Variations in fluid chemical potential induce fibroblast mechano-response in 3D hydrogels.

Mechanical deformation of skin creates variations in fluid chemical potential, leading to local changes in hydrostatic and osmotic pressure, whose effects on mechanobiology remain poorly understood. To study these effects, we investigate the specific influences of hydrostatic and osmotic pressure on primary human dermal fibroblasts in three-dimensional hydrogel culture models. Cyclic hydrostatic pressure and hyperosmotic stress enhanced the percentage of cells expressing the proliferation marker Ki67 in both collagen and PEG-based hydrogels. Osmotic pressure also activated the p38 MAPK stress response pathway and increased the expression of the osmoresponsive genes PRSS35 and NFAT5. When cells were cultured in two-dimension (2D), no change in proliferation was observed with either hydrostatic or osmotic pressure. Furthermore, basal, and osmotic pressure-induced expression of osmoresponsive genes differed in 2D culture versus 3D hydrogels, highlighting the role of dimensionality in skin cell mechanotransduction and stressing the importance of 3D tissue-like models that better replicate in vivo conditions. Overall, these results indicate that fluid chemical potential changes affect dermal fibroblast mechanobiology, which has implications for skin function and for tissue regeneration strategies.

Optimization of Radiolabeling of a [90Y]Y-Anti-CD66-Antibody for Radioimmunotherapy before Allogeneic Hematopoietic Cell Transplantation.

For patients with acute myeloid leukemia, myelodysplastic syndrome, or acute lymphoblastic leukemia, allogeneic hematopoietic cell transplantation (HCT) is a potentially curative treatment. In addition to standard conditioning regimens for HCT, high-dose radioimmunotherapy (RIT) offers the unique opportunity to selectively deliver a high dose of radiation to the bone marrow while limiting side effects. Modification of a CD66b-specific monoclonal antibody (mAb) with a DTPA-based chelating agent should improve the absorbed dose distribution during therapy. The stability and radioimmunoreactive fraction of the radiolabeled mAbs were determined. Before RIT, all patients underwent dosimetry to determine absorbed doses to bone marrow, kidneys, liver, and spleen. Scans were performed twenty-four hours after therapy for quality control. A radiochemical purity of >95% and acceptable radioimmunoreactivity was achieved. Absorbed organ doses for the liver and kidney were consequently improved compared to reported historical data. All patients tolerated RIT well with no treatment-related acute adverse events. Complete remission could be observed in 4/5 of the patients 3 months after RIT. Two patients developed delayed liver failure unrelated to the radioimmunotherapy. The improved conjugation and radiolabeling procedure resulted in excellent stability, radiochemical purity, and CD66-specific radioimmunoreactivity of 90Y-labeled anti-CD66 mAb. RIT followed by conditioning and HCT was well tolerated. Based on these promising initial data, further prospective studies of [90Y]Y-DTPA-Bn-CHX-A″-anti-CD66-mAb-assisted conditioning in HCT are warranted.

Evaluation of the EPR Effect in the CAM-Model by Molecular Imaging with MRI and PET Using 89Zr-Labeled HSA.

Mouse models are commonly used to study the biodistribution of novel radioligands, but alternative models corresponding to the 3Rs principles, such as the chorioallantoic membrane (CAM) model, are highly required. While there are promising data from the CAM model regarding target-specific radiolabeled compounds, its utility for assessing macromolecule biodistribution and analyzing the EPR effect remains to demonstrated. Using 89Zr-labeled human serum albumin, the accumulation of nontarget-specific macromolecules in CAM and mouse xenograft models was studied using PET and MRI. Therefore, the radioligand [89Zr]Zr-DFO-HSA was analyzed in both chicken embryos (n = 5) and SCID mice (n = 4), each with TZM-bl and PC-3 tumor entities. Dynamic PET and anatomical MRI, as well as ex vivo biodistribution analyses, were performed to assess ligand distribution over 24 h. Histological staining and autoradiography verified the intratumoral accumulation. The tumors were successfully visualized for CAM and mouse models by PET, and the albumin influx from the blood into the respective tumors did not differ significantly. The accumulation and retention of HSA in tumors due to the EPR effect was demonstrated for both models. These results highlight that the CAM model is a potential alternative to the mouse model for initial studies with novel radiolabeled macromolecules with respect to the 3Rs principles.

Effectiveness and efficiency of a special program to reduce the bariatric surgery waiting list at a tertiary hospital. / Eficacia y eficiencia de un programa especial para la disminución de la lista de espera de cirugía bariátrica en un hospital terciario.

