOMS) were enrolled for the present study and matched to participants from a previous study (n = 16, L-PAIN) who had undergone selective electrical stimulation of the thoracolumbar fascia and the multifidus muscle. DOMS was induced in the lower back of the L-DOMS group using eccentric trunk extensions performed until exhaustion. On subsequent days, pain on palpation (100-mm analogue scale), pressure pain threshold (PPT), and the Pain Sensation Scale (SES) were used to examine the sensory characteristics of DOMS. Pain on palpation showed a significant increase 24 and 48 h after eccentric training, whereas PPT was not affected (p > 0.05). Factor analysis of L-DOMS and L-PAIN sensory descriptors (SES) yielded a stable three-factor solution distinguishing superficial thermal ("heat pain ") from superficial mechanical pain ("sharp pain") and "deep pain." "Heat pain " and "deep pain" in L-DOMS were almost identical to sensory descriptors from electrical stimulation of fascial tissue (L-PAIN, all p > 0.679) but significantly different from muscle pain (all p < 0.029). The differences in sensory description patterns as well as in PPT and self-reported DOMS for palpation pain scores suggest that DOMS has a fascial rather than a muscular origin.

Vestibular control of deep and superficial lumbar muscles.

The active control of the lumbar musculature provides a stable platform critical for postures and goal-directed movements. Voluntary and perturbation-evoked motor commands can recruit individual lumbar muscles in a task-specific manner according to their presumed biomechanics. Here, we investigated the vestibular control of the deep and superficial lumbar musculature. Ten healthy participants were exposed to noisy electrical vestibular stimulation while balancing upright with their head facing forward, left, or right to characterize the differential modulation in the vestibular-evoked lumbar extensor responses in generating multidirectional whole body motion. We quantified the activation of the lumbar muscles on the right side using indwelling [deep multifidus, superficial multifidus, caudal longissimus (L4), and cranial longissimus (L1)] and high-density surface recordings. We characterized the vestibular-evoked responses using coherence and peak-to-peak cross-covariance amplitude between the vestibular and electromyographic signals. Participants exhibited responses in all lumbar muscles. The vestibular control of the lumbar musculature exhibited muscle-specific modulations: responses were larger in the longissimus (combined cranio-caudal) compared with the multifidus (combined deep-superficial) when participants faced forward (P < 0.001) and right (P = 0.011) but not when they faced left. The high-density surface recordings partly supported this observation: the location of the responses was more lateral when facing right compared with left (P < 0.001). The vestibular control of muscle subregions within the longissimus or the multifidus was similar. Our results demonstrate muscle-specific vestibular control of the lumbar muscles in response to perturbations of vestibular origin. The lack of differential activation of lumbar muscle subregions suggests the vestibular control of these subregions is co-regulated for standing balance.NEW & NOTEWORTHY We investigated the vestibular control of the deep and superficial lumbar extensor muscles using electrical vestibular stimuli. Vestibular stimuli elicited preferential activation of the longissimus muscle over the multifidus muscle. We did not observe clear regional activation of lumbar muscle subregions in response to the vestibular stimuli. Our findings show that the central nervous system can finely tune the vestibular control of individual lumbar muscles and suggest minimal regional variations in the activation of lumbar muscle subregions.

Protectin D1 ameliorates non-compressive lumbar disc herniation through SIRT1-mediated CGRP signaling.

