Enantioselective Transfer Hydrogenative Cycloaddition Unlocks the Total Synthesis of SF2446 B3: An Aglycone of Arenimycin and SF2446 Type II Polyketide Antibiotics.

The first total synthesis and structure validation of an arenimycin/SF2446 type II polyketide is described, as represented by de novo construction of SF2446 B3, the aglycone shared by this family of type II polyketides. Ruthenium-catalyzed α-ketol-benzocyclobutenone [4 + 2] cycloaddition, which occurs via successive stereoablation-stereoregeneration, affects a double dynamic kinetic asymmetric transformation wherein two racemic starting materials combine to form the congested angucycline bay region with control of regio-, diastereo-, and enantioselectivity. This work represents the first application of transfer hydrogenative cycloaddition and enantioselective intermolecular metal-catalyzed C-C bond activation in target-oriented synthesis.

Ruthenium-Catalyzed Cycloadditions to Form Five-, Six-, and Seven-Membered Rings.

Ruthenium-catalyzed cycloadditions to form five-, six-, and seven-membered rings are summarized, including applications in natural product total synthesis. Content is organized by ring size and reaction type. Coverage is limited to processes that involve formation of at least one C-C bond. Processes that are stoichiometric in ruthenium or exploit ruthenium as a Lewis acid (without intervention of organometallic intermediates), ring formations that occur through dehydrogenative condensation-reduction, σ-bond activation-initiated annulations that do not result in net reduction of bond multiplicity, and photochemically promoted ruthenium-catalyzed cycloadditions are not covered.

Total Synthesis of (±)-Brazilin Using [4 + 1] Palladium-Catalyzed Carbenylative Annulation.

Palladium-catalyzed carbene insertion was utilized in a formal synthesis of (±)-picropodophyllone and a total synthesis of (±)-brazilin. All prior syntheses of brazilin have involved a Friedel-Crafts alkylation in the key carbon-carbon bond forming events. The palladium-catalyzed [4 + 1] reaction generates a 1-arylindane with all of the functionalities needed for formation of the indano[2,1-c]chroman ring system of brazilin. The synthesis of (±)-brazilin was achieved in 11 steps (longest linear sequence) with an overall 11% yield.

Statin therapy associated with improved thrombus resolution in patients with deep vein thrombosis.

OBJECTIVE: Statin therapy has been associated with a decreased incidence of venous thromboembolism (VTE) in clinical trials and enhanced thrombus resolution in animal models. The effect of statins on thrombus resolution has not been reported clinically. This study investigates the association of statins with thrombus resolution or improvement in patients with deep venous thrombosis (DVT). METHODS: A retrospective study of the electronic medical records of consecutive adult patients presenting with lower extremity DVT was performed. Patients were divided into two groups based on statin therapy (statin group) or lack thereof (nonstatin group). The two groups were compared with respect to demographics, comorbidities, and risk factors for VTE. Initial as well as all subsequent ultrasound reports were reviewed for each patient to determine extent of DVT and subsequent change in thrombus characteristics. Long-term outcomes examined were mortality, VTE recurrence, and thrombus improvement or resolution on follow-up ultrasound examination. Multivariable analysis was used to determine independent predictors of thrombus resolution or improvement, VTE recurrence, and mortality. RESULTS: A total of 818 patients with DVT were identified (statin group, n = 279 [34%]; nonstatin group, n = 539 [66%]). The patients in the statin group were significantly older (P < .001). Patients on statins were more likely to have risk factors for and manifestations of atherosclerosis and to be on antiplatelet therapy (P < .001), whereas those in the nonstatin group were more likely to have a hypercoagulable disorder (P = .009) or prior DVT (P = .033). There was no significant difference in provoked DVT, extent of DVT, or association with pulmonary embolism (PE), but patients on statins were more likely to have high-risk PE (P = .046). There was no difference in patients receiving anticoagulation, type and duration of anticoagulation, inferior vena cava filter placement, or treatment with lytic therapy. There was no difference in thrombus resolution, mortality, or recurrence of DVT, PE, or VTE between the groups. On multivariable analysis, age, proximal DVT, CAD, and cancer were associated with higher mortality, whereas anticoagulation with coumadin and direct oral anticoagulants and antiplatelet therapy were associated with lower mortality. Statin therapy, antiplatelet therapy, and younger age were associated with thrombus resolution or improvement. CONCLUSIONS: Statin therapy is associated with greater thrombus resolution or improvement in patients with DVT. However, statin therapy in this study was not associated with different clinical outcomes of VTE recurrence or mortality.

