Differences in the Surgical Outcomes of Glaucoma Surgery in Patients of African Caribbean Descent.

PURPOSE: People of African Caribbean Descent (ACD) have a higher prevalence of glaucoma compared to people of European Descent (ED) and there is uncertainty if treatment outcomes are equivalent between the two groups. To assess surgical failure rates comparing ACD with ED focusing on trabeculectomy, aqueous shunt implantation, non-penetrating filtering surgery (NPFS), and minimally invasive glaucoma surgery (MIGS) by performing a systematic review in accordance with the PRISMA guidelines and to determine whether there is any evidence in to show a difference in success rates based on race. METHODS: A systematic review of articles using the CENTRAL, Ovid MEDLINE, PubMed, EMBASE, and ClinicalTrials.gov databases was completed. Additional studies were identified by contacting clinical experts and searching bibliographies. All retrospective and prospective studies on trabeculectomy, aqueous shunt implantation, NPFS, and MIGS that included at least 20% ACD were included. Two review authors independently screened search results for eligibility and inclusion and extracted the data using pre-determined fields. RESULTS: A total of 76 studies were identified for inclusion in the review. Glaucoma surgical outcomes in ACD appear to be poorer compared to ED overall, particularly for trabeculectomy. Data on NPFS are limited, but the studies completed thus far demonstrate surprisingly good results for ACD, particularly when compared to ED, who have significantly lower pre-operative IOPs. Evidence from studies investigating aqueous shunts does not suggest that ACD have poorer outcomes than ED. There is not enough data on MIGS to provide a significant conclusion. CONCLUSION: In a population where trabeculectomy may no longer be the gold standard, sufficiently powered studies assessing surgical outcomes in aqueous shunts, NPFS, and MIGS are needed to guide clinicians.

2 µm passively mode-locked thulium-doped fiber lasers with Ta2AlC-deposited tapered and side-polished fibers.

In this work, mode-locked thulium-doped fiber lasers operating in the 2 µm wavelength region were demonstrated using tantalum aluminum carbide (Ta2AlC)-based saturable absorbers (SAs) utilizing the evanescent wave interaction. The Ta2AlC MAX Phase was prepared by dissolving the Ta2AlC powder in isopropyl alcohol and then deposited onto three different evanescent field-based devices, which were the tapered fiber, side-polished fiber, and arc-shaped fiber. Flame-brushing and wheel-polishing techniques were used to fabricate the tapered and arc-shaped fibers, respectively, while the side-polished fiber was purchased commercially. All three SA devices generated stable mode-locked pulses at center wavelengths of 1937, 1931, and 1929 nm for the tapered, side-polished, and arc-shaped fibers. The frequency of the mode-locked pulses was 10.73 MHz for the tapered fiber, 9.58 MHz for the side-polished fiber, and 10.16 MHz for the arc-shaped fiber. The measured pulse widths were 1.678, 1.734, and 1.817 ps for each of the three SA devices. The long-term stability of the mode-locked lasers was tested for each configuration over a 2-h duration. The lasers also showed little to no fluctuations in the center wavelengths and the peak optical intensities, demonstrating a reliable, ultrafast laser system.

Depression, Anxiety, Perceived Stress, and Their Changes Predict Greater Decline in Physical Health Functioning over 12 Months Among Patients with Coronary Heart Disease.