Background. Neuro-inflammatory response promotes the initiation and sustenance of lumbar disc herniation (LDH). Protectin D1 (PD1), as a new type of specialized pro-resolving mediator (SPM), can improve the prognosis of various inflammatory diseases. Recent studies have shown that over representation of calcitonin gene-related peptides (CGRP) may activate nociceptive signaling following nerve injury. Silent information regulator 1 (SIRT1) is ubiquitously expressed in the dorsal horn of the spinal cord and plays a role in the pathogenesis of LDH. In this study, we investigated the analgesic effects of PD1 and elucidated the impact of neurogenic inflammation in the pathogenesis of neuropathic pain induced by non-compressive lumbar disc herniation (NCLDH) in a rat model. Methods. NCLDH models were established by applying protruding autologous nucleus pulposus to the L5 Dorsal root ganglion (DRG). PD1, SIRT1 antagonist or agonist, CGRP or antagonist were administered as daily intrathecal injections for three consecutive days postoperatively. Behavioral tests were conducted to assess mechanical and thermal hyperalgesia. The ipsilateral lumbar (L4-6) segment of the spinal dorsal horn was isolated for further analysis. Alterations in the release of SIRT1 and CGRP were explored using western blot and immunofluorescence. Results. Application of protruded nucleus (NP) materials to the DRG induced mechanical and thermal allodynia symptoms, and deregulated the expression of pro-inflammatory and anti-inflammatory cytokines in rats. Intrathecal delivery of PD1 significantly reversed the NCLDH-induced imbalance in neuro-inflammatory response and alleviated the symptoms of mechanical and thermal hyperalgesia. In addition, NP application to the DGRs resulted the spinal upregulation of CGRP and SIRT1 expression, which was almost restored by intrathecal injection of PD1 in a dose-dependent manner. SIRT1 antagonist or agonist and CGRP or antagonist treatment further confirmed the result. Conclusion. Our findings indicate PD1 has a potent analgesic effect, and can modulate neuro-inflammation by regulating SIRT1-mediated CGRP signaling in NCLDH.

Sex differences in zymosan-induced behavioral visceral hypersensitivity and colorectal afferent sensitization.

Sex differences in visceral nociception have been reported in clinical and preclinical studies, but the potential differences in sensory neural encoding of the colorectum between males and females are not well understood. In this study, we systematically assessed sex differences in colorectal neural encoding by conducting high-throughput optical recordings in intact dorsal root ganglia (DRGs) from control and visceral hypersensitive mice. We found an apparent sex difference in zymosan-induced behavioral visceral hypersensitivity: enhanced visceromotor responses to colorectal distension were observed only in male mice, not in female mice. In addition, a higher number of mechanosensitive colorectal afferents were identified per mouse in the zymosan-treated male group than in the saline-treated male group, whereas the mechanosensitive afferents identified per mouse were comparable between the zymosan- and saline-treated female groups. The increased number of identified afferents in zymosan-treated male mice was predominantly from thoracolumbar (TL) innervation, which agrees with the significant increase in the TL afferent proportion in the zymosan group as compared with the control group in male mice. In contrast, female mice showed no difference in the proportion of colorectal neurons between saline- and zymosan-treated groups. Our results revealed a significant sex difference in colorectal afferent innervation and sensitization in the context of behavioral visceral hypersensitivity, which could drive differential clinical symptoms in male and female patients.NEW & NOTEWORTHY We used high-throughput GCaMP6f recordings to study 2,275 mechanosensitive colorectal afferents in mice. Our results revealed significant sex differences in the zymosan-induced behavioral visceral hypersensitivity, which were present in male but not female mice. Male mice also showed sensitization of colorectal afferents in the thoracolumbar pathway, whereas female mice did not. These findings highlight sex differences in sensory neural anatomy and function of the colorectum, with implications for sex-specific therapies for treating visceral pain.

Racial and Ethnic Differences in Hospital Admission and Diagnostic Evaluation for Febrile Seizures in the Emergency Department.

