Iron coatings on carbonate rocks shape the attached bacterial aquifer community.

Most studies of groundwater ecosystems target planktonic microbes, which are easily obtained via water samples. In contrast, little is known about the diversity and function of microbes adhering to rock surfaces, particularly to consolidated rocks. To investigate microbial attachment to rock surfaces, we incubated rock chips from fractured aquifers in limestone-mudstone alternations in bioreactors fed with groundwater from two wells representing oxic and anoxic conditions. Half of the chips were coated with iron oxides, representing common secondary mineralization in fractured rock. Our time-series analysis showed bacteria colonizing the chips within two days, reaching cell numbers up to 4.16 × 105 cells/mm2 after 44 days. Scanning electron microscopy analyses revealed extensive colonization but no multi-layered biofilms, with chips from oxic bioreactors more densely colonized than from anoxic ones. Estimated attached-to-planktonic cell ratios yielded values of up to 106: 1 and 103: 1, for oxic and anoxic aquifers, respectively. We identified distinct attached and planktonic communities with an overlap between 17 % and 42 %. Oxic bioreactors were dominated by proteobacterial genera Aquabacterium and Rhodoferax, while Rheinheimera and Simplicispira were the key players of anoxic bioreactors. Motility, attachment, and biofilm formation traits were predicted in major genera based on groundwater metagenome-assembled genomes and reference genomes. Early rock colonizers appeared to be facultative autotrophs, capable of fixing CO2 to synthesize biomass and a biofilm matrix. Late colonizers were predicted to possess biofilm degrading enzymes such as beta-glucosidase, beta-galactosidase, amylases. Fe-coated chips of both bioreactors featured more potential iron reducers and oxidizers than bare rock chips. As secondary minerals can also serve as energy source, they might favor primary production and thus contribute to subsurface ecosystem services like carbon fixation. Since most subsurface microbes seem to be attached, their contribution to ecosystem services should be considered in future studies.

Generation of myoglobin (MB)-knockout human embryonic stem cell (hESC) line (KAIMRCe002-A-1S) using CRISPR/Cas9 technology.

Myoglobin (MB) is a cytoplasmic hemoprotein that is predominantly expressed in the heart and oxidative myofibers of skeletal muscle. It has been demonstrated that MB binds to oxygen and promotes its diffusion for energy production in the mitochondria. Recently, MB was found to be expressed in different forms of malignant tumors and cancer cell lines. Further studies using gene disruption technology will enhance the understanding of MB's role in human cardiovascular biology and cancers. Here, we describe the generation of a homozygous MB knockout in human embryonic stem cells (hESC-MB-/-) via CRISPR/Cas9 to study MB function in human biology and diseases.

Clinical performance of a hybrid presbyopia-correcting intraocular lens in patients undergoing cataract surgery in a multicenter trial.

PURPOSE: To compare the clinical performance of TECNIS Synergy intraocular lens (IOL), model ZFR00V, vs TECNIS IOL, model ZCB00, in cataract patients. SETTING: Multicenter clinical setting. DESIGN: Prospective, randomized, subject/evaluator-masked clinical trial. METHODS: Cataract patients aged ≥22 years were randomly assigned 1:1 to bilateral implantation with ZFR00V or ZCB00. Key end points at 6 months postsurgery included monocular and binocular visual acuities at 4 m, 66 cm, 33 cm, and/or 40 cm, binocular distance-corrected defocus testing, patient-reported outcomes, and safety. RESULTS: 272 patients were implanted with ZFR00V (135) or ZCB00 (137). At 6 months, 83/131 (63.4%) ZFR00V patients demonstrated 20/25 or better combined monocular distance-corrected vision at far, intermediate, or near, compared with 5/130 (3.8%) ZCB00 patients. ZFR00V demonstrated excellent binocular uncorrected vision at intermediate (0.022 logMAR) and distance-corrected vision at 40 cm (0.047 logMAR). Strong ZFR00V performance persisted under mesopic conditions (0.244 logMAR or ∼20/32 Snellen), where improvement over ZCB00 with distance-corrected vision at near was 3.5 lines. ZFR00V provided a broad range of functional vision (20/32 or better) through -3.5 diopters of defocus (29 cm). Most ZFR00V patients reported no spectacle wear overall (93.1%) or at all 4 viewing distances combined (87.8%), and 55.7% qualified as completely spectacle independent. Relatively low proportions of ZFR00V patients reported being very/extremely bothered by halos (13.7%), starbursts (11.5%), or night glare (8.4%). The safety profile was similar between IOL groups. CONCLUSIONS: TECNIS Synergy ZFR00V demonstrated improved intermediate and near vision, increased range of vision, and greater spectacle independence vs TECNIS monofocal ZCB00.

Mycobacterium tuberculosis Affects Protein and Lipid Content of Circulating Exosomes in Infected Patients Depending on Tuberculosis Disease State.

