Clinical and radiographic outcomes after lateral lumbar interbody fusion in patients older than 75 years.

OBJECTIVE: There is an increasing need for optimal surgical techniques for older patients with degenerative spine disease. The authors evaluated perioperative complications and clinical and long-term radiographic outcomes in patients older than 75 years after lateral lumbar interbody fusion (LLIF) for degenerative spine disease. METHODS: The authors conducted a single-center, retrospective case series of consecutive patients older than 75 years who underwent single-level or multilevel LLIF between January 1, 2017, and December 31, 2022. Postoperative transient neurapraxia or permanent neurological deficits were documented. Outcomes were assessed using patient-reported outcome scales. Bone density was measured at the femoral neck and L1 vertebra. Sagittal vertical axis (SVA), segmental lordosis (stratified by level), lumbar lordosis (LL), pelvic incidence-LL mismatch, sacral slope, and pelvic tilt were measured on upright radiographs. Fusion status was assessed using the Lenke classification system on CT scans obtained at least 1 year postoperatively. Clinical and radiographic outcomes were assessed using paired t-tests and multivariable regression. The values for continuous variables are expressed as the mean (SD). RESULTS: Fifty-two patients (mean age 78.6 years; range 75-87 years) met the inclusion criteria; 94 levels were treated in these patients, and the mean follow-up was 12.2 (6.3) months. All outcome measures showed significant improvement at latest follow-up, including the mean changes in scores on the Oswestry Disability Index (-14.5 [17.5]); visual analog scale (VAS) for back pain (-2.2 [3.8]); and VAS for leg pain (-3.3 [3.9]) (all p < 0.001). Age was not associated with perioperative outcomes, except change in VAS score for back pain (r = 0.4, p = 0.03). One year postoperatively, 88% of levels (52 of 59 levels in 31 patients available for follow-up) demonstrated bony fusion. Patients experienced significant improvements in the mean change in SVA (-1 [2.7] cm); segmental lordosis (5.9° [4.1°]); LL (5.3° [9.8°]); and pelvic incidence-LL mismatch (-2.9° [6.4°]) (all p < 0.01). Cage subsidence was observed in 7 of 94 levels (7%). On multivariable regression analysis, increasing age was a significant predictor of reduced radiographic correction with respect to the change in SVA (ß 0.43; 95% CI 0.10-0.77; p = 0.01) and the change in LL (ß -1.18; 95% CI -2.12 to -0.23; p = 0.02). CONCLUSIONS: This series demonstrates safe clinical outcomes and stable long-term radiographic outcomes in patients older than 75 years undergoing LLIF for degenerative lumbar spine disease.

Itaconate drives mtRNA-mediated type I interferon production through inhibition of succinate dehydrogenase.

Itaconate is one of the most highly upregulated metabolites in inflammatory macrophages and has been shown to have immunomodulatory properties. Here, we show that itaconate promotes type I interferon production through inhibition of succinate dehydrogenase (SDH). Using pharmacological and genetic approaches, we show that SDH inhibition by endogenous or exogenous itaconate leads to double-stranded mitochondrial RNA (mtRNA) release, which is dependent on the mitochondrial pore formed by VDAC1. In addition, the double-stranded RNA sensors MDA5 and RIG-I are required for IFNß production in response to SDH inhibition by itaconate. Collectively, our data indicate that inhibition of SDH by itaconate links TCA cycle modulation to type I interferon production through mtRNA release.

Rhythmic IL-17 production by γδ T cells maintains adipose de novo lipogenesis.