OBJECTIVE: To examine differences in hospital admission and diagnostic evaluation for febrile seizure by race and ethnicity. STUDY DESIGN: We conducted a cross-sectional study among children 6 months to 6 years with simple or complex febrile seizure between January 1, 2016, and December 31, 2021, using data from the Pediatric Health Information System. The primary outcome was hospital admission. Secondary outcomes included the proportion of encounters with neuroimaging or lumbar puncture. We used mixed-effects logistic regression model with random intercept for hospital and patient to estimate the association between outcomes and race and ethnicity after adjusting for covariates, including seizure type. RESULTS: In total, 94 884 encounters were included. Most encounters occurred among children of non-Hispanic White (37.0%), Black (23.9%), and Hispanic/Latino (24.6%) race and ethnicity. Black and Hispanic/Latino children had 29% (aOR 0.71; 95% CI 0.66-0.75) and 26% (aOR 0.74; 95% CI 0.69-0.80) lower odds of hospital admission compared with non-Hispanic White children, respectively. Black and Hispanic/Latino children had 21% (aOR 0.79; 95% CI 0.73-0.86) and 22% (aOR 0.78; 95% CI 0.71-0.85) lower adjusted odds of neuroimaging compared with non-Hispanic White children. For complex febrile seizure, the adjusted odds of lumbar puncture was significantly greater among Asian children (aOR 2.12; 95% CI 1.19-3.77) compared with non-Hispanic White children. There were no racial differences in the odds of lumbar puncture for simple febrile seizure. CONCLUSIONS: Compared with non-Hispanic White children, Black and Hispanic/Latino children with febrile seizures are less likely to be hospitalized or receive neuroimaging.

Causal relationships between anthropometric traits, bone mineral density, osteoarthritis and spinal stenosis: A Mendelian randomisation investigation.

OBJECTIVE: Spinal stenosis is a common condition among older individuals, with significant morbidity attached. Little is known about its risk factors but degenerative conditions, such as osteoarthritis (OA) have been identified for their mechanistic role. This study aims to explore causal relationships between anthropometric risk factors, OA, and spinal stenosis using Mendelian randomisation (MR) techniques. DESIGN: We applied two-sample MR to investigate the causal relationships between genetic liability for select risk factors and spinal stenosis. Next, we examined the genetic relationship between OA and spinal stenosis with linkage disequilibrium score regression and Causal Analysis Using Summary Effect estimates MR method. Finally, we used multivariable MR (MVMR) to explore whether OA and body mass index (BMI) mediate the causal pathways identified. RESULTS: Our analysis revealed strong evidence for the effect of higher BMI (odds ratio [OR] = 1.54, 95%CI: 1.41-1.69, p-value = 2.7 × 10-21), waist (OR = 1.43, 95%CI: 1.15-1.79, p-value = 1.5 × 10-3) and hip (OR = 1.50, 95%CI: 1.27-1.78, p-value = 3.3 × 10-6) circumference on spinal stenosis. Strong evidence of causality was also observed for higher bone mineral density (BMD): total body (OR = 1.21, 95%CI: 1.12-1.29, p-value = 1.6 × 10-7), femoral neck (OR = 1.35, 95%CI: 1.09-1.37, p-value = 7.5×10-7), and lumbar spine (OR = 1.38, 95%CI: 1.25-1.52, p-value = 4.4 × 10-11). We detected high genetic correlations between spinal stenosis and OA (rg range: 0.47-0.66), with Causal Analysis Using Summary Effect estimates results supporting a causal effect of OA on spinal stenosis (ORallOA = 1.6, 95%CI: 1.41-1.79). Direct effects of BMI, BMD on spinal stenosis remained after adjusting for OA in the MVMR. CONCLUSIONS: Genetic susceptibility to anthropometric risk factors, particularly higher BMI and BMD can increase the risk of spinal stenosis, independent of OA status. These results may inform preventative strategies and treatments.

Three-dimensional freehand ultrasonography to measure muscle volume of the lumbar multifidus: Reliability of processing technique and validity through comparison to magnetic resonance imaging.

