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Background: Angiogenic imbalances, characterized by an excess of antiangiogenic factors (soluble fms-like tyrosine kinase 1) and reduced angiogenic factors (vascular endothelial growth factor and placental growth factor), contribute to the mechanisms of disease in preeclampsia. The ratio of soluble fms-like tyrosine kinase 1 to placental growth factor has been used as a biomarker for preeclampsia, but the cutoff values may vary with gestational age and assay platform., Objective: This study aimed to compare multiples of the median of the maternal plasma soluble fms-like tyrosine kinase 1 to placental growth factor ratio, soluble fms-like tyrosine kinase 1, placental growth factor, and conventional clinical and laboratory values in their ability to predict preeclampsia with severe features., Study Design: We conducted a cohort study across 18 United States centers involving hospitalized individuals with hypertension between 23 and 35 weeks' gestation. Receiver operating characteristic curve analyses of maternal plasma biomarkers, highest systolic or diastolic blood pressures, and laboratory values at enrollment were performed for the prediction of preeclampsia with severe features. The areas under the curve were compared, and quasi-Poisson regression models were fitted to estimate relative risks. The primary outcome was preeclampsia with severe features within 2 weeks of enrollment. Secondary outcomes were a composite of severe adverse maternal outcomes (elevated liver enzymes, low platelets count, placental abruption, eclampsia, disseminated intravascular coagulation, and pulmonary edema) and a composite of severe adverse perinatal outcomes (birth weight below the third percentile, very preterm birth [<32 weeks' gestation], and fetal or neonatal death)., Results: Of the 543 individuals included in the study, preeclampsia with severe features within 2 weeks was observed in 33.1% (n=180) of them. A receiver operating characteristic curve-derived cutoff of 11.5 multiples of the median for the soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio provided good sensitivity (90.6%), specificity (76.9%), positive predictive value (66.0%), negative predictive value (94.3%), positive likelihood ratio (3.91), negative likelihood ratio (0.12), and accuracy (81.4%) for preeclampsia with severe features within 2 weeks. This cutoff was used to compare test positive cases (≥ cutoff) and test negative cases (< cutoff). Preeclampsia with severe features (66.0% vs 5.7%; P<.001) and composites of severe adverse maternal (8.11% vs 2.7%; P=.006) or perinatal (41.3% vs 10.14%; P=.001) outcomes within 2 weeks were more frequent in test positive cases than in test negative cases. A soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio ≥11.5 multiples of the median was independently associated with preeclampsia with severe features (adjusted incidence rate ratio, 9.08; 95% confidence interval, 6.11-14.06; P<.001) and a composite of severe adverse perinatal outcomes (adjusted incidence rate ratio, 9.42; 95% confidence interval, 6.36-14.53; P<.001) but not with a composite of severe adverse maternal outcomes (adjusted incidence rate ratio, 2.20; 95% confidence interval, 0.95-5.54; P=.08). The area under the curve for the soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio in multiples of the median (0.91; 95% confidence interval, 0.89-0.94) for preeclampsia with severe features within 2 weeks was significantly higher (P<.001 for all comparisons) than either plasma biomarker alone or any other parameter with the exception of absolute soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio values., Conclusion: A soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio ≥11.5 multiples of the mean among hospitalized patients with hypertension between 23 and 35 week's gestation predicts progression to preeclampsia with severe features and severe adverse perinatal outcomes within 2 weeks., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Pre-exposure prophylaxis (PrEP) utilization among cisgender women (subsequently 'women') is low across age groups, relative to their risk of HIV acquisition. We hypothesize that age-related differences in psychosocial factors also influence women's intention to initiate oral PrEP in Washington, D.C., Methods: A secondary analysis of a cross-sectional survey data was performed to evaluate factors influencing intention to initiate oral PrEP among women seen at a family planning and a sexual health clinic. A bivariate analysis was performed to identify differences by age group in demographic characteristics, indications for PrEP, and attitudes toward PrEP; we then performed additional bivariate analysis to assess these variables in relation to PrEP intention., Results: Across age groups, perceived risk of HIV acquisition was not significantly different and was not associated with intention to initiate PrEP. Awareness of and attitude toward PrEP, injunctive norms, descriptive norms, and self-efficacy were not different across age, however there were significant age-associated differences in relation to PrEP intention. Specifically, among 18-24-year-olds, intention to start PrEP was associated with support from provider ( p  = 0.03), main sexual partner ( p  < 0.01), and peers ( p  < 0.01). For women 25-34 years old, having multiple sexual partners ( p  = 0.03) and support from casual sexual partners ( p  = 0.03) was also important. Among women 35-44 years old, prior awareness of PrEP ( p  = 0.02) and their children's support of PrEP uptake ( p  < 0.01) were associated with intention to initiate PrEP. Among 45-55 year-old women intention to initiate PrEP was positively associated with engaging in casual sex ( p  = 0.03) and negatively associated with stigma ( p  < 0.01)., Conclusion: Overall, there were more similarities than differences in factors influencing intention to initiate PrEP across age groups. Observed differences offer an opportunity to tailor PrEP delivery and HIV prevention interventions to increase awareness and uptake for cisgender women., (© The Author(s), 2024.)

