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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]

Key points: •Longissimus activity in the lumbar region was measured using indwelling electromyography to characterize the territory of its motor units.•The distribution of motor units in the longissimus pars lumborum muscle was mainly grouped into two distinct regions.•Regional activation of the longissimus pars lumborum was also observed during functional tasks involving trunk movements.•The regional activation of the longissimus pars lumborum muscle may play a role in segmental stabilization of the lumbar spine. The longissimus pars lumborum contributes to lumbar postural control and movement. While animal studies suggest a segmental control of this muscle, the territory of motor units constituting the human longissimus pars lumborum remains unknown. The aims of this study were to identify the localization of motor unit territories in the longissimus and assess the activation of this muscle during functional tasks. Eight healthy participants were recruited. During isometric back extension contractions, single motor‐unit (at L1, L2, L3 and L4) and multi‐unit indwelling recordings (at L1, L1‐L2, L2, L2‐L3, L3, L3‐L4 and L4) were used to estimate motor unit territories in the longissimus pars lumborum based on the motor‐unit spike‐triggered averages from fine‐wire electrodes. A series of functional tasks involving trunk and arm movements were also performed. A total of 73 distinct motor units were identified along the length of the longissimus: only two motor units spanned all recording sites. The majority of the recorded motor units had muscle fibres located in two main rostro‐caudal territories (32 motor units spanned L1 to L3 and 30 spanned ∼L3 to L4) and 11 had muscle fibres outside these two main territories. We also observed distinct muscle activation between the rostral and caudal regions of the longissimus pars lumborum during a trunk rotation task. Our results show clear rostral and caudal motor unit territories in the longissimus pars lumborum muscle and suggest that the central nervous system can selectively activate regions of the superficial lumbar muscles to provide local stabilization of the spine. Key points: •Longissimus activity in the lumbar region was measured using indwelling electromyography to characterize the territory of its motor units.•The distribution of motor units in the longissimus pars lumborum muscle was mainly grouped into two distinct regions.•Regional activation of the longissimus pars lumborum was also observed during functional tasks involving trunk movements.•The regional activation of the longissimus pars lumborum muscle may play a role in segmental stabilization of the lumbar spine. [ABSTRACT FROM AUTHOR]

Study Design: Multicenter retrospective cohort study.Objective: The aim of this study was to compare reoperation rates at 5-year follow-up of unilateral laminotomy for bilateral decompression (ULBD) versus posterior decompression with instrumented fusion (Fusion) for patients with low-grade degenerative spondylolisthesis (DS) with lumbar spinal stenosis (LSS) in a multicenter database.Summary Of Background Data: Controversy exists regarding whether fusion should be used to augment decompression surgery in patients with LSS with DS. For years, the standard has been fusion with standard laminectomy to prevent postoperative instability. However, this strategy is not supported by Level 1 evidence. Instability and reoperations may be reduced or prevented using less invasive decompression techniques.Methods: We identified 164 patients with DS and LSS who underwent ULBD between January 2007 and December 2011 in a multicenter database. These patients were propensity score-matched on age, sex, race, and smoking status with patients who underwent Fusion (n = 437). Each patient required a minimum of 5-year follow-up. The primary outcome was 5-year reoperation. Secondary outcome measures included postoperative complication rates, blood loss during surgery, and length of stay. Logistic regression models were used to estimate the odds ratio of the 5-year reoperation rate between the two surgical groups.Results: The reoperation rate at 5-year follow-up was 10.4% in the ULBD group and 17.2% in the Fusion group. ULBD reoperations were more frequent at the index surgical level; Fusion reoperations were more common at an adjacent level. The two types of operations had similar postoperative complication rates, and both groups tended to have fusion reoperations.Conclusion: For patients with stable DS and LSS, ULBD is a viable, durable option compared to fusion with decreased blood loss and length stay, as well as a lower reoperation rate at 5-year follow-up. Further prospective studies are required to determine the optimal clinical scenario for ULBD in the setting of DS.Level Of Evidence: 3. [ABSTRACT FROM AUTHOR]

Objective: Humans are susceptible to traumatic brain injuries from rapid head rotations that shear and stretch the brain tissue. Conversely, animals such as woodpeckers intentionally undergo repetitive head impacts without apparent injury. Here, we represent the head as the end effector of a rigid linkage cervical spine model to quantify how head angular accelerations are affected by the linkage positioning (head-neck configuration) and the soft tissue properties (muscles, ligaments, tendons). Methods: We developed a two-pivot manipulator model of the human cervical spine with passive torque elements to represent soft tissue forces. Passive torque parameters were fit against five human subjects undergoing mild laboratory head impacts with tensed and relaxed neck muscle activations. With this representation, we compared the effects of the linkage configuration dependent end-effector inertial properties and the soft tissue resistive forces on head impact rotation. Results: Small changes in cervical spine positioning (<5 degrees) can drastically affect the resulting rotational head accelerations (>100%) following an impact by altering the effective end-effector inertia. Comparatively, adjusting the soft tissue torque elements from relaxed to tensed muscle activations had a smaller (<30%) effect on maximum rotational head accelerations. Extending our analysis to a woodpecker rigid linkage model, we postulate that woodpeckers experience relatively minimal head impact rotation due to the configuration of their skeletal anatomy. Conclusion: Cervical spine positioning dictates the head angular acceleration following an impact, rather than the soft tissue torque elements. Significance: This analysis quantifies the importance of head positioning prior to impact, and may help us to explain why other species are naturally more resilient to head impacts than humans. [ABSTRACT FROM AUTHOR]

