Reconstruction of Soft-Tissue Defects of the Thumb Using Reverse-Flow Homodigital Flaps: A Systematic Review.

Introduction: Soft-tissue thumb defects are common reconstructive challenges, the main goals being restoration of tactile sensibility, range of movement, pulp padding, length, and cosmesis. The reverse-flow dorsoulnar and dorsoradial collateral artery flaps are homodigital flaps used to cover both distal dorsal and volar thumb defects. These flaps can be used as compound flaps including skin, fat, and/or nerves. As there is no critical analysis of these studies, this study aims to create a synthesized comprehensive systematic review. Methods: Systematic review was performed using the databases PubMed, Embase, and Medline. Eligible studies followed the inclusion criteria: English language and all studies published to date. The primary outcome was flap survival. Other data collected included anatomical area of the defect, flap constituents and dimensions, donor-site closure and complications, transfer method, reoperation, revision, and functional outcomes. Results: A total of 19 articles incorporating 189 flaps met the inclusion criteria. These flaps were categorized and analyzed as dorsoradial (50%), dorsoulnar (39%), and turnover flaps (11%). Dorsoradial flaps were used in fasciocutaneous fashion alone. Partial flap failures occurred in five cases. Dorsoulnar flaps were used as fasciocutaneous or as osteocutaneous flaps. Complete flap failure was reported in one patient alone, whereas partial necrosis was reported in four patients. Adipofascial turnover flaps had two partial flap failures reported but no complete failures. The overall complete and partial flap failure rates were 0.5 and 6.5%, respectively. Conclusion: Reverse-flow homodigital random or axial-based flaps provide a reliable means of reconstruction for soft-tissue defects with reasonable success rate and good functional outcomes. They have a consistent anatomy with a good potential for personalization and therefore increased versatility.

Perceptions of theatre team members to robotic assisted surgery and the aid of technology in colorectal surgery.

The implementation of robotic assisted surgery (RAS) has brought in a change to the perception and roles of theatre staff, as well as the dynamics of the operative environment and team. This study aims to identify and describe current perceptions of theatre staff in the context of RAS. 12 semi-structured interviews were conducted in a tertiary level university hospital, where RAS is utilised in selected elective settings. Interviews were conducted by an experienced research nurse to staff of the colorectal department operating theatre (nursing, surgical and anaesthetics) with some experience in operating within open, laparoscopic and RAS surgical settings. Thematic analysis on all interviews was performed, with formation of preliminary themes. Respondents all discussed advantages of all modes of operating. All respondents appreciated the benefits of minimally invasive surgery, in the reduced physiological insult to patients. However, interviewees remarked on the current perceived limitations of RAS in terms of logistics. Some voiced apprehension and anxieties about the safety if an operation needs to be converted to open. An overarching theme with participants of all levels and backgrounds was the 'Teamwork' and the concept of the [robotic] team. The physical differences of RAS changes the traditional methods of communication, with the loss of face-to-face contact and the physical 'separation' of the surgeon from the rest of the operating team impacting theatre dynamics. It is vital to understand the staff cultures, concerns and perception to the use of this relatively new technology in colorectal surgery.

Factors Related to Limb Occlusion After Endovascular Abdominal Aortic Aneurysm Repair (EVAR).

BACKGROUND: Limb occlusion is a potentially serious consequence of endovascular abdominal aortic aneurysm (EVAR). This case-control study identifies factors that predispose to limb occlusion. METHODS: A consecutive series of patients from 2 centers undergoing EVAR over an 11-year period 2007-2017 were identified retrospectively. Patient records were interrogated allowing collations of demographics, intraoperative and perioperative data and surveillance data. The preoperative computed tomography angiogram was analyzed to determine EVAR relevant anatomical data. The primary outcome was occlusion of the iliac limb of the implanted EVAR. Raw data are presented as percentages, with comparative data analyzed using Mann-Whitney U-test and binomial logistic regression. RESULTS: A total of 787 patients (702 males; median age 78 years, range 53-94 years old) were analyzed. Fifty patients reached the primary outcome, resulting in an overall limb occlusion rate of 6.35%. Factors predictive of limb occlusion were oversizing by >10% native vessel diameter, with oversizing of >20% in 50% of those that occluded. External iliac artery landing zone (12/50 limb occlusions) 24% and postoperative kinking (5/50 limb occlusions) 10% were also more common in those that occluded. Fifty randomly selected controls with similar baseline characteristics were studied. Oversizing of the iliac endograft was found to be significantly greater in the limb occlusion group compared to the controls (P < 0.001) which remained significant on regression analysis. There was no correlation with iliac tortuosity. The Cook stent graft had a 9% limb occlusion rate across sites. Medtronic and Vascutek endografts had 2.4% and 2.5% limb occlusion rates respectively. CONCLUSIONS: Oversizing of iliac limbs by >20% could be a contributing factor to limb occlusion after EVAR and judicious oversizing should be used.

