Interplay between ATRX and IDH1 mutations governs innate immune responses in diffuse gliomas.

Stimulating the innate immune system has been explored as a therapeutic option for the treatment of gliomas. Inactivating mutations in ATRX, defining molecular alterations in IDH-mutant astrocytomas, have been implicated in dysfunctional immune signaling. However, little is known about the interplay between ATRX loss and IDH mutation on innate immunity. To explore this, we generated ATRX-deficient glioma models in the presence and absence of the IDH1R132H mutation. ATRX-deficient glioma cells are sensitive to dsRNA-based innate immune agonism and exhibit impaired lethality and increased T-cell infiltration in vivo. However, the presence of IDH1R132H dampens baseline expression of key innate immune genes and cytokines in a manner restored by genetic and pharmacological IDH1R132H inhibition. IDH1R132H co-expression does not interfere with the ATRX deficiency-mediated sensitivity to dsRNA. Thus, ATRX loss primes cells for recognition of dsRNA, while IDH1R132H reversibly masks this priming. This work reveals innate immunity as a therapeutic vulnerability of astrocytomas.

Understanding and therapeutically exploiting cGAS/STING signaling in glioblastoma.

Since the discovery that cGAS/STING recognizes endogenous DNA released from dying cancer cells and induces type I interferon and antitumor T cell responses, efforts to understand and therapeutically target the STING pathway in cancer have ensued. Relative to other cancer types, the glioma immune microenvironment harbors few infiltrating T cells, but abundant tumor-associated myeloid cells, possibly explaining disappointing responses to immune checkpoint blockade therapies in cohorts of patients with glioblastoma. Notably, unlike most extracranial tumors, STING expression is absent in the malignant compartment of gliomas, likely due to methylation of the STING promoter. Nonetheless, several preclinical studies suggest that inducing cGAS/STING signaling in the glioma immune microenvironment could be therapeutically beneficial, and cGAS/STING signaling has been shown to mediate inflammatory and antitumor effects of other modalities either in use or being developed for glioblastoma therapy, including radiation, tumor-treating fields, and oncolytic virotherapy. In this Review, we discuss cGAS/STING signaling in gliomas, its implications for glioma immunobiology, compartment-specific roles for STING signaling in influencing immune surveillance, and efforts to target STING signaling - either directly or indirectly - for antiglioma therapy.

Characterizing Acute Low Back Pain in a Community-Based Cohort.

Acute low back pain (LBP) is a common experience, however, the associated pain severity, pain frequency, and characteristics of individuals with acute LBP in community settings have yet to be well understood. In this manuscript, three acute LBP severity categorization definitions were used based on LBP frequency combined with either 1) pain impact frequency (impact-based) or 2) pain intensity (intensity-based), as well as LBP pain interference frequency (interference only-based) severity categories. The purpose of this manuscript is to describe and then compare these acute LBP severity groups in the following characteristics: 1) sociodemographic, 2) general and physical health, and 3) psychological. This cross-sectional study used baseline data from 131 community-based participants with acute LBP (<4 weeks duration before screening and ≥30 pain-free days before acute LBP onset). Descriptive associations were calculated as prevalence ratios for categorical variables and Hedges' g for continuous variables. Our analyses identified several large associations for impact-based and intensity-based categories with global mental health, global physical health, STarT Back Screening Tool risk category, and general health. Larger associations were found with social constructs (racially and ethnically minoritized, performance of social roles, and isolation) when using the intensity-based versus impact-based categorization. The interference-based category did not capture as much variability between acute LBP severity categories. This study adds to the literature by providing standard ways to characterize community-based individuals experiencing acute LBP. The robust differences observed between these categorization approaches suggest that how we define acute LBP severity is consequential; these different approaches may be used to improve the early identification of factors potentially contributing to the development of chronic LBP.

Transcriptional and epigenetic regulators of human CD8+ T cell function identified through orthogonal CRISPR screens.