BACKGROUND: Although the deleterious impact of psychological distress on patients with coronary heart disease (CHD) is recognized, few studies have examined the influence of change in psychological distress on health outcomes over time. This study investigated whether three common manifestations of distress (depression, anxiety, and perceived stress) and their changes predicted the decline in physical functioning in CHD patients over 12 months. In addition, perceived social support was examined as a buffer of psychological distress or a direct predictor of physical functioning. METHODS: Participants were 255 CHD patients with a mean age of 63 (SD = 8.65) years, including 208 men and 47 women. Psychological distress and physical functioning were assessed at baseline, 6 months and 12 months. Hierarchical regression analyses were conducted to examine the influences of psychological factors on physical functioning over 12 months. All models were adjusted for baseline physical functioning, age, gender, marital status, education, BMI, and length of participation at a wellness center. RESULTS: For each psychological distress variable (depression, anxiety, or perceived stress), both the baseline (ßs = - 0.19 to - 0.32, ps = 0.008 to < 0.001) and its respective change over time (ßs = - 0.17 to - 0.38, ps = 0.020 to < 0.001) independently and significantly predicted greater decline in physical functioning at 6 and 12 months, after adjusting for covariates. Perceived social support predicted greater improvement in physical functioning at 12 months (ß = 0.13, p = 0.050), but it did not buffer impact of psychological distress. CONCLUSIONS: Findings underscore the importance of monitoring various forms of psychological distress continuously over time for CHD patients.

Intact vitreous humor as a potential extracellular matrix hydrogel for cartilage tissue engineering applications.

Decellularisation of tissues, utilising their biochemical cues, poses exciting tissue engineering (TE) opportunities. However, removing DNA from cartilage (dCart) requires harsh treatments due to its dense structure, causing loss of bioactivity and limiting its application as a cartilaginous extra cellular matrix (ECM). In this study, we demonstrate for the first time the successful application of vitreous humor (VH), a highly hydrated tissue closely resembling the glycosaminoglycan (GAG) and collagen composition of cartilage, as an ECM hydrogel to support chondrogenic differentiation. Equine VH was extracted followed by biochemical quantifications, histological examinations, cytotoxicity (human mesenchymal stromal cells, hMSCs and human articular chondrocytes, hACs) and U937 cell proliferation studies. VH was further seeded with hACs or hMSCs and cultured for 3-weeks to study chondrogenesis compared to scaffold-free micro-tissue pellet cultures and collagen-I hydrogels. Viability, metabolic activity, GAG and DNA content, chondrogenic gene expression (aggrecan, collagen I/II mRNA) and mechanical properties were quantified and matrix deposition was visualised using immunohistochemistry (Safranin-O, collagen I/II). VH was successfully extracted, exhibiting negligible amounts of DNA (0.4 ±â€¯0.4 µg/mg dry-weight) and notable preservation of ECM components. VH displayed neither cytotoxic responses nor proliferation of macrophage-like U937 cells, instead enhancing both hMSC and hAC proliferation. Interestingly, encapsulated cells self-assembled the VH-hydrogel into spheroids, resulting in uniform distribution of both GAGs and collagen type II with increased compressive mechanical properties, rendering VH a permissive native ECM source to fabricate cartilaginous hydrogels for potential TE applications. STATEMENT OF SIGNIFICANCE: Fabricating bioactive and cell-instructive cartilage extracellular matrix (ECM) derived biomaterials and hydrogels has over recent years proven to be a challenging task, often limited by poor retention of inherent environmental cues post decellularisation due to the dense and avascular nature of native cartilage. In this study, we present an alternative route to fabricate highly permissive and bioactive ECM hydrogels from vitreous humor (VH) tissue. This paper specifically reports the discovery of optimal VH extraction protocols and cell seeding strategy enabling fabrication of cartilaginous matrix components into a hydrogel support material for promoting chondrogenic differentiation. The work showcases a naturally intact and unmodified hydrogel design that improves cellular responses and may help guide the development of cell instructive and stimuli responsive hybrid biomaterials in a number of TERM applications.

A 96-well microplate bioreactor platform supporting individual dual perfusion and high-throughput assessment of simple or biofabricated 3D tissue models.

