Where do we stand On Organ Printing

Abstract Attitude towards organ donation and the risks associated with organ transplantation drive the search for alternatives. One such alternative, albeit a conceptual level, could be the generation of an organ replacement in a controlled setting. For instance, growing suitable cells onto a printed matrix under appropriate conditions would then lead to the formation of a functional organ. How about the practical issues surrounding either duplication or de novo generation of an organ with, say, a device to print a suitable matrix and grow and differentiate cells on it? Here, we wish to outline selected safety-related questions arising from the ex vivo growth, differentiation and maintenance of cells or cell systems

Multi-disciplinary efforts to evaluate the therapeutic potential of CDK11, a novel transcription associated cyclin dependent kinase.

View full abstracthttps://openworks.mdanderson.org/leading-edge/1043/thumbnail.jp

Apolipoprotein E Deficiency Increases Remnant Lipoproteins and Accelerates Progressive Atherosclerosis, But Not Xanthoma Formation, in Gene-Modified Minipigs

Deficiency of apolipoprotein E (APOE) causes familial dysbetalipoproteinemia in humans resulting in a higher risk of atherosclerotic disease. In mice, APOE deficiency results in a severe atherosclerosis phenotype, but it is unknown to what extent this is unique to mice. In this study, APOE was targeted in Yucatan minipigs. APOE−/− minipigs displayed increased plasma cholesterol and accumulation of apolipoprotein B-48–containing chylomicron remnants on low-fat diet, which was significantly accentuated upon feeding a high-fat, high-cholesterol diet. APOE−/− minipigs displayed accelerated progressive atherosclerosis but not xanthoma formation. This indicates that remnant lipoproteinemia does not induce early lesions but is atherogenic in pre-existing atherosclerosis

Conservative Treatment with Arch Support Inflatable Ankle-Foot Orthosis Does Not Correct Progressive Collapsing Foot Deformity: A Prospective Comparative and Controlled Study

Category: Midfoot/Forefoot; Hindfoot Introduction/Purpose: Progressive Collapsing Foot Deformity (PCFD) can present with independent deformities, characterized by five classes: hindfoot valgus (Class A), midfoot abduction (Class B), forefoot varus (Class C), Peritalar Subluxation (PTS) (Class D) and ankle valgus (Class E). Conservative treatment includes the use of corrective insoles and orthotics. Arch support inflatable Ankle-Foot orthoses (IAFO) can help control symptoms in PCFD patients. However, the ability of IAFOs to correct deformities in PCFD is unknown. The aim of this prospective comparative and controlled study was to assess the ability of arch support IAFOs to correct 3D overall PCFD alignment as well as the five different PCFD classes independently. We hypothesized that IAFOs would correct PCFD 3D overall alignment as well as the five independent classes of deformity. Methods: After IRB approval, we enrolled 24 symptomatic PCFD and 24 controls matched on age, sex, and BMI. Flexible PCFD patients and controls were scanned using Weight-Bearing CT (WBCT) with and without an arch support IAFO. The Foot and Ankle Offset (FAO) was used to assess the 3D foot overall alignment. We measured the Hindfoot moment arm (HMA, Class A), the Talonavicular coverage angle (TNCA, Class B), the Meary’s angle and medial cuneiform-to-floor distance (C1-floor) for the Class C and the middle facet uncoverage (MFunco, Class D). No Class E patients were included. Measurements were performed by two fellowship-trained surgeons. A power-analysis hypothesizing that IAFOs would be two times less efficient than the PCFD surgery in correcting the FAO, the requisite number of subjects was 24 per group. Data normality was assessed by Shapiro-Wilk test. Comparisons used normality based paired T-tests or paired-Wilcoxon tests. P-values < 0.05 were considered significant. Results: PCFD measurements performed in controls were all significantly less pronounced than unbraced PCFD patients, confirming the presence of collapse (ps < 0.0001). Comparing PCFD without and with IAFO, the FAO did not show significant improvement (respectively 6.6+/-3.7% vs 5.5+/-4.2%, p=0.101). The HMA (8.8+/-5.8 vs 8.1+/-5.8, p=0.66), the TNCA (24.2+/-10.6 vs 21.9+/-9.7, p=0.44) and the MFunco (37+/-12% vs 31+/-18%, p=0.17) also did not portray significant improvements when applying the IAFOs. The Meary’s angle (17.6+/-7.2 vs 10.8+/-7.3, p=0.002) and C1-floor (17.2+/-3.3mm vs 24.1+/-5.3mm, p< 0.001) were the only to improve significantly with use of IAFOs. When comparing braced PCFD and controls, the only measurement that improved to normal values, similar to controls, in braced PCFD was the C1-floor (24.1+/-5.3mm in PCFD with IAFO vs 25.7+/- 5.4mm in controls, p=0.31). Conclusion: In this prospective comparative and controlled study, we found that arch support IAFOs was not able to correct overall 3D deformity and most of the specific classes in PCFD. The orthosis did not improve hindfoot valgus (Class A), midfoot abduction (Class B) or peritalar subluxation (Class D) in PCFD. The only deformity pattern to improve with the use of IAFOs was the medial longitudinal arch height (Class C). These improvements were expected by the presence of the inflatable bladder of the IAFO on the plantar aspect of the foot, pushing the longitunal arch up but not correcting the entire PCFD

Three-Dimensional Assessment to Hallux Valgus Correction Using Lapicotton Technique

