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An in vitro model of human ovarian follicles would greatly benefit the study of female reproduction. Ovarian development requires the combination of germ cells and several types of somatic cells. Among these, granulosa cells play a key role in follicle formation and support for oogenesis. Whereas efficient protocols exist for generating human primordial germ cell-like cells (hPGCLCs) from human induced pluripotent stem cells (hiPSCs), a method of generating granulosa cells has been elusive. Here, we report that simultaneous overexpression of two transcription factors (TFs) can direct the differentiation of hiPSCs to granulosa-like cells. We elucidate the regulatory effects of several granulosa-related TFs and establish that overexpression of NR5A1 and either RUNX1 or RUNX2 is sufficient to generate granulosa-like cells. Our granulosa-like cells have transcriptomes similar to human fetal ovarian cells and recapitulate key ovarian phenotypes including follicle formation and steroidogenesis. When aggregated with hPGCLCs, our cells form ovary-like organoids (ovaroids) and support hPGCLC development from the premigratory to the gonadal stage as measured by induction of DAZL expression. This model system will provide unique opportunities for studying human ovarian biology and may enable the development of therapies for female reproductive health.

PURPOSE: To qualitatively explore exercise barriers and facilitators experienced by rural female cancer survivors from the program interventionist and recipient perspective for the purpose of enhancing exercise program implementation and uptake in rural settings. METHODS: A descriptive qualitative study design was utilized. Focus groups were conducted prior to implementation of an evidence-based exercise program by a rural non-research cancer clinical site. Nineteen rural female cancer survivors (mean age = 61.7 ± 10.9 years) and 11 potential interventionists (mean age = 42.3 ± 15.3 years) completed focus groups (stratified by participant role). Focus groups were audio recorded, transcribed, coded, and analyzed using inductive thematic analysis with NVivo 11. RESULTS: Cancer survivors identified twelve barrier themes (cancer specific adverse effects, lack of support, lack of knowledge, perceived negative aspects of exercise, cost, lack of resources, motivation, inconvenience, lack of program flexibility, time, weather, safety) and eight facilitator themes (knowledge, ease of access, resources, awareness, cost, options, organized, fun) related to exercise. Interventionists identified seven barrier themes (cost, transportation, lack of cancer survivor and interventionist knowledge, fear, motivation, lack of support, lack of resources) and four facilitator themes (resources, support, knowledge, motivation). Narratives revealed differing role-specific perspectives on shared themes between survivors and interventionists as well as potential implementation strategies for enhancing exercise participation and exercise program uptake among rural female cancer survivors. CONCLUSION: Exploring multi-level stakeholder perspectives on cancer survivors’ exercise needs and related strategies yields important information for organizations to consider when implementing exercise programs in rural contexts.

Feminizing hormone therapy (FHT) may interact with human immunodeficiency virus preexposure prophylaxis (PrEP). We found that transgender women who took FHT exhibited a 7-fold lower rectal tissue ratio of PrEP’s active metabolites vs competing deoxynucleotides compared to cisgender women and men (P = .03) that inversely correlated with estradiol (ρ = –0.79; P < .05). Thus, FHT may negatively impact PrEP efficacy. Clinical Trials Registration . NCT02983110.

This prospective cohort study enrolled people living with HIV initiating antiretroviral therapy (ART) containing the integrase inhibitors, dolutegravir (DTG) or elvitegravir (EVG) and administered the Montreal Cognitive Assessment (MoCA) at baseline and again after approximately six months to compare changes in MoCA scores. The proportion of patients found to have cognitive impairment, as indicated by a MoCA score26/30, on each agent were also compared and comparisons were made between changes in each domain assessed by the MoCA (visuospatial/executive, naming, attention, language, abstraction, delayed recall, and orientation). Thirty-five evaluable participants were enrolled, 18 on DTG and 17 on EVG. The median [interquartile range(IQR)] age was 44 (32 to 54) years, 63% were male, 57% were African American. The median (IQR) MoCA score at baseline was 25 (23 to 27) with no difference between groups (

