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Introduction: Temporomandibular joint subluxation is defined as self-reducing partial dislocation of the TMJ during which the condyle passes anterior to the articular eminence., Material and Method: The study consisted of 30 patients, 19 females and 11 males with 14 unilateral and 16 bilateral cases of chronic symptomatic subluxation. Treatment consisted of arthrocentesis followed by 2 ml of autologous blood injection into upper joint space and 1 ml into pericapsular tissues using an autoclaved soldered double needle with single puncture technique. Parameters evaluated were pain, maximum mouth opening, excursive jaw movements, deviation on mouth opening and quality of life, hard and soft tissue changes on X-ray TMJ view and MRI., Results: At 12 month follow-up, average reduction in maximum interincisal opening, deviation on mouth opening, range of excursive movements on right and left sides and VAS scores were 20.54%, 32.84%, 29.59%, 27.37% and 74.53%, respectively. Out of 93.3% who responded to therapy, 66.7%, 20% and 6.7% responded after 1st, 2nd and 3rd AC + ABI, respectively. Remaining 6.7% patients had persistent painful subluxation and underwent open joint surgery. 93.3% patients responded to therapy, 80% were relieved of painful subluxation, 13.3% had painless subluxation and kept on follow-up. X-ray TMJ and MRI did not show any hard and soft tissue changes., Conclusion: A soldered double needle, single puncture, AC + ABI are a simple, safe, cost-effective, repeatable and minimally invasive nonsurgical therapy for treatment of CSS without any permanent radiographically evident soft or hard tissue changes., Competing Interests: Conflict of interestNone of the authors has any conflict of interest., (© The Association of Oral and Maxillofacial Surgeons of India 2021.)

Gene therapy is emerging as a modality in 21st-century medicine. Adeno-associated viral (AAV) gene transfer is a leading technology to achieve efficient and durable expression of a therapeutic transgene. However, the structural complexity of the capsid has constrained efforts to engineer the particle toward improved clinical safety and efficacy. Here, we generate a curated library of barcoded AAVs with mutations across a variety of functionally relevant motifs. We then screen this library in vitro and in vivo in mice and nonhuman primates, enabling a broad, multiparametric assessment of every vector within the library. Among the results, we note a single residue that modulates liver transduction across all interrogated models while preserving transduction in heart and skeletal muscles. Moreover, we find that this mutation can be grafted into AAV9 and leads to profound liver detargeting while retaining muscle transduction-a finding potentially relevant to preventing hepatoxicities seen in clinical studies., Competing Interests: Declaration of interests L.H.V. holds equity in Affinia Therapeutics, Akouos, and ciendias bio. He serves on the Board of Directors of Affinia Therapeutics, Addgene, ciendias bio, and Odylia. L.H.V. is an employee of ciendias bio. L.H.V. and E.Z. are inventors of AncAAV technology licensed to Affinia, Akouos, and/or other biopharmaceutical companies from which they may receive royalties. L.H.V. is compensated for his scientific advisory position with Affinia and Akouos. L.H.V. is a SAB member to Akouos, consultant to Affinia and Novartis, and receives research support from Novartis. L.H.V.’s interests were reviewed and are managed by Mass Eye and Ear and Mass General Brigham in accordance with their conflict-of-interest policies. L.H.V., E.Z., C.U., P.F.S., C.T., and H.T.T. are inventors on patent applications relating to AAVSeq, CombiAAV, or the liver toggle technology contained in this publication. A.J.W. and L.H.V. are inventors on patents related to use of AAVs for therapeutic gene delivery in the muscle and other tissues., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Peanut is among the main oil crops in India with huge economic importance. The unpredictable rainy season during the growing time of peanuts causes waterlogging in peanut fields. Waterlogging triggers major environmental limitations that negatively affect the growth, physiology, and development of peanuts. Thus, the export and production of peanuts are severely affected by waterlogging. Therefore, the understanding of metabolic mechanisms under waterlogging is important to future water-stress tolerance breeding in peanuts. This study aimed to evaluate how peanuts responded to various waterlogging conditions in terms of their development, metabolic processes, and chlorophyll fluorescence characteristics. The evaluations were carried out at different stages of peanut variety DH-86 treated with waterlogging. The peanut plants were subjected to different waterlogging periods of 20, 40, 60, 80, and 100 days. The growth parameters including total dry mass, total leaf area, and total leaves number were calculated in all treatments. The phenomenological and specific energy fluxes and maximum photosystem II efficiency (F V /Fm) were also determined. The measurements were done statistically using PCA, G-Means clustering, and correlation analysis to explore the interaction between different physiological parameters. The waterlogging for 100 days caused a significant reduction in the total number of leaves, dry mass, and total leaf area. The most sensitive parameters are specific and phenomenological energy fluxes and Fv/Fm, which notably decreased as waterlogging duration increased. The results indicated the growth and physiological performance of the peanut cv. DH-86 was affected significantly due to waterlogging and the interaction between all these parameters in waterlogging. This research focused on how peanuts respond to waterlogging stress and provides the basis for future plant breeding efforts to improve peanut waterlogging tolerance, especially in rainy regions. This will improve the sustainability of the entire peanut industry., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sharma, Bhatt, Sharma, Darkalt, Mojski and Soni.)

The COVID-19 pandemic continues to have devastating consequences on health and economy, even after the approval of safe and effective vaccines. Waning immunity, the emergence of variants of concern, breakthrough infections, and lack of global vaccine access and acceptance perpetuate the epidemic. Here, we demonstrate that a single injection of an adenoassociated virus (AAV)-based COVID-19 vaccine elicits at least 17-month-long neutralizing antibody responses in non-human primates at levels that were previously shown to protect from viral challenge. To improve the scalability of this durable vaccine candidate, we further optimized the vector design for greater potency at a reduced dose in mice and non-human primates. Finally, we show that the platform can be rapidly adapted to other variants of concern to robustly maintain immunogenicity and protect from challenge. In summary, we demonstrate this class of AAV can provide durable immunogenicity, provide protection at dose that is low and scalable, and be adapted readily to novel emerging vaccine antigens thus may provide a potent tool in the ongoing fight against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)., Competing Interests: Declaration of interests J.M.W. is a paid advisor to and holds equity in Scout Bio and Passage Bio; he holds equity in Surmount Bio; he also has sponsored research agreements with Amicus Therapeutics, Biogen, Elaaj Bio, Janssen, Moderna, Passage Bio, Regeneron, Scout Bio, Surmount Bio, and Ultragenyx, which are licensees of Penn technology. L.H.V. and J.M.W. are inventors on patents that have been licensed to various biopharmaceutical companies and for which they may receive payments. L.H.V. is a paid advisor to Novartis, Akouos, and Affinia Therapeutics and serves on the Board of Directors of Affinia, Addgene, and Odylia Therapeutics. L.H.V. holds equity in Akouos and Affinia and receives sponsored research funding from Albamunity, to which he is an unpaid consultant. L.H.V. is co-founder and an employee of Ciendias Bio, a biotechnology company that pursues the development of AAV-based vaccines. L.H.V. further is a listed inventor on various gene transfer technologies, including some relevant to AAVCOVID. L.H.V. is a scientific advisory board member to Akouos, and board member of Affinia Therapeutics, companies of which he is a co-founder. U.B., N.Z. and L.H.V. are listed inventors on several patent applications on the described technologies., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The purpose of this study is to evaluate the survival rate of the basal cortical screw (BCS) implant system inserted in healed edentulous ridges ( E ) or extraction sockets (ES) with immediate loading functional protocol in varying clinical situations., Methods: A total of 125 BCS implants were placed in 14 patients, immediately loaded and observed for 20.07(± 4.23) months. Ninety-four were placed in E sites and 31 were placed in ES sites. They were evaluated for bone loss, soft tissue shrinkage around the prosthesis, improvement in quality of life (QOL), and their survival after 1 year., Results: Total of 121/125(96.8%) implants survived while 4/125(3.2%) failed at the end of follow-up. Average bone loss after 1 year was 0.33 mm ( E ) and - 1.57 mm (ES), average soft tissue shrinkage was 0.50 mm ( E ) and 1.42 mm (ES) and average Patient's Global Impression of Change (PGIC) scale score was 6.36(± 0.63) at 1 year. The complications observed were mobility {3(2.4%)}, pain/discomfort {1(0.8%)} and fracture of abutment at the neck {1(0.8%)}, prosthesis loosening {2(9%)} and requirement of relining {3(13%)}. No periimplantitis was observed., Conclusion: This is the only study to report the marginal bone loss and soft tissue changes around BCS implants and an index-based improvement in QOL of such patients. The BCS implant system with immediate functional loading protocol is a versatile modality to rehabilitate a single tooth, a segment or a full arch with healed ridges as well as extraction sites; it gives high success rate and minimal complications., Competing Interests: Conflict of interestNone of the authors has any conflict of interest., (© The Association of Oral and Maxillofacial Surgeons of India 2021.)