The circadian rhythm of the immune system helps to protect against pathogens1-3; however, the role of circadian rhythms in immune homeostasis is less well understood. Innate T cells are tissue-resident lymphocytes with key roles in tissue homeostasis4-7. Here we use single-cell RNA sequencing, a molecular-clock reporter and genetic manipulations to show that innate IL-17-producing T cells-including γδ T cells, invariant natural killer T cells and mucosal-associated invariant T cells-are enriched for molecular-clock genes compared with their IFNγ-producing counterparts. We reveal that IL-17-producing γδ (γδ17) T cells, in particular, rely on the molecular clock to maintain adipose tissue homeostasis, and exhibit a robust circadian rhythm for RORγt and IL-17A across adipose depots, which peaks at night. In mice, loss of the molecular clock in the CD45 compartment (Bmal1∆Vav1) affects the production of IL-17 by adipose γδ17 T cells, but not cytokine production by αß or IFNγ-producing γδ (γδIFNγ) T cells. Circadian IL-17 is essential for de novo lipogenesis in adipose tissue, and mice with an adipocyte-specific deficiency in IL-17 receptor C (IL-17RC) have defects in de novo lipogenesis. Whole-body metabolic analysis in vivo shows that Il17a-/-Il17f-/- mice (which lack expression of IL-17A and IL-17F) have defects in their circadian rhythm for de novo lipogenesis, which results in disruptions to their whole-body metabolic rhythm and core-body-temperature rhythm. This study identifies a crucial role for IL-17 in whole-body metabolic homeostasis and shows that de novo lipogenesis is a major target of IL-17.

Intraoperative Intercostal Nerve Block for Pain Management After Retropleural Thoracic Discectomy: Anatomy and Technique.

BACKGROUND: Thoracic discectomy procedures require early and adequate pain control to alleviate patient discomfort after surgery. The intraoperative placement of a nerve block after intercostal nerve violation can offer early pain management after thoracic discectomy. METHODS: The anatomy and technique of placing an intercostal nerve block after retropleural thoracic discectomy are described. Patient data were collected for patients who underwent this technique. RESULTS: This approach is presented with an illustrative figure and a review of relevant anatomical landmarks to describe the technique and ensure its reproducibility. Data for 93 patients (57 [61%] women; 36 [39%] men; mean [SD] age, 54.1 [14.1] years) who underwent the procedure are provided to assess the reliability of this technique. CONCLUSIONS: Intercostal nerve blockage offers a valuable addition to postoperative pain management and may be considered as an available pain relief option for patients undergoing thoracic discectomy.

Endogenously produced itaconate negatively regulates innate-driven cytokine production and drives global ubiquitination in human macrophages.

A wide variety of electrophilic derivatives of itaconate, the Kreb's cycle-derived metabolite, are immunomodulatory, yet these derivatives have overlapping and sometimes contradictory activities. Therefore, we generated a genetic system to interrogate the immunomodulatory functions of endogenously produced itaconate in human macrophages. Endogenous itaconate is driven by multiple innate signals restraining inflammatory cytokine production. Endogenous itaconate directly targets cysteine 13 in IRAK4 (disrupting IRAK4 autophosphorylation and activation), drives the degradation of nuclear factor κB, and modulates global ubiquitination patterns. As a result, cells unable to make itaconate overproduce inflammatory cytokines such as tumor necrosis factor alpha (TNFα), interleukin-6 (IL-6), and IL-1ß in response to these innate activators. In contrast, the production of interferon (IFN)ß, downstream of LPS, requires the production of itaconate. These data demonstrate that itaconate is a critical arbiter of inflammatory cytokine production downstream of multiple innate signaling pathways, laying the groundwork for the development of itaconate mimetics for the treatment of autoimmunity.

The socioeconomic impacts of Rift Valley fever: A rapid review.

