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Pollen elimination provides an effective containment method to reduce direct gene flow from transgenic trees to their wild relatives. Until now, only limited success has been achieved in controlling pollen production in trees. A pine (Pinus radiata) male cone-specific promoter, PrMC2, was used to drive modified barnase coding sequences (barnaseH102E, barnaseK27A, and barnaseE73G) in order to determine their effectiveness in pollen ablation. The expression cassette PrMC2-barnaseH102E was found to efficiently ablate pollen in tobacco (Nicotiana tabacum), pine, and Eucalyptus (spp.). Large-scale and multiple-year field tests demonstrated that complete prevention of pollen production was achieved in greater than 95% of independently transformed lines of pine and Eucalyptus (spp.) that contained the PrMC2-barnaseH102E expression cassette. A complete pollen control phenotype was achieved in transgenic lines and expressed stably over multiple years, multiple test locations, and when the PrMC2-barnaseH102E cassette was flanked by different genes. The PrMC2-barnaseH102E transgenic pine and Eucalyptus (spp.) trees grew similarly to control trees in all observed attributes except the pollenless phenotype. The ability to achieve the complete control of pollen production in field-grown trees is likely the result of a unique combination of three factors: the male cone/anther specificity of the PrMC2 promoter, the reduced RNase activity of barnaseH102E, and unique features associated with a polyploid tapetum. The field performance of the PrMC2-barnaseH102E in representative angiosperm and gymnosperm trees indicates that this gene can be used to mitigate pollen-mediated gene flow associated with large-scale deployment of transgenic trees.

Congenital aortic valve stenosis (CAVS) affects up to 10% of the world population without medical therapies to treat the disease. New molecular targets are continually being sought that can halt CAVS progression. Collagen deregulation is a hallmark of CAVS yet remains mostly undefined. Here, histological studies were paired with high resolution accurate mass (HRAM) collagen-targeting proteomics to investigate collagen fiber production with collagen regulation associated with human AV development and pediatric end-stage CAVS (pCAVS). Histological studies identified collagen fiber realignment and unique regions of high-density collagen in pCAVS. Proteomic analysis reported specific collagen peptides are modified by hydroxylated prolines (HYP), a post-translational modification critical to stabilizing the collagen triple helix. Quantitative data analysis reported significant regulation of collagen HYP sites across patient categories. Non-collagen type ECM proteins identified (26 of the 44 total proteins) have direct interactions in collagen synthesis, regulation, or modification. Network analysis identified BAMBI (BMP and Activin Membrane Bound Inhibitor) as a potential upstream regulator of the collagen interactome. This is the first study to detail the collagen types and HYP modifications associated with human AV development and pCAVS. We anticipate that this study will inform new therapeutic avenues that inhibit valvular degradation in pCAVS and engineered options for valve replacement.

Persons who are infected with human immunodeficiency virus (HIV) are at high risk of human papillomavirus (HPV)-associated cancers. The objectives are to compare antibody titers to HPV 6, 11, 16, and 18 and rate of abnormal cytology between perinatally HIV-infected (PHIV) and perinatally HIV-exposed, uninfected (PHEU) youth. This is a prospective observational cohort study of HPV4 vaccinated youth performed as part of the multicenter Pediatric HIV/AIDS Cohort Study Adolescent Master Protocol. Seroconversion and geometric mean titer (GMT) against HPV types 6, 11, 16, and 18 were calculated. Vaccine effectiveness included rates of abnormal cervical cytology and genital warts. Seroconversion to HPV 6, 11, 16, and 18 occurred in 83%, 84%, 90%, and 62% of 310 vaccinated PHIV youth compared to 94%, 96%, 99%, and 87% of 148 vaccinated PHEU youth, respectively (P < .05 for all comparisons). GMTs were lower in the PHIV vs PHEU within each category of HPV4 doses received. Higher GMTs were associated with younger age, lower HIV type 1 RNA viral load, and higher CD4% at first HPV4 vaccination, as well as shorter duration between last vaccine dose and antibody specimen. Abnormal cytology occurred in 33 of 56 PHIV and 1 of 7 PHEU sexually active vaccinated females, yielding incidence rates per 100 person-years of 15.0 (10.9 to 20.6) and 2.9 (0.4 to 22.3), respectively. Antibody titers to HPV4 were lower for all serotypes in PHIV compared to PHEU youth. Protection against abnormal cytology was also diminished in sexually active PHIV females.