INTRODUCTION: Bariatric surgery is one of the most common surgical practices in Spain. However, this procedure currently has longest delay on surgical waiting lists (SWL). We have developed a special surgical program that aims to reduce this waiting list and to assess the economic and clinical repercussions in a high-volume bariatric surgery unit. METHODS: A three-month prospective study was carried out comparing outcomes, results and perioperative resources consumed for 45 patients who underwent bariatric surgery. The patients were divided into 2 groups: patients who underwent the standard procedure in the operating room, and patients treated in the special program. Epidemiological, healthcare and economic factors were taken into account. RESULTS: Two homogeneous groups of patients were operated on, successfully reducing the SWL. Morbidity was similar in both groups and the average cost of the surgeries performed was €5,331.40; in the standard group, the cost was €5,372.50±€798.10, and the cost of the special program group was €5,290.30±€685.10, with no significant differences. CONCLUSIONS: In hospitals with a high volume of bariatric surgery, it is feasible to incorporate special surgical programs that are able to reduce surgical waiting lists, while maintaining quality criteria and without incurring a greater expense to the healthcare system.

Shortening of the Common Channel as a Rescue Surgery After Gastric Bypass Failure.

BACKGROUND: After Roux-en-Y gastric bypass (RYGB), up to 30% failures in weight loss have been reported. Among multiple solutions available, we report our experience with shortening of the common channel (SCC) by performing a limb distalization of the alimentary or the biliopancreatic limb. SETTINGS: University Hospital. METHODS: We reviewed data from 23 patients that underwent limb distalization between 2001 and 2019 due to inadequate weight loss after an initial RYGB in our center. All patients who failed to achieve an excess weight loss reduction of > 50% or maintained a body mass index (BMI) above 35 kg/m2 were included. Multiple variables were analyzed during the follow-up at five time points: initial, after RYGB, before SCC, after SCC, and current. RESULTS: The mean BMI prior to the RYGB was 51.8 kg/m2, after RYGB was 37.6 kg/m2, before SCC was 43.6 kg/m2, after SCC was 36.1 kg/m2, and the final BMI was 36.3 kg/m2. No morbidity was seen after SCC. Long-term associated nutritional deficiencies were only identified in 3 patients which had iron deficiency and 1 patient with vitamin D deficiency. Patients with associated comorbidities significantly improved or were withdrawn from medications after the RYGB, with minor variations after SCC. CONCLUSIONS: Limb distalization with SCC is a safe and effective technique for patients who failed to achieve an adequate weight loss after RYGB. There is a slight increase in excess of weight loss after the SCC compared with RYGB. In addition, no further weight regain was documented.

Correction to: Massive Hemothorax Due to Intrathoracic Herniation of the Gastric Remnant After Roux-en-Y Gastric Bypass with Concurrent Hiatal Hernia Repair.

The references were incorrectly ordered during production.

Correlation between the Bethesda system for thyroid nodules and post-thyroidectomy histopathological diagnosis / Correlación entre el sistema Bethesda de nódulos tiroideos y el diagnóstico histopatológico postiroidectomía

BACKGROUND: Thyroid nodules are a common clinical condition. Thyroid nodules may be identified with ultrasonography in roughly 50% of the population. The risk of malignancy varies between 4 and 15% of the nodules. Fine needle aspiration (FNA) with a cytopathology report using the Bethesda system is the most utilized methods to diagnose thyroid carcinoma. MATERIAL AND MEHOTDS: A retrospective, descriptive study was performed to investigate the correlation between the cytopathology of the FNA biopsies, and the final histopathology after thyroidectomy. RESULTS: A total of 128 nodules in 128 patients were studied; 24 males and 104 females. In the Bethesda category I, a 67% malignancy rate was reported, Bethesda II 14%, Bethesda III 28% for follicular lesions and 15% for atypia, Bethesda IV 36%, Bethesda V 79% and Bethesda VI 100%. CONCLUSION: The Bethesda system has been widely adopted internationally and has become an unassailable tool for the pathologist and clinicians for the evaluation and management of thyroid nodules. Since its implementation in the ABC Medical Center, the Bethesda system has granted the institution with favorable and reproducible results.