OBJECTIVES We aimed to compare the effectiveness of antiretroviral therapy (ART) classes for achieving HIV RNA suppression to

Introduction Integrase strand transfer inhibitors (INSTI) are currently being investigated for the treatment of HIV in pregnancy. The purpose of this study is to evaluate the differences in maternal and infant outcomes in HIV-positive mothers treated with INSTI-containing antiretroviral therapy (ART) during pregnancy compared to protease inhibitor (PI)-containing ART. Methods A retrospective, cohort study of INSTI- and PI-based ART used in pregnancy between 2007 and 2015 was performed. The primary objective was to evaluate the differences in viral load (VL) suppression prior to delivery. Secondary endpoints included time to and duration of VL suppression and safety parameters in both mothers and infants. For the primary analysis, the two arms were matched 1:2 INSTI to PI based on the presence or absence of viremia at the time of pregnancy determination. Additional analysis was performed on the entire matched and unmatched dataset. Results Twenty-one patients were matched (7 INSTI and 14 PI). There were no significant differences between groups with respect to the proportion of patients with VL suppression prior to delivery (71.4% INSTI vs. 92.9% PI, p = 0.247), and there were no significant differences in any of the secondary endpoints. Patients with documented adherence issues were statistically more likely to not be virologically suppressed prior to delivery (p = 0.002). Conclusion No differences in efficacy or safety were found between patients treated with INSTIs compared to PIs. This study supports the further investigation of the use of INSTIs during pregnancy to reduce HIV transmission.

Persons living with human immunodeficiency virus (HIV) and others receiving antiretrovirals are at risk for medication errors during hospitalization and at transitions of care. These errors may result in adverse effects or viral resistance, limiting future treatment options. A range of interventions is described in the literature to decrease the occurrence or duration of medication errors, including review of electronic health records, clinical checklists at care transitions, and daily review of medication lists. To reduce the risk of medication-related errors, antiretroviral stewardship programs (ARVSPs) are needed to enhance patient safety. This call to action, endorsed by the Infectious Diseases Society of America, the HIV Medicine Association, and the American Academy of HIV Medicine, is modeled upon the success of antimicrobial stewardship programs now mandated by the Joint Commission. Herein, we propose definitions of ARVSPs, suggest resources for ARVSP leadership, and provide a summary of published, successful strategies for ARVSP that healthcare facilities may use to develop locally appropriate programs., Persons receiving antiretrovirals are at risk for medication-related errors in the inpatient setting. This joint policy paper endorses antiretroviral stewardship and antiretroviral stewardship programs, designed to improve patient safety

The antiretroviral combination of emtricitabine-tenofovir disoproxil fumarate (FTC/TDF) was approved by the United States Food and Drug Administration (FDA) for use as Pre-Exposure Prophylaxis (PrEP) in individuals at high risk for acquiring human immunodeficiency virus (HIV) in July 2012. Since then, Centers for Disease Control and Prevention (CDC) guidelines for the use of PrEP have been published and implemented into clinical practice throughout the United States. A number of published open-label and PrEP demonstration projects have evaluated the real-world use of PrEP including analysis of the barriers to its use and addressing major concerns. Despite the approval of FTC/TDF for PrEP, its use for this indication is reliant on patient and provider acceptance, and its effectiveness requires patient adherence and retention in care during periods of high-risk behaviors. Concerns regarding the use of PrEP in healthy individuals persist and include medication adverse effects, including renal dysfunction and bone mineral density loss; risk compensation leading to HIV infections, sexually transmitted infections, and unintended pregnancies and the development of drug resistance in the event of seroconversion. The cost effectiveness of PrEP continues to be assessed with the greatest cost effectiveness remaining in those at highest risk of acquiring HIV. Additionally, cases of HIV acquisition in individuals who are adherent to PrEP highlight scenarios in which PrEP is not 100% effective, including against the transmission of drug-resistant HIV strains. This review examines data on the implementation of PrEP outside the setting of clinical trials with the aim of providing clinicians with a summary of the current barriers and opportunities for PrEP use with a specific focus on the role of pharmacists in optimization of PrEP implementation.