Background. Early antiretroviral therapy (ART) limits proviral reservoirs, a goal for human immunodeficiency virus type 1 (HIV-1) remission strategies. Whether this is an immediate or long-term effect of virologic suppression (VS) in perinatal infection is unknown. Methods. We quantified HIV-1 DNA longitudinally for up to 14 years in peripheral blood mononuclear cells (PBMCs) among 61 perinatally HIV-1–infected youths in the Pediatric HIV/AIDS Cohort Study who achieved VS at different ages. Participants in group 1 (n = 13) were <1 year of age and in group 2 (n = 48) from 1 through 5 years of age at VS. Piecewise linear mixed-effects regression models assessed the effect of age at VS on HIV-1 DNA trajectories during VS. Results. In the first 2 years following VS, HIV-1 DNA levels decreased by −0.25 (95% confidence interval [CI], −.36 to −.13) log10 copies/million PBMCs per year and was faster with early VS by age 1 year compared with after age 1 (−0.50 and −0.15 log10 copies/million PBMCs per year, respectively). Between years 2 and 14 from VS, HIV-1 DNA decayed by −0.05 (95% CI, −.06 to −.03) log10 copies/million PBMCs per year and was no longer significantly different between groups. The estimated mean half-life of HIV-1 DNA from VS was 15.9 years and was shorter for group 1 compared to group 2 at 5.9 years and 18.8 years, respectively (P = .09). Adjusting for CD4 cell counts had no effect on decay estimates. Conclusions. Early effective, long-term ART initiated from infancy leads to decay of HIV-1–infected cells to exceedingly low concentrations desired for HIV-1 remission strategies.

Among 234 US youths with perinatal human immunodeficiency virus, 75% had antiretroviral resistance, substantially higher than that of the reference laboratory overall (36%–44%). Resistance to newer antiretrovirals and to all antiretrovirals in a class was uncommon. The only factor independently associated with future resistance was a higher peak viral load.

In this randomized, phase 2 trial involving previously untreated patients with early, relapsing–remitting multiple sclerosis, alemtuzumab, a monoclonal antibody targeting CD52 on lymphocytes and monocytes, was more effective than interferon beta-1a in reducing the progression of disability and relapse. Alemtuzumab caused autoimmune complications, including immune thrombocytopenic purpura (resulting in one death) and thyroid disorders. In this trial involving previously untreated patients with early, relapsing–remitting multiple sclerosis, alemtuzumab, a monoclonal antibody targeting CD52 on lymphocytes and monocytes, was more effective than interferon beta-1a in reducing the progression of disability and relapse. Multiple sclerosis typically follows a relapsing–remitting course, but most patients eventually convert to a secondary progressive phase characterized by deficits that increase in the absence of further relapses. This clinical evolution reflects the complex interplay of focal inflammation, demyelination, and axonal degeneration in the central nervous system. Current disease-modifying treatments decrease the frequency of relapse and modestly reduce the accumulation of disability but have not been shown to prevent secondary progression. 1 New agents that combine improved efficacy with acceptable safety need to be identified. The humanized monoclonal antibody alemtuzumab (Campath-1H; Campath, or MabCampath; Genzyme) targets CD52 on lymphocytes and monocytes. . . .

Antiretroviral (ARV) adherence is critical in monitoring disease response in youth with perinatally-acquired HIV (PHIV). We used pharmacy refill (PR) information for PHIV youth from the PHACS Memory Sub-study to calculate medication availability over 2, 4, and 6 months. PR, a proxy of adherence, was compared with self-reported 7-day adherence in predicting suppressed viral load (SVL < 400 copies/mL) and higher CD4% (≥ 25%). Among 159 PHIV youth, 79% were adherent by 7-day recall, and 62, 55, and 48% by PR over 2, 4, and 6 months, respectively. Agreement between 7-day recall and PR adherence was weak (Kappa = 0.09–0.25). In adjusted logistic regression models, adherence showed associations with SVL for 7-day recall (OR 2.78, 95% CI 1.08, 7.15) and all PR coverage periods (6-month: OR 3.24, 95% CI 1.22, 8.65). Similar associations were observed with higher CD4%. PR measures were predictive of study retention. Findings suggest a possibly independent role of PR adherence measures.

