Objective
In a previously reported phase II randomized, placebo‐controlled, interventional trial, we demonstrated that treatment with ustekinumab, an anti–interleukin‐12 (IL‐12)/IL‐23 p40 ...neutralizing monoclonal antibody, improved global and organ‐specific measures of disease activity in patients with active systemic lupus erythematosus (SLE). Utilizing the biomarker data from this phase II clinical study, we sought to determine whether modulation of the expression of IL‐12, IL‐23, or both cytokines by ustekinumab is associated with clinical efficacy in patients with SLE.
Methods
This phase II randomized, placebo‐controlled study enrolled 102 patients with autoantibody‐positive SLE whose disease remained active despite standard‐of‐care therapy. Patients were randomized at a 3:2 ratio to receive ~6 mg/kg ustekinumab intravenously or placebo at week 0, followed by subcutaneous injections of 90 mg ustekinumab or placebo every 8 weeks, with placebo crossover to 90 mg ustekinumab every 8 weeks. The SLE Responder Index 4 (SRI‐4) at week 24 was used to determine which patients could be classified as ustekinumab responders and which could be classified as nonresponders. In addition to measurements of p40 and IL‐23, serum levels of interferon‐γ (IFNγ), IL‐17A, IL‐17F, and IL‐22, as a proxy for the IL‐12 and IL‐23 pathways, were quantified by immunoassay.
Results
Changes in the serum levels of IL‐17A, IL‐17F, and IL‐22 at different time points after treatment were not consistently significantly associated with an SRI‐4 clinical response to ustekinumab in patients with SLE. In contrast, an SRI‐4 response to ustekinumab was significantly associated (P < 0.01) with durable reductions in the serum IFNγ protein levels at several time points relative to baseline, which was not observed in ustekinumab nonresponders or patients who received placebo.
Conclusion
While not diminishing a potential role of IL‐23, these serum biomarker assessments indicate that IL‐12 blockade has an important role in the mechanism of action of ustekinumab treatment in patients with SLE.
Ionogels are an emerging class of soft materials that exhibit ionic conductivity and thermal stability without the need to replenish ions or the addition of conductive particle fillers. An ionogel ...ink is reported for direct‐write 3D printing to fabricate conductive structures that can vary in the printed object geometries. This approach relies on a shear‐thinning ionogel ink that can be extruded to afford self‐supporting constructs. After a brief UV cure, the printed construct is transformed into a mechanically tough, transparent structure that is ionically conductive. Upon application of stretching and twisting loads, the 3D‐printed objects exhibit detectable changes in conductivity. To demonstrate the versatility of rapid prototyping with the ionogel inks, an auxetic structure is 3D printed and tested as a strain sensor. The printed auxetic structure exhibits an electrical response to strain, but also demonstrates increased extensibility and operational range in comparison to a casted bulk film with the same outer dimensions.
An ionogel comprised of modified F127‐based polymer and ionic liquid 1‐butyl‐3‐methylimidazolium tetrafluoroborate is presented. This shear‐thinning gel can be extruded and 3D printed via a direct‐write 3D printer to create complex 3D structures. Fabrication of an auxetic sensor is demonstrated to show the use of 3D printing to achieve the mechanical attributes desired in stretchable sensors.
Losing the ability to walk safely and independently is a major concern for many older adults. The Lifestyle Interventions and Independence for Elders study recently demonstrated that a physical ...activity (PA) intervention can delay the onset of major mobility disability. Our objective is to examine the resources required to deliver the PA intervention and calculate the incremental cost-effectiveness compared with a health education intervention.
The Lifestyle Interventions and Independence for Elders study enrolled 1,635 older adults at risk for mobility disability. They were recruited at eight field centers and randomly assigned to either PA or health education. The PA program consisted of 50-minute center-based exercise 2× weekly, augmented with home-based activity to achieve a goal of 150 min/wk of PA. Health education consisted of weekly workshops for 26 weeks, and monthly sessions thereafter. Analyses were conducted from a health system perspective, with a 2.6-year time horizon.
The average cost per participant over 2.6 years was US$3,302 and US$1,001 for the PA and health education interventions, respectively. PA participants accrued 0.047 per person more Quality-Adjusted Life-Years (QALYs) than health education participants. PA interventions costs were slightly higher than other recent PA interventions. The incremental cost-effectiveness ratios were US$42,376/major mobility disability prevented and US$49,167/QALY. Sensitivity analyses indicated that results were relatively robust to varied assumptions.