There is a growing interest in muscle characteristics of the lumbar multifidus related to low back pain, but findings between studies are inconsistent. One of the issues explaining these conflicting findings might be the use of two-dimensional measures of cross-sectional area and thickness of the lumbar multifidus in most studies, which might be a suboptimal representation of the entire muscle volume. A three-dimensional volumetric assessment, combined with standardized imaging and processing measurement protocols, is highly recommended to quantify spinal muscle morphology. Three-dimensional freehand ultrasonography is a technique with large potential for daily clinical practice. It is achieved by combining conventional two-dimensional ultrasound with a motion-tracking system, recording the position and orientation of the ultrasound transducer during acquisition, resulting in a three-dimensional reconstruction. This study investigates intra- and interprocessor reliability for the quantification of muscle volume of the lumbar multifidus based on three-dimensional freehand ultrasound and its validity, in 31 patients with low back pain and 20 healthy subjects. Two processors manually segmented the lumbar multifidus on three-dimensional freehand ultrasound images using Stradwin software following a well-defined method. We assessed the concurrent validity of the measurement of multifidus muscle volume using three-dimensional freehand ultrasound compared with magnetic resonance imaging in 10 patients with low back pain. Processing reliability and agreement were determined using intraclass correlation coefficients, Bland-Altman plots, and calculation of the standard error of measurement and minimal detectable change, while validity was defined based on correlation analysis. The processing of three-dimensional freehand ultrasound images to measure lumbar multifidus volume was reliable. Good to excellent intraclass correlation coefficients were found for intraprocessor reliability. For interprocessor reliability, the intraclass correlation coefficients were moderate to good, emphasizing the importance of processing guidelines and training. A single processor analysis is preferred in clinical studies or when small differences in muscle volume are expected. The correlation between magnetic resonance imaging and three-dimensional freehand ultrasound measurements of lumbar multifidus volume was moderate to good but with a systematically smaller multifidus volume measured on three-dimensional freehand ultrasound. These results provide opportunities for both researchers and clinicians to reliably assess muscle structure using three-dimensional freehand ultrasound in patients with low back pain and to monitor changes related to pathology or interventions. To allow implementation in both research and clinical settings, guidelines on three-dimensional freehand ultrasound processing and training were provided.

The influence of lumbosacral transitional vertebrae on lumbar lordosis and the angle of pelvic incidence.

Pelvic incidence and lumbar lordosis have only normative values for spines comprising five lumbar and five sacral vertebrae. However, it is unclear how pelvic incidence and lumbar lordosis are affected by the common segmentation anomalies at the lumbo-sacral border leading to lumbosacral transitional vertebrae, including lumbarisations and sacralisations. In lumbosacral transitional vertebrae it is not trivial to identify the correct vertebral endplates to measure pelvic incidence and lumbar lordosis because ontogenetically the first sacral vertebra represents the first non-mobile sacral segment in lumbarisations, but the second segment in sacralisations. We therefore assessed pelvic incidence and lumbar lordosis with respect to both of these vertebral endplates. The type of segmentation anomaly was differentiated using spinal counts, spatial relationship with the iliac crest and morphological features. We found significant differences in pelvic incidence and lumbar lordosis between lumbarisations, sacralisations and the control group. The pelvic incidence in the sacralised group was mostly below the range of the lubarisation group and the control group when measured the traditional way at the first non-mobile segment (30.2°). However, the ranges of the sacralisation and lubarisation groups were completely encompassed by the control group when measured at the ontogenetically true first sacral vertebra. The mean pelvic incidence of the sacraliation group thus increased from 30.2° to 58.6°, and the mean pelvic incidence of the total sample increased from 45.6° to 51.2°, making it statistically indistinguishable from the control sample, whose pelvic incidence was 50.2°. Our results demonstrate that it is crucial to differentiate sacralisations from lumbarisation in order to assess the reference vertebra for pelvic incidence measurement. Due to their significant impact on spino-pelvic parameters, lumbosacral transitional vertebrae should be evaluated separately when examining pelvic incidence and lumbar lordosis.

Reducing aneurysm sac growth and secondary interventions following endovascular abdominal aortic aneurysm repair by preemptive coil embolization of the inferior mesenteric artery and lumbar arteries.