Clinical response to adoptive T cell therapies is associated with the transcriptional and epigenetic state of the cell product. Thus, discovery of regulators of T cell gene networks and their corresponding phenotypes has potential to improve T cell therapies. Here we developed pooled, epigenetic CRISPR screening approaches to systematically profile the effects of activating or repressing 120 transcriptional and epigenetic regulators on human CD8+ T cell state. We found that BATF3 overexpression promoted specific features of memory T cells and attenuated gene programs associated with cytotoxicity, regulatory T cell function, and exhaustion. Upon chronic antigen stimulation, BATF3 overexpression countered phenotypic and epigenetic signatures of T cell exhaustion. Moreover, BATF3 enhanced the potency of CAR T cells in both in vitro and in vivo tumor models and programmed a transcriptional profile that correlates with positive clinical response to adoptive T cell therapy. Finally, we performed CRISPR knockout screens that defined cofactors and downstream mediators of the BATF3 gene network.

Early enterovirus translation deficits extend viral RNA replication and elicit sustained MDA5-directed innate signaling.

IMPORTANCE: Multiple pattern recognition receptors sense vRNAs and initiate downstream innate signaling: endosomal Toll-like receptors (TLRs) 3, 7, and 8 and cytoplasmic RIG-I-like receptors (RLRs) RIG-I, and MDA5. They engage distinct signaling scaffolds: mitochondrial antiviral signaling protein (RLR), MyD88, and TLR-adaptor interacting with SLC15A4 on the lysosome (TLR7 and TLR8) and toll/IL-1R domain-containing adaptor inducing IFN (TLR3). By virtue of their unusual vRNA structure and direct host cell entry path, the innate response to EVs uniquely is orchestrated by MDA5. We reported that PVSRIPO's profound attenuation and loss of cytopathogenicity triggers MDA5-directed polar TBK1-IRF3 signaling that generates priming of polyfunctional antitumor CD8+ T-cell responses and durable antitumor surveillance in vivo. Here we unraveled EV-host relations that control suppression of host type-I IFN responses and show that PVSRIPO's deficient immediate host eIF4G cleavage generates unopposed MDA5-directed downstream signaling cascades resulting in sustained type-I IFN release.

Incorporation of Digital Modulation into Vital Sign Detection and Gesture Recognition Using Multimode Radar Systems.

The incorporation of digital modulation into radar systems poses various challenges in the field of radar design, but it also offers a potential solution to the shrinking availability of low-noise operating environments as the number of radar applications increases. Additionally, digital systems have reached a point where available components and technology can support higher speeds than ever before. These advancements present new avenues for radar design, in which digitally controlled phase-modulated continuous wave (PMCW) radar systems can look to support multiple collocated radar systems with low radar-radar interference. This paper proposes a reconfigurable PMCW radar for use in vital sign detection and gesture recognition while utilizing digital carrier modulation and compares the radar responses of various modulation schemes. Binary sequences are used to introduce phase modulation to the carrier wave by use of a field programable gate array (FPGA), allowing for flexibility in the modulation speed and binary sequence. Experimental results from the radar demonstrate the differences between CW and PMCW modes when measuring the respiration rate of a human subject and in gesture detection.

Functional reprogramming of peripheral blood monocytes by soluble mediators in patients with pancreatic cancer and intraductal papillary mucinous neoplasms.