Duplex nucleic acid test for the detection of chikungunya and dengue RNA viruses in blood donations.

BACKGROUND: Chikungunya (CHIKV) and dengue (DENV) viruses are primarily mosquito-borne, but transfusion transmission can occur (DENV) or is likely (CHIKV). In the absence of commercially available blood screening assays, a variety of strategies to ensure recipient safety in the face of expanding CHIKV and/or DENV outbreaks have been used. STUDY DESIGN AND METHODS: Performance of cobas CHIKV/DENV, a qualitative RNA detection assay for use on the cobas 6800/8800 Systems, was evaluated at two sites (Roche Molecular Systems, Inc. [RMS], and the American Red Cross [ARC]). Analytical sensitivity, genotype inclusion, correlation with other assays, and reproducibility used clinical CHIKV- or DENV-positive samples and secondary standards for DENV Types 1 to 4 and for three CHIKV genotypes (Asian; East Central South African; and West African); each secondary standard was traceable to international reference panels or reagents. Evaluation of analytic specificity assessed other microorganisms for interference and cross-reactivity; clinical specificity was determined by individually testing 10,528 volunteer blood donations from the continental United States. RESULTS: The 50 and 95% limit of detection (LoD) obtained by RMS for CHIKV, Asian genotype was 1.8 and 6.8 Detectable Units (DU)/mL, respectively, and 0.14 and 0.63 International Units (IU)/mL, respectively for DENV-1. No significant differences in detection occurred by testing at a second site, the ARC (2.4 and 10.5 DU/mL for CHIKV and 0.15 and 0.60 IU/mL for DENV). Clinical specificity was 100% (95% confidence interval, 99.965%-100%) for CHIKV and DENV. CONCLUSIONS: The high sensitivity and specificity of the cobas CHIKV/DENV test, as demonstrated in these evaluations, indicate its suitability for blood donation screening.

Evaluation of a new West Nile virus nucleic acid test for screening of blood donations.

BACKGROUND: West Nile virus (WNV) is transmitted to humans through mosquito bites and can be further transmitted to humans through transfusion or transplantation. Because most infected individuals are asymptomatic, blood donor screening is important in areas where WNV is endemic. These studies evaluated the performance of a new test for detection of WNV RNA in blood donations. STUDY DESIGN AND METHODS: Analytical performance evaluation included sensitivity, specificity, inclusivity, and correlation. A clinical specificity study was conducted at four blood donor testing laboratories in parallel with the cobas TaqScreen WNV Test (Roche Molecular Systems, Inc.). RESULTS: The 95% and 50% limit of detection for cobas WNV was 12.9 copies/mL (95% confidence interval [CI], 10.8-16.3) and 2.1 copies/mL (95% CI, 1.9-2.4) for WNV lineage 1, respectively, and 6.2 copies/mL (95% CI, 4.8-8.9) and 1.1 copies/mL (95% CI, 0.8-1.3) for WNV lineage 2, respectively. Clinical specificity was 100% in 10,823 donor samples tested individually (95% CI, 99.966%-100%) and 63,243 tested in pools of 6 (95% CI, 99.994%-100%). Samples of other members of the Japanese encephalitis virus serocomplex, including St Louis encephalitis, Japanese encephalitis, Murray Valley encephalitis, Usutu, and Kunjin viruses were detected by cobas WNV. CONCLUSION: The cobas WNV test for use on the cobas 6800/8800 System, a fully automated test system, demonstrated high sensitivity and specificity and is suitable for the detection of WNV in blood donors.

Enantioselective Ruthenium-Catalyzed Benzocyclobutenone-Ketol Cycloaddition: Merging C-C Bond Activation and Transfer Hydrogenative Coupling for Type II Polyketide Construction.

The first enantioselective intermolecular metal-catalyzed cycloadditions of benzocyclobutenones via C-C bond oxidative addition are described. In the presence of a ruthenium(0) complex modified by ( R)-DM-SEGPHOS, tetralone-derived ketols and benzocyclobutenones combine to form cycloadducts with complete regio- and diastereoselectivity and high enantioselectivity. Using this method, the "bay region" substructure of the angucycline natural product arenimycin was prepared.