Very high baseline HIV-1 RNA viral loads require potent and robust antiretroviral regimens to achieve virological suppression. The coformulated single tablet regimen of elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (EVG/COBI/FTC/TDF) is recommended by the US Department of Health and Human Services for the treatment of HIV-1 in treatment-naive adults and adolescents regardless of baseline CD4+ T-cell count and viral load. We report two cases of HIV-infected, treatment-naive patients, with baseline HIV-1 RNA viral loads >1,000,000 copies/ml who were initiated on the single tablet regimen EVG/COBI/FTC/TDF, but failed to attain viral load suppression and developed resistance to the components of EVG/ COBI/FTC/TDF.

Background and purpose Several schools of pharmacy across the United States have taken steps to incorporate international medical mission trips into the doctor of pharmacy (PharmD) curriculum. This study aims to describe the impact of advanced pharmacy practice experience (APPE)-level student pharmacists on an interprofessional team during an international medical mission trip to Jamaica. Educational activity and setting The Jamaica Medical Mission (JMM) trip is an annual event involving healthcare professionals from several disciplines across multiple universities and healthcare systems. At this institution, the JMM trip is included as part of a rural health elective APPE rotation. Students electing to participate in this rotation are provided with the opportunity to serve as active participants on an interprofessional healthcare team in underserved and under-resourced communities throughout Jamaica. The JMM trip that took place during June 2016 included healthcare professionals and students in the fields of medicine, dentistry, optometry, nursing, and pharmacy. A total of five pharmacist preceptors and 10 pharmacy students attended the JMM trip in June 2016. Approximately three to five clinic sites per day were conducted simultaneously on each of the seven clinic days at various locations throughout Jamaica. The interprofessional healthcare teams provided free medical care, including physical exams and access to prescription and non-prescription medications. Findings The interprofessional healthcare team saw a total of 1014 patients and dispensed 1879 prescriptions during the seven clinic days. A total of 811 clinical recommendations were made by student pharmacists and/or pharmacy preceptors. Of these recommendations, 561 (69%) were made by student pharmacists without pharmacy preceptor prompting, 103 (13%) were made by the student pharmacist with preceptor prompting, and 147 (18%) were made by pharmacy preceptors. Over 70% of recommendations made by student pharmacists without pharmacy preceptor prompting were accepted by prescribers. Discussion and summary This study sought to describe the impact of APPE-level student pharmacists on an interprofessional team during an international medical mission trip. Our findings demonstrate that APPE-level student pharmacists were capable of making a substantial number of clinical recommendations without preceptor prompting. The number of recommendations made by students without preceptor prompting were consistently greater than the number of recommendations made with preceptor prompting throughout the trip. Future studies should address student competence in achieving learning objectives associated with international, interprofessional APPE rotations.