Traditional 2D monolayer cell cultures and submillimeter 3D tissue construct cultures used widely in tissue engineering are limited in their ability to extrapolate experimental data to predict in vivo responses due to their simplistic organization and lack of stimuli. The rise of biofabrication and bioreactor technologies has sought to address this through the development of techniques to spatially organize components of a tissue construct, and devices to supply these tissue constructs with an increasingly in vivo-like environment. Current bioreactors supporting both parenchymal and barrier tissue constructs in interconnected systems for body-on-a-chip platforms have chosen to emphasize study throughput or system/tissue complexity. Here, we report a platform to address this disparity in throughput and both system complexity (by supporting multiple in situ assessment methods) and tissue complexity (by adopting a construct-agnostic format). We introduce an ANSI/SLAS-compliant microplate and docking station fabricated via stereolithography (SLA), or precision machining, to provide up to 96 samples (Ø6 × 10 mm) with two individually-addressable fluid circuits (192 total), loading access, and inspection window for imaging during perfusion. Biofabricated ovarian cancer models were developed to demonstrate the in situ assessment capabilities via microscopy and a perfused resazurin-based metabolic activity assay. In situ microscopy highlighted flexibility of the sample housing to accommodate a range of sample geometries. Utility for drug screening was demonstrated by exposing the ovarian cancer models to an anticancer drug (doxorubicin) and generating the dose-response curve in situ, while achieving an assay quality similar to static wellplate culture. The potential for quantitative analysis of temporal tissue development and screening studies was confirmed by imaging soft- (gelatin) and hard-tissue (calcium chloride) analogs inside the bioreactor via spectral computed tomography (CT) scanning. As a proof-of-concept for particle tracing studies, flowing microparticles were visualized to inform the design of hydrogel constructs. Finally, the ability for mechanistic yet high-throughput screening was demonstrated in a vascular coculture model adopting endothelial and mesenchymal stem cells (HUVEC-MSC), encapsulated in gelatin-norbornene (gel-NOR) hydrogel cast into SLA-printed well inserts. This study illustrates the potential of a scalable dual perfusion bioreactor platform for parenchymal and barrier tissue constructs to support a broad range of multi-organ-on-a-chip applications.

Blood lactate concentration and shock index associated with massive transfusion in emergency department patients with primary postpartum haemorrhage.

BACKGROUND: We hypothesised that lactate concentrations are independently associated with massive transfusion in patients with primary postpartum haemorrhage. Moreover, combining lactate concentrations with the shock index, defined as the ratio of heart rate to systolic arterial blood pressure, can improve the predictive performance for massive transfusion. METHODS: We retrospectively analysed patients with primary postpartum haemorrhage in the emergency department of a tertiary referral centre in Korea between January 1, 2004 and December 31, 2015. RESULTS: Of the 302 patients, 101 (33.4%) patients required massive transfusion. Lactate concentration was independently associated with the requirement for massive transfusion [odds ratio, 1.56; 95% confidence interval (CI), 1.31-1.87; P<0.01]. The area under the receiver operating characteristic curve of lactate concentration and shock index for massive transfusion was 0.788 (95% CI: 0.736-0.840; P<0.01) and 0.776 (95% CI: 0.717-0.836; P<0.01), respectively. Lactate elevation (>4.0 mM L-1) was associated with 86.1% specificity and 67.8% positive predictive value for massive transfusion. When combining elevated lactate concentrations (>4.0 mM L-1) with a shock index >1.0, the specificity and positive predictive value increased to 95.5% and 82.4%, respectively. CONCLUSIONS: Point-of-care testing of lactate concentrations in the emergency department may be useful to predict massive transfusion requirements in primary postpartum haemorrhage. Combining initial lactate concentrations with the shock index improves the predictive performance for massive transfusion requirements and may contribute to rapid risk stratification of patients with primary postpartum haemorrhage in need of transfusion and further focus on early interventions to control bleeding.

Engineering of a complex bone tissue model with endothelialised channels and capillary-like networks.