Risk factors for presence and severity of pulmonary embolism in patients with deep venous thrombosis.

OBJECTIVE: The Caprini model estimates patients' risk for venous thromboembolism by 30 different factors. Hemodynamically significant pulmonary embolism (PE), defined as high-risk (massive) or intermediate-risk (submassive) PE, has high morbidity and mortality rates. This study tests whether the Caprini model and deep venous thrombosis (DVT) characteristics correlate with the prevalence of PE and hemodynamically significant PE in patients with DVT. METHODS: A retrospective review of patients diagnosed with DVT between January 2013 and August 2014 in a tertiary care center was performed. Multivariable analysis was used to determine predictors of PE and hemodynamically significant PE. RESULTS: Of 838 consecutive patients with DVT, 217 (25.9%) had concomitant PE at presentation, of whom 135 had hemodynamically significant PE (101 submassive PE, 34 massive PE). The mean age was 65 years, and 51.0% were women. There was no significant relation between age or gender and the occurrence of PE or hemodynamically significant PE. Patients with PE were less likely to have undergone recent surgery (18.4% vs 30.3%; P = .001), to have sepsis (4.6% vs 11.8%; P = .002), and to have higher Caprini scores (6.1 vs 6.5; P = .047). Patients with DVT were less likely to have hemodynamically significant PE after recent surgery (13.3% vs 27.2%; P = .011) but more likely to have hemodynamically significant PE with proximal DVT (80.7% vs 64.2%). There was no association between Caprini score and hemodynamically significant PE (6.3 vs 5.7; P = .171). CONCLUSIONS: The Caprini model has a poor association with PE or hemodynamically significant PE in patients with DVT. Among all patients with DVT, a concomitant diagnosis of PE or hemodynamically significant PE is less common in those with sepsis or undergoing recent surgery but more common in those with proximal DVT.

Sensitivity and specificity of a new automated system for the detection of hepatitis B virus, hepatitis C virus, and human immunodeficiency virus nucleic acid in blood and plasma donations.

BACKGROUND: Use of nucleic acid testing (NAT) in donor infectious disease screening improves transfusion safety. Advances in NAT technology include improvements in assay sensitivity and system automation, and real-time viral target discrimination in multiplex assays. This article describes the sensitivity and specificity of cobas MPX, a multiplex assay for detection of human immunodeficiency virus (HIV)-1 Group M, HIV-2 and HIV-1 Group O RNA, HCV RNA, and HBV DNA, for use on the cobas 6800/8800 Systems. STUDY DESIGN AND METHODS: The specificity of cobas MPX was evaluated in samples from donors of blood and source plasma in the United States. Analytic sensitivity was determined with reference standards. Infectious window periods (WPs) before NAT detectability were calculated for current donor screening assays. RESULTS: The specificity of cobas MPX was 99.946% (99.883%-99.980%) in 11,203 blood donor samples tested individually (IDT), 100% (99.994%-100%) in 63,012 donor samples tested in pools of 6, and 99.994% (99.988%-99.998%) in 108,306 source plasma donations tested in pools of 96. Seven HCV NAT-yield donations and one seronegative occult HBV infection were detected. Ninety-five percent and 50% detection limits in plasma (IU/mL) were 25.7 and 3.8 for HIV-1M, 7.0 and 1.3 for HCV, and 1.4 and 0.3 for HBV. The HBV WP was 1 to 4 days shorter than other donor screening assays by IDT. CONCLUSION: cobas MPX demonstrated high specificity in blood and source plasma donations tested individually and in pools. High sensitivity, in particular for HBV, shortens the WP and may enhance detection of occult HBV.

Characteristics of provoked deep venous thrombosis in a tertiary care center.