Tuberculosis (TB), which is caused by the bacterium Mycobacterium tuberculosis (Mtb), is still one of the deadliest infectious diseases. Understanding how the host and pathogen interact in active TB will have a significant impact on global TB control efforts. Exosomes are increasingly recognized as a means of cell-to-cell contact and exchange of soluble mediators. In the case of TB, exosomes are released from the bacillus and infected cells. In the present study, a comprehensive lipidomics and proteomics analysis of size exclusion chromatography-isolated plasma-derived exosomes from patients with TB lymphadenitis (TBL) and treated as well as untreated pulmonary TB (PTB) was performed to elucidate the possibility to utilize exosomes in diagnostics and knowledge building. According to our findings, exosome-derived lipids and proteins originate from both the host and Mtb in the plasma of active TB patients. Exosomes from all patients are mostly composed of sphingomyelins (SM), phosphatidylcholines, phosphatidylinositols, free fatty acids, triacylglycerols (TAG), and cholesterylesters. Relative proportions of, e.g., SMs and TAGs, vary depending on the disease or treatment state and could be linked to Mtb pathogenesis and dormancy. We identified three proteins of Mtb origin: DNA-directed RNA polymerase subunit beta (RpoC), Diacyglycerol O-acyltransferase (Rv2285), and Formate hydrogenase (HycE), the latter of which was discovered to be differently expressed in TBL patients. Furthermore, we discovered that Mtb infection alters the host protein composition of circulating exosomes, significantly affecting a total of 37 proteins. All TB patients had low levels of apolipoproteins, as well as the antibacterial proteins cathelicidin, Scavenger Receptor Cysteine Rich Family Member (SSC5D), and Ficolin 3 (FCN3). When compared to healthy controls, the protein profiles of PTB and TBL were substantially linked, with 14 proteins being co-regulated. However, adhesion proteins (integrins, Intercellular adhesion molecule 2 (ICAM2), CD151, Proteoglycan 4 (PRG4)) were shown to be more prevalent in PTB patients, while immunoglobulins, Complement component 1r (C1R), and Glutamate receptor-interacting protein 1 (GRIP1) were found to be more abundant in TBL patients, respectively. This study could confirm findings from previous reports and uncover novel molecular profiles not previously in focus of TB research. However, we applied a minimally invasive sampling and analysis of circulating exosomes in TB patients. Based on the findings given here, future studies into host-pathogen interactions could pave the way for the development of new vaccines and therapies.

Rotational Stability of the Clareon Monofocal Aspheric Hydrophobic Acrylic Intraocular Lens 6 Months After Implantation.

PURPOSE: To determine the rotational stability of the Clareon® aspheric, monofocal, intraocular lens (IOL) up to 6 months after implantation. METHODS: This prospective, single-arm clinical study evaluated rotational stability of the Clareon IOL in a subset of subjects (n=141, 6 sites) that participated in an investigational device exemption trial for the Clareon IOL. The Clareon model (SY60CL) used in this subset was a non-toric IOL with toric axis markings to measure IOL rotation. All subjects (adults aged ≥22 years who required cataract extraction by phacoemulsification) received the Clareon IOL unilaterally. The position of the toric markings was captured using dilated retro-illumination slit-lamp photography and ocular anatomical landmarks. Post-operative rotational stability was assessed by an independent reading center. IOL rotation was defined as the difference between IOL axis of orientation on the day of surgery (≤1 hour after surgery) and each post-operative visit. Post-operative IOL-based rotational stability was evaluated at day 0 (day of surgery), day 1, week 1, month 1, and month 6 post-operatively. RESULTS: Compared with day 0, mean absolute IOL rotation was 1.85° on day 1 (n=127) and 2.27° at month 6 (n=124). Absolute IOL rotation ≤5° was observed in 95.3% of subjects on day 1 and 92.7% of subjects at month 6, compared with day 0. Between consecutive months 1 and 6 visits, mean absolute rotation was <1°; 100% of subjects had <10° rotation and 98.4% had ≤5°. The range of rotation on day 1 was 0° to 40.0° because of a subject with ocular trauma; when the trauma-outlier was removed, the mean absolute IOL rotation was 1.6° on day 1 (n=126) and 2.0° at month 6 (n=123). CONCLUSION: These results support the high rotational stability of the Clareon monofocal IOL and serve as reference of the rotational stability of Clareon toric IOLs.

Effectiveness and Safety of the Clareon Monofocal Intraocular Lens: Outcomes from a 12-Month Single-Arm Clinical Study in a Large Sample.