In engineering of tissue analogues, upscaling to clinically-relevant sized constructs remains a significant challenge. The successful integration of a vascular network throughout the engineered tissue is anticipated to overcome the lack of nutrient and oxygen supply to residing cells. This work aimed at developing a multiscale bone-tissue-specific vascularisation strategy. Engineering pre-vascularised bone leads to biological and fabrication dilemmas. To fabricate channels endowed with an endothelium and suitable for osteogenesis, rather stiff materials are preferable, while capillarisation requires soft matrices. To overcome this challenge, gelatine-methacryloyl hydrogels were tailored by changing the degree of functionalisation to allow for cell spreading within the hydrogel, while still enabling endothelialisation on the hydrogel surface. An additional challenge was the combination of the multiple required cell-types within one biomaterial, sharing the same culture medium. Consequently, a new medium composition was investigated that simultaneously allowed for endothelialisation, capillarisation and osteogenesis. Integrated multipotent mesenchymal stromal cells, which give rise to pericyte-like and osteogenic cells, and endothelial-colony-forming cells (ECFCs) which form capillaries and endothelium, were used. Based on the aforementioned optimisation, a construct of 8 × 8 × 3 mm, with a central channel of 600 µm in diameter, was engineered. In this construct, ECFCs covered the channel with endothelium and osteogenic cells resided in the hydrogel, adjacent to self-assembled capillary-like networks. This study showed the promise of engineering complex tissue constructs by means of human primary cells, paving the way for scaling-up and finally overcoming the challenge of engineering vascularised tissues.

Is tranexamic acid toxic to articular cartilage when administered topically? What is the safe dose?

Aims: The intra-articular administration of tranexamic acid (TXA) has been shown to be effective in reducing blood loss in unicompartmental knee arthroplasty and anterior cruciate reconstruction. The effects on human articular cartilage, however, remains unknown. Our aim, in this study, was to investigate any detrimental effect of TXA on chondrocytes, and to establish if there was a safe dose for its use in clinical practice. The hypothesis was that TXA would cause a dose-dependent damage to human articular cartilage. Materials and Methods: The cellular morphology, adhesion, metabolic activity, and viability of human chondrocytes when increasing the concentration (0 mg/ml to 40 mg/ml) and length of exposure to TXA (0 to 12 hours) were analyzed in a 2D model. This was then repeated, excluding cellular adhesion, in a 3D model and confirmed in viable samples of articular cartilage. Results: Increasing concentrations above 20 mg/ml resulted in atypical morphology, reduced cellular adhesion and metabolic activity associated with increased chondrocyte death. However, the cell matrix was not affected by the concentration of TXA or the length of exposure, and offered cellular protection for concentrations below 20 mg/ml. Conclusion: These results show that when in vitro chondrocytes are exposed to higher concentrations of TXA, such as that expected following recommended intra-articular administration, cytotoxicity is observed. This effect is dose-dependent, such that a tissue concentration of 10 mg/ml to 20 mg/ml could be expected to be safe. Cite this article: Bone Joint J 2018;100-B:404-12.

Automated 3D bioassembly of micro-tissues for biofabrication of hybrid tissue engineered constructs.

Bottom-up biofabrication approaches combining micro-tissue fabrication techniques with extrusion-based 3D printing of thermoplastic polymer scaffolds are emerging strategies in tissue engineering. These biofabrication strategies support native self-assembly mechanisms observed in developmental stages of tissue or organoid growth as well as promoting cell-cell interactions and cell differentiation capacity. Few technologies have been developed to automate the precise assembly of micro-tissues or tissue modules into structural scaffolds. We describe an automated 3D bioassembly platform capable of fabricating simple hybrid constructs via a two-step bottom-up bioassembly strategy, as well as complex hybrid hierarchical constructs via a multistep bottom-up bioassembly strategy. The bioassembly system consisted of a fluidic-based singularisation and injection module incorporated into a commercial 3D bioprinter. The singularisation module delivers individual micro-tissues to an injection module, for insertion into precise locations within a 3D plotted scaffold. To demonstrate applicability for cartilage tissue engineering, human chondrocytes were isolated and micro-tissues of 1 mm diameter were generated utilising a high throughput 96-well plate format. Micro-tissues were singularised with an efficiency of 96.0 ± 5.1%. There was no significant difference in size, shape or viability of micro-tissues before and after automated singularisation and injection. A layer-by-layer approach or aforementioned bottom-up bioassembly strategy was employed to fabricate a bilayered construct by alternatively 3D plotting a thermoplastic (PEGT/PBT) polymer scaffold and inserting pre-differentiated chondrogenic micro-tissues or cell-laden gelatin-based (GelMA) hydrogel micro-spheres, both formed via high-throughput fabrication techniques. No significant difference in viability between the construct assembled utilising the automated bioassembly system and manually assembled construct was observed. Bioassembly of pre-differentiated micro-tissues as well as chondrocyte-laden hydrogel micro-spheres demonstrated the flexibility of the platform while supporting tissue fusion, long-term cell viability, and deposition of cartilage-specific extracellular matrix proteins. This technology provides an automated and scalable pathway for bioassembly of both simple and complex 3D tissue constructs of clinically relevant shape and size, with demonstrated capability to facilitate direct spatial organisation and hierarchical 3D assembly of micro-tissue modules, ranging from biomaterial free cell pellets to cell-laden hydrogel formulations.