Pre-exposure prophylaxis (PrEP) is a highly effective daily pill that decreases the likelihood of HIV acquisition by up to 92% among individuals at risk for HIV. PrEP can be discretely used, autonomously controlled, and in place at the time of risk exposure, making it an especially promising method for HIV prevention for cisgender women (CGW). But, PrEP is underutilized by CGW relative to the demonstrable need. We apply the Integrative Model of Behavioral Prediction to identify the critical psychosocial factors that shape CGW's intentions to use PrEP and their relevant underlying beliefs. We surveyed (N = 294) community- and clinic-recruited PrEP eligible CGW to understand the relative importance of attitudes, norms, and efficacy in shaping PrEP intentions. We utilized structural equation modeling to identify the relevant paths. We inspected the summary statistics in relation to three message three selection criteria. We identified beliefs that demonstrated (1) an association with intention, (2) substantial room to move the population, (3) practicality as a target for change through communication intervention. Results show that PrEP awareness was low. When women learned about PrEP, they voiced positive intentions to use it. There were significant and positive direct effects of SE (0.316***), attitudes (0.201**), and subjective norms (0.249***) on intention to initiate PrEP. We illustrate the strategic identification of beliefs within the relevant paths using the 3 belief selection criteria. We also discuss implications for social and structural communication interventions to support women's HIV prevention.

Objective: To evaluate upward-adjustment of tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) pre-exposure prophylaxis (PrEP) dosing during pregnancy in order to maintain target plasma concentrations associated with HIV protection., Design: Population pharmacokinetic (PK) modeling and clinical trial simulation (CTS)., Material and Methods: We developed population pharmacokinetic models for TFV and FTC using data from the Partners Demonstration Project and a PK study of TDF/FTC among cisgender women by Coleman et al., and performed an in-silico simulation. Pregnancy-trimester was identified as a significant covariate on apparent clearance in the optimized final model. We simulated 1,000 pregnant individuals starting standard daily oral TDF/FTC (300 mg/200 mg) prior to pregnancy. Upon becoming pregnant, simulated patients were split into two study arms: one continuing standard-dose and the other receiving double standard-dose throughout pregnancy., Results: Standard-dose trough TFV concentrations were significantly lower in pregnancy compared to pre-pregnancy, with 34.0%, 43.8%, and 65.1% of trough plasma concentrations below the lower bound of expected trough concentrations presumed to be the protective threshold in the 1st, 2nd, and 3rd trimesters, respectively. By comparison, in the simulated double-dose group, 10.7%, 14.4%, and 27.8% of trough concentrations fell below the estimated protective thresholds in the 1st, 2nd, and 3rd trimesters, respectively. The FTC trough plasma concentration during pregnancy was also lower than pre-pregnancy, with 45.2% of the steady-state trough concentrations below the estimated protective trough concentrations of FTC. In the pregnancy-adjusted double-dose group, 24.1% of trough plasma concentrations were lower than protective levels., Conclusions: Our simulation shows >50% of research participants on standard dosing would have 3rd trimester trough plasma TFV concentrations below levels associated with protection. This simulation provides the quantitative basis for the design of prospective TDF/FTC studies during pregnancy to evaluate the safety and appropriateness of pregnancy-adjusted dosing., Competing Interests: CH holds two patents related to HIV prevention and is founder of Prionde Biopharma, LLC, an HIV prevention product company. RB serves as a consultant for Advanced Bioscience Laboratories (NIAID). RS is the recipient of grant funding from Gilead Sciences, Inc. and ViV Healthcare, managed by MedStar Health. MM is the recipient of grant funding from Gilead Sciences, Inc. and Merck. CH is the recipient of grant funding from Gilead Sciences, Inc. and Merck. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Scott, Yu, Marzinke, Coleman, Hendrix and Bies.)