Rift Valley fever (RVF) is a neglected vector-borne disease which is endemic in many countries across Africa and has seen recent geographical expansions into the Arabian Peninsula. RVF can cause severe infections in both animals and humans. RVF infections in livestock can lead to mass fatalities. In humans, the symptoms are nonspecific and can often lead to misdiagnosis. However, a small proportion progresses to haemorrhagic infection with a significantly higher mortality rate. The culmination of this can cause severe socioeconomic impacts. This review aims to identify the main socioeconomic impacts caused by RVF outbreaks as well as existing knowledge gaps. Ninety-three academic and grey papers were selected, covering 19 countries and 10 methodological approaches. A variety of socioeconomic impacts were found across all levels of society: Livestock trade disruptions consequently impacted local food security, local and national economies. Most livestock farmers in endemic countries are subsistence farmers and so rely on their livestock for sustenance and income. RVF outbreaks resulted in a variety of socioeconomic impacts, e.g., the inability to pay for school fees. Main barriers to vaccine uptake in communities were lack of access, funds, interest along with other social aspects. The occupational risks for women (and pregnant women) are largely unknown. To our knowledge, this is the first review on RVF to highlight the clear knowledge gap surrounding the potential gender differences on risks of RVF exposure, as well as differences on occupational health risk in pastoral communities. Further work is required to fill the gaps identified in this review and inform control policies.

High-dimensional single-cell analysis of human natural killer cell heterogeneity.

Natural killer (NK) cells are innate lymphoid cells (ILCs) contributing to immune responses to microbes and tumors. Historically, their classification hinged on a limited array of surface protein markers. Here, we used single-cell RNA sequencing (scRNA-seq) and cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) to dissect the heterogeneity of NK cells. We identified three prominent NK cell subsets in healthy human blood: NK1, NK2 and NK3, further differentiated into six distinct subgroups. Our findings delineate the molecular characteristics, key transcription factors, biological functions, metabolic traits and cytokine responses of each subgroup. These data also suggest two separate ontogenetic origins for NK cells, leading to divergent transcriptional trajectories. Furthermore, we analyzed the distribution of NK cell subsets in the lung, tonsils and intraepithelial lymphocytes isolated from healthy individuals and in 22 tumor types. This standardized terminology aims at fostering clarity and consistency in future research, thereby improving cross-study comparisons.

Anatomical Reduction of Spondylolisthesis Through Lateral Lumbar Interbody Fusion With Percutaneous Pedicle Screw Fixation: An Intraoperative Technical Note.

BACKGROUND: Surgical management of lumbar spondylolisthesis requires neural decompression, stabilization, and alignment restoration. Minimally invasive spine approaches offer a wide variety of advantages for spondylolisthesis management. This intraoperative note describes the treatment of L4-L5 lumbar spondylolisthesis with lateral lumbar interbody fusion (LLIF) and percutaneous pedicle screw fixation (PSF). METHODS: The surgical technique for treating L4-L5 lumbar spondylolisthesis using a minimally invasive approach with LLIF and percutaneous PSF is described. This operative technique is illustrated with figures, and an intraoperative case example of its application is described. RESULTS: LLIF with percutaneous PSF can be a safe, effective, and reliable option for treating lumbar spondylolisthesis when applied with appropriate surgical technique in a selected patient population. This technique is a valuable addition to the range of available spine surgical options. CONCLUSIONS: LLIF with percutaneous PSF can be an effective technique for treating lumbar L4-L5 spondylolisthesis.

Incidence of radiographic and clinically significant pneumothorax or hemothorax after thoracic discectomy via mini-open lateral retropleural approach without prophylactic chest tube placement.