Freezing process influences cake appearance of a lyophilized amorphous protein formulation with low solid content and high fill configuration.

Low solid content and high fill drug product configuration pose special challenges for achieving elegant cake appearance after lyophilization. In this study, such a configuration for a protein formulation required lyophilization within a narrow primary drying operating space to obtain elegant cakes. Freezing process optimization was explored as a solution. A Design of Experiment (DoE) approach was used to evaluate the effect of shelf cooling rate, annealing temperature, and their interaction on cake appearance. The slope of product resistance (Rp) vs. dried layer thickness (Ldry) was used as the quantitative response because elegant cake appearance correlated with a lower initial Rp and positive slope. As the Rp vs. Ldry slope can be experimentally established within the first 1/6th of the total primary drying duration, partial lyophilization runs were executed, allowing for rapid screening. The DoE model revealed that a slow cooling rate (≤0.3 °C/min) and high annealing temperature (≥-10 °C) resulted in a better cake appearance. Furthermore, X-ray micro-computed tomography showed that elegant cakes exhibited uniform porous structure and larger pores, while inelegant cakes showed dense top layers with smaller pores. With the optimized freezing process, the primary drying operating space was broadened with improved cake appearance and batch homogeneity.

Key factors governing the reconstitution time of high concentration lyophilized protein formulations.

Lyophilized protein formulations containing highly concentrated proteins often have long and variable reconstitution times. Reconstitution time is dependent on a number of factors in a complex manner. Furthermore, factors influencing the reconstitution of partially crystalline cakes are reportedly different from those of amorphous cakes. The objectives of this work were to identify the key factors governing reconstitution and understand the mechanisms involved in reconstitution of both amorphous and partially crystalline cakes. Partial crystallinity in the final cake, larger pores and low "concentrated formulation viscosity" (i.e., viscosity near the surface of the dissolving cake) were identified as desirable characteristics for expediting reconstitution. Crystallinity and larger pores dramatically improved wettability and liquid penetration into partially crystalline cakes, ultimately resulting in well dispersed small pieces of partially dissolved cake. The smaller disintegrated cake pieces dissolved faster because of the increased surface area. The amorphous cakes exhibited poorer wettability than partially crystalline cakes. Moreover, the ability of the reconstitution fluid to penetrate the pores, and the resulting cake disintegration was much lower than that observed for partially crystalline cakes. In fact, for some of the amorphous cakes, the reconstitution fluid did not penetrate the cake at all. As a result, the undissolved intact cake or a large cake chunk floated on the reconstitution fluid amidst foam or bubbles generated during reconstitution. Dissolution of the floating cake appeared to proceed via gradual surface erosion where reconstitution time was found to be highly correlated with the viscosity near the surface of the dissolving cake solids. A higher viscosity prolonged reconstitution. Thus, both formulation and processing conditions can be tailored to achieve faster reconstitution. Including a crystallizable excipient proved to be beneficial. Incorporating an annealing step to facilitate crystallization of the crystallizable excipient and to promote larger pores was also found to be advantageous. A viscosity lowering excipient in the formulation could potentially be helpful but needs to be explored further.

Effect of kidney donation on bone mineral metabolism.

Kidney donation results in reductions in kidney function and lasting perturbations in phosphate homeostasis, which may lead to adverse cardiovascular sequelae. However, the acute effects of kidney donation on bone mineral parameters including regulators of calcium and phosphate metabolism are unknown. We conducted a prospective observational controlled study to determine the acute effects of kidney donation on mineral metabolism and skeletal health. Biochemical endpoints were determined before and after donation on days 1, 2 and 3, 6 weeks and 12 months in donors and at baseline, 6 weeks and 12 months in controls. Baseline characteristic of donors (n = 34) and controls (n = 34) were similar: age (53±10 vs 50±14 years, p = 0.33), BMI (26.3±2.89 vs 25.9±3.65, p = 0.59), systolic BP (128±13 vs 130±6 mmHg, p = 0.59), diastolic BP (80±9 vs 81±9 mmHg, p = 0.68) and baseline GFR (84.4±20.2 vs 83.6±25.2 ml/min/1.73m2, p = 0.89). eGFR reduced from 84.4±20.2 to 52.3±17.5 ml/min/1.73m2 (p<0.001) by day 1 with incomplete recovery by 12 months (67.7±22.6; p = 0.002). Phosphate increased by day 1 (1.1(0.9-1.2) to 1.3(1.1-1.4) mmol/L, p <0.001) but declined to 0.8(0.8-1.0) mmol/L (p<0.001) before normalizing by 6 weeks. Calcium declined on day 1 (p = 0.003) but recovered at 6 weeks or 12 months. PTH and FGF-23 remained unchanged, but α-Klotho reduced by day 1 (p = 0.001) and remained low at 6 weeks (p = 0.02) and 1 year (p = 0.04). In this study, we conclude that kidney donation results in acute disturbances in mineral metabolism characterised by a reduced phosphate and circulating α-Klotho concentration without acute changes in the phosphaturic hormones FGF23 and PTH.