Objective: Our objective was to identify the individual, interpersonal, community, health-system, and structural factors that influence HIV pre-exposure prophylaxis (PrEP) initiation among cisgender women seeking sexual and reproductive health care in a high HIV prevalence community to inform future clinic-based PrEP interventions., Methods: We collected anonymous, tablet-based questionnaires from a convenience sample of cisgender women in family planning and sexual health clinics in the District of Columbia. The survey used the lens of the socio-ecological model to measure individual, interpersonal, community, institutional, and structural factors surrounding intention to initiate PrEP. The survey queried demographics, behavioral exposure to HIV, perceived risk of HIV acquisition, a priori awareness of PrEP, intention to initiate PrEP, and factors influencing intention to initiate PrEP., Results: A total of 1437 cisgender women completed the survey. By socio-ecological level, intention to initiate PrEP was associated with positive attitudes toward PrEP (odds ratio [OR], 1.56; 95% confidence interval [CI], 1.13-2.15) and higher self-efficacy (OR, 1.32; 95% CI, 1.02-1.72) on the individual level, perceived future utilization of PrEP among peers and low fear of shame/stigma (OR, 1.65; 95% CI, 1.33-2.04) on the community level, and having discussed PrEP with a provider (OR. 2.39; 95% CI, 1.20-4.75) on the institutional level., Conclusion: Our findings highlight the importance of multilevel, clinic-based interventions for cisgender women, which promote sex-positive and preventive PrEP messaging, peer navigation to destigmatize PrEP, and education and support for women's health medical providers in the provision of PrEP services for cisgender women., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

To test the hypothesis that implementation of a multicomponent, educational HIV pre-exposure prophylaxis (PrEP) intervention to promote universal PrEP services for cisgender women (subsequently "women") in sexual and reproductive health centers would improve the proportion of women screened, offered, and prescribed PrEP, we implemented a multicomponent, educational intervention in a Washington D.C. Department of Health-sponsored sexual health clinic. The clinic serves a patient population with high-potential exposure to HIV. The intervention included clinic-wide PrEP trainings, an electronic health record prompt for PrEP counseling by providers, and educational videos in the waiting room. We collected preimplementation data from March 22, 2018 to July 4, 2018, including 331 clinical encounters for 329 women. Between July 5, 2018 and July 1, 2019, there were 1733 clinical encounters for 1720 HIV-negative women. We used mixed methods to systematically assess intervention implementation using the Reach Effectiveness Adoption Implementation Maintenance framework. Additionally, we assessed the interventions' acceptability and feasibility among providers through semistructured interviews. The proportion of women screened by providers for PrEP (5.6% preimplementation to a mean of 89.2% of women during the implementation period, p  < 0.01), offered (6.2 to 69.8%, p  < 0.01), and prescribed PrEP (2.6 to 8.1%, p  < 0.01) by providers increased significantly in the implementation period. Providers and clinic staff found the intervention both highly feasible and acceptable and demonstrated increased knowledge of PrEP and HIV prevention associated with the clinic-wide trainings. Our results demonstrate the effectiveness of a low-cost educational intervention to increase provision of integrated PrEP services in an urban sexual health clinic serving women with high-potential exposure to HIV. ClinicalTrials.gov ID NCT03705663.