PURPOSE: This study assessed effectiveness and safety of the novel Clareon intraocular lens (IOL; model SY60CL; Alcon Vision LLC). PATIENTS AND METHODS: This was a prospective, single-arm, unmasked clinical trial at 16 investigative clinical sites in the United States. Included were adults ≥22 years who required cataract extraction by phacoemulsification. Following phacoemulsification, 350 subjects received SY60CL IOL unilaterally; 342 completed the study. Monocular best corrected distance visual acuity (CDVA) and uncorrected distance visual acuity (UDVA) were evaluated. The primary effectiveness endpoint was the percentage of subjects with CDVA ≤0.3 logMAR at month 12. Safety was assessed by monitoring adverse events (AEs). Visual acuity and safety outcomes were compared with historical safety and performance endpoint (SPE) rates. RESULTS: At 12 months post-implantation, 99.7% of subjects receiving the SY60CL IOL achieved monocular CDVA ≤0.3 logMAR (primary effectiveness endpoint; 1-sided 95% upper confidence limit >SPE rate); 99.7% and 86.8% of subjects achieved monocular CDVA of ≤0.34 (20/40 Snellen or better) and ≤0.04 logMAR (20/20 Snellen or better), respectively. At 12 months, >95% of subjects achieved mean monocular UDVA ≤0.3 logMAR; 97.1% and 57.6% of subjects achieved monocular CDVA of ≤0.34 and ≤0.04 logMAR, respectively. Mean monocular CDVA and UDVA were -0.05 and 0.04 logMAR, respectively. AEs were within SPE limits. The most common nonserious ocular AE was posterior capsule opacification (5.4%). Serious AEs were <1%, and no serious ocular AEs were assessed as related to the device. There were no observations for IOL glistenings at 12 months. CONCLUSION: Results of this study supported effectiveness and safety of the SY60CL IOL. Visual acuity outcomes with the SY60CL IOL exceeded the SPE rates for monocular CDVA and AEs were within the limit of historic SPE rates. (Model number SY60WF is the Clareon lens approved by the FDA.).

Visual and Patient-Reported Outcomes of a Diffractive Trifocal Intraocular Lens Compared with Those of a Monofocal Intraocular Lens.

PURPOSE: To evaluate the effectiveness and safety of a trifocal intraocular lens (IOL), the TFNT00 (Alcon, Fort Worth, TX), versus a monofocal IOL, the SN60AT (Alcon). DESIGN: Food and Drug Administration-approved, prospective, multicenter, nonrandomized, parallel-group, assessor-masked, confirmatory trial. PARTICIPANTS: Patients enrolled were 22 years of age or older with a diagnosis of bilateral cataract with planned removal by phacoemulsification with a clear corneal incision. METHODS: Consented participants selected their preferred IOL, which was implanted sequentially into each eye of patients meeting eligibility criteria. MAIN OUTCOME MEASURES: The coprimary effectiveness outcomes were mean photopic monocular best-corrected distance visual acuity (BCDVA; 4 m) and distance-corrected near visual acuity (DCNVA; 40 cm) at 6 months after surgery. Secondary effectiveness outcomes included mean monocular distance-corrected intermediate visual acuity (DCIVA; 66 cm) and proportion of participants responding "never" to question 1 of the Intraocular Lens Satisfaction questionnaire (regarding frequency of spectacle use in the past 7 days). Safety outcomes included frequency of "severe" and "most bothersome" visual disturbances. RESULTS: Two hundred forty-three patients underwent cataract surgery with bilateral implantation of the TFNT00 (n = 129) or SN60AT (n = 114) and were followed up for 6 months. Noninferiority of TFNT00 to SN60AT in mean photopic monocular BCDVA (95% upper confidence limit of the difference was <0.1 logarithm of the minimum angle of resolution [logMAR] margin), and superiority in mean photopic monocular DCNVA (difference of 0.42 logMAR; P < 0.001) and DCIVA (difference of 0.26 logMAR; P < 0.001) were demonstrated. The proportion of patients never requiring glasses overall was superior for TFNT00 versus SN60AT (80.5% and 8.2%, respectively). Starbursts, halos, and glare were the most frequently rated severe symptoms with TFNT00; however, less than 5% of patients were very bothered at month 6. CONCLUSIONS: The TFNT00 exhibited superior monocular DCNVA and DCIVA to a spherical monofocal IOL, with comparable monocular BCDVA. Binocular visual acuity was 20/25 or better for distance to near (+0.5 D to -2.5 D), resulting in high levels of spectacle independence. Less than 5% of patients were very bothered by the photic visual disturbances associated with the TFNT00 at 6 months after surgery.

Cyclopamine and Rapamycin Synergistically Inhibit mTOR Signalling in Mouse Hepatocytes, Revealing an Interaction of Hedgehog and mTor Signalling in the Liver.