Reconstitution Time for Highly Concentrated Lyophilized Proteins: Role of Formulation and Protein.

Lyophilized protein formulations containing highly concentrated proteins often have long reconstitution times. The goal was to understand the role of formulation in mediating the reconstitution time. Formulation variables such as % total solids, protein concentration, protein-to-sugar ratio, different proteins and inclusion of a crystallizable excipient were investigated for their effect on cake properties influencing reconstitution namely, cake wettability, penetration of reconstitution fluid into the cake, cake disintegration and cake porous structure. Additionally, several measures of viscosity were also evaluated for their effect on reconstitution time. Reconstitution time was primarily influenced by the "concentrated formulation viscosity" with negligible contributions from % total solids and protein concentration. "Concentrated formulation viscosity" was sensitive to both protein-to-sugar ratio and the protein itself. Partial crystallinity in the final cake also expedited reconstitution. Wettability, liquid penetration into the cake, cake disintegration tendency and cake porous structure were found to be invariant for amorphous cakes and did not correlate with reconstitution time. However, these properties were sensitive to the presence of crystallinity and resulted in faster reconstitution at least of the partially crystalline cakes. "Concentrated formulation viscosity" strongly correlated with reconstitution times of amorphous cakes, providing insights on the steps involved in the reconstitution of amorphous formulations.

Evaluation of the Console in Acquiring Laparoscopic Skills through Video Gaming.

STUDY OBJECTIVE: Video gaming experience and practice is known to help attain and improve laparoscopic skills. We compared the impact of Wii (Nintendo, Kyoto, Japan) and XBox (Microsoft Inc., Redmond, WA) gaming experience on laparoscopic skills. DESIGN: Observational study. SETTING: Tertiary hospital. PARTICIPANTS: Twenty-seven selected medical student volunteers with no previous laparoscopy experience. INTERVENTIONS: A selected cohort of medical students completed a questionnaire on their video gaming experience and were asked to play a game each on the Wii console and on the Xbox for 10 minutes each. They were then assessed on predefined laparoscopic skills with standardized objective scoring by 2 independent assessors. The skills tested were stacking ice cubes in set time, putting discs through strings in set time, and circle cutting. MEASUREMENTS AND MAIN RESULTS: Score was allocated for each video gaming session and for the laparoscopic session. The video gaming skills score was based on points achieved during a stipulated time period on 2 different consoles. Laparoscopy skills were assessed based on an agreed scoring matrix that involved appropriate weighting of the score based on importance of the task. The laparoscopy skills scores correlated significantly with both Xbox and Wii scores. Correlations between laparoscopic task scores were further analyzed by game console, Wii and Xbox. There was a stronger correlation between the Wii highest score and the total of the laparoscopic skills score (Spearman correlation coefficient = .734; p = .0001) compared with the correlation between the Xbox and the total laparoscopic skills score (Spearman correlation coefficient = .412; p = .033). CONCLUSION: We confirm the correlation between video gaming and laparoscopic skills. Further, we conclude that the correlation is stronger with the Wii console compared with the Xbox for psychomotor skills, perhaps due to the similarity of action between the Nintendo Wii remote and laparoscopic instruments. Thus, practicing video gaming on the Nintendo Wii console over Xbox may improve manual dexterity laparoscopic skills. However, research of larger cohort studies with different games would provide further insight into the best methods for future simulated learning.

Mechanisms by which crystalline mannitol improves the reconstitution time of high concentration lyophilized protein formulations.