Background: Monocytes and monocyte-derived tumor infiltrating cells have been implicated in the immunosuppression and immune evasion associated with pancreatic adenocarcinoma (PDAC). Yet, precisely how monocytes in the periphery and tumor microenvironment in patients with intraductal papillary mucinous neoplasm (IPMN), a precursor lesion to PDAC, change during disease progression has not been defined. Here we functionally profiled the peripheral immune system and characterized the tumor microenvironment of patients with both IPMN and PDAC. We also tested if sera from patients with IPMN and PDAC functionally reprogram monocytes relative to that of healthy donors. Methods: Pancreatic tissue and peripheral blood were collected at the time of resection from 16 patients with IPMN and 32 patients with PDAC. Peripheral blood and pancreatic tissue/tumor were immunophenotyped using flow cytometry. Whole blood was plated and incubated with R848 (a TLR 7/8 agonist) or LPS (a TLR4 agonist) for 6 hours and TNF expression in monocytes was measured by flow cytometry to measure monocyte activation. To test if TLR sensitivity is determined by factors in patient sera, we preconditioned healthy donor monocytes in serum from PDAC (n=23), IPMN (n=15), or age-matched healthy donors (n=10) followed by in vitro stimulation with R848 or LPS and multiplex cytokine measurements in the supernatant. Results: TNF expression in R848-stimulated peripheral blood monocytes was higher in patients with low grade vs high grade IPMN (65% vs 32%, p = 0.03) and stage 1 vs stage 2/3 PDAC (58% vs 42%, p = 0.03), this was not observed after LPS stimulation. TLR activation correlated with increasing grade of dysplasia from low grade IPMN to high grade IPMN. Serum from patients with IPMN and PDAC recapitulated suppression of TNF induction after R848 stimulation in naïve, healthy donor monocytes. Conclusion: Peripheral blood monocyte TNF secretion inversely correlates with the degree of dysplasia in IPMN and cancer stage in PDAC, suggesting innate immune reprogramming as IPMNs progress to invasive disease. These effects are, at least in part, mediated by soluble mediators in sera.

Clinical Applications of Immunotherapy for Recurrent Glioblastoma in Adults.

Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. Despite standard therapies, including resection and chemoradiation, recurrence is virtually inevitable. Current treatment for recurrent glioblastoma (rGBM) is rapidly evolving, and emerging therapies aimed at targeting primary GBM are often first tested in rGBM to demonstrate safety and feasibility, which, in recent years, has primarily been in the form of immunotherapy. The purpose of this review is to highlight progress in clinical trials of immunotherapy for rGBM, including immune checkpoint blockade, oncolytic virotherapy, chimeric antigen receptor (CAR) T-cell therapy, cancer vaccine and immunotoxins. Three independent reviewers covered literature, published between the years 2000 and 2022, in various online databases. In general, the efficacy of immunotherapy in rGBM remains uncertain, and is limited to subsets/small cohorts of patients, despite demonstrating feasibility in early-stage clinical trials. However, considerable progress has been made in understanding the mechanisms that may preclude rGBM patients from responding to immunotherapy, as well as in developing new approaches/combination strategies that may inspire optimism for the utility of immunotherapy in this devastating disease. Continued trials are necessary to further assess the best therapeutic avenues and ascertain which treatments might benefit each patient individually.

Interplay between ATRX and IDH1 mutations governs innate immune responses in diffuse gliomas.

Stimulating the innate immune system has been explored as a therapeutic option for the treatment of gliomas. Inactivating mutations in ATRX , defining molecular alterations in IDH -mutant astrocytomas, have been implicated in dysfunctional immune signaling. However, little is known about the interplay between ATRX loss and IDH mutation on innate immunity. To explore this, we generated ATRX knockout glioma models in the presence and absence of the IDH1 R 132 H mutation. ATRX-deficient glioma cells were sensitive to dsRNA-based innate immune agonism and exhibited impaired lethality and increased T-cell infiltration in vivo . However, the presence of IDH1 R 132 H dampened baseline expression of key innate immune genes and cytokines in a manner restored by genetic and pharmacological IDH1 R132H inhibition. IDH1 R132H co-expression did not interfere with the ATRX KO-mediated sensitivity to dsRNA. Thus, ATRX loss primes cells for recognition of dsRNA, while IDH1 R132H reversibly masks this priming. This work reveals innate immunity as a therapeutic vulnerability of astrocytoma.

Orthogonal CRISPR screens to identify transcriptional and epigenetic regulators of human CD8 T cell function.

