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Study Design: A retrospective cohort study with chart review.Objective: To determine if there is a difference in risk of adverse outcomes following elective posterior instrumented lumbar spinal fusions for patients aged 80 years and above compared with patients aged 50 to 79 years.Summary Of Background Data: Patients aged 80 years and above are undergoing elective lumbar spinal fusion surgery in increasing numbers. There are conflicting data on the risks of intraoperative and postoperative complications in these patients.Materials and Methods: Patients aged 80 years and above were compared with 50 to 79 years (reference group) using time-dependent multivariable Cox proportional hazards regression with a competing risk of death for longitudinal outcomes and multivariable logistic regression for binary outcomes. Outcome measures used were: (1) intraoperative complications (durotomy), (2) postoperative complications: 30-day outcomes (pneumonia); 90-day outcomes (deep vein thrombosis, pulmonary embolism, emergency room visits, readmission, reoperations, and mortality); and two-year outcomes (reoperations and mortality).Results: The cohort consisted of 7880 patients who underwent primary elective posterior instrumented lumbar spinal fusion (L1-S1) for degenerative disk disease or spondylolisthesis. This was subdivided into 596 patients were aged 80 years and above and 7284 patients aged 50 to 79. After adjustment, patients aged 80 years and above had a higher likelihood of durotomy [odds ratio (OR)=1.43, 95% confidence interval (CI)=1.02-2.02] and 30-day pneumonia (OR=1.81, 95% CI=1.01-3.23). However, there was a lower risk of reoperation within two years of the index procedure (hazard ratio=0.69, 95% CI=0.48-0.99). No differences were observed for mortality, readmissions, emergency room visits, pulmonary embolism, or deep vein thrombosis.Conclusions: In a cohort of 7880 elective posterior instrumented lumbar fusion patients for degenerative disk disease or spondylolisthesis, we did not observe any significant risks of adverse events between patients aged 80 years and above and those aged 50 to 79 except for higher durotomies and 30-day pneumonia in the former. We believe octogenarians can safely undergo lumbar fusions, but proper preoperative screening is necessary to reduce the risks of 30-day pneumonia. [ABSTRACT FROM AUTHOR]

The vestibular system encodes head motion in space which is naturally accompanied by other sensory cues. Electrical stimuli, applied across the mastoid processes, selectively activate primary vestibular afferents which has spurred clinical and biomedical applications of electrical vestibular stimulation (EVS). When properly matched to head motion, EVS may also manipulate the closed-loop relationship between actions and vestibular feedback to reveal the mechanisms of sensorimotor recalibration and learning. We designed a portable, low-cost real-time EVS system using an Arduino microcontroller programmed through Simulink that provides electrical currents based on head angular motion. We used well-characterized vestibular afferent physiological responses to head angular velocity and electrical current to compute head-motion equivalent of real-time modulatory EVS currents. We also examined if our system induced recalibration of the vestibular system during human balance control. Our system operated at 199.997 Hz (± 0.005 Hz) and delivered head-motion-equivalent electrical currents with ∼10 ms delay. The output driving the current stimulator matched the implemented linear model for physiological vestibular afferent dynamics with minimal background noise (<0.2% of ± 10 V range). Participants recalibrated to the modulated closed-loop vestibular feedback using visual cues during standing balance, replicating earlier findings. EVS is typically used to impose external perturbations that are independent of one's own movement. We provided a solution using open-source hardware to implement a real-time, physiology based, and task-relevant vestibular modulations using EVS. Our portable, low-cost vestibular modulation system will make physiological closed-loop vestibular manipulations more accessible thus encouraging novel investigations and biomedical applications of EVS. [Display omitted] • Electrical vestibular stimulation (EVS) activates vestibular afferents. • Our system generates EVS based on the physiology of the vestibular system. • Designed a portable system to modulate human vestibular sense in real-time. • Closed-loop manipulation of the vestibular sense induces vestibular recalibration. • Our system opens opportunities to reveal how we learn and interact with the world. [ABSTRACT FROM AUTHOR]