Lyophilized high concentration protein formulations often have long and variable reconstitution times. The aim is to understand the role of crystalline mannitol in lowering the reconstitution time of these formulations. Novel methods were developed for quantifying the effect of crystalline mannitol on cake attributes influencing reconstitution, specifically, cake wettability, liquid penetration into the cake and cake disintegration. Amorphous and partially crystalline cakes were obtained by varying the freeze-drying conditions, particularly, the freezing rate (slow vs. fast), annealing (annealed vs. unannealed), and primary drying (aggressive vs. conservative). Mannitol crystallinity was quantified using X-ray powder diffractometry. Phase separation of crystalline mannitol from the amorphous, protein rich matrix improved wettability of the cake solids and promoted penetration of the reconstitution fluid into the cake interior. The partially crystalline cakes offered less resistance to crushing in the dry state than the amorphous cakes. Crystalline mannitol provided "weak points" in the freeze-dried cakes, potentially enabling easier cake disintegration upon addition of the reconstitution fluid. There was no evident correlation between the degree of crystallinity and reconstitution time. While crystalline mannitol generally decreased reconstitution time by favorably affecting the cake attributes influencing reconstitution, it did not always reduce reconstitution time.

A Large-Scale RNAi Screen Identifies SGK1 as a Key Survival Kinase for GBM Stem Cells.

Glioblastoma multiforme (GBM) is the most common type of primary malignant brain cancer and has a very poor prognosis. A subpopulation of cells known as GBM stem-like cells (GBM-SC) have the capacity to initiate and sustain tumor growth and possess molecular characteristics similar to the parental tumor. GBM-SCs are known to be enriched in hypoxic niches and may contribute to therapeutic resistance. Therefore, to identify genetic determinants important for the proliferation and survival of GBM stem cells, an unbiased pooled shRNA screen of 10,000 genes was conducted under normoxic as well as hypoxic conditions. A number of essential genes were identified that are required for GBM-SC growth, under either or both oxygen conditions, in two different GBM-SC lines. Interestingly, only about a third of the essential genes were common to both cell lines. The oxygen environment significantly impacts the cellular genetic dependencies as 30% of the genes required under hypoxia were not required under normoxic conditions. In addition to identifying essential genes already implicated in GBM such as CDK4, KIF11, and RAN, the screen also identified new genes that have not been previously implicated in GBM stem cell biology. The importance of the serum and glucocorticoid-regulated kinase 1 (SGK1) for cellular survival was validated in multiple patient-derived GBM stem cell lines using shRNA, CRISPR, and pharmacologic inhibitors. However, SGK1 depletion and inhibition has little effect on traditional serum grown glioma lines and on differentiated GBM-SCs indicating its specific importance in GBM stem cell survival.Implications: This study identifies genes required for the growth and survival of GBM stem cells under both normoxic and hypoxic conditions and finds SGK1 as a novel potential drug target for GBM. Mol Cancer Res; 16(1); 103-14. ©2017 AACR.

Chronic Paroxetine Treatment Prevents the Emergence of Abnormal Electroencephalogram Oscillations in Huntington's Disease Mice.

Disturbance of rapid eye movement (REM) sleep appears early in both patients with Huntington's disease (HD) and mouse models of HD. Selective serotonin reuptake inhibitors are widely prescribed for patients with HD, and are also known to suppress REM sleep in healthy subjects. To test whether selective serotonin reuptake inhibitors can correct abnormal REM sleep and sleep-dependent brain oscillations in HD mice, we treated wild-type and symptomatic R6/2 mice acutely with vehicle and paroxetine (5, 10, and 20 mg/kg). In addition, we treated a group of R6/2 mice chronically with vehicle or paroxetine (20 mg/kg/day) for 8 weeks, with treatment starting before the onset of overt motor symptoms. During and after treatment, we recorded electroencephalogram/electromyogram from the mice. We found that both acute and chronic paroxetine treatment normalized REM sleep in R6/2 mice. However, only chronic paroxetine treatment prevented the emergence of abnormal low-gamma (25-45 Hz) electroencephalogram oscillations in R6/2 mice, an effect that persisted for at least 2 weeks after treatment stopped. Chronic paroxetine treatment also normalized REM sleep theta rhythm in R6/2 mice, but, interestingly, this effect was restricted to the treatment period. By contrast, acute paroxetine treatment slowed REM sleep theta rhythm in WT mice but had no effect on abnormal theta or low-gamma oscillations in R6/2 mice. Our data show that paroxetine treatment, when initiated before the onset of symptoms, corrects both REM sleep disturbances and abnormal brain oscillations, suggesting a possible mechanistic link between early disruption of REM sleep and the subsequent abnormal brain activity in HD mice.

Regulation of the JMJD3 (KDM6B) histone demethylase in glioblastoma stem cells by STAT3.