Pharmacokinetic (PK) studies in pregnant, postpartum, and breastfeeding people are critical to informing appropriate medication use and dosing. A key component of translating PK results in these complex populations into clinical practice involves the systematic review and interpretation of data by guideline panels, composed of clinicians, scientists, and community members, to leverage available data for informed decision making by clinicians and patients and offer clinical best practices. Interpretation of PK data in pregnancy involves evaluation of multiple factors such as the study design, target population, and type of sampling performed. Assessments of fetal and infant drug exposure while in utero or during breastfeeding, respectively, are also critical for informing whether medications are safe to use during pregnancy and throughout postpartum in lactating people. This review will provide an overview of this translational process, discussion of the various factors considered by guideline panels, and practical aspects of implementing certain recommendations, using the HIV field as an example., (© 2023, The American College of Clinical Pharmacology.)

The Supreme Court decision in Dobbs v. Jackson in June 2022 reversed precedent which had previously protected abortion prior to fetal viability as a universal right within the United States. This decision almost immediately led to abortion restrictions across 25 states. The resulting lack of access to abortion care for millions of pregnant people will have profound physical and mental health consequences, the full effects of which will not be realized for years to come. Approximately 1 in 5 women access abortions in the U.S. each year. These women are diverse and represent all American groups. The Supreme court decision, however, will affect populations that have and continue to be marginalized the most. Forcing pregnant individuals to carry unwanted pregnancies worsens health outcomes and mortality risk for both the perinatal individual and the offspring. The US has one of the highest maternal mortality rates and this rate is projected to increase with abortion bans. Abortion policies also interfere with appropriate medical care of pregnant people leading to less safe pregnancies for all. Beyond the physical morbidity, the psychological sequelae of carrying a forced pregnancy to term will lead to an even greater burden of maternal mental illness, exacerbating the already existing maternal mental health crisis. This perspective piece reviews the current evidence of abortion denial on women's mental health and care. Based on the current evidence, we discuss the clinical, educational, societal, research, and policy implications of the Dobbs v. Jackson Supreme Court decision., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Londoño Tobón, McNicholas, Clare, Ireland, Payne, Moore Simas, Scott, Becker and Byatt.)

Intramuscular injection of long-acting cabotegravir and rilpivirine is a novel, long-acting antiretroviral therapy (ART) combination approved for use as a fully suppressive regimen for people living with HIV. Long-acting cabotegravir with rilpivirine ART has reduced required dosing frequency from once daily to once every month or every 2 months injections. This new era of long-acting ART, which includes other antiretrovirals and formulations in various stages of clinical development, holds tremendous promise to change the standard of HIV treatment. Although long-acting ART has high potential to be revolutionary in the landscape of HIV care, prevention, and treatment cascade, more data are needed to substantiate its efficacy and cost-effectiveness among patients at risk of non-adherence and across age groups, pregnancy, and post partum. Advocacy efforts and policy changes to optimise a sustained, high-quality, equitable reach of long-acting ART, especially in low-income and middle-income countries where most people living with HIV reside, are needed to realise the full benefits of long-acting ART., Competing Interests: Declaration of interests RKS reports investigator-sponsored research awards from Gilead Science and ViiV Healthcare; and awards managed by MedStar Health Research Institute. KKS reports investigator-initiated research funding paid to her institution from Organon. LMM reports funding from ViiV Healthcare provided to the Elizabeth Glaser Pediatric AIDS Foundation for a birth outcomes surveillance project in Eswatini; and serving as a paid consultant to WHO on the safety of antiretroviral drugs in pregnancy. JWM is a consultant to Gilead Sciences and a grant recipient from Gilead Sciences to the University of Pittsburgh. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Erikson's theory of psychosocial development defines generativity as the drive to benefit future generations and leave a legacy. Generativity has been shown to predict life satisfaction, but generative concern and action can be impacted by factors such as perceived respect from younger generations. This study utilized caregiving grandparents aged 40 and older to assess the extent to which perceived respect mediated the relation between generativity and life satisfaction. Perceived respect from a grandchild mediated the relation between generative concern expressed by caregiving grandparents and life satisfaction after controlling for demographic variables that have been shown to influence heterogeneity and overall well-being in caregiving grandparent samples. These findings suggest that the relation between life satisfaction and generativity in grandparents may depend, in part, on perceived respect from grandchildren, intimating that the implications of generativity may be influenced by the perceived appreciation of its recipients.