INTRODUCCIÓN: En la población general, los nódulos tiroideos representan una causa común de consulta al especialista; en poblaciones aleatorizadas, con el uso del ultrasonido se pueden observar hasta en un 50% de los pacientes. El nódulo tiroideo tiene un riesgo de malignidad del 4-15%. El método citopatológico más utilizado para el diagnóstico del cáncer tiroideo es la toma de biopsia por aspiración con aguja fina (BAAF) de los nódulos tiroideos y la utilización del sistema Bethesda para su reporte citopatológico. MATERIAL Y MÉTODOS: Se realizó un estudio descriptivo comparando los porcentajes de malignidad entre las piezas quirúrgicas y el reporte citopatológico de las BAAF utilizando el sistema Bethesda 2010. RESULTADOS: Se estudiaron 128 nódulos en 128 pacientes. En los nódulos Bethesda I se reportó un 67% de malignidad en la histopatología final; en los Bethesda II, un 14%,; en los Bethesda III, un 28% para atipia y un 15% para lesiones foliculares; en los Bethesda IV, un 36%; en los Bethesda V, un 79%; y en los Bethesda VI, un 100%. CONCLUSIÓN: El sistema Bethesda es una herramienta disponible y de gran utilidad para el patólogo y el clínico. Desde su implementación en el Centro Médico ABC ha demostrado ser comparable con los resultados reportados en la literatura internacional.

Towards Evaluating Proactive and Reactive Approaches on Reorganizing Human Resources in IoT-Based Smart Hospitals.

Hospitals play an important role on ensuring a proper treatment of human health. One of the problems to be faced is the increasingly overcrowded patients care queues, who end up waiting for longer times without proper treatment to their health problems. The allocation of health professionals in hospital environments is not able to adapt to the demands of patients. There are times when underused rooms have idle professionals, and overused rooms have fewer professionals than necessary. Previous works have not solved this problem since they focus on understanding the evolution of doctor supply and patient demand, as to better adjust one to the other. However, they have not proposed concrete solutions for that regarding techniques for better allocating available human resources. Moreover, elasticity is one of the most important features of cloud computing, referring to the ability to add or remove resources according to the needs of the application or service. Based on this background, we introduce Elastic allocation of human resources in Healthcare environments (ElHealth) an IoT-focused model able to monitor patient usage of hospital rooms and adapt these rooms for patients demand. Using reactive and proactive elasticity approaches, ElHealth identifies when a room will have a demand that exceeds the capacity of care, and proposes actions to move human resources to adapt to patient demand. Our main contribution is the definition of Human Resources IoT-based Elasticity (i.e., an extension of the concept of resource elasticity in Cloud Computing to manage the use of human resources in a healthcare environment, where health professionals are allocated and deallocated according to patient demand). Another contribution is a cost-benefit analysis for the use of reactive and predictive strategies on human resources reorganization. ElHealth was simulated on a hospital environment using data from a Brazilian polyclinic, and obtained promising results, decreasing the waiting time by up to 96.4% and 96.73% in reactive and proactive approaches, respectively.

Time between recall visits and residual probing depths predict long-term stability in patients enrolled in supportive periodontal therapy.

AIM: To relate the time between recall visits and residual periodontal probing depths (PPDs) to periodontal stability in patients enrolled in supportive periodontal therapy (SPT). MATERIALS AND METHODS: Retrospective data on residual PPDs from 11,842 SPT visits were evaluated in SPT patients at the Medi School of Dental Hygiene (MSDH), Bern, Switzerland, 1985-2011. A residual PPD-based algorithm was developed to compute SPT intervals with no expected change of residual PPD. RESULTS: A total of 883 patients aged 43.9 (±13.0) years and 55.4% (n = 489) being females were identified. Linear mixed model analysis yielded highest statistically significant impact on PPD change with time between SPT visits, presence of residual PPD ≥4 mm, and bleeding on probing (p < 0.0001). Patients returning for SPT five times consecutively earlier than computed presented mean % PPDs ≥4 mm of 5.8% (±3.9) compared with patients returning later (19.2%, ±7.6) (p < 0.0001). Additionally, patients attending >50% of their SPT visits earlier versus later demonstrated increased periodontal stability after 5 years (p = 0.0002) and a reduced frequency of tooth loss (0.60, ±0.93 versus 1.45, ±2.07) after 20 years (p < 0.0001). CONCLUSIONS: To reach and maintain periodontal stability during SPT, individual quantitative data from comprehensive residual PPD profiles may contribute to the improved planning of SPT intervals.

Comparison of Contrast-Enhanced CT and [18F]FDG PET/CT Analysis Using Kurtosis and Skewness in Patients with Primary Colorectal Cancer.