In the liver, energy homeostasis is mainly regulated by mechanistic target of rapamycin (mTOR) signalling, which influences relevant metabolic pathways, including lipid metabolism. However, the Hedgehog (Hh) pathway is one of the newly identified drivers of hepatic lipid metabolism. Although the link between mTOR and Hh signalling was previously demonstrated in cancer development and progression, knowledge of their molecular crosstalk in healthy liver is lacking. To close this information gap, we used a transgenic mouse model, which allows hepatocyte-specific deletion of the Hh pathway, and in vitro studies to reveal interactions between Hh and mTOR signalling. The study was conducted in male and female mice to investigate sexual differences in the crosstalk of these signalling pathways. Our results reveal that the conditional Hh knockout reduces mitochondrial adenosine triphosphate (ATP) production in primary hepatocytes from female mice and inhibits autophagy in hepatocytes from both sexes. Furthermore, in vitro studies show a synergistic effect of cyclopamine and rapamycin on the inhibition of mTor signalling and oxidative respiration in primary hepatocytes from male and female C57BL/6N mice. Overall, our results demonstrate that the impairment of Hh signalling influences mTOR signalling and therefore represses oxidative phosphorylation and autophagy.

Computerized 4-choice reaction time test for the measurement of psychomotor recovery after general anesthesia.

The recovery of patients after general anesthesia is usually estimated by using clinical scores. Since there is a lack of objective methods for assessing psychomotor recovery, the aim of this study was to evaluate three psychological tests for this purpose. Patients, scheduled for ambulatory gynecological surgery, underwent 3 standard psychological tests before (T1), 15 min after the surgery (T2) and on discharge from the recovery room (T3). The tests used were Wechsler memory scale (test 1, working memory capacity), d2-test (test 2, concentration endurance) and computer-based 4-choice-reaction time (4CRT, test 3, reaction time) as well as Postanesthesia Discharge Scoring System (PADSS). The same test battery was used in healthy female volunteers, all test results were compared at the different time points. In 109 patients, working memory capacity and concentration (tests 1 and 2) decreased, the reaction time (test 3) was prolonged at T2 in comparison with T1 and T3 (P < 0.01). PADSS increased from 8 (T2) to 10 (T3) (medians, P < 0.001). Fifty-seven healthy volunteers demonstrated a practice effect in all 3 tests through the course of the study (P <0.01). 4CRT test had shortest duration and enabled computerized data processing. All three tests objectively assess the recovery of psychomotor function in patients after general anesthesia, the computer-based 4CRT seems to be the most convenient for the clinical routine.

Colorectal Cancer Among Gout Patients Undergoing Colonoscopy.

BACKGROUND/OBJECTIVE: The connection between gout and various cancers remains unclear. We assessed the relationship between gout and colorectal cancer in a population of veterans. METHODS: We reviewed the Computerized Patient Record System of the VA New York Harbor Health Care System to assess the 10-year occurrence of colorectal cancer in patients with gout undergoing colonoscopy, versus patients with osteoarthritis but no gout. RESULTS: Gout and osteoarthritis subjects were similar in age, ethnicity, body mass index, and smoking history. Among 581 gout and 598 osteoarthritis subjects with documented colonoscopies, the 10-year prevalence of colorectal cancer was significantly lower in gout (0.8%) versus osteoarthritis (3.7%) (p = 0.0008) patients. Differences in colorectal cancer rates remained significant after stratifying for nonsteroidal anti-inflammatory drug use. Among gout subjects, use of colchicine and/or allopurinol, as well as the presence/absence of concomitant osteoarthritis, did not influence colorectal cancer occurrence. On subanalysis, differences in colorectal cancer occurrence between gout and osteoarthritis subjects persisted among those who underwent diagnostic (0.5% in gout vs 4.6% in osteoarthritis subjects, p < 0.001) but not screening (0.9% in gout subjects vs 1% in osteoarthritis subjects, p = 1.0) colonoscopy. There was no significant difference in nonmalignant colorectal polyp occurrence between gout and osteoarthritis subjects. CONCLUSIONS: Subjects with gout had decreased colonoscopy-documented occurrence of colorectal cancer compared with osteoarthritis subjects, suggesting a possible protective effect.

Effect of Quorum Sensing on the Ability of Desulfovibrio vulgaris To Form Biofilms and To Biocorrode Carbon Steel in Saline Conditions.