Background: Treatment modalities of odontogenic cystic lesions of the jaws range from conservative to radical. "Dredging" may be considered the "middle path" between conservative and radical treatment options. It comprises three entities-decompression, followed by repeated scraping of the lesion, and finally, peripheral ostectomy providing margin clearance but without significant morbidity., Aim: To evaluate the outcome of "dredging" in the management of large cystic lesions of the jaws, without major resections and maintaining normal functions., Methodology: This prospective study was conducted on 30 patients. Inclusion criteria were odontogenic cystic lesions at least 2 cm in size either in the proximity of vital structures or in children with developing tooth germs or so large that upon enucleation, can result in pathological fracture. All underwent decompression followed by dredging performed at every 2 to 3 months intervals., Results: Drastic decrease in size of the lesion as measured on Cone Beam Computed Tomography (CBCT) and new bone formation was evident in all patients. The total Reduction Rate (RR) of the cystic lesions was 88.79% in 9.2 months. RR was highest in Calcifying epithelial odontogenic cyst (CEOC) followed by Unicystic Ameloblastoma (UA), Odontogenic Keratocysts (OKC), Dentigerous cyst (DC), and Radicular Cyst (RC) in CBCT. The mean speed of shrinkage was fastest in CEOC, followed by OKC, UA, RC, and DC after dredging. Shrinkage was higher in patients below 20 years of age ( P 0.012) and patients with large cystic lesions ( P 0.00447)., Conclusion: The results suggest that dredging with regular, long-term follow-up can be a successful treatment method for large cystic lesions in young adults. This method includes the benefits of both conservative and radical treatment methods but lacks the disadvantages of either., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 National Journal of Maxillofacial Surgery.)

The SARS-CoV-2 pandemic has had a disastrous impact on global health. Although some vaccine candidates have been effective in combating SARS-CoV-2, logistical, economical, and sociological aspects still limit vaccine access globally. Recently, we reported on two room-temperature stable AAV-based COVID-19 vaccines that induced potent and protective immunogenicity following a single injection in murine and primate models. Obesity and old age are associated with increased mortality in COVID-19, as well as reduced immunogenicity and efficacy of vaccines. Here, we investigated the effectiveness of the AAVCOVID vaccine candidates in murine models of obesity and aging. Results demonstrate that obesity did not significantly alter the immunogenicity of either vaccine candidate. In aged mice, vaccine immunogenicity was impaired. These results suggest that AAV-based vaccines may have limitations in older populations and may be equally applicable in obese and non-obese populations.

The study of human-machine systems is central to a variety of behavioral and engineering disciplines, including management science, human factors, robotics, and human-computer interaction. Recent advances in artificial intelligence (AI) and machine learning have brought the study of human-AI teams into sharper focus. An important set of questions for those designing human-AI interfaces concerns trust, transparency, and error tolerance. Here, we review the emerging literature on this important topic, identify open questions, and discuss some of the pitfalls of human-AI team research. We present opposition (extreme algorithm aversion or distrust) and loafing (extreme automation complacency or bias) as lying at opposite ends of a spectrum, with algorithmic vigilance representing an ideal mid-point. We suggest that, while transparency may be crucial for facilitating appropriate levels of trust in AI and thus for counteracting aversive behaviors and promoting vigilance, transparency should not be conceived solely in terms of the explainability of an algorithm. Dynamic task allocation, as well as the communication of confidence and performance metrics-among other strategies-may ultimately prove more useful to users than explanations from algorithms and significantly more effective in promoting vigilance. We further suggest that, while both aversive and appreciative attitudes are detrimental to optimal human-AI team performance, strategies to curb aversion are likely to be more important in the longer term than those attempting to mitigate appreciation. Our wider aim is to channel disparate efforts in human-AI team research into a common framework and to draw attention to the ecological validity of results in this field., (© 2022 The Author(s).)

The object recognition concept is being widely used a result of increasing CCTV surveillance and the need for automatic object or activity detection from images or video. Increases in the use of various sensor networks have also raised the need of lightweight process frameworks. Much research has been carried out in this area, but the research scope is colossal as it deals with open-ended problems such as being able to achieve high accuracy in little time using lightweight process frameworks. Convolution Neural Networks and their variants are widely used in various computer vision activities, but most of the architectures of CNN are application-specific. There is always a need for generic architectures with better performance. This paper introduces the Dimension-Based Generic Convolution Block (DBGC), which can be used with any CNN to make the architecture generic and provide a dimension-wise selection of various height, width, and depth kernels. This single unit which uses the separable convolution concept provides multiple combinations using various dimension-based kernels. This single unit can be used for height-based, width-based, or depth-based dimensions; the same unit can even be used for height and width, width and depth, and depth and height dimensions. It can also be used for combinations involving all three dimensions of height, width, and depth. The main novelty of DBGC lies in the dimension selector block included in the proposed architecture. Proposed unoptimized kernel dimensions reduce FLOPs by around one third and also reduce the accuracy by around one half; semi-optimized kernel dimensions yield almost the same or higher accuracy with half the FLOPs of the original architecture, while optimized kernel dimensions provide 5 to 6% higher accuracy with around a 10 M reduction in FLOPs.

Background: Proteinuria is a known risk factor for progression of chronic kidney disease. Proteinuria magnitude can be estimated by measuring spot urine protein-to-creatinine ratio (least accurate), 24-h urine collection for protein (24 P), or 24-h protein-creatinine ratio (24 PCR). The MDRD study found that 24 P measured at baseline was the strongest single predictor of the rate of GFR decline during study follow-up. However, predictive powers of 24 P and 24 PCR have not been compared in the literature. The current study addresses this question using the MDRD cohort data., Methods: The study is a retrospective analysis of prospectively collected data from the MDRD cohort using simple and multiple regression models. Slope of measured GFR (mGFR) over time was used as the response and models that included baseline 24 PCR or 24 P were compared for the entire sample and for subgroups formed by restricting the values of 24-h creatinine and 24 P., Results: Log 24 P and Log 24 PCR correlated almost equally with mGFR slope. However, in simple linear regression models and multivariable linear regression models adjusting for age and sex, the model with 24 PCR had a higher R 2 than the corresponding one that had 24 P except for the subgroup 24 P < 1 g., Conclusion: We observe that 24 PCR may be a better marker of proteinuria magnitude in predicting decline in kidney function compared to 24 P in particular for patients with 24 P ≥ 1. This finding needs validation in prospective clinical trials., Competing Interests: BR reports personal fees from Aurinia, Calliditas, ChemoCentryx, Retrophin, Novartis, Morphosys, EMD Serono, Bristol Myers Squibb, Janssen, Omeros, and AstraZeneca; non-financial support from Lupus Foundation of America; and grants from the National Institutes of Health (NIH), outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ayoub, Nagaraja, Kang, Rovin and Bhatt.)