Background. Two doses of live-attenuated varicella-zoster vaccine are recommended for human immunodeficiency virus 1 (HIV-1)–infected children with CD4% ≥ 15%. We determined the prevalence and persistence of antibody in immunized children with perinatal HIV (PHIV) and their association with number of vaccinations, combination antiretroviral therapy (cART), and HIV status. Methods. The Adolescent Master Protocol is an observational study of children with PHIV and perinatally HIV-exposed but uninfected (PHEU) children conducted at 15 US sites. In a cross-sectional analysis, we tested participants' most recent stored sera for varicella antibody using whole-cell and glycoprotein enzyme-linked immunosorbent assay. Seropositivity predictors were identified using multivariable logistic regression models and C statistics. Results. Samples were available for 432 children with PHIV and 221 PHEU children; 82% of children with PHIV and 97% of PHEU children were seropositive (P < .001). Seropositivity after 1 vaccine dose among children with PHIV and PHEU children was 100% at <3 years (both), 73% and 100% at 3–<7 years (P < .05), and 77% and 97% at ≥7 years (P < .01), respectively. Seropositivity among recipients of 2 vaccine doses was >94% at all intervals. Independent predictors of seropositivity among children with PHIV were receipt of 2 vaccine doses, receipt of 1 dose while on ≥3 months of cART, compared with none (adjusted odds ratio [aOR]: 14.0 and 2.8, respectively; P < .001 for overall dose effect), and in those vaccinated ≥3 years previously, duration of cART (aOR: 1.29 per year increase, P = .02). Conclusions. Humoral immune responses to varicella vaccine are best achieved when children with PHIV receive their first dose ≥3 months after cART initiation and maintained by completion of the 2-dose series and long-term cART use.

Since 1994, the US Department of Health and Human Services has published treatment guidelines for pregnant women living with HIV. Understanding how well prescribing patterns correspond with treatment guidelines could inform health policy and influence future clinical practice. To compare antiretroviral prescribing practices over time among pregnant women living with HIV with Department of Health and Human Services treatment guidelines and identify factors associated with receiving recommended regimens. A prospective cohort study of 1582 pregnant women living with HIV were enrolled in the Pediatric HIV/AIDS Cohort Study Surveillance Monitoring of ART (antiretroviral therapy) Toxicities study between January 1, 2008, and June 30, 2017. The study was conducted at 18 academic research hospitals in the United States. Antiretroviral medications (ARVs) prescribed during pregnancy. Proportion of regimens prescribed to pregnant women living with HIV qualifying as preferred or alternative according to Department of Health and Human Services guidelines, stratified by timing of initiation. Of 1867 pregnancies (among 1582 pregnant women living with HIV with a mean [SD] age of 28.6 [6.1] years at conception), 1264 (67.7%) occurred among women self-identified as black, 480 (25.7%) self-identified as white, and 123 (6.6%) self-identified as other or unreported race/ethnicity. Antiretroviral medications were initiated prior to conception for 790 women (42.3%), resumed during pregnancy for 625 women (33.5%), and initiated during pregnancy for 452 women (24.2%). Only 925 pregnancies (49.5%) were associated with prescribed ARVs designated as preferred or alternative, while 492 (26.4%) involved ARVs with insufficient evidence for use during pregnancy and 136 (7.3%) involved ARVs that were not recommended during pregnancy. A higher proportion of treatment-naive pregnant women initiating ARVs were prescribed preferred or alternative ARVs compared with those resuming ARVs or those treated with ARVs before conception (316 of 452 [69.9%] vs 325 of 625 [52.0%] vs 284 of 790 [35.9%]; P < .001). A total of 91 of 452 women (20.1%) initiating ARVs during pregnancy were prescribed ARVs with insufficient evidence for use during pregnancy or not recommended during pregnancy. Among women resuming ARVs, those with a viral load greater than 1000 copies/mL early in pregnancy had higher odds of being prescribed guideline-recommended ARVs (adjusted odds ratio, 2.03 [95% CI, 1.33-3.10]) compared with those with a viral load of 400 copies/mL or less. This study suggests that US ARV prescribing practices for pregnant women living with HIV do not align well with national guidelines. This finding is particularly concerning when treatment is initiated during pregnancy. Further research is needed to understand disparities between prescribing practices and evidence-based guideline recommendations.

This action research study explored the use of elaborative rehearsal as an intervention and examined differences in metacognition and test performance among college students in a general psychology course. Metacognitive processes are crucial for adequate comprehension. Students often come into college having very little metacognition, knowledge about different strategies, different cognitive tasks, and sometimes even accurate knowledge about how they learn (Pintrich, 2002). Common metacognition strategies are note-taking, summarizing, finding main ideas, writing to learn, self-questioning, outlining, previewing, reflecting, reciting and reviewing (Kisac & Budak, 2014). Elaborative rehearsal is a metacognitive learning strategy that encompasses many of these components. Unfortunately, at the time this research was conducted there were minimal studies investigating it independently. This paper provides a thorough review of the literature, grounded in the theoretical framework of cognitive constructivism, information processing, and metacognition. The methodologies used were a mixed-method design, incorporating both quantitative and qualitative measures providing an in-depth examination. The results of this study not only provide additional research to the small body of literature currently available for elaborative rehearsal but also offers insight into the use and utility of this learning strategy from the student perspective.