The clinical response to adoptive T cell therapies is strongly associated with transcriptional and epigenetic state. Thus, technologies to discover regulators of T cell gene networks and their corresponding phenotypes have great potential to improve the efficacy of T cell therapies. We developed pooled CRISPR screening approaches with compact epigenome editors to systematically profile the effects of activation and repression of 120 transcription factors and epigenetic modifiers on human CD8+ T cell state. These screens nominated known and novel regulators of T cell phenotypes with BATF3 emerging as a high confidence gene in both screens. We found that BATF3 overexpression promoted specific features of memory T cells such as increased IL7R expression and glycolytic capacity, while attenuating gene programs associated with cytotoxicity, regulatory T cell function, and T cell exhaustion. In the context of chronic antigen stimulation, BATF3 overexpression countered phenotypic and epigenetic signatures of T cell exhaustion. CAR T cells overexpressing BATF3 significantly outperformed control CAR T cells in both in vitro and in vivo tumor models. Moreover, we found that BATF3 programmed a transcriptional profile that correlated with positive clinical response to adoptive T cell therapy. Finally, we performed CRISPR knockout screens with and without BATF3 overexpression to define co-factors and downstream factors of BATF3, as well as other therapeutic targets. These screens pointed to a model where BATF3 interacts with JUNB and IRF4 to regulate gene expression and illuminated several other novel targets for further investigation.

Intratumor childhood vaccine-specific CD4+ T-cell recall coordinates antitumor CD8+ T cells and eosinophils.

BACKGROUND: Antitumor mechanisms of CD4+ T cells remain crudely defined, and means to effectively harness CD4+ T-cell help for cancer immunotherapy are lacking. Pre-existing memory CD4+ T cells hold potential to be leveraged for this purpose. Moreover, the role of pre-existing immunity in virotherapy, particularly recombinant poliovirus immunotherapy where childhood polio vaccine specific immunity is ubiquitous, remains unclear. Here we tested the hypothesis that childhood vaccine-specific memory T cells mediate antitumor immunotherapy and contribute to the antitumor efficacy of polio virotherapy. METHODS: The impact of polio immunization on polio virotherapy, and the antitumor effects of polio and tetanus recall were tested in syngeneic murine melanoma and breast cancer models. CD8+ T-cell and B-cell knockout, CD4+ T-cell depletion, CD4+ T-cell adoptive transfer, CD40L blockade, assessments of antitumor T-cell immunity, and eosinophil depletion defined antitumor mechanisms of recall antigens. Pan-cancer transcriptome data sets and polio virotherapy clinical trial correlates were used to assess the relevance of these findings in humans. RESULTS: Prior vaccination against poliovirus substantially bolstered the antitumor efficacy of polio virotherapy in mice, and intratumor recall of poliovirus or tetanus immunity delayed tumor growth. Intratumor recall antigens augmented antitumor T-cell function, caused marked tumor infiltration of type 2 innate lymphoid cells and eosinophils, and decreased proportions of regulatory T cells (Tregs). Antitumor effects of recall antigens were mediated by CD4+ T cells, limited by B cells, independent of CD40L, and dependent on eosinophils and CD8+ T cells. An inverse relationship between eosinophil and Treg signatures was observed across The Cancer Genome Atlas (TCGA) cancer types, and eosinophil depletion prevented Treg reductions after polio recall. Pretreatment polio neutralizing antibody titers were higher in patients living longer, and eosinophil levels increased in the majority of patients, after polio virotherapy. CONCLUSION: Pre-existing anti-polio immunity contributes to the antitumor efficacy of polio virotherapy. This work defines cancer immunotherapy potential of childhood vaccines, reveals their utility to engage CD4+ T-cell help for antitumor CD8+ T cells, and implicates eosinophils as antitumor effectors of CD4+ T cells.

Recombinant polio-rhinovirus immunotherapy for recurrent paediatric high-grade glioma: a phase 1b trial.