HIV remains a significant public health concern in the United States, with 34,800 new cases diagnosed in 2019; of those, 18% were among women. Oral pre-exposure prophylaxis (PrEP) with daily tenofovir disoproxil fumarate/emtricitabine is effective and safe, reducing HIV transmission by up to 92% in women. Though studies demonstrate low rates of PrEP adherence among cisgender women prescribed oral PrEP, little is known about the factors that shape PrEP continuation among them. This study focuses on understanding the experiences of cisgender women who have initiated PrEP to gain insight into the factors that shape PrEP continuation. We conducted semi-structured interviews with ( N  = 20) women who had been prescribed oral PrEP. Interviews were guided by the social-ecological framework to identify multilevel factors affecting PrEP continuation; we specifically examined the experience of engagement and retention in the PrEP cascade. We recruited women who had been prescribed oral PrEP by a government-sponsored sexual health center or a hospital-based family planning clinic in Washington, DC. Factors facilitating PrEP continuation included a positive emotional experience associated with PrEP use, high perceived risk of HIV acquisition, and high-quality communication with health care providers. The most common reason for PrEP discontinuation was low perceived HIV risk ( n  = 11). Other factors influencing discontinuation were side effects, a negative emotional experience while using PrEP, and negative interactions with the health care system. This study underscores the importance of specific multi-level factors, including the provision of high-quality communication designed to resonate with women and shared decision making between women and their health care providers.

Objectives: To assess the analgesic efficacy of preoperative gabapentin among patients undergoing dilation and evacuation (D&E) with moderate sedation., Study Design: We conducted a randomized, controlled, double-blind trial among patients undergoing same-day D&E at 14 to 19 weeks gestation under moderate sedation. We randomized participants 1:1 to gabapentin 600 mg or placebo after cervical preparation at least 1 hour prior to D&E. We assessed pain using a 100-mm visual analog scale before, during, and after the procedure. The primary outcome was postoperative recall of maximum procedural pain with a 13-mm a priori threshold for clinical significance. We standardized initial fentanyl and midazolam dosing. We assessed satisfaction with pain control, nausea, and vomiting via Likert scales and anxiety using a validated instrument., Results: We enrolled 126 participants and randomized 61 to gabapentin and 65 to placebo, with study medication administered a mean of 211 (SD 64) minutes preoperatively. Recall of maximum pain was 41 mm for gabapentin and 49 mm for placebo (p = 0.24). Gabapentin resulted in reduced pain during uterine aspiration (56 vs 71 mm, p= 0.003) compared to placebo, but not for any other time points. The gabapentin group had higher satisfaction (78% vs 65% very or somewhat satisfied, p= 0.01). Median fentanyl dose was lower in the gabapentin group (75 vs 100 mcg, p = 0.005). Midazolam dose, nausea, vomiting, and anxiety did not differ between groups. No serious adverse events occurred in the gabapentin group. Sedation reversal was not required., Conclusions: The addition of gabapentin to moderate sedation during D&E did not result in lower maximum recalled procedural pain. Gabapentin resulted in reduced intra-operative pain during uterine aspiration and increased satisfaction with pain control., Implications: Gabapentin reduces intraoperative pain and improves satisfaction with pain management when administered prior to second-trimester surgical abortion and may be considered as an adjunct to intravenous sedation. Moderate sedation may impair assessment and recall of pain. Additional research is needed to identify the most effective pain management regimens for D&E., (Copyright © 2022. Published by Elsevier Inc.)