Background. Understanding the life history of a species is essential for fully understanding its role within an ecosystem. However, many of the fish species of high ecological value have not been studied due to their less prominent roles in local recreational and commercial fisheries in comparison to other targeted species. These valuable fishes are also important trophic linkages between small neritic fishes and large, economically valuable apex predators. This study describes for the first time the yearly age and growth patterns of three small tuna species inhabiting South Florida (USA) waters: blackfin tuna, Thunnus atlanticus (Lesson, 1831); little tunny, Euthynnus alletteratus (Rafinesque, 1810); and skipjack tuna, Katsuwonus pelamis (Linnaeus, 1758). Materials and methods. Tuna specimens were collected in two ways: via donations obtained from various fishing tournaments and charter captains in the areas of the Florida Straits as well as hook-and-line catches performed especially for this project. Age determination was based on sagittal otolith hyaline deposition patterns. Marginal increment analysis was used as an indirect validation method. Growth parameters were determined by comparison of the fish fork length and the hyaline band measurements. Results. Two hyaline bands formed each year in all three species—one in winter and one in summer. The von Bertalanffy growth equation produced a growth rate for each species: blackfin tuna, L¥ = 95.34 cm, K = 0.28, and t0 = –1.53; little tunny, L¥ = 77.93 cm, K = 0.69, and t0 = –0.69; and skipjack tuna, L¥ = 112.76 cm, K = 0.24, and t0 = –1.70. Parameters of each resulting von Bertalanffy equation were compared among species showing that little tunny grew the fastest, but skipjack had the largest estimated size. Results were also compared with growth rates currently used in stock assessments by fisheries management organizations, such as the International Commission for the Conservation of Atlantic Tunas (ICCAT). Conclusion. Sectioned otoliths indicate two bands a year for these three species in the Florida Straits. Results were comparable to other studies, with a similar finding of two bands per year in hard parts for these species. Further knowledge of these populations will aid in stock assessments for these species and the ongoing shift to ecosystem-based management plans.

Background Antiretrovirals that achieve adequate concentrations in anatomical sites of transmission are of interest for HIV prevention. A Phase I open-label pharmacokinetic (PK) study was performed to describe first dose (PK1) and steady-state (PK2) PKs of the integrase inhibitor dolutegravir (DTG) in blood plasma (BP), cervicovaginal fluid (CVF), cervical tissue (CT) and vaginal tissue (VT) in HIV type-1-negative women. Methods A total of 8 healthy females given DTG 50 mg daily for 5–7 days had 11 paired BP and CVF samples collected over 24 h following the first dose (PK1) and multiple dosing (PK2). Each woman underwent CT and VT biopsies at 1/4 time points at PK1 and PK2 to generate composite PK profiles. DTG concentrations were analysed by validated liquid chromatography-tandem mass spectrometry methods. Non-compartmental PK analysis was performed and Spearman rank correlations determined between matrices. Results BP areas under the concentration–time curve (AUCs) were similar to previous reports and concentrations remained greater than the protein-adjusted (PA) 90% inhibitory concentration (IC90) for wild-type HIV (64 ng/ml). CVF exposures were approximately 6% of BP with low inter-individual variability. CT and VT exposures were 7% of BP at PK1, and 9–10% of BP at PK2 with 94% of samples >PA-IC90. CT and VT concentrations were correlated to each other (ρ=0.70, P=0.003), and to CVF at steady state (ρ=0.52, P=0.04). Accumulation of DTG from PK1 to PK2 occurred in BP, CT and VT, but only marginally in CVF. Conclusions DTG BP PK were consistent with previously published values. CVF, CT and VT exposures were highly correlated. At PK2, DTG accumulated to a greater extent in tissue than in BP or CVF, suggesting increased tissue affinity.

The global HIV epidemic cannot be controlled by current treatment or prevention strategies. Pre-exposure prophylaxis (PrEP) using antiretrovirals is a promising approach to curbing the spread of HIV transmission. Recently, four clinical trials demonstrated favorable results when antiretroviral PrEP was administered topically or orally. However, two additional trials were unable to demonstrate a benefit, indicating that further study is required to define the populations and conditions under which PrEP will be effective. Adherence is highly correlated with protection, yet the exact level of adherence required is unknown. Future studies may require increased drug exposure testing and more objective methods to monitor adherence in real time. Although the development of drug-resistance in the PrEP trials has been low, it remains a concern, as therapeutic options could be compromised for those who seroconvert while on PrEP.