The head is kinematically constrained to the torso through the spine and thus, the spine dictates the amount of output head angular motion expected from an input impact. Here, we investigate the spinal kinematic constraint by analyzing the head instantaneous center of rotation (HICOR) with respect to the torso in head/neck sagittal extension and coronal lateral flexion during mild loads applied to 10 subjects. We found the mean HICOR location was near the C5-C6 intervertebral joint in sagittal extension, and T2-T3 intervertebral joint in coronal lateral flexion. Using the impulse-momentum relationship normalized by subject mass and neck length, we developed a non-dimensional analytical ratio between output angular velocity and input linear impulse as a function of HICOR location. The ratio was 0.65 and 0.50 in sagittal extension and coronal lateral flexion respectively, implying 30% greater angular velocities in sagittal extension given an equivalent impulse. Scaling to subject physiology also predicts larger required impulses given greater subject mass and neck length to achieve equivalent angular velocities, which was observed experimentally. Furthermore, the HICOR has greater motion in sagittal extension than coronal lateral flexion, suggesting the head and spine can be represented with a single inverted pendulum in coronal lateral flexion, but requires a more complex representation in sagittal extension. The upper cervical spine has substantial compliance in sagittal extension, and may be responsible for the complex motion and greater extension angular velocities. In analyzing the HICOR, we can gain intuition regarding the neck’s role in dictating head motion during external loading. [ABSTRACT FROM AUTHOR]

Previous research has sought to quantify head impact exposure using wearable kinematic sensors. However, many sensors suffer from poor accuracy in estimating impact kinematics and count, motivating the need for additional independent impact exposure quantification for comparison. Here, we equipped seven collegiate American football players with instrumented mouthguards, and video recorded practices and games to compare video-based and sensor-based exposure rates and impact location distributions. Over 50 player-hours, we identified 271 helmet contact periods in video, while the instrumented mouthguard sensor recorded 2,032 discrete head impacts. Matching video and mouthguard real-time stamps yielded 193 video-identified helmet contact periods and 217 sensor-recorded impacts. To compare impact locations, we binned matched impacts into frontal, rear, side, oblique, and top locations based on video observations and sensor kinematics. While both video-based and sensor-based methods found similar location distributions, our best method utilizing integrated linear and angular position only correctly predicted 81 of 217 impacts. Finally, based on the activity timeline from video assessment, we also developed a new exposure metric unique to American football quantifying number of cross-verified sensor impacts per player-play. We found significantly higher exposure during games (0.35, 95% CI: 0.29–0.42) than practices (0.20, 95% CI: 0.17–0.23) (p<0.05). In the traditional impacts per player-hour metric, we observed higher exposure during practices (4.7) than games (3.7) due to increased player activity in practices. Thus, our exposure metric accounts for variability in on-field participation. While both video-based and sensor-based exposure datasets have limitations, they can complement one another to provide more confidence in exposure statistics. [ABSTRACT FROM AUTHOR]

Head impact exposure in popular contact sports is not well understood, especially in the youth population, despite recent advances in impact-sensing technology which has allowed widespread collection of real-time head impact data. Previous studies indicate that a custom-instrumented mouthpiece is a superior method for collecting accurate head acceleration data. The objective of this study was to evaluate the efficacy of mounting a sensor device inside an acrylic retainer form factor to measure six-degrees-of-freedom (6DOF) head kinematic response. This study compares 6DOF mouthpiece kinematics at the head center of gravity (CG) to kinematics measured by an anthropomorphic test device (ATD). This study found that when instrumentation is mounted in the rigid retainer form factor, there is good coupling with the upper dentition and highly accurate kinematic results compared to the ATD. Peak head kinematics were correlated with r2 > 0.98 for both rotational velocity and linear acceleration and r2 = 0.93 for rotational acceleration. These results indicate that a rigid retainer-based form factor is an accurate and promising method of collecting head impact data. This device can be used to study head impacts in helmeted contact sports such as football, hockey, and lacrosse as well as nonhelmeted sports such as soccer and basketball. Understanding the magnitude and frequency of impacts sustained in various sports using an accurate head impact sensor, such as the one presented in this study, will improve our understanding of head impact exposure and sports-related concussion. [ABSTRACT FROM AUTHOR]

Real-time quantification of head impacts using wearable sensors is an appealing approach to assess concussion risk. Traditionally, sensors were evaluated for accurately measuring peak resultant skull accelerations and velocities. With growing interest in utilizing model-estimated tissue responses for injury prediction, it is important to evaluate sensor accuracy in estimating tissue response as well. Here, we quantify how sensor kinematic measurement errors can propagate into tissue response errors. Using previous instrumented mouthguard validation datasets, we found that skull kinematic measurement errors in both magnitude and direction lead to errors in tissue response magnitude and distribution. For molar design instrumented mouthguards susceptible to mandible disturbances, 150–400% error in skull kinematic measurements resulted in 100% error in regional peak tissue response. With an improved incisor design mitigating mandible disturbances, errors in skull kinematics were reduced to <50%, and several tissue response errors were reduced to <10%. Applying 30∘ rotations to reference kinematic signals to emulate sensor transformation errors yielded below 10% error in regional peak tissue response; however, up to 20% error was observed in peak tissue response for individual finite elements. These findings demonstrate that kinematic resultant errors result in regional peak tissue response errors, while kinematic directionality errors result in tissue response distribution errors. This highlights the need to account for both kinematic magnitude and direction errors and accurately determine transformations between sensors and the skull. [ABSTRACT FROM AUTHOR]