BACKGROUND: Outcomes of recurrent paediatric high-grade glioma are poor, with a median overall survival of less than 6 months. Viral immunotherapy, such as the polio-rhinovirus chimera lerapolturev, is a novel approach for treatment of recurrent paediatric high-grade glioma and has shown promise in adults with recurrent glioblastoma. The poliovirus receptor CD155 is ubiquitously expressed in malignant paediatric brain tumours and is a treatment target in paediatric high-grade glioma. We aimed to assess the safety of lerapolturev when administered as a single dose intracerebrally by convection enhanced delivery in children and young people with recurrent WHO grade 3 or grade 4 glioma, and to assess overall survival in these patients. METHODS: This phase 1b trial was done at the Duke University Medical Center (Durham, NC, USA). Patients aged 4-21 years with recurrent high-grade malignant glioma (anaplastic astrocytoma, glioblastoma, anaplastic oligoastrocytoma, anaplastic oligodendroglioma, or anaplastic pleomorphic xanthoastrocytoma) or anaplastic ependymoma, atypical teratoid rhabdoid tumour, or medulloblastoma with infusible disease were eligible for this study. A catheter was tunnelled beneath the scalp for a distance of at least 5 cm to aid in prevention of infection. The next day, lerapolturev at a dose of 5 × 107 median tissue culture infectious dose in 3 mL infusate loaded in a syringe was administered via a pump at a rate of 0·5 mL per h as a one-time dose. The infusion time was approximately 6·5 h to compensate for volume of the tubing. The primary endpoint was the proportion of patients with unacceptable toxic effects during the 14-day period after lerapolturev treatment. The study is registered with ClinicalTrials.gov, NCT03043391. FINDINGS: Between Dec 5, 2017, and May 12, 2021, 12 patients (11 unique patients) were enrolled in the trial. Eight patients were treated with lerapolturev. The median patient age was 16·5 years (IQR 11·0-18·0), five (63%) of eight patients were male and three (38%) were female, and six (75%) of eight patients were White and two (25%) were Black or African American. The median number of previous chemotherapeutic regimens was 3·50 (IQR 1·25-5·00). Six of eight patients had 26 treatment-related adverse events attributable to lerapolturev. There were no irreversible (ie, persisted longer than 2 weeks) treatment-related grade 4 adverse events or deaths. Treatment-related grade 3 adverse events included headaches in two patients and seizure in one patient. Four patients received low-dose bevacizumab on-study for treatment-related peritumoural inflammation or oedema, diagnosed by both clinical symptoms plus fluid-attenuated inversion recovery MRI. The median overall survival was 4·1 months (95% CI 1·2-10·1). One patient remains alive after 22 months. INTERPRETATION: Convection enhanced delivery of lerapolturev is safe enough in the treatment of recurrent paediatric high-grade glioma to proceed to the next phase of trial. FUNDING: Solving Kids Cancer, B+ Foundation, Musella Foundation, and National Institutes of Health.

Polio virotherapy targets the malignant glioma myeloid infiltrate with diffuse microglia activation engulfing the CNS.

BACKGROUND: Malignant gliomas commandeer dense inflammatory infiltrates with glioma-associated macrophages and microglia (GAMM) promoting immune suppression, evasion, and tumor progression. Like all cells in the mononuclear phagocytic system, GAMM constitutively express the poliovirus receptor, CD155. Besides myeloid cells, CD155 is widely upregulated in the neoplastic compartment of malignant gliomas. Intratumor treatment with the highly attenuated rhino:poliovirus chimera, PVSRIPO, yielded long-term survival with durable radiographic responses in patients with recurrent glioblastoma (Desjardins et al. New England Journal of Medicine, 2018). This scenario raises questions about the contributions of myeloid versus neoplastic cells to polio virotherapy of malignant gliomas. METHODS: We investigated PVSRIPO immunotherapy in immunocompetent mouse brain tumor models with blinded, board-certified neuropathologist review, a range of neuropathological, immunohistochemical, and immunofluorescence analyses, and RNAseq of the tumor region. RESULTS: PVSRIPO treatment caused intense engagement of the GAMM infiltrate associated with substantial, but transient tumor regression. This was accompanied by marked microglia activation and proliferation in normal brain surrounding the tumor, in the ipsilateral hemisphere and extending into the contralateral hemisphere. There was no evidence for lytic infection of malignant cells. PVSRIPO-instigated microglia activation occurred against a backdrop of sustained innate antiviral inflammation, associated with induction of the Programmed Cell Death Ligand 1 (PD-L1) immune checkpoint on GAMM. Combining PVSRIPO with PD1/PD-L1 blockade led to durable remissions. CONCLUSIONS: Our work implicates GAMM as active drivers of PVSRIPO-induced antitumor inflammation and reveals profound and widespread neuroinflammatory activation of the brain-resident myeloid compartment by PVSRIPO.

Encoding of environmental illumination by primate melanopsin neurons.