The growth factor and cytokine regulated transcription factor STAT3 is required for the self-renewal of several stem cell types including tumor stem cells from glioblastoma. Here we show that STAT3 inhibition leads to the upregulation of the histone H3K27me2/3 demethylase Jmjd3 (KDM6B), which can reverse polycomb complex-mediated repression of tissue specific genes. STAT3 binds to the Jmjd3 promoter, suggesting that Jmjd3 is a direct target of STAT3. Overexpression of Jmjd3 slows glioblastoma stem cell growth and neurosphere formation, whereas knockdown of Jmjd3 rescues the STAT3 inhibitor-induced neurosphere formation defect. Consistent with this observation, STAT3 inhibition leads to histone H3K27 demethylation of neural differentiation genes, such as Myt1, FGF21, and GDF15. These results demonstrate that the regulation of Jmjd3 by STAT3 maintains repression of differentiation specific genes and is therefore important for the maintenance of self-renewal of normal neural and glioblastoma stem cells.

Potential drug delivery approaches for XFS-associated and XFS-associated glaucoma.

Key tissue targets in treating exfoliation syndrome (XFS) and the associated glaucoma include lens, iris, and ciliary body, which produce the exfoliative material, and the trabecular meshwork, which may be impaired by the exfoliative material. In addition to antiglaucoma drug therapy, strategies for treating the disease include approaches for preventing formation of exfoliative material as well as those aimed at digesting exfoliative material. A variety of drug molecules including small molecules, protein drugs, and nucleic acids are potential candidates for treating XFS. Potential drug classes include antioxidants, lysyl oxidase-like 1 enhancers, antifibrotics, anti-inflammatory agents, proteases, and chaperones. However, the delivery of these agents to the target tissues in the anterior segment is hindered by protective static and dynamic barriers of the eye. Thus, unique drug delivery approaches are needed for each drug type (small molecules, proteins, and nucleic acids). In addition, there is a need for sustaining drug therapy for treating XFS, which can potentially be addressed by using nanoparticles, microparticles, implants, and contact lens delivery systems. This article provides an overview of drug delivery challenges and opportunities in treating XFS with the focus being on nanomedicines.

Protein phosphatase 2A isoforms utilizing Aß scaffolds regulate differentiation through control of Akt protein.

Protein phosphatase 2A (PP2A) regulates almost all cell signaling pathways. It consists of a scaffolding A subunit to which a catalytic C subunit and one of many regulatory B subunits bind. Of the more than 80 PP2A isoforms, 10% use Aß as a scaffold. This study demonstrates the isoform-specific function of the A scaffold subunits. Polyomaviruses have shown the importance of phosphotyrosine, PI3K, and p53 in transformation. Comparisons of polyoma and SV40 small T antigens implicate Aß in the control of differentiation. Knockdown of Aß enhanced differentiation. Akt signaling regulated differentiation; its activation or inhibition promoted or blocked it, respectively. Aß bound Akt. Enhancement of PP2A Aß/Akt interaction by polyoma small T antigen increased turnover of Akt Ser-473 phosphorylation. Conversely, knockdown of Aß promoted Akt activity and reduced turnover of phosphate at Ser-473 of Akt. These data provide new insight into the regulation of Akt, a protein of extreme importance in cancer. Furthermore, our results suggest that the role for Aß in differentiation and perhaps tumor suppression may lie partly in its ability to negatively regulate Akt.

Gene expression profiling differentiates autism case-controls and phenotypic variants of autism spectrum disorders: evidence for circadian rhythm dysfunction in severe autism.

Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by delayed/abnormal language development, deficits in social interaction, repetitive behaviors and restricted interests. The heterogeneity in clinical presentation of ASD, likely due to different etiologies, complicates genetic/biological analyses of these disorders. DNA microarray analyses were conducted on 116 lymphoblastoid cell lines (LCL) from individuals with idiopathic autism who are divided into three phenotypic subgroups according to severity scores from the commonly used Autism Diagnostic Interview-Revised questionnaire and age-matched, nonautistic controls. Statistical analyses of gene expression data from control LCL against that of LCL from ASD probands identify genes for which expression levels are either quantitatively or qualitatively associated with phenotypic severity. Comparison of the significant differentially expressed genes from each subgroup relative to the control group reveals differentially expressed genes unique to each subgroup as well as genes in common across subgroups. Among the findings unique to the most severely affected ASD group are 15 genes that regulate circadian rhythm, which has been shown to have multiple effects on neurological as well as metabolic functions commonly dysregulated in autism. Among the genes common to all three subgroups of ASD are 20 novel genes mostly in putative noncoding regions, which appear to associate with androgen sensitivity and which may underlie the strong 4:1 bias toward affected males.