The GPR124/RECK/WNT7 pathway is an essential regulator of CNS angiogenesis and blood-brain barrier (BBB) function. GPR124, a brain endothelial adhesion seven-pass transmembrane protein, associates with RECK, which binds and stabilizes newly synthesized WNT7 that is transferred to frizzled (FZD) to initiate canonical β-catenin signaling. GPR124 remains enigmatic: although its extracellular domain (ECD) is essential, the poorly conserved intracellular domain (ICD) appears to be variably required in mammals versus zebrafish, potentially via adaptor protein bridging of GPR124 and FZD ICDs. GPR124 ICD deletion impairs zebrafish angiogenesis, but paradoxically retains WNT7 signaling upon mammalian transfection. We thus investigated GPR124 ICD function using the mouse deletion mutant Gpr124ΔC. Despite inefficiently expressed GPR124ΔC protein, Gpr124ΔC/ΔC mice could be born with normal cerebral cortex angiogenesis, in comparison with Gpr124−/− embryonic lethality, forebrain avascularity and hemorrhage. Gpr124ΔC/ΔC vascular phenotypes were restricted to sporadic ganglionic eminence angiogenic defects, attributable to impaired GPR124ΔC protein expression. Furthermore, Gpr124ΔC and the recombinant GPR124 ECD rescued WNT7 signaling in culture upon brain endothelial Gpr124 knockdown. Thus, in mice, GPR124- regulated CNS forebrain angiogenesis and BBB function are exerted by ICD-independent functionality, extending the signaling mechanisms used by adhesion seven-pass transmembrane receptors. [ABSTRACT FROM AUTHOR]

The National Center for Advancing Translational Sciences (NCATS) Assay Guidance Manual (AGM) Workshop on 3D Tissue Models for Antiviral Drug Development, held virtually on 7–8 June 2022, provided comprehensive coverage of critical concepts intended to help scientists establish robust, reproducible, and scalable 3D tissue models to study viruses with pandemic potential. This workshop was organized by NCATS, the National Institute of Allergy and Infectious Diseases, and the Bill and Melinda Gates Foundation. During the workshop, scientific experts from academia, industry, and government provided an overview of 3D tissue models' utility and limitations, use of existing 3D tissue models for antiviral drug development, practical advice, best practices, and case studies about the application of available 3D tissue models to infectious disease modeling. This report includes a summary of each workshop session as well as a discussion of perspectives and challenges related to the use of 3D tissues in antiviral drug discovery. [ABSTRACT FROM AUTHOR]

Sudden cardiac arrest (SCA) is a leading cause of mortality worldwide. The SCA-to-resuscitation interval is a key determinant of patient outcomes, highlighting the clinical need for reliable and timely detection of SCA. Near-infrared spectroscopy (NIRS), a non-invasive optical technique, may have utility for this application. We investigated transcutaneous NIRS as a method to detect pentobarbital-induced changes during cardiac arrest in eight Yucatan miniature pigs. NIRS measurements during cardiac arrest were compared to invasively acquired carotid blood pressure and partial oxygen pressure (PO2) of spinal cord tissues. We observed statistically significant decreases in mean arterial pressure (MAP) 64.68 mmHg ± 13.08, p < 0.0001), spinal cord PO2 (38.16 mmHg ± 20.04, p = 0.0028), and NIRS-derived tissue oxygen saturation (TSI%) (14.50% ± 3.80, p < 0.0001) from baseline to 5 min after pentobarbital administration. Euthanasia-to-first change in hemodynamics for MAP and TSI (%) were similar [MAP (10.43 ± 4.73 s) vs TSI (%) (12.04 ± 1.85 s), p = 0.3714]. No significant difference was detected between NIRS and blood pressure-derived pulse rates during baseline periods (p > 0.99) and following pentobarbital administration (p = 0.97). Transcutaneous NIRS demonstrated the potential to identify rapid hemodynamic changes due to cardiac arrest in periods similar to invasive indices. We conclude that transcutaneous NIRS monitoring may present a novel, non-invasive approach for SCA detection, which warrants further investigation. [ABSTRACT FROM AUTHOR]

This paper uses the reconstruction-computation-quantization (RCQ)paradigm to decode low-density parity-check (LDPC) codes. RCQ facilitates dynamic non-uniform quantization to achieve good frame error rate (FER) performance with very low message precision. For message-passing according to a flooding schedule, the RCQ parameters are designed by discrete density evolution. Simulation results on an IEEE 802.11 LDPC code show that for 4-bit messages, a flooding Min Sum RCQ decoder outperforms table-lookup approaches such as information bottleneck (IB) or Min-IB decoding, with significantly fewer parameters to be stored. Additionally, this paper introduces layer-specific RCQ, an extension of RCQ decoding for layered architectures. Layer-specific RCQ uses layer-specific message representations to achieve the best possible FER performance. For layer-specific RCQ, this paper proposes using layered discrete density evolution featuring hierarchical dynamic quantization (HDQ) to design parameters efficiently. Finally, this paper studies field-programmable gate array (FPGA) implementations of RCQ decoders. Simulation results for a (9472, 8192) quasi-cyclic (QC) LDPC code show that a layered Min Sum RCQ decoder with 3-bit messages achieves more than a 10% reduction in LUTs and routed nets and more than a 6% decrease in register usage while maintaining comparable decoding performance, compared to a 5-bit offset Min Sum decoder. [ABSTRACT FROM AUTHOR]