With 300,000,000 riders annually, roller coasters are a popular recreational activity. Although the number of roller coaster injuries is relatively low, the precise effect of roller coaster rides on our brains remains unknown. Here we present the quantitative characterization of brain displacements and deformations during roller coaster rides. For two healthy adult male subjects, we recorded head accelerations during three representative rides, and, for comparison, during running and soccer headers. From the recordings, we simulated brain displacements and deformations using rigid body dynamics and finite element analyses. Our findings show that despite having lower linear accelerations than sports head impacts, roller coasters may lead to brain displacements and strains comparable to mild soccer headers. The peak change in angular velocity on the rides was 9.9 rad/sec, which was higher than the 5.6 rad/sec in soccer headers with ball velocities reaching 7 m/sec. Maximum brain surface displacements of 4.0 mm and maximum principal strains of 7.6% were higher than in running and similar to soccer headers, but below the reported average concussion strain. Brain strain rates during roller coaster rides were similar to those in running, and lower than those in soccer headers. Strikingly, on the same ride and at a similar position, the two subjects experienced significantly different head kinematics and brain deformation. These results indicate that head motion and brain deformation during roller coaster rides are highly sensitive to individual subjects. Although our study suggests that roller coaster rides do not present an immediate risk of acute brain injury, their long-term effects require further longitudinal study. [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]

Wearable sensors are becoming increasingly popular for measuring head motions and detecting head impacts. Many sensors are worn on the skin or in headgear and can suffer from motion artifacts introduced by the compliance of soft tissue or decoupling of headgear from the skull. The instrumented mouthguard is designed to couple directly to the upper dentition, which is made of hard enamel and anchored in a bony socket by stiff ligaments. This gives the mouthguard superior coupling to the skull compared with other systems. However, multiple validation studies have yielded conflicting results with respect to the mouthguard׳s head kinematics measurement accuracy. Here, we demonstrate that imposing different constraints on the mandible (lower jaw) can alter mouthguard kinematic accuracy in dummy headform testing. In addition, post mortem human surrogate tests utilizing the worst-case unconstrained mandible condition yield 40% and 80% normalized root mean square error in angular velocity and angular acceleration respectively. These errors can be modeled using a simple spring–mass system in which the soft mouthguard material near the sensors acts as a spring and the mandible as a mass. However, the mouthguard can be designed to mitigate these disturbances by isolating sensors from mandible loads, improving accuracy to below 15% normalized root mean square error in all kinematic measures. Thus, while current mouthguards would suffer from measurement errors in the worst-case unconstrained mandible condition, future mouthguards should be designed to account for these disturbances and future validation testing should include unconstrained mandibles to ensure proper accuracy. [ABSTRACT FROM AUTHOR]

The goal of this research is to achieve close to real-time dynamics performance for allowing auto-pilot in-the-loop testing of unmanned ground vehicles (UGV) for urban as well as off-road scenarios. The overall vehicle dynamics performance is governed by the multibody dynamics model for the vehicle, the wheel/terrain interaction dynamics and the onboard control system. The topic of this paper is the development of computationally efficient and accurate dynamics model for ground vehicles with complex suspension dynamics. A challenge is that typical vehicle suspensions involve closed-chain loops which require expensive DAE integration techniques. In this paper, we illustrate the use the alternative constraint embedding technique to reduce the cost and improve the accuracy of the dynamics model for the vehicle. [ABSTRACT FROM AUTHOR]

Background: The prevention of medical and surgical harm remains an important public health problem despite increased awareness and implementation of safety programs. Successful introduction and maintenance of surgical safety programs require both surgeon leadership and collaborative surgeon-hospital alignment. Documentation of success of such surgical safety programs in orthopaedic practice is limited. Questions/purposes: We describe the scope of orthopaedic surgical patient safety issues, define critical elements of orthopaedic surgical safety, and outline leadership roles for orthopaedic surgeons needed to establish and sustain a culture of safety in contemporary healthcare systems. Methods: We identified the most common causes of preventable surgical harm based on adverse and sentinel surgical events reported to The Joint Commission. A comprehensive literature review through a MEDLINE database search (January 1982 through April 2012) to identify pertinent orthopaedic surgical safety articles found 14 articles. Where gaps in orthopaedic literature were identified, the review was supplemented by 22 nonorthopaedic surgical references. Our final review included 36 articles. Results: Six important surgical safety program elements needed to eliminate preventable surgical harm were identified: (1) effective surgical team communication, (2) proper informed consent, (3) implementation and regular use of surgical checklists, (4) proper surgical site/procedure identification, (5) reduction of surgical team distractions, and (6) routine surgical data collection and analysis to improve the safety and quality of surgical patient care. Conclusions: Successful surgical safety programs require a culture of safety supported by all six key surgical safety program elements, active surgeon champions, and collaborative hospital and/or administrative support designed to enhance surgical safety and improve surgical patient outcomes. Further research measuring improvements from such surgical safety systems in orthopaedic care is needed. [ABSTRACT FROM AUTHOR]

We retrospectively analyzed whether increased hemoglobin is a surrogate biomarker of efficacy for vascular endothelial growth factor (VEGF) inhibitors in advanced renal cell carcinoma (RCC) patients. Twelve patients were identified who had received bevacizumab alone or as combination therapy. Eleven patients experienced a rise in hemoglobin. Median change was 1.6 g/dL (0-4.0). Degree of peak increase correlated with longer progression-free survival (PFS) in metastatic patients: increase of < 15% yielded a 3.1-month median PFS compared to 8.2 months with rises > 15%. This study identifies increased hemoglobin as a possible consequence of VEGF inhibitors. The correlation with longer PFS suggests that rise in hemoglobin may be a surrogate biomarker of efficacy. [ABSTRACT FROM AUTHOR]