OBJECTIVE: Type II endoleak (EL-2) is the most common complication following endovascular aneurysm repair (EVAR), leading to continued sac growth and potential rupture. In this study, we examined the association between patency of the inferior mesenteric artery (IMA) and lumbar arteries (LAs) with respect to sac growth. The effect of preemptive embolization of the IMA and/or LAs on the need for secondary interventions for sac growth post-EVAR was also evaluated. METHODS: A retrospective cohort study was performed on consecutive patients who underwent EVAR for non-ruptured, infrarenal abdominal aortic aneurysms (AAAs) from January 2012 to December 2020. A select group of patients underwent preemptive embolization of the IMA and/or LA. Patients with any types I, III, or IV endoleaks were excluded. Patency of the IMA and LA on preoperative computed tomography angiogram (CTA) was evaluated on TeraRecon workstation. All secondary interventions to treat EL-2 were recorded. Sac growth was defined as centerline axial diameter increase of ≥5 mm on follow-up CTA. RESULTS: A total of 300 patients (mean age, 74 ± 8.5 years; 83.7% male) underwent EVAR. Ninety-nine patients had preemptive embolization of the IMA and/or LA. Mean follow-up of the cohort was 59.3 ± 30.5 months. Thirty-six patients (12%) demonstrated sac growth on follow-up; 12 of these (33.3%) had preemptive embolization. The median time until detection of sac growth was 28.8 months (interquartile range, 15.2-46.5 months), with a mean growth of 10.1 ± 6.4 mm. Sac growth was significantly associated with presence of EL-2: 27 of 36 (75%) with EL-2 vs 9 of 36 (25%) without EL-2 (P < .001). Patients with sac growth had a higher mean total number (2.6 ± 1.5) of patent lower LAs (L3, L4) compared with those without (2.0 ± 1.4; P = .03). Patency of L1, L2, and L3 LAs were not associated with sac growth. However, patency of at least one L4 LA was significantly associated with sac growth (14.8% vs 7.7%; P = .04). The highest incidence of sac growth (17.6%) was seen when both IMA and L4 LA were patent; significantly different from the lowest incidence (5.3%) when both were occluded preoperatively (P = .018). Preemptive coiling of the IMA and/or LA significantly reduced the need for post-EVAR secondary intervention for sac growth. Freedom from post-EVAR secondary intervention was achieved in 92 of 99 (92.9%) pre-EVAR coiled patients vs 163 of 201 (81.5%) patients who did not undergo pre-EVAR coiling (P = .009). CONCLUSIONS: Preemptive coil embolization of the IMA and LAs, especially L4 LA, reduces the need for secondary interventions for sac growth, potentially improving the long-term durability of EVAR.

Midterm outcomes of side branch embolization and endovascular abdominal aortic aneurysm repair.

OBJECTIVE: To analyze the effects of total side branch embolization at endovascular aneurysm repair (EVAR) for abdominal aortic aneurysms on the incidences of persistent type 2 endoleak (pT2EL), changes in sac diameter, and reintervention. METHODS: Between 2013 and 2021, all patients who underwent primary EVAR with a few exceptions were included. Side branch embolization was considered during EVAR for inferior mesenteric artery (IMA) or IMA plus lumbar artery (LA) when feasible for contrast agent use. Outcomes measured were pT2EL, sac diameters, reintervention, ruptures, and aneurysm-related mortality. Radiation exposure and safety outcomes were also reported. RESULTS: Among 732 patients who underwent EVAR, 616 (84.2%) were included. Of the 616 patients, 223 (36.2%) did not undergo side branch embolization (NO-E), whereas 228 (37.0%) underwent IMA only (IMA-E) and 165 (26.8%) underwent IMA+LA including median sacral artery (IMA+LA-E). The technical success rate of IMA and LA embolization was 97.0% and 74.7%, respectively. Crude incidences of pT2EL were significantly different from 6 months through 3 years (NO-E, 27.8%; IMA-E, 31.7%; IMA+LA-E, 9.4% at 3 years; P = .007). In the multivariate analysis adjusted for background differences, the incidences of pT2EL were significantly higher in the NO-E (odds ratio [OR], 3.21; 95% confidence intervals [CIs], 1.08-9.57; P = .004) and IMA-E (OR, 4.86; 95% CIs, 1.68-14.11; P = .004) compared with the IMA+LA-E group. Similarly, any reintervention until 3 years was significantly frequent in the NO-E (OR, 5.26; 95% CIs, 1.76-15.70; P = .003) and IMA-E group (OR, 4.19; 95% CIs, 1.38-12.67; P = .01). Surgical conversion and secondary rupture were seen only in 1 patient without any aneurysm-related mortality. Percent sac shrinkage from the baseline was significantly promoted in the IMA+LA group (NO-E, 12.1% ± 16.6%; IMA-E, 11.4% ± 16.7%; IMA+LA-E, 18.0% ± 18.8%; P = .047). Fluoroscopy time was significantly longer in the IMA+LA-E group (NO-E, 60.2 ± 47.4 minutes; IMA-E, 59.3 ± 39.5 minutes; IMA+LA-E, 75.5 ± 42.8 minutes; P < .0001), and so do the dose-area product (NO-E, 424.6 ± 333.4 Gy cm2; IMA-E, 477.7 ± 342.4 Gy cm2; IMA+LA-E, 631.8 ± 449.1 Gy cm2; P < .0001). No embolization-related complications or radiation-related adverse events were recorded. CONCLUSIONS: Pre-emptive embolization of IMA, LAs, and median sacral artery at the time of EVAR reduced the incidences of pT2EL and any reintervention and promoted sac shrinkage during the follow-up period of 3 years.