The test for the cancer stem cell (CSC) hypothesis is to find a target expressed on all, and only CSCs in a patient tumor, then eliminate all cells with that target that eliminates the cancer. That test has not yet been achieved, but CSC diagnostics and targets found on CSCs and some other cells have resulted in a few clinically relevant therapies. However, it has become apparent that eliminating the subset of tumor cells characterized by self‐renewal properties is essential for long‐term tumor control. CSCs are able to regenerate and initiate tumor growth, recapitulating the heterogeneity present in the tumor before treatment. As great progress has been made in identifying and elucidating the biology of CSCs as well as their interactions with the tumor microenvironment, the time seems ripe for novel therapeutic strategies that target CSCs to find clinical applicability. On May 19–21, 2021, researchers in cancer stem cells met virtually for the Keystone eSymposium "Cancer Stem Cells: Advances in Biology and Clinical Translation" to discuss recent advances in the understanding of CSCs as well as clinical efforts to target these populations. [ABSTRACT FROM AUTHOR]

Biosensor technologies have been proposed as a solution to provide recognition and facilitate earlier responses to unwitnessed out-of-hospital cardiac arrest (OHCA) cases. We sought to estimate the effect of recognition on survival and modelled the potential incremental impact of increased recognition of unwitnessed cases on survival to hospital discharge, to demonstrate the potential benefit of biosensor technologies. We included cases from the British Columbia Cardiac Arrest Registry (2019–2020), which includes Emergency Medical Services (EMS)-assessed OHCAs. We excluded cases that would not have benefitted from early recognition (EMS-witnessed, terminal illness, or do-not-resuscitate). Using a mediation analysis, we estimated the relative benefits on survival of a witness recognizing vs. intervening in an OHCA; and estimated the expected additional number of survivors resulting from increasing recognition alone using a bootstrap logistic regression framework. Of 13,655 EMS-assessed cases, 11,412 were included (6314 EMS-treated, 5098 EMS-untreated). Survival to hospital discharge was 191/8879 (2.2%) in unwitnessed cases and 429/2533 (17%) in bystander-witnessed cases. Of the total effect attributable to a bystander witness, recognition accounted for 84% (95% CI: 72, 86) of the benefit. If all previously unwitnessed cases had been bystander witnessed, we would expect 1198 additional survivors. If these cases had been recognized, but no interventions performed, we would expect 912 additional survivors. Unwitnessed OHCA account for the majority of OHCAs, yet survival is dismal. Methods to improve recognition, such as with biosensor technologies, may lead to substantial improvements in overall survival. [ABSTRACT FROM AUTHOR]