Light regulates physiology, mood, and behavior through signals sent to the brain by intrinsically photosensitive retinal ganglion cells (ipRGCs). How primate ipRGCs sense light is unclear, as they are rare and challenging to target for electrophysiological recording. We developed a method of acute identification within the live, ex vivo retina. Using it, we found that ipRGCs of the macaque monkey are highly specialized to encode irradiance (the overall intensity of illumination) by blurring spatial, temporal, and chromatic features of the visual scene. We describe mechanisms at the molecular, cellular, and population scales that support irradiance encoding across orders-of-magnitude changes in light intensity. These mechanisms are conserved quantitatively across the ~70 million years of evolution that separate macaques from mice.

Multimodality analysis confers a prognostic benefit of a T-cell infiltrated tumor microenvironment and peripheral immune status in patients with melanoma.

BACKGROUND: We previously reported results from a phase 1 study testing intratumoral recombinant poliovirus, lerapolturev, in 12 melanoma patients. All 12 patients received anti-PD-1 systemic therapy before lerapolturev, and 11 of these 12 patients also received anti-PD-1 after lerapolturev. In preclinical models lerapolturev induces intratumoral innate inflammation that engages antitumor T cells. In the current study, prelerapolturev and postlerapolturev tumor biopsies and blood were evaluated for biomarkers of response. METHODS: The following analyses were performed on tumor tissue (n=11): (1) flow cytometric assessment of immune cell density, (2) NanoString Digital Spatial profiling of protein and the transcriptome, and (3) bulk RNA sequencing. Immune cell phenotypes and responsiveness to in vitro stimulation, including in vitro lerapolturev challenge, were measured in peripheral blood (n=12). RESULTS: Three patients who received anti-PD-1 therapy within 30 days of lerapolturev have a current median progression-free survival (PFS) of 2.3 years and had higher CD8+T cell infiltrates in prelerapolturev tumor biopsies relative to that of 7 patients with median PFS of 1.6 months and lower CD8+T cell infiltrates in prelerapolturev tumor biopsies. In peripheral blood, four patients with PFS 2.3 years (including three that received anti-PD-1 therapy within 30 days before lerapolturev and had higher pretreatment tumor CD8+T cell infiltrates) had significantly higher effector memory (CD8+, CCR7-, CD45RA-) but lower CD8+PD-1+ and CD4+PD-1+ cells compared with eight patients with median PFS 1.6 months. In addition, pretreatment blood from the four patients with median PFS 2.3 years had more potent antiviral responses to in vitro lerapolturev challenge compared with eight patients with median PFS 1.6 months. CONCLUSION: An inflamed pretreatment tumor microenvironment, possibly induced by prior anti-PD-1 therapy and a proficient peripheral blood pretreatment innate immune response (antiviral/interferon signaling) to lerapolturev was associated with long term PFS after intratumoral lerapolturev in a small cohort of patients. These findings imply a link between intratumoral T cell inflammation and peripheral immune function. TRIAL REGISTRATION NUMBER: NCT03712358.

PKR Binds Enterovirus IRESs, Displaces Host Translation Factors, and Impairs Viral Translation to Enable Innate Antiviral Signaling.

For RNA virus families except Picornaviridae, viral RNA sensing includes Toll-like receptors and/or RIG-I. Picornavirus RNAs, whose 5' termini are shielded by a genome-linked protein, are predominately recognized by MDA5. This has important ramifications for adaptive immunity, as MDA5-specific patterns of type-I interferon (IFN) release are optimal for CD4+T cell TH1 polarization and CD8+T cell priming. We are exploiting this principle for cancer immunotherapy with recombinant poliovirus (PV), PVSRIPO, the type 1 (Sabin) PV vaccine containing a rhinovirus type 2 internal ribosomal entry site (IRES). Here we show that PVSRIPO-elicited MDA5 signaling is preceded by early sensing of the IRES by the double-stranded (ds)RNA-activated protein kinase (PKR). PKR binding to IRES stem-loop domains 5-6 led to dimerization and autoactivation, displaced host translation initiation factors, and suppressed viral protein synthesis. Early PKR-mediated antiviral responses tempered incipient viral translation and the activity of cytopathogenic viral proteinases, setting up accentuated MDA5 innate inflammation in response to PVSRIPO infection. IMPORTANCE Among the RIG-I-like pattern recognition receptors, MDA5 stands out because it senses long dsRNA duplexes independent of their 5' features (RIG-I recognizes viral [v]RNA 5'-ppp blunt ends). Uniquely among RNA viruses, the innate defense against picornaviruses is controlled by MDA5. We show that prior to engaging MDA5, recombinant PV RNA is sensed upon PKR binding to the viral IRES at a site that overlaps with the footprint for host translation factors mediating 40S subunit recruitment. Our study demonstrates that innate antiviral type-I IFN responses orchestrated by MDA5 involve separate innate modules that recognize distinct vRNA features and interfere with viral functions at multiple levels.