Longer photoperiod in form of continuous light (24-h photoperiod without dark interruption) can alter the various physiological and biochemical processes of the plant. This study aimed to evaluate the effects of continuous light on various biochemical parameters associated with the growth and development of Vigna radiata L. (mung bean). The findings showed that leaf size and chlorophyll content of seedlings grown under continuous light were significantly greater than control plants subjected to 12h light/12h dark (12/12h). The activity of antioxidant enzymes superoxide dismutase (SOD, 30.81%), catalase (CAT, 16.86%), guaiacol peroxidase (GPOD, 12.27%), malondialdehyde, (MDA, 39.31) and proline (14.81%) were notably higher in 24/0h light period than 12/12h light period grown seedling at an early stage (on Day 6) while they were constant at the later stage of development. Increased activity of amylase and invertase reveals higher assimilation and consumption of photosynthetic products. This study revealed that plants were stressed at first. However, they gradually became acclimated to continuous light and efficiently used the excess light in carbon assimilation.

Paraspeckles are RNA-protein structures within the nucleus of mammalian cells, capable of orchestrating various biochemical processes. An overexpression of the architectural component of paraspeckles, a long non-coding RNA called NEAT1 (Nuclear Enriched Abundant Transcript 1), has been linked to a variety of cancers and is often associated with poor patient prognosis. Thus, there is an accumulating interest in the role of paraspeckles in carcinogenesis, however there is a limited understanding of how NEAT1 expression is regulated. Here, we demonstrate that both nuclear G-quadruplex (G4) and paraspeckle formation are significantly increased in a human breast cancer cell line compared to non-tumorigenic breast cells. Moreover, we identified and characterized G4-forming sequences within the NEAT1 promoter and demonstrate stabilization of G4 DNA with a G4-stabilizing small molecule results in a significant alteration in both paraspeckle formation and NEAT1 expression. This G4-mediated alteration of NEAT1 at both the transcriptional and post-transcriptional levels was evident in U2OS osteosarcoma cells, MCF-7 breast adenocarcinoma and MDA-MB-231 triple negative breast cancer cells., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2021 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)

The selection of an appropriate matrix for the preparation of amorphous extrudate in hot-melt extrusion (HME) deals with the study of various solid-state properties of drugs and polymers. Therefore, it is necessary to have an appropriate knowledge of drug-polymer miscibility, the interaction between the drug-polymer on mixing, and Gibb's free thermal energy of mixing to screen polymers through thermodynamic phase diagrams, to be suitable amorphous matrix system for HME. Here, we evaluated the possibility of three different polymers, namely, Eudragit®EPO, polyvinyl alcohol (PVA), Kollicoat®IR (KIR) with Praziquantel (PZQ), with proper validation of the Flory-Huggins theory and construction of the phase diagram using the melting point depression approach to determine a suitable matrix for HME. The solubility parameter theoretical calculation approach was used as a preliminary study to validate the miscibility of PZQ with three different polymers. Theoretical and experimental validation studies using the Flory-Huggins interaction parameter value using the melting point depression approach and the effect of PZQ loading on the interaction parameter were systematically validated to predict thermodynamic phase diagrams and Gibbs free energy of mixing for screening these polymers for the preparation of amorphous extrudate. Using the phase diagram, the thermal processing temperature for the HME was determined using a T-φ phase diagram to obtain an appropriate matrix. The obtained extrudates were further validated through physical appearance, microscopic structure, thermal and functional group characterizations, followed by the PZQ assay. Thus, considering the solid-state properties, the processing parameters of HME were selected to obtain stable extrudates and an appropriate matrix for PZQ loading., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The SARS-CoV-2 pandemic has affected more than 185 million people worldwide resulting in over 4 million deaths. To contain the pandemic, there is a continued need for safe vaccines that provide durable protection at low and scalable doses and can be deployed easily. Here, AAVCOVID-1, an adeno-associated viral (AAV), spike-gene-based vaccine candidate demonstrates potent immunogenicity in mouse and non-human primates following a single injection and confers complete protection from SARS-CoV-2 challenge in macaques. Peak neutralizing antibody titers are sustained at 1 year and complemented by functional memory T cell responses. The AAVCOVID vector has no relevant pre-existing immunity in humans and does not elicit cross-reactivity to common AAVs used in gene therapy. Vector genome persistence and expression wanes following injection. The single low-dose requirement, high-yield manufacturability, and 1-month stability for storage at room temperature may make this technology well suited to support effective immunization campaigns for emerging pathogens on a global scale., Competing Interests: Declaration of interests J.M.W. is a paid advisor to and holds equity in Scout Bio and Passage Bio; he holds equity in Surmount Bio; he also has sponsored research agreements with Amicus Therapeutics, Biogen, Elaaj Bio, Janssen, Moderna, Passage Bio, Regeneron, Scout Bio, Surmount Bio, and Ultragenyx, which are licensees of Penn technology. J.M.W. had a sponsored research agreement with Albamunity that funded this work. He also has a sponsored research agreement with G2 Bio. L.H.V. and J.M.W. are inventors on patents that have been licensed to various biopharmaceutical companies and for which they may receive payments including vector and vaccine technologies herein described. L.H.V., W.D., U.B., N.Z. are named inventors on two patent applications relevant to AAVCOVID. W.Q., E.H., S.Y., and R.H. are employees of Novartis. M.W.F. is a paid consultant to 5AM Ventures and to Mitobridge/Astellas. L.H.V. is a paid advisor to Novartis, Akouos, and Affinia Therapeutics and serves on the Board of Directors of Affinia, Addgene, and Odylia Therapeutics. L.H.V. holds equity in Akouos and Affinia and receives sponsored research funding from Albamunity Inc. to which he is an unpaid consultant. M.R.B. receives consulting fees from Interius Biotherapeutics. R.C.L. is a subcontractor with the CDC Foundation and receives royalties from UpToDate., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

In this work, hot-melt extrusion (HME) is coupled with fused deposition modeling (FDM) mediated 3D printing to demonstrate additive manufacturing to fabricate immediate release (IR) prototypes of olanzapine with the aim of enhanced solubility using a fast disintegrating polymer (Kollicoat ® IR). Drug-polymer solubility and interaction parameters were estimated by Hansen solubility parameters and Hildebrand-Scott equation. The obtained values signified drug-polymer miscibility. The detailed in vitro physicochemical evaluations of the developed filament through HME and its derived 3D printed tablet by FDM technique were assessed thoroughly by several analytical means such as light microscopy, DSC, XRD, FT-IR, SEM, etc. The average disintegration time of this developed 3D printed IR tablet was found to be 63.33 (±3.6) sec complying with the USP limit. Additionally, in vitro dissolution study data revealed almost close correlations and both showed 100% of drug release within 15 min, thus complying with the definition of IR tablet. Thus, this study demonstrates the feasibility of directly using olanzapine-Kollicoat ® IR through the HME process without the addition of any plasticizers, organic solvents, etc. and coupling of HME with 3D printing technology allowing prototypes of IR tablet of olanzapine.

With growing human culture and industrialization, many pollutants are being introduced into aquatic ecosystems. In recent years, dyes have become a major water pollutant used in the manufacture of paints and other production purposes. In this research, the potential of duckweed (Lemna gibba) plant was investigated spectrophotometrically as an obvious bioagent for the biological decolorization of the organic dye C.I. Basic Green 4 (Malachite Green, BG4). Photosynthetic efficiency analysis showed that the photosynthetic apparatus of L. gibba is very tolerant to BG4. Significant induction of reactive oxygen species (ROS) scavenging enzymes was observed after 24h of biodecolorization process in L. gibba treated with 15 and 30 mg/l BG4. The experimental results showed that L. gibba has a strong ability to extract BG4 from contaminated water and the best results were obtained at 25-30°C and pH 8.0. We conclude that duckweed L. gibba can be used as a potent decolorization organism for BG4.