Degenerative spondylolisthesis (DS) with lumbar spinal stenosis (LSS) is commonly treated with decompression and fusion. The LimiFlex Dynamic Sagittal Tether (DST) is an investigational stabilization device for patients with DS and LSS. The purpose of this study is to assess the clinical and radiographic outcomes of decompression and DST compared to transforaminal lumbar interbody fusion (TLIF) for patients with DS and LSS. Multicenter prospective concurrently controlled study. Patients undergoing treatment (decompression and DST or TLIF stabilization) of Grade I Meyerding lumbar degenerative spondylolisthesis. Patients undergoing treatment (decompression and DST or TLIF stabilization) of Grade I Meyerding lumbar degenerative spondylolisthesis. Patients with single-level Grade I DS with LSS were enrolled in the FDA-IDE study (NCT03115983) comparing decompression with DST and decompression with TLIF. Clinical and radiographic outcomes were assessed at baseline and 6-week, 3, 6, 12 and 24-month follow-up. All propensity score (PS) selected patients who had 24-month follow-up were included in this interim analysis. Summary statistics are reported, as well as paired t-tests to assess within-group changes. At 24 months, 228 PS-selected patients (129DST/99TLIF) had clinical follow-up and 197 (117DST/80TLIF) had radiographic follow-up. Mean characteristics of DST and TLIF groupswere: age 65.5/64.1 yrs; BMI 28.1/30.5; CCI 0.43/0.41, respectively. Mean perioperative outcomes for DST/TLIF were: procedure time 112/189 min; EBL 53/232 mL; LOS 0.7/3.2 nights. A significant reduction at 24 months for mean VAS-leg/hip (79.5 to 22.9), VAS-back (66.8 to 19.0) and ODI (52.8 to 13.2) was reported for DST patients (all p < 0.01) with 91% achieving 15-point ODI improvement. TLIF patients demonstrated similar improvements for VAS-leg (80.6 to 24.4), VAS-back (68.1 to 26.1) and ODI (52.3 to 20.9) (all p < 0.01), with 80% achieving 15-point ODI improvement. While there was no difference at baseline, the DST group had lower ODI at all postoperative timepoints. Within the 24 months, 9% of each group had additional surgery at the index or adjacent level. At 24 months, the DST group had mean reductions of 1.7° ROM and 0.4mm translation in flexion/extension images compared to 3.8° and 1.0mm reductions in the TLIF group. Considering the index and adjacent segments together (IAS), the index segment accounted for 30% of IAS ROM at baseline and 27% at 24 months in the DST group compared to 29% at baseline and 13% at 24 months in the TLIF group. These results suggest that decompression with DST stabilization for spondylolisthesis can achieve significant clinical improvement as is expected with fusion, without an increase in reoperations during the 24 months postoperative period. Similarly, statistically significant improvements in patient-reported outcomes were demonstrated in each group, with lower disability scores in the DTB group at all postoperative timepoints. Imaging demonstrated no increased instability in the DST group with maintained distribution of motion between the index and adjacent segments. While these groups were PS-selected, further analyses should include quantitative comparison between groups with PS-adjusted differences per the predefined composite clinical success criteria for a definitive comparison of outcomes. LimiFlex Dynamic Sagittal Tether (Investigational/Not Approved). [ABSTRACT FROM AUTHOR]

Degenerative spondylolisthesis (DS) with lumbar spinal stenosis (LSS) is commonly treated with decompression and fusion. The LimiFlex Dynamic Sagittal Tether (DST) is an investigational stabilization device for patients with DS and LSS. Assess return to work (RTW) and activities of daily living (ADL) receiving either decompression and DST stabilization (D+DST) or decompression and transforaminal lumbar interbody fusion (D+TLIF). Interim analysis from a multicenter, concurrently controlled study. Patients undergoing treatment (D+DST or D+TLIF) of Grade I Meyerding lumbar DS. Propensity score (PS) selected patients with 12-month follow-up were included. Time to RTW and activities of daily living, as well as Oswestry disability index (ODI). PS-selected IDE study subjects with 12 months of follow-up were included in this analysis. Study records queried for work status preoperatively and at 12 months, as well as time to RTW and ADL, and change in disability (Oswestry Disability Index; ODI) at 12 months vs preop. Outcomes were compared using student's t-tests. PS-selected subjects totaled 267 (136 D+DST, 131 D+TLIF). Preoperatively, 49% of D+DST and 43% of D+TLIF subjects were working (p=0.14) and 7% D+DST and 11% D+TLIF were not working due to spinal condition (NWSC) (p=0.13). At 12 months postop, 44% of D+DST and 34% of D+TLIF subjects were working (p=0.05) and 2% D+DST and 10% D+TLIF were NWSC (p<0.01). Proportion of D+DST NWSC was significantly lower 12 months postop compared to preop (p=0.02). Mean±SD RTW time for D+DST/D+TLIF subjects was 5.4±6.6/11.8±9.6 weeks (p<0.01) and return to ADL time was 5.5±6.5/10.0±9.5 weeks (p<0.01). Mean±SD reduction in disability at 12 months from baseline was 38.1±18.4 for the D+DST group and 31.8±20.7 for the D+TLIF group (p<0.01) with effect sizes of -2.1 and -1.5, respectively. The primary objective of surgery for symptomatic DS is resolution of symptoms so patients can return to their normal ADL and work. Both D+DST and D+TLIF treated patients demonstrated a significant reduction in disability at 12-month follow-up. Significantly faster RTW and ADL were observed for D+DST compared to D+TLIF patients, by an average of more than 5 weeks. The proportion of D+DST patients NWSC was significantly less than at 12 months. Results indicate a significant advantage of earlier recovery for the D+DST patients allowing earlier RTW and earlier increase in ADLs compared to D+TLIF, with similar or greater improvements in disability after one year for patients treated with decompression and stabilization for symptomatic DS. Longer-term follow-up assessment with propensity score-adjusted outcomes will demonstrate whether this advantage and long-term outcomes are durable and generalizable. This abstract does not discuss or include any applicable devices or drugs. [ABSTRACT FROM AUTHOR]