Comparing CT-Like Images Based on Ultra-Short Echo Time and Gradient Echo T1-Weighted MRI Sequences for the Assessment of Vertebral Disorders Using Histology and True CT as the Reference Standard.

BACKGROUND: Several magnetic resonance (MR) techniques have been suggested for radiation-free imaging of osseous structures. PURPOSE: To compare the diagnostic value of ultra-short echo time and gradient echo T1-weighted MRI for the assessment of vertebral pathologies using histology and computed tomography (CT) as the reference standard. STUDY TYPE: Prospective. SUBJECTS: Fifty-nine lumbar vertebral bodies harvested from 20 human cadavers (donor age 73 ± 13 years; 9 male). FIELD STRENGTH/SEQUENCE: Ultra-short echo time sequence optimized for both bone (UTEb) and cartilage (UTEc) imaging and 3D T1-weighted gradient-echo sequence (T1GRE) at 3 T; susceptibility-weighted imaging (SWI) gradient echo sequence at 1.5 T. CT was performed on a dual-layer dual-energy CT scanner using a routine clinical protocol. ASSESSMENT: Histopathology and conventional CT were acquired as standard of reference. Semi-quantitative and quantitative morphological features of degenerative changes of the spines were evaluated by four radiologists independently on CT and MR images independently and blinded to all other information. Features assessed were osteophytes, endplate sclerosis, visualization of cartilaginous endplate, facet joint degeneration, presence of Schmorl's nodes, and vertebral dimensions. Vertebral disorders were assessed by a pathologist on histology. STATISTICAL TESTS: Agreement between T1GRE, SWI, UTEc, and UTEb sequences and CT imaging and histology as standard of reference were assessed using Fleiss' κ and intra-class correlation coefficients, respectively. RESULTS: For the morphological assessment of osteophytes and endplate sclerosis, the overall agreement between SWI, T1GRE, UTEb, and UTEc with the reference standard (histology combined with CT) was moderate to almost perfect for all readers (osteophytes: SWI, κ range: 0.68-0.76; T1GRE: 0.92-1.00; UTEb: 0.92-1.00; UTEc: 0.77-0.85; sclerosis: SWI, κ range: 0.60-0.70; T1GRE: 0.77-0.82; UTEb: 0.81-0.92; UTEc: 0.61-0.71). For the visualization of the cartilaginous endplate, UTEc showed the overall best agreement with the reference standard (histology) for all readers (κ range: 0.85-0.93). DATA CONCLUSIONS: Morphological assessment of vertebral pathologies was feasible and accurate using the MR-based bone imaging sequences compared to CT and histopathology. T1GRE showed the overall best performance for osseous changes and UTEc for the visualization of the cartilaginous endplate. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 2.