Fine particulate matter <2.5 µm (PM 2.5 ) air pollution is implicated in global mortality, especially from cardiovascular causes. A large body of evidence suggests a link between PM 2.5 and elevation in blood pressure (BP), with the latter implicated as a potential mediator of cardiovascular events. We sought to determine if the outcomes of intensive BP lowering (systolic BP <120 mm Hg) on cardiovascular events are modified by PM 2.5 exposure in the SPRINT (Systolic BP Intervention Trial). We linked annual PM 2.5 exposure estimates derived from an integrated model to subjects participating in SPRINT. We evaluated the effect of intensive BP lowering by PM 2.5 exposure on the primary outcome in SPRINT using cox-proportional hazard models. A total of 9286 participants were linked to PM 2.5 levels (mean age 68±9 years). Intensive BP-lowering decreased risk of the primary outcome more among patients exposed to higher PM 2.5 ( P interaction =0.047). The estimate for lowering of primary outcome was numerically lower in the highest than in the lower quintiles. The benefits of intensive BP-lowering were larger among patients chronically exposed to PM 2.5 levels above US National Ambient Air Quality Standards of 12 µg/m 3 (hazard ratio, 0.47 [95% CI, 0.29-0.74]) compared with those living in cleaner locations (hazard ratio, 0.81 [95% CI, 0.68-0.97]), P interaction =0.037. This exploratory nonprespecified post hoc analysis of SPRINT suggests that the benefits of intensive BP lowering on the primary outcome was greater in patients exposed to higher PM 2.5 , suggesting that the magnitude of benefit may depend upon the magnitude of antecedent PM 2.5 exposure.

An efficient and reproducible protocol for in vitro propagation of Dolichandra unguis-cati has been established for the first time from nodal segments. In order to enhance survival rate under ex vitro conditions, photosynthetic potential of in vitro grown plantlets was also studied through JIP test based analysis of polyphasic OJIP chlorophyll a fluorescence OJIP transients, density of active reaction centers, light harvesting efficiency, electron transfer rate, dissipation energy, maximum quantum yield of primary PSII photochemistry and photosynthetic performance index. The best morphogenetic in term of explants response (92.2 %), shoot number (3.43 ± 0.07) and shoot length (4.7 ± 0.31 cm) was obtained on Murashige and Skoog medium supplemented with 0.5 mg l -1 BAP and 1.0 mg l -1 TDZ. The shoots exhibited high frequency rhizogenesis on half strength medium augmented with 2.0 mg l -1 IAA. In vitro plantlets developed highest rate of photosynthesis on day 18 after the initiation of rhizogenesis. High survival rate (96.16%) under ex vitro conditions was observed when in vitro plantlets having high photosynthetic efficiency (Fv/Fm > 0.75) were subjected to hardening and acclimatization process. Plantlets with reduced photosynthetic performance exhibited low survival rate under natural conditions. The developed in vitro protocol will be useful for genetic improvement and multiplication of D. unguis-cati . The results of this study also show that photosynthetic screening of in vitro developed plantlets is highly essential after the rhizogenesis process to achieve higher survival rate under field conditions., Competing Interests: The authors declare no conflict of interest., (© 2021 The Author(s).)

Purpose: To clinically evaluate visual performance of the AcrySof IQ PanOptix TFNT00 and AT LISA tri 839MP intraocular lenses (IOLs) in binocular visual acuity (VA) and to characterize low-contrast visual performance at 6 months postimplantation., Setting: Multicenter, 15 sites., Design: Prospective, parallel-group, randomized, double-masked, postmarketing clinical study., Methods: Binocular uncorrected distance (UDVA, 4 m), intermediate (UIVA, 60 cm), and near (UNVA, 40 cm) visual acuities and binocular defocus curves were evaluated under photopic lighting conditions. Photopic and mesopic contrast sensitivities with and without glare were assessed., Results: The study included 182 subjects (62% women; mean age, 66 ± 9.4 years) who were implanted bilaterally with the TFNT00 IOL (n = 93) or 839MP IOL (n = 89), and binocular VA was evaluated 4 to 6 months (120-180 days) postimplantation. The TFNT00 IOL group showed superior visual outcomes compared with the 839MP IOL group in binocular UIVA (P = .001) and UNVA (P = .003) and noninferior outcomes in UDVA (95% CI, -0.023 to 0.041; upper limit <0.1 logarithm of the minimum angle of resolution [logMAR] [margin of noninferiority]). Mean defocus curve from 0.00 to -3.00 diopter (D) ranged from 0.1 to 0.0 logMAR for both IOLs; better mean VA values (logMAR) were observed in the TFNT00 IOL group between -1.50 and -2.50 D compared with those of the 839MP IOL group. Contrast sensitivity values were similar between the 2 groups in all conditions., Conclusions: The results of this study showed improved visual performance at near and intermediate distances with the TFNT00 IOL compared with that of the 839MP IOL.

Background and Objectives: It is unclear whether the presence of albuminuria modifies the effects of intensive systolic BP control on risk of eGFR decline, cardiovascular events, or mortality., Design, Setting, Participants, & Measurements: The Systolic Blood Pressure Intervention Trial randomized nondiabetic adults ≥50 years of age at high cardiovascular risk to a systolic BP target of <120 or <140 mm Hg, measured by automated office BP. We compared the absolute risk differences and hazard ratios of ≥40% eGFR decline, the Systolic Blood Pressure Intervention Trial primary cardiovascular composite outcome, and all-cause death in those with or without baseline albuminuria (urine albumin-creatinine ratio ≥30 mg/g)., Results: Over a median follow-up of 3.1 years, 69 of 1723 (4%) participants with baseline albuminuria developed ≥40% eGFR decline compared with 61 of 7162 (1%) participants without albuminuria. Incidence rates of ≥40% eGFR decline were higher in participants with albuminuria (intensive, 1.74 per 100 person-years; standard, 1.17 per 100 person-years) than in participants without albuminuria (intensive, 0.48 per 100 person-years; standard, 0.11 per 100 person-years). Although effects of intensive BP lowering on ≥40% eGFR decline varied by albuminuria on the relative scale (hazard ratio, 1.48; 95% confidence interval, 0.91 to 2.39 for albumin-creatinine ratio ≥30 mg/g; hazard ratio, 4.55; 95% confidence interval, 2.37 to 8.75 for albumin-creatinine ratio <30 mg/g; P value for interaction <0.001), the absolute increase in ≥40% eGFR decline did not differ by baseline albuminuria (incidence difference, 0.38 events per 100 person-years for albumin-creatinine ratio ≥30 mg/g; incidence difference, 0.58 events per 100 person-years for albumin-creatinine ratio <30 mg/g; P value for interaction =0.60). Albuminuria did not significantly modify the beneficial effects of intensive systolic BP lowering on cardiovascular events or mortality evaluated on relative or absolute scales., Conclusions: Albuminuria did not modify the absolute benefits and risks of intensive systolic BP lowering., (Copyright © 2020 by the American Society of Nephrology.)

Scar formation after wound healing is a major medical problem. A better understanding of the dynamic nuclear architecture of the genome during wound healing could provide insights into the underlying pathophysiology and enable novel therapeutic strategies. Here, we demonstrate that TGF-β-induced fibrotic stress increases formation of the dynamic secondary DNA structures called G-quadruplexes in skin fibroblasts, which is coincident with increased expression of collagen 1. This G-quadruplex formation is attenuated by a small molecule inhibitor of intracellular Ca 2+ influx and an anti-fibrotic compound. In addition, we identify G-quadruplex-forming sequences in the promoter region of COL1A1, which encodes collagen 1, and confirm their ability to form G-quadruplex structures under physiologically relevant conditions. Our findings reveal a link between G-quadruplexes and scar formation that may lead to novel therapeutic interventions., (© 2019 Federation of European Biochemical Societies.)