BACKGROUND: The active metabolites of tenofovir (TFV) and emtricitabine (FTC) in peripheral blood mononuclear cells (PBMCs) have been used as markers of long-term antiretroviral (ARV) adherence. However, the process of isolating PBMCs is expensive, complex, and not feasible in many settings. We compared concentrations of TFV-diphosphate (TFV-DP) and FTC-triphosphate (FTC-TP) in the upper layer packed cells (ULPC) obtained after whole blood centrifugation to isolated PBMCs as a possible alternative marker of adherence. METHODS:: Ten HIV+ adults with HIV RNA

Objectives The pharmacokinetics (PK) of antiretrovirals (ARVs) in older HIV-infected patients are poorly described. Here, the steady-state PK of two common ARV regimens [tenofovir (TFV)/emtricitabine (FTC)/efavirenz (EFV) and TFV/FTC/atazanavir (ATV)/ritonavir (RTV)] in older nonfrail HIV-infected patients are presented. Methods HIV-infected subjects ≥55 years old not demonstrating the frailty phenotype were enrolled in an unblinded, intensive-sampling PK study. Blood plasma (for TFV, FTC, EFV, ATV and RTV concentrations) and peripheral blood mononuclear cells [PBMCs; for tenofovir diphosphate (TFV-DP) and emtricitabine triphosphate (FTC-TP) concentrations] were collected at 11 time-points over a 24-hour dosing interval. Drug concentrations were analysed using validated liquid chromatography–ultraviolet detection (LC-UV) or liquid chromatography tandem mass spectrometry (LC-MS/MS) methods. Noncompartmental pharmacokinetic analysis was used to estimate PK parameters [area under the concentration–time curve over 24 h (AUC0-24h) and maximal concentration (Cmax)]. These parameters were compared with historical values from the general HIV-infected population. Results Six subjects on each regimen completed the study. Compared with the general population, these elderly subjects had 8–13% decreased TFV AUC0-24h and Cmax, and 19–78% increased FTC and RTV AUC0-24h and Cmax. Decreased ATV AUC0-24h (12%) and increased Cmax (9%) were noted, while EFV exposure was unchanged (5%) with a 16% decrease in Cmax. Intracellular nucleoside/tide metabolite concentrations and AUC are also reported for these subjects. Conclusions This study demonstrates that the PK of these ARVs are altered by 5–78% in an older HIV-infected population. Implications of PK differences for clinical outcomes, particularly with the active nucleoside metabolites, remain to be explored. This study forms the basis for further study of ARV PK, efficacy, and toxicity in older HIV-infected patients.

The development of safe topical microbicides that effectively prevent human immunodeficiency virus (HIV) infection is a major goal in curbing the human immunodeficiency virus pandemic. A number of past failures resulting from mucosal toxicity or lack of efficacy have informed the field. Products that caused toxicity to the female genital tract mucosa, and thereby increased the likelihood of HIV acquisition, included nonoxynol 9, cellulose sulfate, and C31 G vaginal gel Savvy ® . Topical products that were ineffective in preventing HIV infection include BufferGel ® , Carraguard ® , and PRO 2000 ® . Antiretroviral drugs such as tenofovir and dapivirine formulated into microbicide products have shown promise, but there is much to learn about ideal product formulation and acceptability, and drug distribution and disposition (pharmacokinetics). Current formulations for water-soluble molecules include vaginally or rectally applied gels, vaginal rings, films and tablets. Dosing strategies (e.g. coitally dependent or independent) will be based on the pharmacokinetics of the active ingredient and the tolerance for less than perfect adherence.