Periostin increased by mechanical stress upregulates interleukin-6 expression in the ligamentum flavum.

Ligamentum flavum (LF) hypertrophy is a major cause of lumbar spinal canal stenosis. Although mechanical stress is thought to be a major factor involved in LF hypertrophy, the exact mechanism by which it causes hypertrophy has not yet been fully elucidated. Here, changes in gene expression due to long-term mechanical stress were analyzed using RNA-seq in a rabbit LF hypertrophy model. In combination with previously reported analysis results, periostin was identified as a molecule whose expression fluctuates due to mechanical stress. The expression and function of periostin were further investigated using human LF tissues and primary LF cell cultures. Periostin was abundantly expressed in human hypertrophied LF tissues, and periostin gene expression was significantly correlated with LF thickness. In vitro, mechanical stress increased gene expressions of periostin, transforming growth factor-ß1, α-smooth muscle actin, collagen type 1 alpha 1, and interleukin-6 (IL-6) in LF cells. Periostin blockade suppressed the mechanical stress-induced gene expression of IL-6 while periostin treatment increased IL-6 gene expression. Our results suggest that periostin is upregulated by mechanical stress and promotes inflammation by upregulating IL-6 expression, which leads to LF degeneration and hypertrophy. Periostin may be a pivotal molecule for LF hypertrophy and a promising therapeutic target for lumbar spinal stenosis.

Circular RNA PDK1 targets miR-4731-5p to enhance TNXB expression in ligamentum flavum hypertrophy.

Hypertrophic ligamentum flavum (LF) is a main factor responsible for lumbar spinal stenosis (LSS); however, the exact mechanisms of the pathogenesis of these processes remain unknown. This study aimed to elucidate whether circular RNAs and microRNAs regulate the pathogenesis of LF and LSS, especially focusing on circPDK1 (hsa_circ_0057105), a circRNA targeting pyruvate dehydrogenase kinase 1 and differentially expressed in LF tissues between lumbar disk herniation and LSS patients. The circPDK1/miR-4731 and miR-4731/TNXB (Tenascin XB) interactions were predicted and validated by luciferase reporter assay. Colony formation, wound-healing, and MTT assays were used for estimating cell proliferation and migration. Protein expression levels were evaluated using Western blotting. TNXB expression was verified using immunohistochemistry (IHC). Overexpressing circPDK1 promoted the proliferation, migration, and expression of fibrosis-related protein (alpha smooth muscle actin (α-SMA), lysyl oxidase like 2 (LOXL2), Collagen I, matrix metalloproteinase-2 (MMP-2) and TNXB) in LF whereas miR-4731-5p showed opposite effects. The expression of TNXB was promoted by circPDK1; contrary results were observed with miR-4731-5p. Co-overexpression of miR-4731-5p partially reversed the proliferative and fibrosis-prompting effects of circPDK1 or TNXB. The circPDK1-miR-4731-TNXB pathway may be proposed as a regulatory axis in LF hypertrophy, which might shed light on in-depth research of LSS, as well as providing a novel therapeutic target for LF hypertrophy-induced LSS.

LUMBAR syndrome-OEIS complex overlap: A case series and review.

We present three new and six published infants with overlapping features of LUMBAR syndrome (lower body hemangioma, urogenital anomalies, spinal cord malformations, bony deformities, anorectal/arterial anomalies and renal anomalies) and OEIS complex (omphalocele, exstrophy, imperforate anus, and spinal defects), also known as cloacal exstrophy. OEIS is included under the recently proposed umbrella coined recurrent constellations of embryonic malformations (RCEMs). The RCEMs represent a phenotypically overlapping spectrum of rare disorders of caudal dysgenesis with unknown cause but likely shared pathogenesis. It has recently been proposed that LUMBAR be considered an RCEM. This report of infants with combined features of OEIS and LUMBAR is the first to demonstrate an overlap between LUMBAR and another RCEM, which supports LUMBAR's inclusion within the RCEM spectrum.