Aims: Biomarkers of kidney tubule injury, inflammation and fibrosis have been studied extensively and established as risk markers of adverse kidney and cardiovascular disease (CVD) outcomes. However, associations of markers of kidney tubular function with adverse clinical events have not been well studied, especially in persons with chronic kidney disease (CKD)., Methods and Results: Using a sample of 2377 persons with CKD at the baseline Systolic Blood Pressure Intervention Trial (SPRINT) visit, we evaluated the association of three urine tubular function markers, alpha-1 microglobulin (α1m), beta-2 microglobulin (β2m), and uromodulin, with a composite CVD endpoint (myocardial infarction, acute coronary syndrome, stroke, acute decompensated heart failure, or death from cardiovascular causes) and mortality using Cox proportional hazards regression, adjusted for baseline estimated glomerular filtration rate (eGFR), albuminuria, and CVD risk factors. In unadjusted analysis, over a median follow-up of 3.8 years, α1m and β2m had positive associations with composite CVD events and mortality, whereas uromodulin had an inverse association with risk for both outcomes. In multivariable analysis including eGFR and albuminuria, a two-fold higher baseline concentration of α1m was associated with higher risk of CVD [hazard ratio (HR) 1.25; 95% confidence interval (CI): 1.10-1.45] and mortality (HR 1.25; 95% CI: 1.10-1.46), whereas β2m had no association with either outcome. A two-fold higher uromodulin concentration was associated with lower CVD risk (HR 0.79; 95% CI: 0.68-0.90) but not mortality (HR 0.86; 95% CI: 0.73-1.01) after adjusting for similar confounders., Conclusion: Among non-diabetic persons with CKD, biomarkers of tubular function are associated with CVD events and mortality independent of glomerular function and albuminuria., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Questions: How do plant communities on zonal loamy vs. sandy soils vary across the full maritime Arctic bioclimate gradient? How are plant communities of these areas related to existing vegetation units of the European Vegetation Classification? What are the main environmental factors controlling transitions of vegetation along the bioclimate gradient?, Location: 1700-km Eurasia Arctic Transect (EAT), Yamal Peninsula and Franz Josef Land (FJL), Russia., Methods: The Braun-Blanquet approach was used to sample mesic loamy and sandy plots on 14 total study sites at six locations, one in each of the five Arctic bioclimate subzones and the forest-tundra transition. Trends in soil factors, cover of plant growth forms (PGFs) and species diversity were examined along the summer warmth index (SWI) gradient and on loamy and sandy soils. Classification and ordination were used to group the plots and to test relationships between vegetation and environmental factors., Results: Clear, mostly non-linear, trends occurred for soil factors, vegetation structure and species diversity along the climate gradient. Cluster analysis revealed seven groups with clear relationships to subzone and soil texture. Clusters at the ends of the bioclimate gradient (forest-tundra and polar desert) had many highly diagnostic taxa, whereas clusters from the Yamal Peninsula had only a few. Axis 1 of a DCA was strongly correlated with latitude and summer warmth; Axis 2 was strongly correlated with soil moisture, percentage sand and landscape age., Conclusions: Summer temperature and soil texture have clear effects on tundra canopy structure and species composition, with consequences for ecosystem properties. Each layer of the plant canopy has a distinct region of peak abundance along the bioclimate gradient. The major vegetation types are weakly aligned with described classes of the European Vegetation Checklist, indicating a continuous floristic gradient rather than distinct subzone regions. The study provides ground-based vegetation data for satellite-based interpretations of the western maritime Eurasian Arctic, and the first vegetation data from Hayes Island, Franz Josef Land, which is strongly separated geographically and floristically from the rest of the gradient and most susceptible to on-going climate change.

Two antidiabetic compounds named 4-methoxybenzo[b]azet-2(1H)-one (1) and 3β-hydroxy-35-(cyclohexyl-5'-propan-7'-one)-33-ethyl-34-methyl-bacteriohop-16-ene (2) together with stigmasterol and β-sitosterol were isolated from the aerial part of Roylea cinerea (D.Don) Baill. The structures of these compounds were elucidated by advanced spectroscopic methods, including two-dimensional NMR and MS techniques. These compounds were evaluated for their antidiabetic efficacy using in vitro and in vivo methods. Both compounds (1 and 2) showed a significant decline in blood glucose level of alloxan-induced diabetic rats at 10 mg/kg, p.o. when compared with glibenclamide at a similar dose. The in vitro studies revealed that compound 1 reduced α-amylase and α-glucosidase by 83.0 and 78.5%, respectively, whereas compound 2 reduced the same by 58.2 and 58.4%, respectively, at 100 μM. The present study supports the role of R. cinerea in Ayurvedic medicine for diabetes.

Background: Treating to a lower blood pressure (BP) may increase acute kidney injury (AKI) events., Study Design: Data for AKI resulting in or during hospitalization or emergency department visits were collected as part of the serious adverse events reporting process of the Systolic Blood Pressure Intervention Trial (SPRINT)., Setting & Participants: 9,361 participants 50 years or older with 1 or more risk factors for cardiovascular disease., Interventions: Participants were randomly assigned to a systolic BP target of <120 (intensive arm) or <140mmHg (standard arm)., Outcomes & Measurements: Primary outcome was the number of adjudicated AKI events. Secondary outcomes included severity of AKI and degree of recovery of kidney function after an AKI event. Baseline creatinine concentration was defined as the most recent SPRINT outpatient creatinine value before the date of the AKI event., Results: There were 179 participants with AKI events in the intensive arm and 109 in the standard arm (3.8% vs 2.3%; HR, 1.64; 95% CI, 1.30-2.10; P<0.001). Of 288 participants with an AKI event, 248 (86.1%) had a single AKI event during the trial. Based on modified KDIGO (Kidney Disease: Improving Global Outcomes) criteria for severity of AKI, the number of AKI events in the intensive versus standard arm by KDIGO stage was 128 (58.5%) versus 81 (62.8%) for AKI stage 1, 42 (19.2%) versus 18 (14.0%) for AKI stage 2, and 42 (19.2%) versus 25 (19.4%) for AKI stage 3 (P=0.5). For participants with sufficient data, complete or partial resolution of AKI was seen for 169 (90.4%) and 9 (4.8%) of 187 AKI events in the intensive arm and 86 (86.9%) and 4 (4.0%) of 99 AKI events in the standard arm, respectively., Limitations: Trial results are not generalizable to patients with diabetes mellitus or without risk factors for cardiovascular disease., Conclusions: More intensive BP lowering resulted in more frequent episodes of AKI. Most cases were mild and most participants had complete recovery of kidney function., Trial Registration: Registered at ClinicalTrials.gov with study number NCT01206062., (Copyright © 2017 National Kidney Foundation, Inc. All rights reserved.)