Abstract: Background context: Noninvasive strength assessment techniques are the clinical standard in the diagnosis and treatment of osteoporotic vertebral fractures, and the efficacy of these protocols depends on their ability to predict vertebral strength at all at-risk spinal levels under multiple physiological loading conditions. Purpose: To assess differences in vertebral strength between loading modes and across spinal levels. Study design/setting: This study examined the relative strength of isolated vertebral bodies in compression versus flexion. Methods: Destructive biomechanical tests were conducted on 30 pairs of donor-matched, isolated thoracic vertebral bodies (T9 and T10; F=19, M=11; 87+5 years old, max=97 years old, min=80 years old) in both uniform axial compression and flexion using previously described protocols. Quantitative computed tomography (QCT) scans were taken before mechanical testing and used to obtain bone mineral density (BMD) and “mechanics of solids” (MOS) measures, such as axial and bending rigidities. Results: Compressive strength was higher than flexion strength for each donor by 940+152N (p<.001, paired t test), and vertebral strengths in the two loading modes were moderately correlated (adjusted R 2=0.50, p<.001). For both compression and flexion loading modes, adjacent-level BMD and MOS metrics had approximately half the predictive capacity as same-level measurements, and BMD and MOS values were only moderately correlated across spinal levels. Conclusions: The results of this study are important in designing clinical test protocols for assessing vertebral fracture risk. Because vertebral body flexion and compressive strength are not strongly correlated and flexion strength is significantly less than compressive strength, it is imperative to investigate a patient''s spinal structural capacity under bending loading conditions. Furthermore, our work suggests that clinicians using QCT-based measures should perform site-specific strength assessments on each at-risk spinal level. Future work should focus on improving the accuracy of densitometric measures in predicting vertebral strength in flexion and also on examining same- versus adjacent-level strength assessment for radiographic techniques with lower X-ray dosage, such as dual-energy X-ray absorptiometry. [Copyright &y& Elsevier]

The article offers information on personalization of pancreatic cancer organoids using human pluripotent stem cells (hPSCs). Topics discussed include application of pharmacologic inhibition to restrict transforming growth factor (TGF) and notch signaling, testing of drug sensitivity and mislocalization of sox proteins.

Abstract: While the development of anti-angiogenic therapy, as it pertains to cancer treatment, may still be in its infancy relative to well-established modalities such as chemotherapy, radiation, and surgery, major strides made in the past several decades have allowed translation of basic science discoveries in this field into clinical reality. The discovery of key molecular modulators of angiogenesis, notably vascular endothelial growth factor (VEGF), has catalyzed the development of numerous neutralizing therapeutic agents. The validity of VEGF inhibition as a therapeutic strategy has been well supported in randomized clinical trials, as well as U.S. Food and Drug Administration approval of the VEGF antagonists bevacizumab, sunitinib malate, sorafenib, pegaptinib and ranibizumab. Accordingly, this review will (1) briefly review the basic molecular biology of VEGF and (2) summarize recent progress in targeting the VEGF molecular pathway as therapy for angiogenic diseases such as cancer and age-related macular degeneration. [Copyright &y& Elsevier]

Presents a comparative evaluation of the antitumor activity of antiangiogenic proteins delivered by gene transfer. Systemic inhibition of tumor growth by antiangiogenic adenoviruses; Correlation between the effects of viruses on tumor growth and activity of the viruses in the inhibition of corneal micrpocket angiogenesis.

Focuses on the function of collagen XVIII (c18) noncollagenous (NC1)/endostatin (ES) domain as a motility-inducing factor regulating the extracellular matrix-dependent morphogenesis of endothelial and other cell types. ES domain oligomerization; Role of physiologic product ES monomer in blocking the protein kinase-simulating activities of c18 NC1.

The article presents the author's views on the use of cancer precision medicine for treating cancer. Topics discussed includes the Cancer Genome Atlas (TCGA), initiative taken by the U.S. government for promoting precision medicine, its validation and presence of cancer cells in the wild-type tissue organoids.

Rapamycin is an immunosuppressant which antagonizes cellular proliferation by inhibiting the function of mTOR. The mTOR : FKBP12 : rapamycin complex blocks G1/S transition by inhibiting downstream targets essential for cell cycle progression. One such target is p70S6k1 (S6K1), a serine/threonine kinase which is inactivated by the mTOR : FKBP12 : rapamycin complex, and which has been linked to translational control by virtue of its ability to phosphorylate the ribosomal protein S6. In the current work, we describe cloning and characterization of a novel S6K1 homolog, p54 S6 kinase 2 (p54S6k2/S6K2). Similar to S6K1, S6K2 is activated by mitogens and by constitutively active PI3K, and is inhibited by rapamycin as well as wortmannin. Differences between activation of S6K1 and S6K2 by PDK1 were observed, suggesting potential differences in the regulation of these homologs. Strikingly, S6K2 activity and S6 phosphorylation were both intact in S6K1-/-ES cell, indicating a possible role for S6K2 in in vivo S6 phosphorylation. Interestingly, we found two isoforms of S6K2 which are localized to distinct cellular compartments; the smaller form resides in the detergent-soluble fraction, whereas the larger form is found in the particulate fraction. Our findings demonstrate the existence of a family of rapamycin-sensitive protein kinases potentially involved in S6 phosphorylation, translational control, and transduction of mTOR signals. [ABSTRACT FROM AUTHOR]

Shows that interleukin-2 selectively stimulates the phosphorylation and activation of p70 S6 kinase but not the erk-encoded MAP kinases and rsk-encoded S6 kinases. The macrolide rapamycin and its ability to induce cell cycle G1 arrest in yeast and mammalian cells; Details.