An intervention to improve lumbar puncture rates for meningitis surveillance in children at four secondary health facilities in Malawi: A before/after analysis.

OBJECTIVES: A lumbar puncture (LP) procedure plays a key role in meningitis diagnosis. In Malawi and other sub-Saharan African countries, LP completion rates are sometimes poor, making meningitis surveillance challenging. Our objective was to measure LP rates following an intervention to improve these during a sentinel hospital meningitis surveillance exercise in Malawi. METHODS: We conducted a before/after intervention analysis among under-five children admitted to paediatric wards at four secondary health facilities in Malawi. We used local and World Health Organization (WHO) guidelines to determine indications for LP, as these are widely used in low- and middle-income countries (LMIC). The intervention comprised of refresher trainings for facility staff on LP indications and procedure, use of automated reminders to perform LP in real time in the wards, with an electronic data management system, and addition of surveillance-specific clinical officers to support existing health facility staff with performing LPs. Due to the low numbers in the before/after analysis, we also performed a during/after analysis to supplement the findings. RESULTS: A total of 13,375 under-five children were hospitalised over the 21 months window for this analysis. The LP rate was 10.4% (12/115) and 60.4% (32/53) in the before/after analysis, respectively, and 43.8% (441/1006) and 72.5% (424/599) in the supplemental during/after analysis, respectively. In our intervention-specific analysis among the three individual components, there were improvements in the LP rate by 48% (p < 0.001) following the introduction of surveillance-specific clinical officers, 10% (p < 0.001) following the introduction of automated reminders to perform an LP and 13% following refresher training. CONCLUSIONS: This analysis demonstrated a rise in LP rates following our intervention. This intervention package may be considered for planning future facility-based meningitis surveillances in similar low-resource settings.

Electron density dual-energy CT can improve the detection of lumbar disc herniation with higher image quality than standard and virtual non-calcium images.

OBJECTIVES: To compare the diagnostic performance and image quality of dual-energy computed tomography (DECT) with electron density (ED) image reconstruction with those of DECT with standard CT (SC) and virtual non-calcium (VNCa) image reconstructions, for diagnosing lumbar disc herniation (L-HIVD). METHODS: A total of 59 patients (354 intervertebral discs from T12/L1 to L5/S1; mean age, 60 years; 30 women and 29 men) who underwent DECT with spectral reconstruction and 3-T MRI within 2 weeks were enrolled between March 2021 and February 2022. Four radiologists independently assessed three image sets of randomized ED, SC, and VNCa images to detect L-HIVD at 8-week intervals. The coefficient of variance (CV) and the Weber contrast of the ROIs in the normal and diseased disc to cerebrospinal fluid space (NCR-normal/-diseased, respectively) were calculated to compare the image qualities of the noiseless ED and other series. RESULTS: Overall, 129 L-HIVDs were noted on MRI. In the detection of L-HIVD, ED showed a higher AUC and sensitivity than SC and VNCa; 0.871 vs 0.807 vs 833 (p = 0.002) and 81% vs 70% vs 74% (p = 0.006 for SC), respectively. CV was much lower in all measurements of ED than those for SC and VNCa (p < 0.001). Furthermore, NCR-normal and NCR-diseased were the highest in ED (ED vs SC in NCR-normal and NCR-diseased, p = 0.001 and p = 0.004, respectively; ED vs VNCa in NCR-diseased, p = 0.044). CONCLUSION: Compared to SC and VNCa images, DECT with ED reconstruction can enhance the AUC and sensitivity of L-HIVD detection with a lower CV and higher NCR. CLINICAL RELEVANCE STATEMENT: To our knowledge, this is the first study to quantify the image quality of noiseless ED images. ED imaging may be helpful for detecting L-HIVD in patients who cannot undergo MRI. KEY POINTS: ED images have diagnostic potential, but relevant quantitative analyses of image quality are limited. ED images detect disc herniation, with a better coefficient of variance and normalized contrast ratio values. ED images could detect L-HIVD when MRI is not an option.