The Arctic has warmed more than twice as fast as the global average since the mid 20th century, a phenomenon known as Arctic amplification (AA). These profound changes to the Arctic system have coincided with a period of ostensibly more frequent events of extreme weather across the Northern Hemisphere (NH) mid-latitudes, including extreme heat and rainfall events and recent severe winters. Though winter temperatures have generally warmed since 1960 over mid-to-high latitudes, the acceleration in the rate of warming at high-latitudes, relative to the rest of the NH, started approximately in 1990. Trends since 1990 show cooling over the NH continents, especially in Northern Eurasia. The possible link between Arctic change and mid-latitude climate and weather has spurred a rush of new observational and modeling studies. A number of workshops held during 2013-2014 have helped frame the problem and have called for continuing and enhancing efforts for improving our understanding of Arctic-mid-latitude linkages and its attribution to the occurrence of extreme climate and weather events. Although these workshops have outlined some of the major challenges and provided broad recommendations, further efforts are needed to synthesize the diversified research results to identify where community consensus and gaps exist. Building upon findings and recommendations of the previous workshops, the US CLIVAR Working Group on Arctic Change and Possible Influence on Mid-latitude Climate and Weather convened an international workshop at Georgetown University in Washington, DC, on February 1-3, 2017. Experts in the fields of atmosphere, ocean, and cryosphere sciences assembled to assess the rapidly evolving state of understanding, identify consensus on knowledge and gaps in research, and develop specific actions to accelerate progress within the research community. With more than 100 participants, the workshop was the largest and most comprehensive gathering of climate scientists to address the topic to date. In this white paper, we synthesize and discuss outcomes from this workshop and activities involving many of the working group members., Workshop Findings: Rapid Arctic change - Emergence of new forcing (external and internal) of atmospheric circulation: Rapid Arctic change is evident in the observations and is simulated and projected by global climate models. AA has been attributed to sea ice and snow decline (regionally and seasonally varying). However this cannot explain why AA is greatest in winter and weakest in summer. It was argued at the workshop that other factors can also greatly contribute to AA including: increased downwelling longwave radiation from greenhouse gases (including greater water vapor concentrations from local and remote sources); increasing ocean heat content, due to local and remote processes; regional and hemispheric atmospheric circulation changes; increased poleward heat transport in the atmosphere and ocean; and cloud radiative forcing. In particular, there is emerging observational evidence that an enhanced poleward transport of sensible and latent heat plays a very important role in the AA of the recent decades, and that this enhancement is mostly fueled by changes in the atmospheric circulation. We concluded that our understanding of AA is incomplete, especially the relative contributions from the different radiative, thermodynamic, and dynamic processes. Arctic mid-latitude linkages - Focusing on seasonal and regional linkages and addressing sources of inconsistency and uncertainty among studies: The topic of Arctic mid-latitude linkages is controversial and was vigorously debated at the workshop. However, we concluded that rapid Arctic change is contributing to changes in mid-latitude climate and weather, as well as the occurrence of extreme events. But how significant the contribution is and what mechanisms are responsible are less well understood. Based on the synthesis efforts of observational and modeling studies, we identified a list of proposed physical processes or mechanisms that may play important roles in linking Arctic change to mid-latitude climate and weather. The list, ordered from high to low confidence, includes: increasing geopotential thickness over the polar cap; weakening of the thermal wind; modulating stratosphere-troposphere coupling; exciting anomalous planetary waves or stationary Rossby wave trains in winter and modulating transient synoptic waves in summer; altering storm tracks and behavior of blockings; and increasing frequency of occurrence of summer wave resonance. The pathway considered most robust is the propagation of planetary/Rossby waves excited by the diminished Barents-Kara sea ice, contributing to a northwestward expansion and intensification of the Siberian high leading to cold Eurasian winters., Opportunities and Recommendations: An important goal of the workshop was achieved: to hasten progress towards consensus understanding and identification of knowledge gaps. Based on the workshop findings, we identify specific opportunities to utilize observations and models, particularly a combination of them, to enable and accelerate progress in determining the mechanisms of rapid Arctic change and its mid-latitude linkages. Observations: Due to the remoteness and harsh environmental conditions of the Arctic, in situ observational time series are highly limited spatially and temporally in the region.Six recommendations to expand approaches using observational datasets and analyses of Arctic change and mid-latitude linkages include: Synthesize new Arctic observations;Create physically-based sea ice-ocean surface forcing datasets;Systematically employ proven and new metrics;Analyze paleoclimate data and new longer observational datasets;Utilize new observational analysis methods that extend beyond correlative relationships; andConsider both established and new theories of atmospheric and oceanic dynamics to interpret and guide observational and modeling studies. Model experiments: We acknowledge that models provide the primary tool for gaining a mechanistic understanding of variability and change in the Arctic and at mid-latitudes. Coordinated modeling studies should include approaches using a hierarchy of models from conceptual, simple component, or coupled models to complex atmospheric climate models or fully coupled Earth system models. We further recommend to force dynamical models with consistent boundary forcings.Three recommendations to advance modeling and synthesis understanding of Arctic change and mid-latitude linkages include: Establish a Modeling Task Force to plan protocols, forcing, and output parameters for coordinated modeling experiments (Polar Amplification Model Intercomparison Project; PAMIP);Furnish experiment datasets to the community through open access (via Earth System Grid); andPromote analysis within the community of the coordinated modeling experiments to understand mechanisms for AA and to further understand pathways for Arctic mid-latitude linkages.

Background: The public health significance of the reported higher incidence of chronic kidney disease (CKD) with intensive systolic blood pressure (SBP) lowering is unclear., Objective: To examine the effects of intensive SBP lowering on kidney and cardiovascular outcomes and contrast its apparent beneficial and adverse effects., Design: Subgroup analyses of SPRINT (Systolic Blood Pressure Intervention Trial). (ClinicalTrials.gov: NCT01206062)., Setting: Adults with high blood pressure and elevated cardiovascular risk., Participants: 6662 participants with a baseline estimated glomerular filtration rate (eGFR) of at least 60 mL/min/1.73 m2., Intervention: Random assignment to an intensive or standard SBP goal (120 or 140 mm Hg, respectively)., Measurements: Differences in mean eGFR during follow-up (estimated with a linear mixed-effects model), prespecified incident CKD (defined as a >30% decrease in eGFR to a value <60 mL/min/1.73 m2), and a composite of all-cause death or cardiovascular event, with surveillance every 3 months., Results: The difference in adjusted mean eGFR between the intensive and standard groups was -3.32 mL/min/1.73 m2 (95% CI, -3.90 to -2.74 mL/min/1.73 m2) at 6 months, was -4.50 mL/min/1.73 m2 (CI, -5.16 to -3.85 mL/min/1.73 m2) at 18 months, and remained relatively stable thereafter. An incident CKD event occurred in 3.7% of participants in the intensive group and 1.0% in the standard group at 3-year follow-up, with a hazard ratio of 3.54 (CI, 2.50 to 5.02). The corresponding percentages for the composite of death or cardiovascular event were 4.9% and 7.1% at 3-year follow-up, with a hazard ratio of 0.71 (CI, 0.59 to 0.86)., Limitation: Long-term data were lacking., Conclusion: Intensive SBP lowering increased risk for incident CKD events, but this was outweighed by cardiovascular and all-cause mortality benefits., Primary Funding Source: National Institutes of Health.

The appropriate target for BP in patients with CKD and hypertension remains uncertain. We report prespecified subgroup analyses of outcomes in participants with baseline CKD in the Systolic Blood Pressure Intervention Trial. We randomly assigned participants to a systolic BP target of <120 mm Hg (intensive group; n =1330) or <140 mm Hg (standard group; n =1316). After a median follow-up of 3.3 years, the primary composite cardiovascular outcome occurred in 112 intensive group and 131 standard group CKD participants (hazard ratio [HR], 0.81; 95% confidence interval [95% CI], 0.63 to 1.05). The intensive group also had a lower rate of all-cause death (HR, 0.72; 95% CI, 0.53 to 0.99). Treatment effects did not differ between participants with and without CKD ( P values for interactions ≥0.30). The prespecified main kidney outcome, defined as the composite of ≥50% decrease in eGFR from baseline or ESRD, occurred in 15 intensive group and 16 standard group participants (HR, 0.90; 95% CI, 0.44 to 1.83). After the initial 6 months, the intensive group had a slightly higher rate of change in eGFR (-0.47 versus -0.32 ml/min per 1.73 m 2 per year; P <0.03). The overall rate of serious adverse events did not differ between treatment groups, although some specific adverse events occurred more often in the intensive group. Thus, among patients with CKD and hypertension without diabetes, targeting an SBP<120 mm Hg compared with <140 mm Hg reduced rates of major cardiovascular events and all-cause death without evidence of effect modifications by CKD or deleterious effect on the main kidney outcome., (Copyright © 2017 by the American Society of Nephrology.)