OBJECTIVE: The mini-open lateral retropleural (MO-LRP) approach is an effective option for surgically treating thoracic disc herniations, but the approach raises concerns for pneumothorax (PTX). However, chest tube placement causes insertion site tenderness, necessitates consultation services, increases radiation exposure (requires multiple radiographs), delays the progression of care, and increases narcotic requirements. This study examined the incidence of radiographic and clinically significant PTX and hemothorax (HTX) after the MO-LRP approach, without the placement of a prophylactic chest tube, for thoracic disc herniation. METHODS: This study was a single-institution retrospective evaluation of consecutive cases from 2017 to 2022. Electronic medical records were reviewed, including postoperative chest radiographs, radiology and operative reports, and postoperative notes. The presence of PTX or HTX was determined on chest radiographs obtained in all patients immediately after surgery, with interval radiographs if either was present. The size was categorized as large (≥ 3 cm) or small (< 3 cm) based on guidelines of the American College of Chest Physicians. PTX or HTX was considered clinically significant if it required intervention. RESULTS: Thirty patients underwent thoracic discectomy via the MO-LRP approach. All patients were included. Twenty patients were men (67%), and 10 (33%) were women. The patients ranged in age from 25 to 74 years. The most commonly treated level was T11-12 (n = 11, 37%). Intraoperative violation of parietal pleura occurred in 5 patients (17%). No patient had prophylactic chest tube placement. Fifteen patients (50%) had PTX on postoperative chest radiographs; 2 patients had large PTXs, and 13 had small PTXs. Both patients with large PTXs had expansion on repeat radiographs and were treated with chest tube insertion. Of the 13 patients with a small PTX, 1 required 100% oxygen using a nonrebreather mask; the remainder were asymptomatic. One patient, who had no abnormal findings on the immediate postoperative chest radiograph, developed an incidental HTX on postoperative day 6 and was treated with chest tube insertion. Thus, 3 patients (10%) required a chest tube: 2 for expanding PTX and 1 for delayed HTX. CONCLUSIONS: Most patients who undergo thoracic discectomy via the MO-LRP approach do not develop clinically significant PTX or HTX. PTX and HTX in this patient population should be treated with a chest tube only when there are postoperative clinical and radiographic indications.

Octyl itaconate enhances VSVΔ51 oncolytic virotherapy by multitarget inhibition of antiviral and inflammatory pathways.

The presence of heterogeneity in responses to oncolytic virotherapy poses a barrier to clinical effectiveness, as resistance to this treatment can occur through the inhibition of viral spread within the tumor, potentially leading to treatment failures. Here we show that 4-octyl itaconate (4-OI), a chemical derivative of the Krebs cycle-derived metabolite itaconate, enhances oncolytic virotherapy with VSVΔ51 in various models including human and murine resistant cancer cell lines, three-dimensional (3D) patient-derived colon tumoroids and organotypic brain tumor slices. Furthermore, 4-OI in combination with VSVΔ51 improves therapeutic outcomes in a resistant murine colon tumor model. Mechanistically, we find that 4-OI suppresses antiviral immunity in cancer cells through the modification of cysteine residues in MAVS and IKKß independently of the NRF2/KEAP1 axis. We propose that the combination of a metabolite-derived drug with an oncolytic virus agent can greatly improve anticancer therapeutic outcomes by direct interference with the type I IFN and NF-κB-mediated antiviral responses.

Reciprocal Changes in Sagittal Spinal Alignment After L5-S1 Anterior Lumbar Interbody Fusion.

OBJECTIVE: Degenerative diseases of the lumbar spine decrease lumbar lordosis (LL). Anterior lumbar interbody fusion (ALIF) at the L5-S1 disc space improves segmental lordosis, LL, and sagittal balance. This study investigated reciprocal changes in spinopelvic alignment after L5-S1 ALIF. METHODS: A retrospective chart review identified patients who underwent L5-S1 ALIF with or without posterior fixation at a single institution (November 1, 2016 to October 1, 2021). Changes in pelvic tilt, sacral slope, proximal LL (L1-L4), distal LL (L4-S1), total LL (L1-S1), segmental lordosis, pelvic incidence-LL mismatch, thoracic kyphosis, cervical lordosis, and sagittal vertical axis were measured on preoperative and postoperative radiographs. RESULTS: Forty-eight patients were identified. Immediate postoperative radiographs were obtained at a mean (SD) of 17 (20) days after surgery; delayed radiographs were obtained 184 (82) days after surgery. After surgery, patients had significantly decreased pelvic tilt (15.71° [7.25°] vs. 17.52° [7.67°], P = 0.003) and proximal LL (11.86° [10.67°] vs. 16.03° [10.45°], P < 0.001) and increased sacral slope (39.49° [9.27°] vs. 36.31° [10.39°], P < 0.001), LL (55.35° [13.15°] vs. 51.63° [13.38°], P = 0.001), and distal LL (43.17° [9.33°] vs. 35.80° [8.02°], P < 0.001). Segmental lordosis increased significantly at L5-S1 and decreased significantly at L2-3, L3-4, and L4-5. Lordosis distribution index increased from 72.55 (19.53) to 81.38 (22.83) (P < 0.001). CONCLUSIONS: L5-S1 ALIF was associated with increased L5-S1 segmental lordosis accompanied by pelvic anteversion and a reciprocal decrease in proximal LL. These changes may represent a reversal of compensatory mechanisms, suggesting an overall relaxation of spinopelvic alignment after L5-S1 ALIF.