Background Vancomycin has historically been the mainstay of therapy for MRSA bacteremia, but severe infections due to vancomycin-intermediate Staphylococcus aureus have emerged. In vitro studies have shown that the combination of a β-lactam antibiotic, such as ceftaroline with daptomycin, was synergistic against MRSA. The purpose of this study was to compare outcomes in patients who received daptomycin and ceftaroline in combination vs. vancomycin for the treatment of MRSA bacteremia. Methods This was a retrospective exploratory cohort study approved by the institutional review board at Cooper University Hospital. Patients were included if they received daptomycin/ceftaroline (cases) or vancomycin (controls) for the treatment of MRSA bacteremia between November 2010 and March 2017. Cases were matched 1:1 with controls based on source of MRSA bacteremia, age within 10 years, and renal function. The primary endpoint was clinical cure, defined as the improvement of signs and symptoms of bacteremia. Secondary endpoints included microbiologic cure, time to sterilization of blood cultures, duration of hospital stay, overall mortality, and MRSA-related mortality. Results Forty-one cases were included. There was no statistical difference between the two groups in microbiologic cure, time to sterilization of blood cultures, overall mortality, or MRSA-related mortality. There were no significant differences between patients in each group including in those with ICU admissions and who required vasopressors. Cases were significantly more likely to have hardware compared with the control group (43.9% vs. 12.2%; P = 0.0014). Clinical cure was achieved in 27 patients (65.9%) in the case group and 26 patients (63.4%) in the control group (P = 0.8173). Patients in the case group had a statistically longer mean hospital duration (29 days vs. 21 days, respectively, P = 0.0206) and more secondary complications such as bone infection (P = 0.0076). Conclusion Time to sterilization of blood cultures and overall mortality were similar in both groups. Patients in the combination group had longer hospital stays compared with vancomycin monotherapy. Daptomycin/ceftaroline combination therapy is an option for complicated MRSA bacteremia. Larger studies should be conducted to further evaluate this combination. Disclosures All authors: No reported disclosures.

Protease inhibitors (PIs) are a potent class of antiretroviral agents which have been used to successfully treat many patients with HIV disease. As with other classes of antiretroviral agents, drug resistance has been described with each of the PIs. PI resistance can occur in newly infected individuals due to transmission of drug resistant strains or, more commonly, evolves from the selective pressure of antiretroviral therapy. When present, PI resistance results in an increased likelihood of drug failure. Individual protease gene mutations have been identified which are associated with phenotypic resistance to these agents. However, protease mutations can exert different effects on individual PIs, as some will produce resistance to one agent and may enhance susceptibility to another. In patients failing PIs, particularly in the setting of prior treatment with multiple agents, protease resistance patterns may be complex and result in broad cross-resistance to the class. Strategies to limit the development of resistance to these agents and manage its occurrence are important for the on-going care of individuals with HIV infection.

OBJECTIVES To describe first-dose and steady state pharmacokinetics (PKs) of dolutegravir (DTG) in blood plasma (BP), seminal fluid (SF), colorectal tissue (RT), and rectal mucosal fluid (RF) of healthy HIV-negative men. DESIGN A phase 1, open-label, PK study that enrolled 12 healthy men taking 50 mg DTG daily for 8 days. METHODS Eleven paired BP samples and 3 SF and RF samples were collected over 24 hours after first (PK1) and multiple (PK2) dosing. RT biopsies were collected at 1 of 6 time points at PK1 and PK2 to generate composite PK profiles. DTG concentrations were analyzed by validated liquid chromatography-tandem mass spectrometry (LC-MS/MS). Noncompartmental PK analysis was conducted with Phoenix WinNonlin v6.3, and Spearman rank correlations were determined using SAS v9.3. RESULTS BP area under the concentration-time curves (AUCs) were similar to previous reports, and concentrations at 24 hours (C24 h) were 6- to 34-fold greater than the protein-adjusted concentration required for 90% viral inhibition (PA-IC90) of 64 ng/mL. SF exposures were

The purpose of this study is to review recent and relevant pharmacology data for three HIV integrase inhibitors: raltegravir (marketed), dolutegravir, and elvitegravir (both in phase III drug development).Data from January 2011 to April 2012 were evaluated. These data better characterized integrase inhibitor pharmacokinetics, assessed dosing regimens, and investigated previously undescribed drug-drug interactions. Due to formulation challenges, raltegravir inter-patient and intra-patient pharmacokinetic variability is high. Twice-daily 400 mg dosing has been shown to be clinically superior to 800 mg once-daily dosing. A pediatric formulation of raltegravir with less variable pharmacokinetics and greater bioavailability was US Food and Drug Administration (US FDA)-approved in December 2011. Cobicistat-boosted elvitegravir, and the second-generation integrase inhibitor dolutegravir, have lower pharmacokinetic variability and are dosed once daily. Dolutegravir drug interactions are similar to raltegravir, whereas boosted elvitegravir participates in additional CYP3A-mediated interactions.Raltegravir's potent antiretroviral activity has resulted in widespread use in both treatment-naïve and experienced patients. Dolutegravir and cobicistat-boosted elvitegravir have some pharmacokinetic advantages. Pharmacokinetic data in special populations (pregnancy, pediatrics) to optimize dosing are still required.