The PA intervention costs and QALYs gained are comparable to those found in other studies. The ICERS are less than many commonly recommended medical treatments. Implementing the intervention in non-research settings may reduce costs further.
We report stone comminution in the first 19 human subjects by burst wave lithotripsy (BWL), which is the transcutaneous application of focused, cyclic ultrasound pulses.
This was a prospective ...multi-institutional feasibility study recruiting subjects undergoing clinical ureteroscopy (URS) for at least 1 stone ≤12 mm as measured on computerized tomography. During the planned URS, either before or after ureteroscope insertion, BWL was administered with a handheld transducer, and any stone fragmentation and tissue injury were observed. Up to 3 stones per subject were targeted, each for a maximum of 10 minutes. The primary effectiveness outcome was the volume percent comminution of the stone into fragments ≤2 mm. The primary safety outcome was the independent, blinded visual scoring of tissue injury from the URS video.
Overall, median stone comminution was 90% (IQR 20, 100) of stone volume with 21 of 23 (91%) stones fragmented. Complete fragmentation (all fragments ≤2 mm) within 10 minutes of BWL occurred in 9 of 23 stones (39%). Of the 6 least comminuted stones, likely causative factors for decreased effectiveness included stones that were larger than the BWL beamwidth, smaller than the BWL wavelength or the introduction of air bubbles from the ureteroscope. Mild reddening of the papilla and hematuria emanating from the papilla were observed ureteroscopically.
The first study of BWL in human subjects resulted in a median of 90% comminution of the total stone volume into fragments ≤2 mm within 10 minutes of BWL exposure with only mild tissue injury.
Our goal was to test transcutaneous focused ultrasound in the form of ultrasonic propulsion and burst wave lithotripsy to reposition ureteral stones and facilitate passage in awake subjects.
Adult ...subjects with a diagnosed proximal or distal ureteral stone were prospectively recruited. Ultrasonic propulsion alone or with burst wave lithotripsy was administered by a handheld transducer to awake, unanesthetized subjects. Efficacy outcomes included stone motion, stone passage, and pain relief. Safety outcome was the reporting of associated anticipated or adverse events.
Twenty-nine subjects received either ultrasonic propulsion alone (n = 16) or with burst wave lithotripsy bursts (n = 13), and stone motion was observed in 19 (66%). The stone passed in 18 (86%) of the 21 distal ureteral stone cases with at least 2 weeks follow-up in an average of 3.9±4.9 days post-procedure. Fragmentation was observed in 7 of the burst wave lithotripsy cases. All subjects tolerated the procedure with average pain scores (0-10) dropping from 2.1±2.3 to 1.6±2.0 (
= .03). Anticipated events were limited to hematuria on initial urination post-procedure and mild pain. In total, 7 subjects had associated discomfort with only 2.2% (18 of 820) propulsion bursts.
This study supports the efficacy and safety of using ultrasonic propulsion and burst wave lithotripsy in awake subjects to reposition and break ureteral stones to relieve pain and facilitate passage.
Performing a small bowel anastomosis, or reconnecting small bowel segments, remains a core competency and critical step for the successful surgical management of numerous bowel and urinary ...conditions. As surgical education and technology moves toward improving patient outcomes through automation and increasing training opportunities, a detailed characterization of the interventional biomechanical properties of the human bowel is important. This is especially true due to the prevalence of anastomotic leakage as a frequent (3.02%) postoperative complication of small bowel anastomoses. This study aims to characterize the forces required for a suture to tear through human small bowel (suture pullout force, SPOF), while analyzing how these forces are affected by tissue orientation, suture material, suture size, and donor demographics. 803 tests were performed on 35 human small bowel specimens. A uni-axial test frame was used to tension sutures looped through 10 × 20 mm rectangular bowel samples to tissue failure. The mean SPOF of the small bowel was 4.62±1.40 N. We found no significant effect of tissue orientation (p = 0.083), suture material (p = 0.681), suture size (p = 0.131), age (p = 0.158), sex (p = .083), or body mass index (BMI) (p = 0.100) on SPOF. To our knowledge, this is the first study reporting human small bowel SPOF. Little research has been published about procedure-specific data on human small bowel. Filling this gap in research will inform the design of more accurate human bowel synthetic models and provide an accurate baseline for training and clinical applications.