From periphery to center stage: 50 years of advancements in innate immunity.

Over the past 50 years in the field of immunology, something of a Copernican revolution has happened. For a long time, immunologists were mainly concerned with what is termed adaptive immunity, which involves the exquisitely specific activities of lymphocytes. But the other arm of immunity, so-called "innate immunity," had been neglected. To celebrate Cell's 50th anniversary, we have put together a review of the processes and components of innate immunity and trace the seminal contributions leading to the modern state of this field. Innate immunity has joined adaptive immunity in the center of interest for all those who study the body's defenses, as well as homeostasis and pathology. We are now entering the era where therapeutic targeting of innate immune receptors and downstream signals hold substantial promise for infectious and inflammatory diseases and cancer.

Metabolic regulation of type I interferon production.

Over the past decade, there has been a surge in discoveries of how metabolic pathways regulate immune cell function in health and disease, establishing the field of immunometabolism. Specifically, pathways such as glycolysis, the tricarboxylic acid (TCA) cycle, and those involving lipid metabolism have been implicated in regulating immune cell function. Viral infections cause immunometabolic changes which lead to antiviral immunity, but little is known about how metabolic changes regulate interferon responses. Interferons are critical cytokines in host defense, rapidly induced upon pathogen recognition, but are also involved in autoimmune diseases. This review summarizes how metabolic change impacts interferon production. We describe how glycolysis, lipid metabolism (specifically involving eicosanoids and cholesterol), and the TCA cycle-linked intermediates itaconate and fumarate impact type I interferons. Targeting these metabolic changes presents new therapeutic possibilities to modulate type I interferons during host defense or autoimmune disorders.

Itaconate boosts malaria via induction of PD-L1.

The Krebs-cycle-derived metabolite itaconate has been shown to be immunomodulatory, targeting multiple processes in macrophages. Ramalho et al. reveal an additional role for itaconate in malaria.1Plasmodium Chabaudi induces itaconate in dendritic cells (DCs), leading to programmed death-ligand 1 (PD-L1) induction. This suppresses CD8+ T cells, important for host defense against malaria, thereby promoting parasitemia.

Unlocking potential: the role of the electron transport chain in immunometabolism.

The electron transport chain (ETC) couples electron transfer with proton pumping to generate ATP and it also regulates particular innate and adaptive immune cell function. While NLRP3 inflammasome activation was initially linked to reactive oxygen species (ROS) produced from Complexes I and III, recent research suggests that an intact ETC fueling ATP is needed. Complex II may be responsible for Th1 cell proliferation and in some cases, effector cytokine production. Complex III is required for regulatory T (Treg) cell function, while oxidative phosphorylation (OXPHOS) and Complexes I, IV, and V sustain proliferation and antibody production in B lymphocytes, with OXPHOS also being required for B regulatory (Breg) cell function. Despite challenges, the ETC shows therapeutic targeting potential for immune-related diseases and in immuno-oncology.

A break in mitochondrial endosymbiosis as a basis for inflammatory diseases.