The human respiratory epithelium is derived from a progenitor cell in the distal buds of the developing lung. These "bud tip progenitors" are regulated by reciprocal signaling with surrounding mesenchyme; however, mesenchymal heterogeneity and function in the developing human lung are poorly understood. We interrogated single-cell RNA sequencing data from multiple human lung specimens and identified a mesenchymal cell population present during development that is highly enriched for expression of the WNT agonist RSPO2, and we found that the adjacent bud tip progenitors are enriched for the RSPO2 receptor LGR5. Functional experiments using organoid models, explant cultures, and FACS-isolated RSPO2+ mesenchyme show that RSPO2 is a critical niche cue that potentiates WNT signaling in bud tip progenitors to support their maintenance and multipotency. [Display omitted] • scRNA-seq of developing human distal lung mesenchyme identified cellular heterogeneity • RSPO2+ mesenchymal cells lie adjacent to LGR5+ epithelial bud tip progenitors • Blocking RSPO2/LGR5 in vitro reduced WNT signaling and led to airway differentiation • RSPO2+ mesenchyme provides a niche for bud tips in co-cultures Hein et al. present the scRNA-seq of the developing human distal lung, showing transcriptionally distinct populations of mesenchyme. Spatial profiling showed that RSPO2+ mesenchymal cells are physically adjacent to LGR5+ epithelial bud tips. Organoid experiments revealed that RSPO2+ cells create a high WNT signaling environment, supporting bud tip identity and multipotency. [ABSTRACT FROM AUTHOR]

R5339 --> 731.8 --> Background: Small intestinal bicarbonate transport, is critical for epithelial protection, digestion, and absorption. Membrane trafficking and/or recycling of transporters is a critical means to modulate their function, however, the cellular mechanisms that drive these processes in the duodenum remain unclear. The inositol 1,4,5‐trisphosphate (IP3) receptor binding protein released with IP3 (IRBIT) is an intracellular protein that has been shown to regulate localization of bicarbonate transporters outside of the intestine, yet its role in regulating duodenal bicarbonate secretion is unknown. Aim: To examine duodenal expression and function of IRBIT in regulating bicarbonate transport. Methods: Duodenal endoscopic biopsies from subjects without gross or histological evidence of disease were used directly or cultured using traditional apical‐in or flipped apical‐out enteroids. mRNA expression was evaluated using qPCR and re‐analysis of a duodenal sc‐RNAseq dataset. Protein expression and localization was determined by Western blot and confocal immunofluorescence, respectively. In vivo bicarbonate secretion was measured in anesthetized mice by duodenal perfusion and back‐titration. Results: IRBIT is highly expressed in human duodenal biopsies, with protein densitometric analysis showing ≥3.5‐fold higher expression than Calu‐3 airway submucosal gland cells or HEK293 kidney‐derived cells (n=1 each). Analysis of duodenal sc‐RNAseq data (1,625 cells) showed ACHYL1 in crypts and villi. Immunofluorescence staining of human duodenal biopsies (n=3) showed IRBIT staining along the crypt‐villus axis, primarily localizing in E‐cadherin positive epithelial cells, but also present in the lamina propria. In patient‐derived duodenal enteroids, IRBIT was expressed in both crypt‐like (undifferentiated) and villus‐like (differentiated) enteroids (n=3 each), with greater IRBIT mRNA and protein expression in the latter, a pattern similar to SLC26A3 and SLC26A6 chloride/bicarbonate exchangers (n=3 each). In sc‐RNAseq analysis, AHCYL1 and SLC26A3 were co‐expressed in 38% of all villus cells, compared to only 5% co‐expressing AHCYL1 and SLC26A6. CFTR‐independent duodenal bicarbonate secretion stimulated by linaclotide (10‐7 M) was significantly inhibited by phospholipase C inhibition (U7312, 10‐6 M; 91±11%, n=3), which we showed disrupts IRBIT membrane localization, or SLC26A3 inhibition (DRAinh‐A250, 10‐5 M; 68±8%, n=10). Linaclotide stimulation of apical‐out enteroids increased both IRBIT (n=3) and SLC26A3 (n=12) membrane trafficking. Summary and Conclusions: IRBIT is highly expressed in the duodenum and appears to functionally interact with SLC26A3. IRBIT may be an attractive target to modulate small intestinal pH in diseases like cystic fibrosis, where impaired bicarbonate secretion contributes to intestinal disease and malnutrition. [ABSTRACT FROM AUTHOR]