Validation of Intrinsic Left Ventricular Assist Device Data Tracking Algorithm for Early Recognition of Centrifugal Flow Pump Thrombosis.

Advanced stage heart failure patients can benefit from the unloading effects of an implantable left ventricular assist device. Despite best clinical practice, LVADs are associated with adverse events, such as pump thrombosis (PT). An adaptive algorithm alerting when an individual's appropriate levels in pump power uptake are exceeded, such as in the case of PT, can improve therapy of patients implanted with a centrifugal LVAD. We retrospectively studied 75 patients implanted with a centrifugal LVAD in a single center. A previously optimized adaptive pump power-tracking algorithm was compared to clinical best practice and clinically available constant threshold algorithms. Algorithm performances were analyzed in a PT group (n = 16 patients with 30 PT events) and a thoroughly selected control group (n = 59 patients, 34.7 patient years of LVAD data). Comparison of the adaptive power-tracking algorithm with the best performing constant threshold algorithm resulted in sensitivity of 83.3% vs. 86.7% and specificity of 98.9% vs. 95.3%, respectively. The power-tracking algorithm produced one false positive detection every 11.6 patient years and early warnings with a median of 3.6 days prior to PT diagnosis. In conclusion, a retrospective single-center validation study with real-world patient data demonstrated advantageous application of a power-tracking algorithm into LVAD systems and clinical practice.

Twelve-month evaluation of a novel mineral-organic adhesive material used to stabilize dental implants placed in oversized osteotomies in vivo in an animal model.

OBJECTIVES: The aim of this study is to evaluate long-term in vivo stability of dental implants stabilized at time of placement in oversized osteotomies with a novel, self-setting, mineral-organic bone adhesive. MATERIALS/METHODS: Canine (26) mandibular teeth were removed, and three oversized osteotomies prepared bilaterally. Implants were placed with either adhesive, particulate xenograft, or with blood clot filling the implant/osteotomy gaps. Removal torque and histology were assessed. RESULTS: The adhesive provided significant and clinically relevant immediate implant stability of 22.2 N-cm (95% CI 5.3; 39.0), which continued throughout the early postoperative course and persisted through the nine- (155 N-cm 95% CI 113; 197) and 12-month (171 N-cm 95% CI 134.2; 209.4) time points. This is in comparison with the blood clot of 1.4 N-cm (95% CI 0.7; 2.1), 128.6 N-cm (95% CI 66.8; 190.4), and 140.7 N-cm (95% CI 78.8; 202.5) and particulate xenograft, 1.3 N-cm (95% CI 0.6; 2.0), 132.1 N-cm (95% CI 94.5; 169.7), and 101.5 (95% CI 59.5; 143.5), respectively. Histological examination shows the adhesive establishes intimate contact with the implant and bony walls and is replaced with new bone without compromising stability. Soft tissue does not penetrate the adhesive, and marginal bone/biomaterial level is maintained. Control sites filled with xenograft or blood clot heal with reduced bone levels, and in some cases, xenograft particles were encapsulated in connective tissue. CONCLUSIONS: Implants placed in oversized osteotomies and lacking primary stability can be stabilized at placement with a novel, highly osteoconductive, and resorbable adhesive. Gradual replacement of the biomaterial allows osseointegration without loss of stability through 12 months of follow-up. This novel adhesive has the potential to stabilize implants placed in sites with inadequate bony support.