Mitochondria retain bacterial traits due to their endosymbiotic origin, but host cells do not recognize them as foreign because the organelles are sequestered. However, the regulated release of mitochondrial factors into the cytosol can trigger cell death, innate immunity and inflammation. This selective breakdown in the 2-billion-year-old endosymbiotic relationship enables mitochondria to act as intracellular signalling hubs. Mitochondrial signals include proteins, nucleic acids, phospholipids, metabolites and reactive oxygen species, which have many modes of release from mitochondria, and of decoding in the cytosol and nucleus. Because these mitochondrial signals probably contribute to the homeostatic role of inflammation, dysregulation of these processes may lead to autoimmune and inflammatory diseases. A potential reason for the increased incidence of these diseases may be changes in mitochondrial function and signalling in response to such recent phenomena as obesity, dietary changes and other environmental factors. Focusing on the mixed heritage of mitochondria therefore leads to predictions for future insights, research paths and therapeutic opportunities. Thus, whereas mitochondria can be considered 'the enemy within' the cell, evolution has used this strained relationship in intriguing ways, with increasing evidence pointing to the recent failure of endosymbiosis being critical for the pathogenesis of inflammatory diseases.

4-Octyl Itaconate Alleviates Airway Eosinophilic Inflammation by Suppressing Chemokines and Eosinophil Development.

4-Octyl itaconate (4-OI) is a derivative of the Krebs cycle-derived metabolite itaconate and displays an array of antimicrobial and anti-inflammatory properties through modifying cysteine residues within protein targets. We have found that 4-OI significantly reduces the production of eosinophil-targeted chemokines in a variety of cell types, including M1 and M2 macrophages, Th2 cells, and A549 respiratory epithelial cells. Notably, the suppression of these chemokines in M1 macrophages was found to be NRF2-dependent. In addition, 4-OI can interfere with IL-5 signaling and directly affect eosinophil differentiation. In a model of eosinophilic airway inflammation in BALB/c mice, 4-OI alleviated airway resistance and reduced eosinophil recruitment to the lungs. Our findings suggest that itaconate derivatives could be promising therapeutic agents for the treatment of eosinophilic asthma.

Characterization and inhibition of inflammasome responses in severe and non-severe asthma.

BACKGROUND: Increased airway NLRP3 inflammasome-mediated IL-1ß responses may underpin severe neutrophilic asthma. However, whether increased inflammasome activation is unique to severe asthma, is a common feature of immune cells in all inflammatory types of severe asthma, and whether inflammasome activation can be therapeutically targeted in patients, remains unknown. OBJECTIVE: To investigate the activation and inhibition of inflammasome-mediated IL-1ß responses in immune cells from patients with asthma. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from patients with non-severe (n = 59) and severe (n = 36 stable, n = 17 exacerbating) asthma and healthy subjects (n = 39). PBMCs were stimulated with nigericin or lipopolysaccharide (LPS) alone, or in combination (LPS + nigericin), with or without the NLRP3 inhibitor MCC950, and the effects on IL-1ß release were assessed. RESULTS: PBMCs from patients with non-severe or severe asthma produced more IL-1ß in response to nigericin than those from healthy subjects. PBMCs from patients with severe asthma released more IL-1ß in response to LPS + nigericin than those from non-severe asthma. Inflammasome-induced IL-1ß release from PBMCs from patients with severe asthma was not increased during exacerbation compared to when stable. Inflammasome-induced IL-1ß release was not different between male and female, or obese and non-obese patients and correlated with eosinophil and neutrophil numbers in the airways. MCC950 effectively suppressed LPS-, nigericin-, and LPS + nigericin-induced IL-1ß release from PBMCs from all groups. CONCLUSION: An increased ability for inflammasome priming and/or activation is a common feature of systemic immune cells in both severe and non-severe asthma, highlighting inflammasome inhibition as a universal therapy for different subtypes of disease.