Perampanel, an AMPA receptor antagonist: From clinical research to practice in clinical settings.

Epileptic seizures are refractory to treatment in approximately one-third of patients despite the recent introduction of many newer antiepileptic drugs (AEDs). Development of novel AEDs therefore remains a high priority. Perampanel is a first-in-class non-competitive selective AMPA receptor antagonist with a unique mechanism of action. Clinical efficacy and safety of perampanel as adjunctive treatment for focal seizures with/without secondary generalization (±SG) and primary generalized tonic-clonic (PGTC) seizures have been established in five phase 3 randomized controlled trials (RCTs), and a long-term extension study, and perampanel is approved as monotherapy for focal seizures ±SG in the USA. In patients with focal seizures ±SG, add-on perampanel resulted in median percent reduction in seizure frequency 23.3%-34.5% and ≥50% responder rate 28.5%-37.6%; in PGTC seizures, these results were 76.5% and 64.2%, respectively. Efficacy among adolescents (reduction in seizure frequency 34.8%-35.6%; ≥50% responder rate 40.9%-45.0%) and elderly people (reduction in seizure frequency 12.5%-16.9%; ≥50% responder rate 22.2%-42.9%) is similar to those in adults, and results remain comparable between Asian (reduction in seizure frequency 17.3%-38.0%) and global populations. Perampanel has been extensively studied in real-world clinical practice, with similar efficacy and safety results to the RCTs (≥50% responder rate 12.8%-75.0%; adverse events of somnolence/sedation, dizziness, ataxia, and behavioral changes). Real-world observational studies suggest that perampanel tolerability can be improved by slow titration (2 mg every 2-4 weeks), and bedtime administration can mitigate somnolence and dizziness. Counseling about the potential for behavioral changes and close monitoring are recommended.

DEPDC5 mutations in familial and sporadic focal epilepsy.

BACKGROUND AND AIMS: Mutations in the disheveled, Egl-10 and pleckstrin domain-containing protein 5 (DEPDC5) gene have emerged as an important cause of various familial focal epilepsy syndromes. However, the significance of DEPDC5 mutations in patients with sporadic focal epilepsy has yet to be characterized. MATERIALS AND METHODS: We studied a kindred of familial focal epilepsy with variable foci using whole-exome sequencing. We subsequently studied a cohort of 293 patients with focal epilepsy and sequenced all exons of DEPDC5 using targeted resequencing. RESULTS: We reported a Taiwanese family with a novel splice site mutation which affected mRNA splicing and activated the downstream mammalian target of rapamycin (mTOR) pathway. Among patients with focal epilepsies, the majority (220/293) of these patients had sporadic focal epilepsy without malformation of cortical development. Two (0.9%) of these patients had probably pathogenic mutations in the DEPDC5 gene. DISCUSSION AND CONCLUSIONS: Our finding suggests that DEPDC5 is not only the most common gene for familial focal epilepsy but also could be a significant gene for sporadic focal epilepsy. Since focal epilepsies account for more than 60% of all epilepsies, the effect of mTORC1 inhibitor on patients with focal epilepsy due to DEPDC5 mutations will be an important future direction of research.

Association of HLA-B*15:13 and HLA-B*15:02 with phenytoin-induced severe cutaneous adverse reactions in a Malay population.