PURPOSE: Heterogeneity is a key feature of malignancy associated with adverse tumor biology. Texture analysis with different imaging modalities has been shown to reflect tumor heterogeneity. The current study analyzed and compared pre-treatment (contrast-enhanced) ceCT and positron emission tomography/computed tomography (PET/CT) tumor heterogeneity using the parameters skewness and kurtosis in patients with primary colorectal cancer with and without liver metastases. PROCEDURES: The histogram-derived texture parameters skewness and kurtosis were retrospectively analyzed obtained on PET/CT and ceCT images from 50 patients with histopathology proven primary colorectal cancer (32 patients without liver metastases and 18 with liver metastases). All patients underwent pretreatment ceCT and a 2-deoxy-2-[18F]Fluoro-D-glucose PET/CT of the whole body for initial staging before treatment. The following parameters were analyzed: (1) skewness ceCT and PET/CT combined, (2) skewness ceCT, (3) skewness PET/CT, (4) kurtosis ceCT and PET/CT combined, (5) kurtosis ceCT, and (6) kurtosis PET/CT. For each parameter, the following comparisons were analyzed: (A) colon tumors in 32 patients without liver metastasis versus colon tumors in 18 patients with liver metastasis, (B) colon tumors (all 50 patients, with and without liver metastases) versus 56 liver metastases of patients with metastatic disease to the liver, (C) colon tumors in 32 patients without liver metastasis versus 56 summed metastasis of the 18 patients with metastatic disease to the liver, and (D) colon tumors in 18 patients with liver metastasis versus summed 56 liver metastasis. Furthermore, ceCT parameters were compared to PET/CT parameters (separately for skewness and kurtosis), and the correlation of the clinical stage with skewness and kurtosis was analyzed. RESULTS: Skewness and kurtosis were not statistically significantly different in primary colon cancer lesions between patients with or without liver metastases (p > 0.05). However, there were significant differences found between primary colon cancer and hepatic metastases (p < 0.05). Thus, skewness and kurtosis derived by ceCT and PET/CT showed significantly different heterogeneities between primary colon cancer lesions and hepatic metastases. The clinical stage was not associated with skewness or kurtosis (r = 0.06 and r = 0.05). CONCLUSION: Texture analysis with relatively simple first-order parameters skewness and kurtosis on ceCT and on PET/CT was able to differentiate between primary colon cancer and hepatic metastases. No differentiation was observed between primary colon tumor lesions in patients with or without hepatic metastases. Overall, skewness and kurtosis measured with ceCT and PET/CT seem to have complementary roles in the evaluation of heterogeneity.

Improving the stability of peptidic radiotracers by the introduction of artificial scaffolds: which structure element is most useful?

Peptidic radiotracers are highly potent substances for the specific in vivo imaging of various biological targets with Single Photon Emission Computed Tomography and Positron Emission Tomography. However, some radiolabeled peptides such as bombesin analogs were shown to exhibit only a limited stability, hampering a successful target visualization. One option to positively influence the stability of radiolabeled peptides is the introduction of certain artificial molecular scaffolds. In order to comparatively assess the influence of different structure elements on the stability of radiolabeled peptides and to identify those structure elements being most useful for peptide radiotracer stabilization, several monomeric and dimeric bombesin derivatives were synthesized, exhibiting differing molecular designs and the chelator NODAGA for (68) Ga-labeling. The radiolabeled peptides were evaluated regarding their in vitro stability in human serum to determine the influence of the introduced molecular scaffolds on the peptides' serum stabilities. The results of the evaluations showed that the introduction of scaffold structures and the overall molecular design have a substantial impact on the stabilities of the resulting peptidic radiotracers. But besides some general trends found using certain scaffold structures, the obtained results point to the necessity to empirically assess their influence on stability for each susceptible peptidic radiotracer individually.

Optimized solid phase-assisted synthesis of dendrons applicable as scaffolds for radiolabeled bioactive multivalent compounds intended for molecular imaging.

Dendritic structures, being highly homogeneous and symmetric, represent ideal scaffolds for the multimerization of bioactive molecules and thus enable the synthesis of compounds of high valency which are e.g., applicable in radiolabeled form as multivalent radiotracers for in vivo imaging. As the commonly applied solution phase synthesis of dendritic scaffolds is cumbersome and time-consuming, a synthesis strategy was developed that allows for the efficient assembly of acid amide bond-based highly modular dendrons on solid support via standard Fmoc solid phase peptide synthesis protocols. The obtained dendritic structures comprised up to 16 maleimide functionalities and were derivatized on solid support with the chelating agent DOTA. The functionalized dendrons furthermore could be efficiently reacted with structurally variable model thiol-bearing bioactive molecules via click chemistry and finally radiolabeled with 68Ga. Thus, this solid phase-assisted dendron synthesis approach enables the fast and straightforward assembly of bioactive multivalent constructs for example applicable as radiotracers for in vivo imaging with Positron Emission Tomography (PET).