OBJECTIVE: Provoked deep venous thrombosis (DVT) is precipitated by a specific event. This paper compares the characteristics of provoked DVT in patients with transient risk (TR) factors and patients with continuous risk (CR) factors. METHODS: A retrospective review of records of all consecutive patients diagnosed with DVT between January 2013 and August 2014 was performed. Patients with provoked DVT were included in the TR group if the provoking event resolved in 2 weeks and they did not have ongoing risk of thrombosis. Patients in the CR group had a provoked DVT with ongoing risk of thrombosis due to individual factors deemed to be ongoing risks of thrombosis, such as cancer, hypercoagulable disorder, and prolonged immobilization. Demographics, risk factors, association with pulmonary embolism (PE) and its severity, risk of recurrent venous thromboembolism (VTE), and mortality were compared between the two groups. RESULTS: A total of 838 patients were diagnosed with DVT, and 50.7% (425) were provoked. There were 127 (29.9%) patients with TR and 298 (70.1%) with CR. TR patients were younger (60.4 ± 16.3 vs 65.9 ± 16.0; P = .001). TR was more likely to be provoked by surgery (70.9% vs 55.4%; P = .003), whereas CR was more likely to be provoked by immobilization (21.5% vs 12.6%; P = .032). CR patients were affected by cancer (48.7%) and hypercoagulable disorders (4.4%). TR patients were more likely to have calf DVTs (36.2% vs 26.2%; P = .047). There was a trend toward lower association with PE on presentation in TR (17.3% vs 21.1%; P = .072), but that did not reach statistical significance. However, TR factors were more likely to be associated with low-risk PE compared with CR factors (30.2% vs 54.6%; P = .040). After mean follow-up of 7.2 months, CR had higher risk of recurrent VTE (14.0% vs 6.8%; P = .045) and mortality (23.5% vs 7.1%; P < .0001). CONCLUSIONS: Provoked DVT with CR factors affects older patients and is associated with high recurrence of VTE and mortality compared with provoked DVT with TR factors.

May-Thurner syndrome and iliac arteriovenous fistula in an elderly woman.

May-Thurner syndrome most commonly involves compression of the left common iliac vein by the right common iliac artery and can result in leg pain and swelling as well as potentially precipitate deep venous thrombosis. These symptoms can be exacerbated by additional vascular abnormalities. This is a case report of a 91-year-old woman with intractable massive left lower extremity edema that interfered with walking. She was diagnosed with concurrent May-Thurner syndrome and pelvic arteriovenous fistula. Treatment with embolization of the fistula and stenting of the left common iliac vein relieved her symptoms and allowed her to walk again.

Correlation between Retinal Changes and Visual Function in Late-Stage Vogt-Koyanagi-Harada Disease: An Optical Coherence Tomography Study.

Purpose. To characterize the optical coherence tomography (OCT) findings in late-stage Vogt-Koyanagi-Harada (VKH) disease and its correlation with visual function. Methods. The records of patients with late-stage VKH disease (defined as ≥12 months from disease onset) were retrospectively reviewed. The analysis focused on the OCT findings and microperimetry, in addition to the possible correlation between morphology and functional findings. Results. Twenty-nine patients (58 eyes) were included. Mean age at onset was 34.24 ± 10.67 years. The OCT revealed that the outer retina and retinal pigment epithelium (RPE) were mainly affected. These effects included RPE thickening and breakage or disappearance of the cone outer segment tip (COST) line and/or inner segment/outer segment (IS/OS) junction. The COST line and IS/OS results were related to macular function and the interval between symptom onset and initiation of high-dose corticosteroid treatment (all P < 0.01). Eyes with intact COST lines demonstrated intact IS/OS and normal RPE layers as well as better visual function and normal retinal sensitivity. Conclusions. The OCT findings are strongly correlated with macular function, as well as other clinical findings in late-stage VKH. With respect to the COST line and retinal sensitivity especially, the OCT and microperimetry findings may be useful for evaluating later-stage VKH.

Subjective and objective screening tests for hydroxychloroquine toxicity.