Sulfate-reducing bacteria (SRB) are key contributors to microbe-induced corrosion (MIC), which can lead to serious economic and environmental impact. The presence of a biofilm significantly increases the MIC rate. Inhibition of the quorum-sensing (QS) system is a promising alternative approach to prevent biofilm formation in various industrial settings, especially considering the significant ecological impact of conventional chemical-based mitigation strategies. In this study, the effect of the QS stimulation and inhibition on Desulfovibrio vulgaris is described in terms of anaerobic respiration, cell activity, biofilm formation, and biocorrosion of carbon steel. All these traits were repressed when bacteria were in contact with QS inhibitors but enhanced upon exposure to QS signal molecules compared to the control. The difference in the treatments was confirmed by transcriptomic analysis performed at different time points after treatment application. Genes related to lactate and pyruvate metabolism, sulfate reduction, electron transfer, and biofilm formation were downregulated upon QS inhibition. In contrast, QS stimulation led to an upregulation of the above-mentioned genes compared to the control. In summary, these results reveal the impact of QS on the activity of D. vulgaris, paving the way toward the prevention of corrosive SRB biofilm formation via QS inhibition.IMPORTANCE Sulfate-reducing bacteria (SRB) are considered key contributors to biocorrosion, particularly in saline environments. Biocorrosion imposes tremendous economic costs, and common approaches to mitigate this problem involve the use of toxic and hazardous chemicals (e.g., chlorine), which raise health and environmental safety concerns. Quorum-sensing inhibitors (QSIs) can be used as an alternative approach to inhibit biofilm formation and biocorrosion. However, this approach would only be effective if SRB rely on QS for the pathways associated with biocorrosion. These pathways would include biofilm formation, electron transfer, and metabolism. This study demonstrates the role of QS in Desulfovibrio vulgaris on the above-mentioned pathways through both phenotypic measurements and transcriptomic approach. The results of this study suggest that QSIs can be used to mitigate SRB-induced corrosion problems in ecologically sensitive areas.

Efficacy of nepafenac ophthalmic suspension 0.1% in improving clinical outcomes following cataract surgery in patients with diabetes: an analysis of two randomized studies.

OBJECTIVE: To assess the efficacy of nepafenac 0.1% ophthalmic suspension in improving the clinical outcomes following cataract surgery (CS) in patients with nonproliferative diabetic retinopathy. METHODS: In two similar multicenter, randomized studies, patients received either nepafenac 0.1% or vehicle, instilled three times daily starting a day prior to surgery and continuing for 90 days postoperatively. A post hoc analysis of these two studies was conducted to assess 1) the likelihood for development of postoperative macular edema (ME), based on the percentage of patients who developed ME (≥30% increase from preoperative baseline in central subfield macular thickness) within 90 days following CS and 2) best-corrected visual acuity (BCVA) endpoints, including the percentage of patients with a BCVA improvement of ≥15 letters from preoperative baseline to Day 14 and maintained through Day 90. Results for individual studies and their pooled estimates (only visual acuity endpoints) are reported. Primary inference was based on odds ratio (OR). RESULTS: This post hoc analysis included 411 patients (nepafenac 0.1%: 205; vehicle: 206). The incidence of postoperative ME within 90 days of CS was notably lower in the nepafenac-treated patients than in vehicle-treated patients (study 1: 3.2% vs 16.7%; OR =0.2, 95% confidence interval [CI] =0.1, 0.5, P=0.001; study 2: 5.0% vs 17.5%; OR =0.2, 95% CI =0.1, 0.8, P=0.018). A higher percentage of nepafenac-treated patients than vehicle-treated patients gained ≥15 letters from preoperative baseline to Day 14, which was maintained through Day 90 (study 1: 38.4% vs 21.4%; OR =2.4, 95% CI =1.4, 4.2, P=0.003; study 2: 35.0% vs 25.0%; OR =1.6, 95% CI =0.8, 3.2, P=0.172; pooled: 37.1% vs 22.8%; OR =2.0, 95% CI =1.3, 3.1, P=0.001). The odds of >5-letter and >10-letter loss in BCVA from postoperative Day 7 were higher in vehicle-treated than in nepafenac-treated patients. CONCLUSION: These results support the clinical benefit of prophylactic use of nepafenac 0.1% for reducing the risk of postoperative ME and for improvement in BCVA outcomes following CS in patients with nonproliferative diabetic retinopathy.

Nepafenac 0.3% after Cataract Surgery in Patients with Diabetic Retinopathy: Results of 2 Randomized Phase 3 Studies.