BACKGROUND CONTEXT Controversy exists regarding whether fusion should be used to augment decompression surgery in patients with symptomatic lumbar spinal stenosis with grade I/II (low-grade), stable degenerative spondylolisthesis. For years, the standard has been fusion with laminectomy in order to prevent postoperative instability. However, instability and reoperations may be reduced or prevented using less invasive, structure sparing decompression techniques without the need for fusion. PURPOSE To compare reoperation rates within a 5-year follow-up period of unilateral laminotomy for bilateral decompression (ULBD) versus posterior lumbar decompression with instrumented fusion (fusion) for patients with degenerative spondylolisthesis with spinal stenosis in a multicenter database. STUDY DESIGN/SETTING Retrospective cohort study. PATIENT SAMPLE A final cohort of 601 Kaiser Permanente Northern California members with diagnoses of lumbar degenerative spondylolisthesis and lumbar spinal stenosis of whom 164 patients underwent ULBD and 437 underwent fusion between January 2007 and December 2011. OUTCOME MEASURES The primary outcome measure was reoperation rate at 5-year postoperative follow-up. Secondary outcome measures included blood loss during surgery, length of stay, reoperation type, reoperation level, and 90-day postoperative complication rates. METHODS We identified 164 patients with lumbar degenerative spondylolisthesis and lumbar stenosis who underwent ULBD between January 2007 and December 2011. These patients were propensity score matched on age at surgery, gender, race and smoking status with patients who underwent fusion (n=437). The primary outcome was 5-year reoperation rate and secondary outcome measures included postoperative complication rates, reoperation type, reoperation level, blood loss during surgery, and length of stay. RESULTS The reoperation rate within 5-year follow-up was significantly lower at 10.4% in the ULBD group compared to 17.2% in the fusion group (p=.0393). Type of reoperation was similar between the two groups. Reoperation at the index or adjacent level was not significant different between the two groups. Patients that underwent ULBD had significantly less mean estimated blood loss compared to fusion (82 vs. 445 ml, p<.0001) and significantly shorter mean length of stay (2.3 vs. 4.6 days, p<.0001). The two types of operations had similar postoperative complication rates, with less surgical site infections for ULBD compared with fusion (1 vs. 11 cases). There was no difference in the Charlson Comorbidity Index between the two groups. CONCLUSIONS For patients with stable degenerative spondylolisthesis and lumbar stenosis, ULBD is a viable, durable option compared to fusion with a lower reoperation rate within a 5-year follow-up period, as well as decreased blood loss and length of stay. Further prospective studies are required to determine the optimal clinical scenario for ULBD in the setting of degenerative spondylolisthesis. FDA DEVICE/DRUG STATUS This abstract does not discuss or include any applicable devices or drugs [ABSTRACT FROM AUTHOR]

The contact nature of American football has made head acceleration exposure a concern. We aimed to quantify the head kinematics associated with direct helmet contact and inertial head loading events in collegiate-level American football. A cohort of collegiate-level players were equipped with instrumented mouthguards synchronised with time-stamped multiple camera-view video footage of matches and practice. Video-verified contact events were identified as direct helmet contact or inertial head loading events and categorised as blocking, blocked, tackling, tackled or ground contact. Linear mixed-effects models were utilised to compare peak head kinematics between contact event categories. The timestamp-based cross-verification of the video analysis and instrumented mouthguard approach resulted in 200 and 328 direct helmet contact and inertial head loading cases, respectively. Median linear acceleration, angular acceleration and angular velocity for inertial head loading cases was greater than direct helmet contact events by 8% (p = 0.007), 55% (p < 0.001) and 4% (p = 0.007), respectively. Median head kinematics for all contact event categories appeared similar with no pairwise comparison resulting in statistical significance (p > 0.05). The study highlights the potential of combining qualitative video analysis with in-vivo head kinematics measurements. The findings suggest that a number of direct helmet contact events sustained in American football are of lower magnitude to what is sustained during regular play (i.e. from inertial head loading). Additionally, the findings illustrate the importance of including all contact events, including direct helmet contact and inertial head loading cases, when assessing head acceleration exposure and player load during a season of American football. [ABSTRACT FROM AUTHOR]

The article presents a study on mice which shows the potential of platelet-derived growth factor-B (PDGF-B) to promote tumor growth. It states that the growth factor exerts double function following the induction of the erythropoietin (EPO) expression. The study shows that EPO production from the tumor stromal compartment plays an important role in tumor progression.

Wearable sensors embedded with inertial measurement units have become commonplace for the measurement of head impact biomechanics, but individual systems often suffer from a lack of measurement fidelity. While some researchers have focused on developing highly accurate, single sensor systems, we have taken a parallel approach in investigating optimal estimation techniques with multiple noisy sensors. In this work, we present a sensor network methodology that utilizes multiple skin patch sensors arranged on the head and combines their data to obtain a more accurate estimate than any individual sensor in the network. Our methodology visually localizes subject-specific sensor transformations, and based on rigid body assumptions, applies estimation algorithms to obtain a minimum mean squared error estimate. During mild soccer headers, individual skin patch sensors had over 100% error in peak angular velocity magnitude, angular acceleration magnitude, and linear acceleration magnitude. However, when properly networked using our visual localization and estimation methodology, we obtained kinematic estimates with median errors below 20%. While we demonstrate this methodology with skin patch sensors in mild soccer head impacts, the formulation can be generally applied to any dynamic scenario, such as measurement of cadaver head impact dynamics using arbitrarily placed sensors. [ABSTRACT FROM AUTHOR]

The article discusses the significant of human organoids in colorectal cancer modeling discovered during the study on oncogenic mutations engineering. Topics discussed include the application of organoid culture method in colon modeling through culturing intestinal tissue or stem cells, the implication of the progression of the normal colon epithelial cell on colorectal carcinoma, and the conclusion which states the significant of human organoid in cancer modeling.