OBJECTIVE: To compare subjective and objective clinical tests used in the screening for hydroxychloroquine retinal toxicity to multifocal electroretinography (mfERG) reference testing. DESIGN: Prospective, single-center, case control study. PARTICIPANTS: Fifty-seven patients with a previous or current history of hydroxychloroquine treatment of more than 5 years' duration. METHODS: Participants were evaluated with a detailed medical history, dilated ophthalmologic examination, color fundus photography, fundus autofluorescence (FAF) imaging, spectral-domain (SD) optical coherence tomography (OCT), automated visual field testing (10-2 visual field mean deviation [VFMD]), and mfERG testing. We used mfERG test parameters as a gold standard to divide participants into 2 groups: those affected by hydroxychloroquine-induced retinal toxicity and those unaffected. MAIN OUTCOME MEASURES: We assessed the association of various imaging and psychophysical variables in the affected versus the unaffected group. RESULTS: Fifty-seven study participants (91.2% female; mean age, 55.7±10.4 years; mean duration of hydroxychloroquine treatment, 15.0±7.5 years) were divided into affected (n = 19) and unaffected (n = 38) groups based on mfERG criteria. Mean age and duration of hydroxychloroquine treatment did not differ statistically between groups. Mean OCT retinal thickness measurements in all 9 macular subfields were significantly lower (<40 µm) in the affected group (P < 0.01 for all comparisons) compared with those in the unaffected group. Mean VFMD was 11 dB lower in the affected group (P < 0.0001). Clinical features indicative of retinal toxicity were scored for the 2 groups and were detected in 68.4% versus 0.0% using color fundus photographs, 73.3% versus 9.1% using FAF images, and 84.2% versus 0.0% on the scoring for the perifoveal loss of the photoreceptor ellipsoid zone on SD-OCT for affected and unaffected participants, respectively. Using a polynomial modeling approach, OCT inner ring retinal thickness measurements and Humphrey 10-2 VFMD were identified as the variables associated most strongly with the presence of hydroxychloroquine as defined by mfERG testing. CONCLUSIONS: Optical coherence tomography retinal thickness and 10-2 VFMD are objective measures demonstrating clinically useful sensitivity and specificity for the detection of hydroxychloroquine toxicity as identified by mfERG, and thus may be suitable surrogate tests.

Visual acuity after cataract surgery in patients with age-related macular degeneration: age-related eye disease study 2 report number 5.

OBJECTIVE: To evaluate visual acuity outcomes after cataract surgery in persons with varying degrees of severity of age-related macular degeneration (AMD). DESIGN: Cohort study. PARTICIPANTS: A total of 1232 eyes of 793 participants who underwent cataract surgery during the Age-Related Eye Disease Study 2, a prospective, multicenter, randomized controlled trial of nutritional supplements for treatment of AMD. METHODS: Preoperative and postoperative characteristics of participants who underwent cataract extraction during the 5-year trial were analyzed. Both clinical data and standardized red-reflex lens and fundus photographs were obtained at baseline and annually. Photographs were graded by a centralized reading center for cortical and posterior subcapsular lens opacities and for AMD severity. Cataract surgery was documented at annual study visits or by history during the 6-month telephone calls. Analyses were conducted using multivariate repeated-measures regression. MAIN OUTCOME MEASURES: Change in best-corrected visual acuity (BCVA) after cataract surgery compared with preoperative BCVA. RESULTS: Adjusting for age at time of surgery, gender, interval between preoperative and postoperative visits, and type and severity of cataract, the mean changes in visual acuity were as follows: eyes with mild AMD (n = 30) gained 11.2 letters (95% confidence interval [CI], 6.9-15.5), eyes with moderate AMD (n = 346) gained 11.1 letters (95% CI, 9.1-13.2), eyes with severe AMD (n = 462) gained 8.7 letters (95% CI, 6.7-10.7), eyes with noncentral geographic atrophy (n = 70) gained 8.9 letters (95% CI, 5.8-12.1), and eyes with advanced AMD (central geographic atrophy, neovascular disease, or both; n = 324) gained 6.8 letters (95% CI, 4.9-8.8). The visual acuity gain across all AMD severity groups was statistically significant from preoperative values (P < 0.0001). CONCLUSIONS: Mean visual acuities improved significantly after cataract surgery across varying degrees of AMD severity.

Sorting out co-occurrence of rare monogenic retinopathies: Stargardt disease co-existing with congenital stationary night blindness.