Phenytoin (PHT) is a common cause of severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS). Although HLA-B*15:02 is associated with PHT-induced SJS/TEN (PHT-SJS/TEN) in Han Chinese and Thais, the genetic basis for susceptibility to PHT-induced SCARs (PHT-SCAR) in other populations remains unclear. We performed a case-control association study by genotyping the human leukocyte antigen (HLA)-B alleles of 16 Malay PHT-SCAR patients (13 SJS/TEN and 3 DRESS), 32 PHT-tolerant controls and 300 healthy ethnicity-matched controls. A novel genetic biomarker, HLA-B*15:13, showed significant association with PHT-SJS/TEN (53.8%, 7/13 cases) (odds ratio (OR) 11.28, P=0.003) and PHT-DRESS (100%, 3/3 cases) (OR 59.00, P=0.003) when compared with PHT-tolerant controls (9.4%, 3/32 controls). We also confirmed HLA-B*15:02 association with PHT-SJS/TEN (61.5%, 8/13 cases vs 21.9%, 7/32 controls; OR 5.71, P=0.016) when compared with PHT-tolerant controls. These alleles may serve as markers to predict PHT-SCAR in Malays.

Exploration of Biomarkers for Amoxicillin/Clavulanate-Induced Liver Injury: Multi-Omics Approaches.

To explore potential biomarkers for amoxicillin/clavulanate-induced liver injury (AC-DILI), we conducted a clinical trial in 32 healthy subjects based on multi-omics approaches. Every subject was administered amoxicillin/clavulanate for 14 days. The liver-specific microRNA-122 (miR-122) level increased prior to and correlated well with the observed alanine aminotransferase (ALT) level increase. This result indicates its potential as a sensitive early marker for AC-DILI. We also identified urinary metabolites, such as azelaic acid and 7-methylxanthine, with levels that significantly differed among the groups classified by ALT elevation level on day 8 after drug administration (P < 0.05). Lymphocyte proliferation in response to the drug was also observed. These findings demonstrate sequential changes in the process of AC-DILI, including metabolic changes, increased miR-122 level, increased liver enzyme activity, and enhanced lymphocyte proliferation after drug administration. In conclusion, this study provides potential biomarkers for AC-DILI based on currently known mechanisms using comprehensive multi-omics approaches.

Identification of differentially expressed genes in longissimus muscle of pigs with high and low intramuscular fat content using RNA sequencing.

Intramuscular fat (IMF) content in pork is an important element of consumer preference and is positively correlated with meat quality, including tenderness and juiciness. With advances in RNA sequencing technologies, transcriptome-related differences can be associated with specific traits in animals. The objective of this study was to investigate differentially expressed genes (DEGs) closely related to IMF content in porcine longissimus muscle using RNA sequencing. A total of 107 Berkshire pigs were used for IMF content measurements, and significant differences between extremely high (H, n = 3) and low (L, n = 3) IMF content groups were found (P < 0.0001). From multi-dimensional scaling analyses, it was observed that the relationships between H and L groups were similar to each other. Here, we identified a total of 134 genes that were differentially expressed between the groups (false discovery rate <0.05; fold change ≥2). Functional analyses with DEGs revealed that lipid metabolism (SCD and FASN) was one of the significant biological processes related to IMF content determination. In addition, we found that DEGs related to muscle regeneration (MYOG and VEGFA) and extracellular matrix (COL1A1, COL1A2, COL5A1, COL14A1 and COL15A1) were changed among individuals with extreme IMF contents. These results will aid in understanding the regulation of IMF content in pigs.

Antiepileptic-induced Psychosis as a Possible Predictor of Post-temporal Lobectomy Alternative Psychosis.

We present a patient with topiramate-induced psychosis who developed alternative psychosis following temporal lobectomy. The number of surgical candidates for temporal lobectomy is increasing as is the frequency of psychiatric co-morbidities. Preoperative planning should take account of these psychiatric co-morbidities. In particular, precautions should be taken when antiepileptic drug-induced psychosis occurs, as this could predict the occurrence of alternative psychosis following lobectomy.