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]

Objective: Ligamentum flavum (LF) is an important anatomical structure for prevention of postoperative adhesions, but the opening of LF is necessary for percutaneous endoscopic lumbar interlaminar discectomy (PEID). Although the defect in LF is small with conventional PEID, the defect could be minimized with LF splitting technique. The objective of this study was to compare clinical outcomes of PEID with opening of LF versus splitting of LF. Methods: A retrospective study was performed for patients underwent PEID for L5-S1. PEID with the opening of LF (open-group) was performed for 55 patients and with splitting of LF (split-group) was performed for 34 patients. The defect of LF in Open-group was 3-5 mm, but the defect was negligible in split-group because the split LF was reapproximated by its elasticity. Clinical outcomes were evaluated with Korean version of the Oswestry Disability Index (K-ODI) and visual analogue pain scores for back (VASB) and leg (VASL). The changes of clinical outcomes during postoperative 24 months between groups were evaluated with linear mixed-effects model. Results: The clinical outcomes were similar between groups for K-ODI (p=0.98), VASB (p=0.52), and VASL (p=0.59). Each outcome demonstrated significant improvement from preoperative baseline throughout the postoperative 24 months (p<0.05). Complications included recurrence in 4 patients and dural tear in 1 in open-group (9.1%), and residual disc herniation in 2 patients and transient weakness in 1 in split-group (8.8%). Conclusion: Splitting versus opening LF in PEID may be left to the surgeon's discretion. The potential risks and benefits of LF handling should be considered when performing this surgical technique in PEID. [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]

Wearable inertial sensors measure human head impact kinematics important to the on-going development and validation of head injury criteria. However, sensor specifications have not been scientifically justified in the context of the anticipated field impact dynamics. The objective of our study is to determine the minimum bandwidth and sample rate required to capture the impact frequency response relevant to injury. We used high-bandwidth head impact data as ground-truth measurements, and investigated the attenuation of various injury criteria at lower bandwidths. Given a 10% attenuation threshold, we determined the minimum bandwidths required to study injury criteria based on skull kinematics and brain deformation in three different model systems: helmeted cadaver (no neck), unhelmeted cadaver (no neck), and helmeted dummy impacts (with neck). We found that higher bandwidths are required for unhelmeted impacts in general and for studying strain rate injury criteria. Minimum gyroscope bandwidths of 300 Hz in helmeted sports and 500 Hz in unhelmeted sports are necessary to study strain rate based injury criteria. A minimum accelerometer bandwidth of 500 Hz in unhelmeted sports is necessary to study most injury criteria. Current devices typically sample at 1000 Hz, with gyroscope bandwidths below 200 Hz, which are not always sufficient according to these requirements. With hard contact test conditions, the identified requirements may be higher than most soft contacts on the field, but should be satisfied to capture the worst contact, and often higher risk, scenarios relative to the specific sport or activity. Our findings will help establish standard guidelines for sensor choice and design in traumatic brain injury research. [ABSTRACT FROM AUTHOR]

Wnt signalling is involved in multiple aspects of embryonic development and adult tissue homeostasis, notably via controlling cellular proliferation and differentiation. Wnt signalling is subject to stringent positive and negative regulation to promote proper development and homeostasis yet avoid aberrant growth. Such multi-layer regulation includes post-translational modification and processing of Wnt proteins themselves, R-spondin (Rspo) amplification of Wnt signalling, diverse receptor families, and intracellular and extracellular antagonists and destruction and transcription complexes. In the gastrointestinal tract, Wnt signalling is crucial for development and renewal of the intestinal epithelium. Intestinal stem cells (ISCs) undergo symmetric division and neutral drift dynamics to renew the intestinal epithelium. Sources of Wnts and Wnt amplifers such as R-spondins are beginning to be elucidated as well as their functional contribution to intestinal homeostasis. In this review we focus on regulation of ISCs and intestinal homeostasis by the Wnt/Rspo pathway, the potential cellular sources of Wnt signalling regulators and highlight potential future areas of study. [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]

Despite extensive literature on vascular endothelial growth factor (VEGF) expression and regulation by steroid hormones, the lack of clear understanding of the mechanisms of angiogenesis in the endometrium is a major limitation for use of antiangiogenic therapy targeting endometrial vessels. In the current work, we used the rhesus macaque as a primate model and the decidualized mouse uterus as a murine model to examine angiogenesis during endometrial breakdown and regeneration. We found that blockade of VEGF action with VEGF Trap, a potent VEGF blocker, completely inhibited neovascularization during endometrial regeneration in both models but had no marked effect on preexisting or newly formed vessels, suggesting that VEGF is essential for neoangiogenesis but not survival of mature vessels in this vascular bed. Blockade of VEGF also blocked reepithelialization in both the postmenstrual endometrium and the mouse uterus after decidual breakdown, evidence that VEGF has pleiotropic effects in the endometrium. In vitro studies with a scratch wound assay showed that the migration of luminal epithelial cells during repair involved signaling through VEGF receptor 2-neuropilin 1 (VEGFR2-NP1) receptors on endometrial stromal cells. The leading front of tissue growth during endometrial repair was strongly hypoxic, and this hypoxia was the local stimulus for VEGF expression and angiogenesis in this tissue. In summary, we provide novel experimental data indicating that VEGF is essential for endometrial neoangiogenesis during postmenstrual/ postpartum repair. [ABSTRACT FROM AUTHOR]

The use of recombinant adenoviruses (Ad) to express secreted antagonists of growth factors represents a powerful strategy for studying physiologic functions of growth factor pathways in experimental animals. Indeed, a single adenoviral injection can produce characteristic high-level and persistent plasma expression of soluble receptor ectodomains or secreted protein antagonists, allowing highly stringent conditional inactivation of target pathways in vivo. In this review, we describe our experience using recombinant Ad to inactivate growth factor pathways in vivo and discuss their advantages and limitations. Using our studies on vascular endothelial growth factor and Wnt systems as examples, we further describe how recombinant Ad can unveil previously unknown physiological roles of signaling pathways. Finally, we discuss the potential physiological and therapeutic relevance of our findings. [ABSTRACT FROM AUTHOR]