PESIN multimerization improves receptor avidities and in vivo tumor targeting properties to GRPR-overexpressing tumors.

The gastrin releasing peptide receptor (GRPR), being overexpressed on several tumor types, represents a promising target for specific noninvasive in vivo tumor imaging using positron emission tomography. Many of the radiolabeled bombesin analogs being applied in tumor imaging, however, suffer from shortcomings such as limited in vivo stability and poor tumor to background ratios. These obstacles can be overcome by peptide multimerization, as this approach results in constructs comprising several copies of the same peptide, thus retaining the ability to specifically bind to the target structure even if one peptide is cleaved. Furthermore, peptide multimers can result in increased binding avidities to the target, which can entail higher absolute tumor uptakes and also tumor to background levels. We therefore synthesized monomers and multimers of the peptide PESIN on dendrimer scaffolds comprising linkers of different lengths. The monomers/multimers were functionalized with the chelator NODAGA, efficiently radiolabeled with (68)Ga and evaluated in vitro regarding their GRPR binding affinity. The results show that shorter distances between the peptide moieties result in substantially higher binding affinities/avidities of the monovalent/multivalent PESIN ligands to the GRPR. Furthermore, the bivalent ligands gave the best results in terms of binding avidity, achieving a 2.5-fold increase in avidity compared to the respective monomer. Moreover, the most potent bivalent ligand showed an about 2-fold higher absolute tumor uptake and twice as high tumor-to-background ratios than the monomeric reference DOTA-PESIN in an initial animal PET study in tumor-bearing mice. Thus, besides high avidities, multivalency also positively influences the in vivo pharmacokinetics of peptide multimers.

(89)Zr, a radiometal nuclide with high potential for molecular imaging with PET: chemistry, applications and remaining challenges.

Molecular imaging-and especially Positron Emission Tomography (PET)-is of increasing importance for the diagnosis of various diseases and thus is experiencing increasing dissemination. Consequently, there is a growing demand for appropriate PET tracers which allow for a specific accumulation in the target structure as well as its visualization and exhibit decay characteristics matching their in vivo pharmacokinetics. To meet this demand, the development of new targeting vectors as well as the use of uncommon radionuclides becomes increasingly important. Uncommon nuclides in this regard enable the utilization of various selectively accumulating bioactive molecules such as peptides, antibodies, their fragments, other proteins and artificial structures for PET imaging in personalized medicine. Among these radionuclides, 89Zr (t1/2 = 3.27 days and mean Eß+ = 0.389 MeV) has attracted increasing attention within the last years due to its favorably long half-life, which enables imaging at late time-points, being especially favorable in case of slowly-accumulating targeting vectors. This review outlines the recent developments in the field of 89Zr-labeled bioactive molecules, their potential and application in PET imaging and beyond, as well as remaining challenges.

Radiolabeled heterobivalent peptidic ligands: an approach with high future potential for in vivo imaging and therapy of malignant diseases.

Two-pronged synergism: We review the recently developed approach of using heterobivalent peptide ligands that interact concomitantly with different receptors on tumor cells. These ligands exhibit highly favorable tumor-targeting properties and pave the way for the development of drugs for specific, sensitive, and noninvasive tumor imaging and therapy.

The early recovery of cognitive function after total-hip replacement under hypotensive epidural anesthesia.

BACKGROUND AND OBJECTIVES: Recovery of cognitive function immediately after major surgery has not been previously reported, partly because of residual drug effects and pain. METHODS: Changes in cognitive function were assessed using the Stroop Color and Word Test (SCWT), which was performed preoperatively, and 1 and 2 hours after total-hip replacement performed under hypotensive epidural anesthesia. In this case series, patients were sedated with propofol alone and had a lumbar plexus block performed at the end of surgery. RESULTS: The SCWT was completed in 52 of 55 patients at either 1 or 2 hours after surgery. A significant reduction in cognitive function was noted 1 hour after surgery but a return toward baseline occured 2 hours after surgery. Age older than 70 years adversely affected recovery of cognitive function, but neither the preoperative diagnosis of hypertension nor the degree or duration of intraoperative hypotension (mean arterial pressure less than 45 mmHg) influenced cognitive function. CONCLUSION: The Stroop Color and Word Test can be used to assess change in cognitive function immediately after surgery. Total-hip replacement performed under regional anesthesia with propofol sedation enables recovery of cognitive function (as assessed by SCWT) 2 hours after surgery.