Adequate bone volume is imperative for the osseointegration of endosseous implants, but postextraction resorption and remodeling may challenge implant placement. The use of bone biomaterials has been advocated to fill extraction sites and to enhance primary implant stability during osseointegration. The objective of the case series was to evaluate bone formation histologically and biomechanically in extraction sites following implantation of three commercially available bone biomaterials to compare their ability to allow guided bone regeneration.Thirty-six periodontally involved teeth were extracted from eight healthy non-smoking subjects. At least two bone biomaterials, a synthetic sponge based on polylactic-polyglycolic acid technology (FIS), bovine porous bone mineral (BPBM), or a natural coral derivative physically and chemically transformed into a calcium carbonate ceramic (COR), and one non-grafted control were applied to the extraction sockets within each subject and were covered by an expanded polytetrafluoroethylene device. The devices were removed after 2 months, and trephine biopsies were obtained from each site 4 months later. At that time, endosseous implants were placed in 25 of the sites, and healing abutments were placed; measurements were taken 4 to 6 months later with an electronic mobility testing device.The percentage of residual biomaterial was 5.6% +/- 8.9% for FIS (P0.001), 20.2% +/- 17.0% for BPBM (P0.05), and 12.0% +/- 16.4% for COR (P0.001). The amount of residual biomaterial after 6 months showed a significant relationship with the insertion torque measurements during the first third of implant insertion (P0.05) and with values of the electronic mobility testing device at the abutment connection (P = 0.05). Histologically, new bone apposition was seen on BPBM particles. FIS sites showed similar ingrowth of blood vessels and osteocytes as empty controls.All sites revealed good primary stability at implant insertion and proper implant rigidity at abutment placement, indicating that early implant osseointegration was not influenced by the application of bone biomaterials used in this study.

"Golden Rice" is a variety of rice engineered to produce beta-carotene (pro-vitamin A) to help combat vitamin A deficiency, and it has been predicted that its contribution to alleviating vitamin A deficiency would be substantially improved through even higher beta-carotene content. We hypothesized that the daffodil gene encoding phytoene synthase (psy), one of the two genes used to develop Golden Rice, was the limiting step in beta-carotene accumulation. Through systematic testing of other plant psys, we identified a psy from maize that substantially increased carotenoid accumulation in a model plant system. We went on to develop "Golden Rice 2" introducing this psy in combination with the Erwinia uredovora carotene desaturase (crtI) used to generate the original Golden Rice. We observed an increase in total carotenoids of up to 23-fold (maximum 37 microg/g) compared to the original Golden Rice and a preferential accumulation of beta-carotene.

Gonococci treated with the quinone antibiotic streptonigrin develop KCN insensitive respiration resulting in the formation of superoxide. Streptonigrin effects require iron suggesting that catalysis of hydroxyl radical is involved. We have found that extracellular iron appears to be more important than intracellular iron in these events. Highly streptonigrin resistant bacteria were isolated; these organisms demonstrated significant reduction in superoxide formation, and moderate reduction in total cellular iron. Iron transport mutants demonstrated superoxide fromation equivalent to the parent strain. Quinone antibiotics induce superoxide dismutase and catalase in E. coli, but this effect could not be demonstrated in gonococci. Our results suggest multiple possible mechanisms of streptonigrin resistance of N. gonorrhoeae including: failue to reduce the quinone; decreased intracellular iron, altered catalysis of hydroxyl radical at the cell surface.