PURPOSE: To demonstrate the efficacy and safety of once-daily nepafenac 0.3% ophthalmic suspension versus vehicle, based on clinical outcomes, after cataract surgery in patients with diabetes. DESIGN: Two prospective, randomized, multicenter, double-masked, vehicle-controlled phase 3 studies. PARTICIPANTS: Total, 615 patients in study 1 and 605 patients in study 2. METHODS: Patients were randomized (1:1) to topical nepafenac 0.3% or vehicle once-daily starting the day before surgery and continuing for 90 days thereafter. MAIN OUTCOME MEASURES: Key efficacy variables were: patients (%) in whom macular edema (ME) developed (≥30% increase from preoperative baseline central subfield macular thickness) within 90 days after cataract surgery and the patients (%) with a best-corrected visual acuity (BCVA) improvement of ≥15 letters from preoperative baseline through day 14 maintained through day 90. Secondary end points included: patients (%) with a BCVA improvement of ≥15 letters from preoperative baseline through days 90 and 60 and safety over 3 months. RESULTS: A significantly lower percentage of patients demonstrated ME within 90 days after surgery with nepafenac 0.3% versus vehicle (study 1: 2.3% vs. 17.3%; P < 0.001; study 2: 5.9% vs. 14.3%; P = 0.001; pooled: 4.1% vs. 15.9%; P < 0.001). The percentage of patients achieving a ≥15-letter improvement from baseline through day 14 maintained through day 90 with nepafenac 0.3% versus vehicle was 61.7% versus 43.0% (P < 0.001) in study 1, 48.8% versus 50.5% (P = 0.671) in study 2, and 55.4% versus 46.7% (P = 0.003) in the pooled analysis. A greater percentage of patients treated with nepafenac 0.3% versus vehicle in study 1 and similar percentage in study 2 had a BCVA improvement of ≥15 letters from preoperative baseline through day 90 (77.2% vs. 67.7% [P = 0.009] and 65.4% vs. 65.9% [P = 0.888]) and through day 60 (76.2% vs. 64.7% [P = 0.002] and 68.9% vs. 62.1% [P = 0.092]). No unanticipated adverse events were observed. CONCLUSIONS: These studies demonstrated the clinical benefits of nepafenac 0.3% over vehicle in reducing the risk of postoperative ME, with the integrated analysis showing improved BCVA after cataract surgery in patients with diabetic retinopathy, with no unanticipated safety events.

Intraoperative aberrometry versus standard preoperative biometry and a toric IOL calculator for bilateral toric IOL implantation with a femtosecond laser: One-month results.

PURPOSE: To compare astigmatic outcomes in patients with bilateral cataracts having toric intraocular lens (IOL) implantation with intraoperative aberrometry measurements in 1 eye and standard power calculation and a toric IOL calculator with inked axis marking in the contralateral eye. SETTING: Twelve sites in the United States. DESIGN: Prospective cohort study. METHODS: The eye with the more visually significant cataract was randomized to intraoperative aberrometry measurements (Ocular Response Analyzer with Verifeye) or standard preoperative biometry and use of a toric calculator with the contralateral eye automatically assigned to the other group. The primary effectiveness outcome was the proportion of eyes with a postoperative refractive astigmatism of 0.50 diopter (D) or less at 1 month. RESULTS: Of the 130 patients (260 eyes) enrolled, 124 (248 eyes) were randomized; 121 (242 eyes) completed the trial. The percentage of eyes with astigmatism of 0.50 D or less at 1 month was higher in the intraoperative aberrometry group than in the standard group (89.2% versus 76.6%) (P = .006). The mean postoperative refractive astigmatism was lower in the intraoperative aberrometry group (0.29 D ± 0.28 [SD] versus 0.36 ± 0.35 D) (P = .041). Secondary effectiveness endpoints, including manifest refraction spherical equivalent prediction error, uncorrected distance visual acuity, and corrected distance visual acuity, were similar. CONCLUSIONS: Compared with standard methods, the use of the intraoperative aberrometry system increased the proportion of eyes with postoperative refractive astigmatism of 0.50 D or less and reduced the mean postoperative refractive astigmatism at 1 month. Other efficacy outcomes were similar. FINANCIAL DISCLOSURES: Drs. Woodcock, Lehmann, and Cionni are consultants to Alcon Laboratories, Inc. Dr. Breen is an employee of Alcon Laboratories, Inc. Dr. Scott has no financial or proprietary interest in any material or method mentioned.

Cardiovascular Disease Prevalence in Patients with Osteoarthritis, Gout, or Both.

OBJECTIVE: Osteoarthritis (OA) and gout have each been associated with increased cardiovascular disease (CVD), but their relative impact is unknown. We compared CVD rates among patients with gout versus patients with OA and no gout (OA-only). METHODS: We identified male patients at the VA New York Harbor Healthcare System with gout (with or without concur - rent OA) and with OA-only between August 2007 and August 2008. For each group, we collected baseline demographic data and CVD risk factors. The primary outcome was a composite index (CV4) of any diagnosis of coronary artery disease (CAD), angina, myocardial infarction (MI), or coro- nary bypass surgery (CABG). Secondary outcomes included individual diagnoses within the CV4, CHF, and death. We subsequently divided the gout patients into those who did versus did not have concurrent diagnoses of OA (gout-only; gout+OA). Logistic regression was used to compare the associations of OA-only, gout-only, and gout+OA with CV outcomes. RESULTS: 1,280 gout subjects met inclusion criteria (983 gout- only and 297 gout+OA), along with 1,231 OA-only subjects. Gout subjects overall had more CVD risk factors at baseline, including hypertension, hyperlipidemia, and chronic kidney disease, versus OA-only. Compared with OA-only, gout subjects overall had increased rates of all outcomes except MI. Both the gout-only and gout+OA subgroups also had increased risk for all outcomes except MI, and CABG in the case of gout+OA subjects. After adjusting for traditional CVD risk factors, both gout-only and gout+OA subjects continued to have increased risk for multiple CVD outcomes. Gout+OA did not impart ad- ditional risk over gout-only for any outcome studied. CONCLUSION: Our data suggest that gout is associated with higher risk of CVD compared with OA, and that OA does not impart any additive CVD risk to patients who also have gout. Significance and Innovations: • In our dataset, gout subjects both with and without con- comitant OA had more cardiovascular disease (CVD) risk factors at baseline, and higher prevalence of CVD outcomes, than patients with OA only. • After adjusting for traditional CVD risk factors, gout-only and gout+OA subjects continued to have increased rates of multiple CVD outcomes, suggesting an intrinsic CVD risk to the diagnosis of gout, compared with OA. • These observations underline that gout patients represent a group at increased CVD risk, for whom both rheumatic disease management and CVD prevention need to be addressed.