Ferric citrate is a novel phosphate binder that allows the simultaneous treatment of hyperphosphatemia and iron deficiency in patients being treated for end-stage renal disease with hemodialysis (HD). Multiple clinical trials in HD patients have uniformly and consistently demonstrated the efficacy of the drug in controlling hyperphosphatemia with a good safety profile, leading the US Food and Drug Administration in 2014 to approve its use for that indication. A concurrent beneficial effect, while using ferric citrate as a phosphate binder, is its salutary effect in HD patients with iron deficiency being treated with an erythropoietin-stimulating agent (ESA) in restoring iron that becomes available for reversing chronic kidney disease (CKD)-related anemia. Ferric citrate has also been shown in several studies to diminish the need for intravenous iron treatment and to reduce the requirement for ESA. Ferric citrate is thus a preferred phosphate binder that helps resolve CKD-related mineral bone disease and iron-deficiency anemia.

A series of 4-bicyclic heteroaryl 1,2,3,4-tetrahydroisoquinoline inhibitors of the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT) was discovered. The synthesis and structure-activity relationship (SAR) of these triple reuptake inhibitors (TRIs) will be discussed. Compound 10i (AMR-2), a very potent inhibitor of SERT, NET, and DAT, showed efficacy in the rat forced-swim and mouse tail suspension models with minimum effective doses of 0.3 and 1 mg/kg (po), respectively. At efficacious doses in these assays, 10i exhibited substantial occupancy levels at the three transporters in both rat and mouse brain. The study of the metabolism of 10i revealed the formation of a significant active metabolite, compound 13.

Purpose: To assess clinical outcomes and subjective experience after bilateral implantation of a diffractive trifocal intraocular lens (IOL)., Setting: Midland Eye Institute, Solihull, United Kingdom., Design: Cohort study., Methods: Patients had bilateral implantation of Finevision trifocal IOLs. Uncorrected distance visual acuity, corrected distance visual acuity (CDVA), and manifest refraction were measured 2 months postoperatively. Defocus curves were assessed under photopic and mesopic conditions over a range of +1.50 to -4.00 diopters (D) in 0.50 D steps. Contrast sensitivity function was assessed under photopic conditions. Halometry was used to measure the angular size of monocular and binocular photopic scotomas arising from a glare source. Patient satisfaction with uncorrected near vision was assessed using the Near Activity Visual Questionnaire (NAVQ)., Results: The mean monocular CDVA was 0.08 logMAR ± 0.08 (SD) and the mean binocular CDVA, 0.06 ± 0.08 logMAR. Defocus curve testing showed an extended range of clear vision from +1.00 to -2.50 D defocus, with a significant difference in acuity between photopic conditions and mesopic conditions at -1.50 D defocus only. Photopic contrast sensitivity was significantly better binocularly than monocularly at all spatial frequencies. Halometry showed a glare scotoma of a mean size similar to that in previous studies of multifocal and accommodating IOLs; there were no subjective complaints of dysphotopsia. The mean NAVQ Rasch score for satisfaction with near vision was 15.9 ± 10.7 logits., Conclusions: The trifocal IOL implanted binocularly produced good distance visual acuity and near and intermediate visual function. Patients were very satisfied with their uncorrected near vision., (Copyright © 2012 ASCRS and ESCRS. Published by Elsevier Inc. All rights reserved.)

Purpose: To assess the clinical outcomes after implantation of a new hydrophobic acrylic toric intraocular lens (IOL) to correct preexisting corneal astigmatism in patients having routine cataract surgery., Setting: Four hospital eye clinics throughout Europe., Design: Cohort study., Methods: This study included eyes with at least 0.75 diopter (D) of preexisting corneal astigmatism having routine cataract surgery. Phacoemulsification was performed followed by insertion and alignment of a Tecnis toric IOL. Patients were examined 4 to 8 weeks postoperatively; uncorrected distance visual acuity (UDVA), corrected distance visual acuity, manifest refraction, and keratometry were measured. Individual patient satisfaction with uncorrected vision and the surgeon's assessment of ease of handling and performance of the IOL were also documented. The cylinder axis of the toric IOL was determined by dilated slitlamp examination., Results: The study enrolled 67 eyes of 60 patients. Four to 8 weeks postoperatively, the mean UDVA was 0.15 logMAR ± 0.17 (SD) and the UDVA was 20/40 or better in 88% of eyes. The mean refractive cylinder decreased significantly postoperatively, from -1.91 ± 1.07 D to -0.67 ± 0.54 D. No significant change in keratometric cylinder was observed. The mean absolute IOL misalignment from the intended axis was 3.4 degrees (range 0 to 12 degrees). The good UDVA resulted in high levels of patient satisfaction., Conclusion: Implantation of the new toric IOL was an effective, safe, and predictable method to manage corneal astigmatism in patients having routine cataract surgery., (Copyright © 2012 ASCRS and ESCRS. Published by Elsevier Inc. All rights reserved.)

Background: The utility of cardiac stress testing as a risk-stratification tool before kidney transplantation remains debatable owing to discordance with coronary angiography and outcome yields at different centers., Methods: We conducted a retrospective study of 273 diabetic kidney transplant recipients from 2006 to 2010. By protocol, all diabetic patients underwent pharmacological radionucleotide stress test or dobutamine stress echocardiography before transplant. We compared the 1-year cardiac outcomes between those with negative stress test results and those with positive stress test results., Results: Patients with a positive stress test result (n=67) underwent coronary angiogram, and significant coronary artery disease (≥70% coronary stenosis) was found in 35 (52.2%) patients. Of the latter, 32 (91.4%) underwent cardiac revascularization (24 underwent cardiac stenting and 8 underwent coronary artery bypass grafting). The rest (n=35) were treated medically. Within 1 year after transplant, the group with positive stress test results experienced more cardiac events (34.3% vs. 3.9%, P<0.001) including acute myocardial infarction (22.4% vs. 3.4%, P<0.001) and ventricular arrhythmias (8.9% vs. 0.05%, P=0.001), higher all-cause mortality (19.4% vs. 4.8%, P<0.001), and cardiac mortality (17.9% vs. 0.9%, P<0.001) compared with the group with negative stress test results., Conclusions: In this diabetic population, stress testing showed positive and negative predictive values of 34.3% and 96.1%, respectively. Pharmacological cardiac stress testing provided excellent risk stratification in diabetic kidney transplant recipients.

Background: Blood pressure (BP) reduction in patients with chronic kidney disease (CKD), particularly with a renin-angiotensin system inhibitor (RASI), commonly leads to an initial decrease in glomerular filtration rate. The current clinical guideline, based on studies with single RASIs, is to tolerate an increase in the serum creatinine only up to 30%. This guideline has aptly guided CKD care for over a decade, but should be updated in the contemporary context of more aggressive RASI and diuretic use., Methods: This study is a retrospective review of 48 mostly African-American patients with CKD treated with multiple and/or high-dose renin-angiotensin system (RAS) inhibition and diuretics, targeting both low BP and reduction of urine protein. RASI was not reduced in response to initial increases in serum creatinine greater than 30%., Results: A clinically well-tolerated increase in serum creatinine over 30% during the first year occurred in 41% of the patients. Treatment was unaltered, and target goals for BP and urine protein were typically achieved. After the point of maximal serum creatinine in the first year, these patients had minimal progression of disease over the next 6 years, with a long-term estimated glomerular filtration rate slope of only -0.52 ml/min/year/1.73 m(2). Only 25% progressed to end-stage renal disease or death., Conclusion: The 30% limitation to initial increases in the serum creatinine still pertains for single RASI at usual doses. However, favorable long-term outcomes suggest that initial increases over 30% should be tolerated in the context of dual goal-directed, more aggressive RASI and diuretic use., (Copyright © 2012 S. Karger AG, Basel.)