Achieving proper renal access is arguably the most challenging component of percutaneous nephrolithotomy. A core skill required during this procedure is the use of C-arm fluoroscopic imaging and ...parallax techniques for proper needle insertion into a predetermined calyceal papilla. The trainers available for these skills include virtual reality (VR) simulators and physical models requiring actual fluoroscopy and radiation exposure precautions. In this study we present the successful proof-of-concept of a low-cost physical fluoro-less C-arm trainer (CAT) for training percutaneous renal access.
The SimPORTAL CAT includes a mini C-arm for simulating fluoroscopic imaging and a silicon flank simulation model for needle insertion. The C-arm has two mounted video cameras and is jointed to tilt and rainbow. The flank model contains an anatomically accurate cast of the upper urinary tract, including the ureter, calyces, and the renal pelvis, with an overlay of ribs to visually and tactically simulate the 10th-12th ribs. The simulated fluoroscopic imaging is viewed on a computer screen allowing for real-time visualization. Preliminary surveys were completed by participants (n=14) at a training course that took place in Hemel Hampsted to obtain information on the acceptability of version 2.1 of the model.
We have successfully created a fluoro-less CAT that achieves the goals of training percutaneous access of the kidney. All participants (100%) considered the concept of avoiding radiation exposure during training as a highly valuable feature. About 92.8% of the enrolled participants considered the CAT of at least equal value to existing VR training models.
The fluoroscopy-less CAT is an economically feasible and accurate model for training parallax. It effectively replicates the functions of a C-arm X-ray system for percutaneous access to the kidney without any radiation exposure to the learner. Further studies will examine construct validity for training and assessing percutaneous access skills.
Background The American College of Surgeons-Accredited Education Institutes (ACS-AEI) Consortium aims to enhance patient safety and advance surgical education through the use of cutting-edge ...simulation-based training and assessment methods. The annual ACS-AEI Consortium meeting provides a forum to discuss the latest simulation-based training and assessment methods and includes special panel presentations on key topics. Methods During the 8th annual Consortium, there was a panel presentation on simulation-based summative assessments, during which experiences from across surgical disciplines were presented. The formal presentations were followed by a robust discussion between the conference attendees and the panelists. Results This report summarizes the panelists' presentations and their ensuing discussion with attendees. Conclusion The focus of this report is on the basis for and advances in simulation-based summative assessments, the current practices employed across various surgical disciplines, and future directions that may be pursued by the ACS-AEI Consortium.
We have used x-ray crystallography to determine the structures of sperm whale myoglobin (Mb) in four different ligation states (unligated, ferric
aquomet, oxygenated, and carbonmonoxygenated) to a ...resolution of better than 1.2
Å. Data collection and analysis were performed in as much the same way as possible to reduce model bias in differences between structures. The structural differences among the ligation states are much smaller than previously estimated, with differences of <0.25
Å root-mean-square deviation among all atoms. One structural parameter previously thought to vary among the ligation states, the proximal histidine (His-93) azimuthal angle, is nearly identical in all the ferrous complexes, although the tilt of the proximal histidine is different in the unligated form. There are significant differences, however, in the heme geometry, in the position of the heme in the pocket, and in the distal histidine (His-64) conformations. In the CO complex the majority conformation of ligand is at an angle of 18
±
3° with respect to the heme plane, with a geometry similar to that seen in encumbered model compounds; this angle is significantly smaller than reported previously by crystallographic studies on monoclinic Mb crystals, but still significantly larger than observed by photoselection. The distal histidine in unligated Mb and in the dioxygenated complex is best described as having two conformations. Two similar conformations are observed in MbCO, in addition to another conformation that has been seen previously in low-pH structures where His-64 is doubly protonated. We suggest that these conformations of the distal histidine correspond to the different conformational substates of MbCO and MbO
2 seen in vibrational spectra. Full-matrix refinement provides uncertainty estimates of important structural parameters. Anisotropic refinement yields information about correlated disorder of atoms; we find that the proximal (F) helix and heme move approximately as rigid bodies, but that the distal (E) helix does not.
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