Tumor-endothelial interaction contributes to local prostate tumor growth and distant metastasis. In this communication, we designed a novel approach to target both cancer cells and their“crosstalk”with surrounding microvascular endothelium in an experimental hormone refractory human prostate cancer model. We evaluated the in vitro and in vivo synergistic and/or additive effects of a combination of conditional oncolytic adenovirus plus an adenoviral-mediated antiangiogenic therapy. In the in vitro study, we demonstrated that human umbilical vein endothelial cells (HUVEC) and human C4-2 androgen-independent (AI) prostate cancer cells, when infected with an antiangiogenic adenoviral (Ad)-Flk1-Fc vector secreting a soluble form of Flk1, showed dramatically inhibited proliferation, migration and tubular formation of HUVEC endothelial cells. C4-2 cells showed maximal growth inhibition when coinfected with Ad-Flk1-Fc and Ad-hOC-E1, a conditional replication-competent Ad vector with viral replication driven by a human osteocalcin (hOC) promoter targeting both prostate cancer epithelial and stromal cells. Using a three-dimensional (3D) coculture model, we found that targeting C4-2 cells with Ad-hOC-E1 markedly decreased tubular formation in HUVEC, as visualized by confocal microscopy. In a subcutaneous C4-2 tumor xenograft model, tumor volume was decreased by 40-60%in animals treated with Ad-Flk1-Fc or Ad-hOC-E1 plus vitamin D3 alone and by 90%in a combined treatment group, compared to untreated animals in an 8-week treatment period. Moreover, three of 10 (30%) pre-established tumors completely regressed when animals received combination therapy. Cotargeting tumor and tumor endothelium could be a promising gene therapy strategy for the treatment of both localized and metastatic human prostate cancer.Cancer Gene Therapy (2005) 12, 257-267. doi:10.1038/sj.cgt.7700790 Published online 26 November 2004 [ABSTRACT FROM AUTHOR]

Tumors are often infiltrated by T lymphocytes recognizing either self- or mutated antigens but are generally inactive, although they often show signs of prior clonal expansion. Hypothesizing that this may be due to peripheral tolerance, we formulated nanoparticles containing innate immune stimulants that we found were sufficient to activate self-specific CD8+ T cells and injected them into two different mouse tumor models, B16F10 and MC38. These nanoparticles robustly activated and/or expanded antigen-specific CD8+ tumor-infiltrating T cells, along with a decrease in regulatory CD4+ T cells and an increase in Interleukin-17 producers, resulting in significant tumor growth retardation or elimination and the establishment of immune memory in surviving mice. Furthermore, nanoparticles with modification of stimulating human T cells enabled the robust activation of endogenous T cells in patientderived tumor organoids. These results indicate that breaking peripheral tolerance without regard to the antigen specificity creates a promising pathway for cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Human intestinal organoids from primary human tissues have the potential to revolutionize personalized medicine and preclinical gastrointestinal disease models. A tunable, fully defined, designer matrix, termed hyaluronan elastin‐like protein (HELP) is reported, which enables the formation, differentiation, and passaging of adult primary tissue‐derived, epithelial‐only intestinal organoids. HELP enables the encapsulation of dissociated patient‐derived cells, which then undergo proliferation and formation of enteroids, spherical structures with polarized internal lumens. After 12 rounds of passaging, enteroid growth in HELP materials is found to be statistically similar to that in animal‐derived matrices. HELP materials also support the differentiation of human enteroids into mature intestinal cell subtypes. HELP matrices allow stiffness, stress relaxation rate, and integrin‐ligand concentration to be independently and quantitatively specified, enabling fundamental studies of organoid–matrix interactions and potential patient‐specific optimization. Organoid formation in HELP materials is most robust in gels with stiffer moduli (G' ≈ 1 kPa), slower stress relaxation rate (t1/2 ≈ 18 h), and higher integrin ligand concentration (0.5 × 10−3–1 × 10−3m RGD peptide). This material provides a promising in vitro model for further understanding intestinal development and disease in humans and a reproducible, biodegradable, minimal matrix with no animal‐derived products or synthetic polyethylene glycol for potential clinical translation. [ABSTRACT FROM AUTHOR]

Human intestinal organoids from primary human tissues have the potential to revolutionize personalized medicine and preclinical gastrointestinal disease models. A tunable, fully defined, designer matrix, termed hyaluronan elastin‐like protein (HELP) is reported, which enables the formation, differentiation, and passaging of adult primary tissue‐derived, epithelial‐only intestinal organoids. HELP enables the encapsulation of dissociated patient‐derived cells, which then undergo proliferation and formation of enteroids, spherical structures with polarized internal lumens. After 12 rounds of passaging, enteroid growth in HELP materials is found to be statistically similar to that in animal‐derived matrices. HELP materials also support the differentiation of human enteroids into mature intestinal cell subtypes. HELP matrices allow stiffness, stress relaxation rate, and integrin‐ligand concentration to be independently and quantitatively specified, enabling fundamental studies of organoid–matrix interactions and potential patient‐specific optimization. Organoid formation in HELP materials is most robust in gels with stiffer moduli (G' ≈ 1 kPa), slower stress relaxation rate (t1/2 ≈ 18 h), and higher integrin ligand concentration (0.5 × 10−3–1 × 10−3m RGD peptide). This material provides a promising in vitro model for further understanding intestinal development and disease in humans and a reproducible, biodegradable, minimal matrix with no animal‐derived products or synthetic polyethylene glycol for potential clinical translation. [ABSTRACT FROM AUTHOR]