Treatment of Presbyopia in Emmetropes Using a Shape-Changing Corneal Inlay: One-Year Clinical Outcomes.

PURPOSE: To report 1-year safety and efficacy clinical outcomes of a shape-changing corneal inlay for the treatment of presbyopia. DESIGN: Prospective, nonrandomized, multicenter United States Food and Drug Administration Investigational Device Exemption clinical trial (clinicaltrials.gov identifier, NCT01373580). PARTICIPANTS: Nondominant eyes (N = 373) of emmetropic presbyopic subjects were implanted at 11 sites with the Raindrop Near Vision Inlay (ReVision Optics, Lake Forest, CA); 340 eyes underwent the 1-year follow-up visit. METHODS: The corneal inlay was implanted under a corneal flap at the center of the light-constricted pupil created with a femtosecond laser. MAIN OUTCOME MEASURES: For subjects completing the 1-year follow-up, monocular and binocular uncorrected and corrected visual acuity, refractive stability, contrast sensitivity (CS; photopic and mesopic), symptom and satisfaction questionnaire results, and adverse events. RESULTS: At 1 year in the treated eye, on average, uncorrected near visual acuity (UNVA) improved by 5.1 lines, uncorrected intermediate visual acuity (UIVA) improved by 2.5 lines, and uncorrected distance visual acuity (UDVA) decreased by 1.2 lines. From 3 months through 1 year, 93% of subjects achieved UNVA of 20/25 or better, 97% achieve UIVA of 20/32 or better, and 95% achieved UDVA of 20/40 or better. Binocularly, the mean UDVA exceeded 20/20 from 3 months through 1 year. Contrast sensitivity loss occurred only at the highest spatial frequencies, with no loss binocularly. Absent or mild scores were reported in 96% of subjects for visual symptoms (glare, halos, double vision, and fluctuations in vision), in 99% for ocular symptoms (pain, light sensitivity, and discomfort), and in 95% for dryness. Adverse events were treatable and resolved. Eighteen inlays were replaced, usually soon after implantation because of decentration, but UNVA was little affected in this group thereafter. In the 11 cases requiring inlay explantations, 100% achieved a corrected distance visual acuity of 20/25 or better by 3 months after explant. CONCLUSIONS: The Raindrop Near Vision Inlay provides significant improvement in near and intermediate visual performance, with no significant change in binocular distance vision or CS. Subject satisfaction is improved significantly with minimal ocular or visual symptoms.

Assembly of a comprehensive regulatory network for the mammalian circadian clock: a bioinformatics approach.

By regulating the timing of cellular processes, the circadian clock provides a way to adapt physiology and behaviour to the geophysical time. In mammals, a light-entrainable master clock located in the suprachiasmatic nucleus (SCN) controls peripheral clocks that are present in virtually every body cell. Defective circadian timing is associated with several pathologies such as cancer and metabolic and sleep disorders. To better understand the circadian regulation of cellular processes, we developed a bioinformatics pipeline encompassing the analysis of high-throughput data sets and the exploitation of published knowledge by text-mining. We identified 118 novel potential clock-regulated genes and integrated them into an existing high-quality circadian network, generating the to-date most comprehensive network of circadian regulated genes (NCRG). To validate particular elements in our network, we assessed publicly available ChIP-seq data for BMAL1, REV-ERBα/ß and RORα/γ proteins and found strong evidence for circadian regulation of Elavl1, Nme1, Dhx6, Med1 and Rbbp7 all of which are involved in the regulation of tumourigenesis. Furthermore, we identified Ncl and Ddx6, as targets of RORγ and REV-ERBα, ß, respectively. Most interestingly, these genes were also reported to be involved in miRNA regulation; in particular, NCL regulates several miRNAs, all involved in cancer aggressiveness. Thus, NCL represents a novel potential link via which the circadian clock, and specifically RORγ, regulates the expression of miRNAs, with particular consequences in breast cancer progression. Our findings bring us one step forward towards a mechanistic understanding of mammalian circadian regulation, and provide further evidence of the influence of circadian deregulation in cancer.