Category: Bunion; Midfoot/Forefoot Introduction/Purpose: The first-ray and the medial column play a crucial role in preserving the tripod of the foot. Changes to structural properties of the first-ray, along with collapse of the medial-longitudinal-arch, have been associated with hallux valgus (HV). Thus, restoring the first-ray plays an important role when correcting the mechanical function of the foot tripod in the setting of HV combined with medial-longitudinal-arch collapse. The LapiCotton technique combines the mechanical advantages of Cotton osteotomy and modified Lapidus procedures by maintaining the length of the first-ray and preserving the medial- longitudinal-arch by plantar inclination of the distal part of first-ray. The aim of this study was to evaluate the effectiveness of the LapiCotton procedure in correcting selected radiographic parameters in patients with combined VH with medial-longitudinal arch collapse. Methods: Preoperative and postoperative Weight Bearing CT (WBCT) scans were obtained from HV patients who underwent unilateral LapiCotton procedure. Postoperative scans were obtained roughly three months after the date of surgery. Semi- automatic measurements were applied to 22 WBCT images across a total of 11 patients enrolled into the study using the Disior ® Bonelogic ® Software. Measurements of the hallux valgus angle (HVA), meary sagittal measurement, and intermetatarsal angles were taken from preoperative and postoperative scans. These scans were then compared using intraclass correlation coefficients and paired t-tests to evaluate the efficacy of the Lapicotton technique in treating HV with P-valus < 0.05 being significant. Results: HVA was found to be significantly larger (p=.026) in the preoperational group (Mdn = 27.52) than the postoperational group (Mdn = 20). In addition, the Meary sagittal measurement was found to be significantly different between groups (p=.033), with a larger value seen in the preoperational group (Mdn = -14.28) compared to the post-operational group (Mdn = -11.15). It was also observed that the IMA was significantly larger (p=.003) in the preoperative group (Mdn = 15.68) compared to the postoperative group (Mdn = 11.26). The sesamoid rotation was found to be higher in the preoperative group (Mdn = -17.71) than the post operative group (Mdn = -24.98), however, these values were not significantly different from one another (p=.203). Conclusion: The LapiCotton procedure proved to be effective in correcting radiographic parameters in patients with HV combined with collapse of the medial longitudinal arch. Reliable correction of HV, along with correction of medial longitudinal arch collapse, was quantified based on semi-automated WBCT measurements of HVA, IMA and Meary angle. LapiCotton produced significantly different measurements for both HVA and IMA postoperatively, providing evidence that the LapiCotton procedure can successfully correct medial longitudinal arch collapse in patients with HV, as well as radiographically reduce the severity of the deformity

Wafer-scale epitaxial modulation of quantum dot density

Precise control of the properties of semiconductor quantum dots (QDs) is vital for creating novel devices for quantum photonics and advanced opto-electronics. Suitable low QD-densities for single QD devices and experiments are challenging to control during epitaxy and are typically found only in limited regions of the wafer. Here, we demonstrate how conventional molecular beam epitaxy (MBE) can be used to modulate the density of optically active QDs in one- and two- dimensional patterns, while still retaining excellent quality. We find that material thickness gradients during layer-by-layer growth result in surface roughness modulations across the whole wafer. Growth on such templates strongly influences the QD nucleation probability. We obtain density modulations between 1 and 10 QDs/$\mu$$m^{2}$ and periods ranging from several millimeters down to at least a few hundred microns. This method is universal and expected to be applicable to a wide variety of different semiconductor material systems. We apply the method to enable growth of ultra-low noise QDs across an entire 3-inch semiconductor wafer

Sparsentan in patients with IgA nephropathy: a prespecified interim analysis from a randomised, double-blind, active-controlled clinical trial

Background: Sparsentan is a novel, non-immunosuppressive, single-molecule, dual endothelin and angiotensin receptor antagonist being examined in an ongoing phase 3 trial in adults with IgA nephropathy. We report the prespecified interim analysis of the primary proteinuria efficacy endpoint, and safety. Methods: PROTECT is an international, randomised, double-blind, active-controlled study, being conducted in 134 clinical practice sites in 18 countries. The study examines sparsentan versus irbesartan in adults (aged ≥18 years) with biopsy-proven IgA nephropathy and proteinuria of 1·0 g/day or higher despite maximised renin-angiotensin system inhibitor treatment for at least 12 weeks. Participants were randomly assigned in a 1:1 ratio to receive sparsentan 400 mg once daily or irbesartan 300 mg once daily, stratified by estimated glomerular filtration rate at screening (30 to 1·75 g/day). The primary efficacy endpoint was change from baseline to week 36 in urine protein-creatinine ratio based on a 24-h urine sample, assessed using mixed model repeated measures. Treatment-emergent adverse events (TEAEs) were safety endpoints. All endpoints were examined in all participants who received at least one dose of randomised treatment. The study is ongoing and is registered with ClinicalTrials.gov, NCT03762850. Findings: Between Dec 20, 2018, and May 26, 2021, 404 participants were randomly assigned to sparsentan (n=202) or irbesartan (n=202) and received treatment. At week 36, the geometric least squares mean percent change from baseline in urine protein-creatinine ratio was statistically significantly greater in the sparsentan group (-49·8%) than the irbesartan group (-15·1%), resulting in a between-group relative reduction of 41% (least squares mean ratio=0·59; 95% CI 0·51-0·69; p<0·0001). TEAEs with sparsentan were similar to irbesartan. There were no cases of severe oedema, heart failure, hepatotoxicity, or oedema-related discontinuations. Bodyweight changes from baseline were not different between the sparsentan and irbesartan groups. Interpretation: Once-daily treatment with sparsentan produced meaningful reduction in proteinuria compared with irbesartan in adults with IgA nephropathy. Safety of sparsentan was similar to irbesartan. Future analyses after completion of the 2-year double-blind period will show whether these beneficial effects translate into a long-term nephroprotective potential of sparsentan. Funding: Travere Therapeutics