Behavioral observations support clinical in-depth phenotyping but phenotyping and pattern recognition are affected by training background. As Attention Deficit Hyperactivity Disorder, Restless Legs syndrome/Willis Ekbom disease and medication induced activation syndromes (including increased irritability and/or akathisia), present with hyperactive-behaviors with hyper-arousability and/or hypermotor-restlessness (H-behaviors), we first developed a non-interpretative, neutral pictogram-guided phenotyping language (PG-PL) for describing body-segment movements during sitting. The PG-PL was applied for annotating 12 1-min sitting-videos (inter-observer agreements >85%->97%) and these manual annotations were used as a ground truth to develop an automated algorithm using OpenPose, which locates skeletal landmarks in 2D video. We evaluated the algorithm's performance against the ground truth by computing the area under the receiver operator curve (>0.79 for the legs, arms, and feet, but 0.65 for the head). While our pixel displacement algorithm performed well for the legs, arms, and feet, it predicted head motion less well, indicating the need for further investigations. This first automated analysis algorithm allows to start the discussion about distinct phenotypical characteristics of H-behaviors during structured behavioral observations and may support differential diagnostic considerations via in-depth phenotyping of sitting behaviors and, in consequence, of better treatment concepts. [ABSTRACT FROM AUTHOR]

Cellular interactions in the tumor microenvironment (TME) significantly govern cancer progression and drug response. The efficacy of clinical immunotherapies has fostered an exponential interest in the tumor immune microenvironment, which in turn has engendered a pressing need for robust experimental systems modeling patient-specific tumor–immune interactions. Traditional 2D in vitro tumor immunotherapy models have reconstituted immortalized cancer cell lines with immune components, often from peripheral blood. However, newly developed 3D in vitro organoid culture methods now allow the routine culture of primary human tumor biopsies and increasingly incorporate immune components. Here, we present a viewpoint on recent advances, and propose translational applications of tumor organoids for immuno-oncology research, immunotherapy modeling, and precision medicine. Diverse in vitro culture methods allow modeling of tumor immunity. 'Tumor-only' 3D patient-derived organoid (PDO) systems can be reconstituted with exogenously added immune components. Holistic air–liquid interface (ALI) tumor organoid cultures and microfluidic cultures can recapitulate the tumor microenvironment (TME) by preserving endogenous stromal components including diverse immune cells (B, T, and natural killer cells, and macrophages) without reconstitution. Tumor-infiltrating lymphocytes in the native TME of ALI PDOs or microfluidic PDO tumor spheroids can model programmed cell death-1 (PD-1)-dependent immune checkpoint inhibition and tumor cytotoxicity. Regardless of methodology, in vitro culture models of the immune TME allow exploration of tumor immunology and novel immunotherapeutic targets. [ABSTRACT FROM AUTHOR]

Due to their complex anatomy, the general activation of lumbar muscles can be estimated with surface electromyography (sEMG) while intramuscular EMG is recommended to isolate information from different back muscles. Whether high-density sEMG recordings can represent the contribution of individual lumbar muscles, as identified with indwelling EMG, needs to be investigated. Muscle activity from the right longissimus (L1 and L4) and deep and superficial multifidus (L4) was recorded in eleven participants using fine-wire electrodes during isometric trunk flexions at 20-degrees. We positioned a 13 × 5 electrodes grid over the right lumbar region (L1 to L4) to record sEMG. We used cross-correlations between non-rectified signals from indwelling and sEMG. The spatial location was determined as the medio-lateral and cranio-caudal coordinates of the centroid of the electrodes exhibiting the highest cross-correlation values. To establish an automated approach to identify the spatial distribution of sEMG recordings, we used the independent component analysis (ICA). On the sEMG, the centroid of multifidus activity identified with indwelling EMG was medial to that representing longissimus (P < 0.001). The centroid of the longissimus activity at L1 was cranial to that representing caudal (L4) muscles (multiple P -values < 0.001). The spatial localisation of superficial and deep multifidus did not differ (P = 0.86). Preliminary results showed that ICA decomposed the sEMG signals into components representing the longissimus and multifidus. The spatial distribution of sEMG amplitude provides information on the activation of individual lumbar muscles. Automated EMG decomposition approaches are useful to identify the distinct contribution of individual lumbar muscles using sEMG. [ABSTRACT FROM AUTHOR]

Secreted R-spondin1-4 proteins (RSPO1-4) orchestrate stem cell renewal and tissue homeostasis by potentiating Wnt/β-catenin signaling. RSPOs induce the turnover of negative Wnt regulators RNF43 and ZNRF3 through a process that requires RSPO interactions with Leucine-rich repeat-containing G-protein coupled receptors (LGRs), or through an LGR-independent mechanism that is enhanced by RSPO binding to heparin sulfate proteoglycans (HSPGs). Here, we describe the engineering of 'surrogate RSPOs' that function independently of LGRs to potentiate Wnt signaling on cell types expressing a target surface marker. These bispecific proteins were generated by fusing an RNF43- or ZNRF3-specific single chain antibody variable fragment (scFv) to the immune cytokine IL-2. Surrogate RSPOs mimic the function of natural RSPOs by crosslinking the extracellular domain (ECD) of RNF43 or ZNRF3 to the ECD of the IL-2 receptor CD25, which sequesters the complex and results in highly selective amplification of Wnt signaling on CD25+ cells. Furthermore, surrogate RSPOs were able substitute for wild type RSPO in a colon organoid growth assay when intestinal stem cells were transduced to express CD25. Our results provide proof-of-concept for a technology that may be adapted for use on a broad range of cell- or tissue-types and will open new avenues for the development of Wnt-based therapeutics for regenerative medicine. [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]