The hierarchy of transition metal homeostasis: iron controls manganese accumulation in a unicellular cyanobacterium.

Iron and manganese are part of a small group of transition metals required for photosynthetic electron transport. Here, we present evidence for a functional link between iron and manganese homeostasis. In the unicellular cyanobacterium, Synechocystis sp. PCC 6803, Fe and Mn deprivation resulted in distinct modifications of the physiological status. The effect on growth and photosynthetic activity under Fe limitation were more severe than those observed under Mn limitation. Moreover, the intracellular elemental quotas of Fe and Mn were found to be linked. Fe limitation reduced the intracellular Mn quota. Mn limitation did not exert a reciprocal effect on Fe quotas. Microarray analysis comparing Mn and Fe limitation revealed a stark difference in the extent of the transcriptional response to the two limiting conditions, reflective of the physiological responses. The effects of Fe limitation on the transcriptional network are widespread while the effects on Mn limitation are highly specific. Our analysis also revealed an overlap in the transcriptional response of specific Fe and Mn transporters. This overlap provides a framework for explaining Fe limitation induced changes in Mn quotas.

The structural code of cyanobacterial genomes.

A periodic bias in nucleotide frequency with a period of about 11 bp is characteristic for bacterial genomes. This signal is commonly interpreted to relate to the helical pitch of negatively supercoiled DNA. Functions in supercoiling-dependent RNA transcription or as a 'structural code' for DNA packaging have been suggested. Cyanobacterial genomes showed especially strong periodic signals and, on the other hand, DNA supercoiling and supercoiling-dependent transcription are highly dynamic and underlie circadian rhythms of these phototrophic bacteria. Focusing on this phylum and dinucleotides, we find that a minimal motif of AT-tracts (AT2) yields the strongest signal. Strong genome-wide periodicity is ancestral to a clade of unicellular and polyploid species but lost upon morphological transitions into two baeocyte-forming and a symbiotic species. The signal is intermediate in heterocystous species and weak in monoploid picocyanobacteria. A pronounced 'structural code' may support efficient nucleoid condensation and segregation in polyploid cells. The major source of the AT2 signal are protein-coding regions, where it is encoded preferentially in the first and third codon positions. The signal shows only few relations to supercoiling-dependent and diurnal RNA transcription in Synechocystis sp. PCC 6803. Strong and specific signals in two distinct transposons suggest roles in transposase transcription and transpososome formation.

Once-daily nepafenac ophthalmic suspension 0.3% to prevent and treat ocular inflammation and pain after cataract surgery: phase 3 study.

PURPOSE: To evaluate once-daily nepafenac 0.3% to prevent and treat ocular pain and inflammation after cataract surgery. SETTING: Sixty-five centers in the United States and Europe. DESIGN: Randomized double-masked vehicle- and active-controlled phase 3 study. METHODS: Patients received nepafenac 0.3% once daily, nepafenac 0.1% 3 times daily, or their respective vehicles from day -1 to day 14 after cataract extraction. An additional drop of study drug was administered 30 to 120 minutes preoperatively. The primary endpoint was the percentage of patients with a cure for inflammation (score of 0 for both aqueous cells and flare) at day 14. RESULTS: Of randomized patients, 817 received nepafenac 0.3%, 819 received nepafenac 0.1%, and 200 and 206 received the respective vehicles. Significantly more nepafenac 0.3% patients had no inflammation (68.4% versus 34.0%) and were pain free (91.0% versus 49.7%) at day 14 than vehicle patients (both P<.0001). Nepafenac 0.3% was noninferior to nepafenac 0.1% for inflammation (95% confidence interval [CI], -5.73% to 3.17%) and pain-free rates (95% CI, -3.08% to 2.70%). At all postoperative visits, fewer treatment failures (P≤.0012) and more clinical successes (P ≤ .0264) were observed with nepafenac 0.3% versus vehicle. Nepafenac 0.3% was well tolerated and had a safety profile comparable to that of nepafenac 0.1%. CONCLUSIONS: Once-daily nepafenac 0.3% was noninferior to nepafenac 0.1% 3 times daily for prevention and treatment of ocular inflammation and pain following cataract surgery. The safety of nepafenac 0.3% was comparable to that of nepafenac 0.1%, with the added convenience of once-daily dosing. FINANCIAL DISCLOSURE: Drs. Modi, Lehmann, Walters, Fong, Christie, Roel, Nethery, and Reiser have been paid consultants to Alcon Research, Ltd. Ms. Sager is an employee of Alcon Research, Ltd. Drs. Tsorbatzoglou, Philipson, and Traverso have no financial or proprietary interest in any material or method mentioned.