An acute increase in international normalized ratio (INR) to >3.0 in patients with chronic kidney disease (CKD) can associate with an unexplained acute increase in serum creatinine and accelerated progression of CKD. A subset of these patients have renal tubular obstruction by casts of red blood cells, presumably the dominant mechanism of the acute kidney injury described as warfarin-related nephropathy. Here, we developed an animal model of this acute kidney injury that is based on the 5/6-nephrectomy model to aid future investigation of the pathogenesis of this condition. We found that acute excessive anticoagulation with brodifacoum ("superwarfarin") increased serum creatinine levels and hematuria in 5/6-nephrectomized rats but not in controls. In addition, morphologic findings in 5/6-nephrectomized rats included glomerular hemorrhage, occlusive red blood cell casts, and acute tubular injury, similar to the biopsy findings among affected patients. Furthermore, in the rat model, we observed an increase in apoptosis of glomerular endothelial cells. In summary, the 5/6-nephrectomy model combined with excessive anticoagulation may be a useful tool to study the pathogenesis of warfarin-related nephropathy.

Background/aims: We had previously reported that acute kidney injury (AKI) in warfarin-treated chronic kidney disease (CKD) patients may occur shortly after an acute increase in the International Normalization Ratio (INR) >3.0 with formation of occlusive red blood casts. Recovery from this warfarin-associated AKI is poor. Here we investigated whether excessive warfarin therapy could accelerate the progression of CKD., Methods: We analyzed serum creatinine (SC) and INR in 103 consecutive CKD patients on warfarin therapy in our Nephrology program from 2005 to the present., Results: Forty-nine patients experienced at least 1 episode of INR >3.0. Of these, 18 patients (37%, Group 1) developed an unexplained increase in SC > or =0.3 mg/dl coincident with INR >3.0 (mean SC increase 0.61 +/- 0.44 mg/dl); 31 patients (63%, Group 2) showed stable SC (mean SC change 0.04 +/- 0.19 mg/dl). Subsequent CKD progression was accelerated in Group 1, but not in Group 2. The 2 groups were not different with respect to demographics, comorbidities, blood pressure, or therapies. However, African Americans were overrepresented in Group 1 (p = 0.035)., Conclusions: Overanticoagulation is associated with faster progression of CKD in a high percentage of patients. Our results indicate the need for prospective trials. Nevertheless, we suggest that our findings are sufficiently compelling at this point to justify extra caution in warfarin-treated CKD patients to avoid overanticoagulation., (Copyright 2010 S. Karger AG, Basel.)

Purpose: To report serpiginous choroiditis associated with full thickness macular holes (FTMH)., Design: Interventional case report., Methods: A 58-year-old female with bilateral serpiginous choroiditis developed right-sided blurred vision and metamorphopsia. Ocular assessment, FFA, OCT, and right macular hole surgery were performed., Results: Preoperative visual acuity was 6/36 right, 6/9 left. Fundus assessment found bilateral geographic chorioretinal scarring, epiretinal membranes, right FTMH, and mild vitritis. OCT revealed bilateral FTMHs. Pars plana vitrectomy, membrane peel, and gas tamponade resulted in right macular hole closure, visual acuity improvement (6/18) and resolution of metamorphopsia., Conclusions: Macular hole may be another posterior segment complication of serpiginous choroiditis.

The effects of the novel GABA analogue (2R)-(3-amino-2-fluoropropyl)sulphinic acid (AFPSiA) on transient lower oesophageal sphincter relaxations (TLOSRs) were studied in the dog. In addition, the GABA(A)/GABA(B) selectivity was determined in vitro and in vivo, and the pharmacokinetics and the metabolism of the compound were studied in the dog and rat. TLOSRs were reduced by 55 +/- 8% after intragastric administration of AFPSiA at 14 mumol kg(-1) and did not decrease further at higher doses. When evaluated 2 and 4 h after administration, the effect declined to 37 +/- 6 and 16 +/- 9%, respectively. Spontaneous swallowing was only significantly inhibited at 100 micromol kg(-1). The oral availability of AFPSiA was 52 +/- 17 and 71 +/- 4% in the dog and rat, respectively. A fraction of AFPSiA was oxidised to the corresponding sulphonate, (2R)-(3-amino-2-fluoropropyl)sulphonic acid (AFPSoA) after oral administration to the rat and dog. In rat brain membranes, AFPSiA was found to have ten times higher affinity for rat brain GABA(B) (K(i) =47 +/- 4.4 nM) compared to GABA(A) (K(i) = 430 +/- 46 nM) binding sites. The compound was a full agonist at human recombinant GABA(B(1a,2)) receptors (EC(50) = 130 +/- 10 nM). In contrast, the metabolite AFPSoA was considerably more selective for binding to rat brain GABA(A) (K(i) = 37 +/- 3.1 nM) vs GABA(B) (K(i) = 6800 +/- 280 nM) receptors. In the mouse, high doses (1-8 mmol kg(-1)) of AFPSiA induced a rapid and mild hypothermia followed by a profound and sustained hypothermia at the higher doses tested (6 and 8 mmol kg(-1)). This effect was unaffected by the selective GABA(B) receptor antagonist CGP62349. AFPSoA (1 and 2 mmol kg(-1)) produced transient and moderate hypothermia while the hypothermic response was considerably larger at 4 mmol kg(-1).It is concluded that AFPSiA inhibits but does not abolish TLOSRs in the dog. High doses of the compound induce hypothermia in the mouse, which probably is attributable to activation of the GABA(A) receptor. The latter effect may be caused both by AFPSiA and its oxidised sulphonic acid metabolite AFPSoA.

Postoperative peritoneal adhesions are common and serious complications of general abdominal and gynecological surgery that can lead to chronic abdominal pain, small-bowel obstruction and infertility. The specific pathophysiology of peritoneal adhesions remains elusive and current treatment is relegated to prevention through meticulous surgical technique and protective physical barriers, gels and solutions. We have reported that reactive oxygen species (ROS), generated by phagocytic cells at the site of tissue injury, serve as major signaling molecules regulating the expression of vascular endothelial growth factor (VEGF) and subsequent wound repair. We hypothesized that peritoneal adhesions are a product of over-healing surgical wounds and that, like in wound healing, ROS are implicated in their pathogenesis. We examined the presence of footprints of ROS and the ROS-inducible angiogenic factor VEGF in human adhesion tissue. An experimental model of peritoneal adhesion was established in rodents to study of the dynamics of ROS-induced gene expression during de novo adhesion tissue formation. Immunohistochemical analysis demonstrated presence of ROS/oxidant and macrophages in human peritoneal tissue. The presence of ROS and ROS-sensitive transcription factor EGR-1 was also evident in an experimental rodent peritoneal adhesion model. Along with ROS, VEGF, and a large number of mature and immature CD31/vWF positive blood vessels were present in the adhesion tissue. These observations are not consistent with the contention that adhesions are non-functional scar tissue. The newly developed rodent model of adhesion may present a useful approach to reproducibly and objectively study molecular mechanisms underlying the dynamic process of de novo adhesion tissue formation.

The first total synthesis of ratjadone was achieved using a highly convergent approach joining three subunits together with a Wittig olefination and a selective Heck reaction as the pivotal steps. Besides establishing a robust and reliable route for the synthesis of this orphan ligand, the configuration of unknown stereocenters could also be determined. This synthesis not only provides an additional access to a biologically important compound but also enables the synthesis of structural analogues for biological target identification.