BACKGROUND: Inherited retinal diseases are uncommon, and the likelihood of having more than one hereditary disorder is rare. Here, we report a case of Stargardt disease and congenital stationary night blindness (CSNB) in the same patient, and the identification of two novel in-frame deletions in the GRM6 gene. MATERIALS AND METHODS: The patient underwent an ophthalmic exam and visual function testing including: visual acuity, color vision, Goldmann visual field, and electroretinography (ERG). Imaging of the retina included fundus photography, spectral-domain optical coherence tomography (OCT), and fundus autofluorescence. Genomic DNA was PCR-amplified for analysis of all coding exons and flanking splice sites of both the ABCA4 and GRM6 genes. RESULTS: A 46-year-old woman presented with recently reduced central vision and clinical findings of characteristic yellow flecks consistent with Stargardt disease. However, ERG testing revealed an ERG phenotype unusual for Stargardt disease but consistent with CSNB1. Genetic testing revealed two previously reported mutations in the ABCA4 gene and two novel deletions in the GRM6 gene. CONCLUSIONS: Diagnosis of concurrent Stargardt disease and CSNB was made on the ophthalmic history, clinical examination, ERG, and genetic testing. This case highlights that clinical tests need to be taken in context, and that co-existing retinal dystrophies and degenerations should be considered when clinical impressions and objective data do not correlate.

Global methylation in the placenta and umbilical cord blood from pregnancies with maternal gestational diabetes, preeclampsia, and obesity.

Emerging evidence indicates that maternal medical risk during pregnancy, such as gestational diabetes mellitus (GDM), preeclampsia, and obesity, predisposes the offspring to suboptimal development. However, the underlying biological/epigenetic mechanism in utero is still unknown. The current pilot study (N = 50) compared the levels of global methylation in the placenta and umbilical cord blood among women with and without each risk condition (GDM, preeclampsia, and obesity) and explored whether the levels of global methylation were associated with fetal/infant growth. Results show that global methylation levels in the placenta were lower in patients with gestational diabetes (P = .003) and preeclampsia (P = .05) but higher with obesity (P = .01). Suggestive negative associations were found between global methylation level in the placenta and infant body length and head circumference. While preliminary, it is possible that the placenta tissue, but not umbilical cord blood, may be epigenetically programmed by maternal GDM, preeclampsia, and obesity to carry out its own specific functions that influence fetal growth.

The Effects of Preeclampsia on Perinatal Risks and Infant Temperaments Among Mothers With Antenatal Depression.

IMPORTANCE: Preeclampsia and depression are two most prevalent disorders known to affect pregnant women and unborn infant. However, few studies have prospectively examined the adverse influence of the in-utero exposures to the two disorders on the optimal development in their offspring, including mortality, adverse birth outcomes, and infant temperament styles. OBJECTIVES: (1) To examine whether exposures to preeclampsia and antenatal depression were associated with developmental indices of offspring at birth and temperament at 3 months; and (2) To evaluate how preeclampsia and antenatal depression associated with offspring temperamental style. DESIGN: Prospective cohort study with regular assessment of mother's blood pressure at each prenatal visit: offspring were followed till 3 months. SETTING: Two prenatal clinics, New York City, USA. PARTICIPANTS: A cohort of 233 pregnant women was followed throughout pregnancy. Of those, 141 provided ratings of infant temperament at three months. EXPOSURES: Diagnostic outcome of maternal depression by clinical interviewers blind to preeclampsia status, were ascertained using the Structured Clinical Interview for DSM-IV Axis I Disorders. The development of preeclampsia, defined by the onset of hypertension (> 140/90 mm HG) after 20 weeks' gestation, accompanied by 300 mg of protein, monitored via electronic medical records. MAIN OUTCOME MEASURES: Birth outcomes were assessed via standardized ratings at delivery. Infant temperament was reported by the mother at three months, using 91-item IBQ-R (Infant Behavioral Questionnaire-Revised). RESULTS: Preeclampsia was associated with an over 5-fold increased risk for fetal/infant mortality, a 3- to 7-fold increased risk for poorer birth outcomes, and flatter affect and distress in infants. Furthermore, infants born to preeclamptic mothers with co-occurring depression displayed lower levels of smile/laughter, high-intensity pleasure seeking behavior, perceptual sensitivity, and approach behavior. CONCLUSION: Preeclampsia was associated with a few difficult temperament styles in the first three months after birth. Moreover, its negative impact was amplified by mother's antenatal depression. Our findings regarding additive risk for negative infant outcomes in babies exposed to preeclampsia and antenatal depression suggests that the development of early detection programs to identify and monitor women who are at heightened risk for these conditions can potentially have a positive influence on long-term infant neurobehavioral development.