BACKGROUND: Among women with hypertensive disorders of pregnancy, biomarkers may stratify risk for developing preeclampsia with severe features (sPE). METHODS: Across 18 U.S. centers, we prospectively measured the ratio of serum soluble fms-like tyrosine kinase 1 (sFlt-1) to placental growth factor (PlGF) in pregnant women hospitalized between 23 and 35 weeks of gestation. The primary outcome was predicting sPE, and secondary outcomes included predicting adverse outcomes within 2 weeks. The prognostic performance of the sFlt-1:PlGF ratio was assessed by using a derivation/validation design. RESULTS: A total of 1014 pregnant women were evaluated; 299 were included in the derivation cohort and 715 in the validation cohort. In the derivation cohort, the median sFlt-1:PlGF ratio was 200 (interquartile range, 53 to 458) among women who developed sPE compared with 6 (interquartile range, 3 to 26) in those who did not (P<0.001). The discriminatory ratio of ≥40 was then tested in the validation cohort and yielded a 65% positive (95% confidence interval [CI], 59 to 71) and a 96% negative (95% CI, 93 to 98) predictive value for the primary outcome. The ratio performed better than standard clinical measures (area under the receiver-operating characteristic curve, 0.92 versus <0.75 for standard-of-care tests). Compared with women with a ratio <40, women with a ratio ≥40 were at higher risk for adverse maternal outcomes (16.1% versus 2.8%; relative risk, 5.8; 95% CI, 2.8 to 12.2). CONCLUSIONS: In women with a hypertensive disorder of pregnancy presenting between 23 and 35 weeks of gestation, measurement of serum sFlt-1:PlGF provided stratification of the risk of progressing to sPE within the coming fortnight. (Funded by Cedars-Sinai Medical Center and Thermo Fisher Scientific; ClinicalTrials.gov NCT03815110.)

The rate at which children are raised in kincare has steadily been on the rise. Prior research indicates that this group of individuals are at an increased risk of mental health problems. The current study examined the suicidality and depressive symptoms of adults who were raised in kincare compared to those raised by their parents. There were a total of 1,486 participants, 171 of whom were adults raised in kincare, and 1,315 who were raised by one or both of their parents. Participants completed a measure of suicide risk and reported symptoms of depression and anhedonia.Those raised in kincare scored significantly higher on the measures of anhedonia and suicide risk. However, there were no differences in general depressive symptoms. Further analyses found that more frequent attendance of religious activities and higher levels of household income acted as protective factors. These findings suggest kincare is associated with adverse mental health outcomes.

Background: We have a limited understanding on how to best integrate technologies to support antiretroviral therapy (ART) adherence in routine HIV care., Methods: We conducted semi-structured interviews with multidisciplinary providers caring for pregnant and postpartum people with HIV and asked providers about their perspectives on utilizing adherence support technologies such as text messages, video check-ins with providers or automated with facial recognition for directly-observed-therapy, signaling pill bottle, and signaling pill to support ART adherence. Each approach generated an adherence report. The interview instrument was guided by the Consolidated Framework for Implementation Research and included questions on the implementation climate, barriers, and facilitators to the clinical integration of the adherence approach and strategies that could be used to maximize this integration. The order of adherence support technologies was randomized to minimize bias. We used a modified grounded theory to develop the coding structure and two coders applied the codebook to the transcripts after establishing strong inter-rater reliability with 20% of interviews (kappa = 0.82)., Results: Between March and December 2020, we conducted 26 in-depth, semi-structured interviews with providers who weighed several factors when considering each approach, including the approach's effect on patient-provider interaction in and outside of the clinic visit, timing for and duration of the approach's utility, threat of disclosing status, and added burden to providers (e.g., needing to act on generated information) or to patients (e.g., needing to hide the signaling pills, responding to text messages). Providers' most preferred approach was text-messages, and the least preferred was the signaling pill. Barriers to acceptability varied by approach and included perceived surveillance, violation of privacy, added time demand for providers, potential inaccuracy of the adherence data generated, and negative impact on the patient-provider relationship, particularly if the approach was perceived as coercive. Payers anticipated regulatory hurdles with unfamiliar approaches, particularly the signaling pill and signaling pill bottle. Facilitators included strengthened therapeutic alliance, predictable reminder mechanisms, and options for customization according to patient preference., Conclusions: Our study elucidates barriers and facilitators to integrating technology-based adherence support approaches in clinical care to support adherence of pregnant and postpartum people with HIV., (© 2022. The Author(s).)

Pre-exposure prophylaxis (PrEP) for HIV prevention is underutilized by cisgender women at risk for HIV in the USA. Published research on PrEP initiation among cisgender women at risk for HIV focuses on identifying barriers and facilitators associated with intention to initiate, but few apply a behavioral theoretical lens to understand the relative importance of these diverse factors. This study provides a theoretically grounded view of the relative importance of factors associated with intention to initiate PrEP. We conducted an anonymous, cross-sectional survey of 1437 cisgender women seeking care at family planning and sexual health clinics to evaluate hypothesized barriers and facilitators of PrEP initiation. We categorized cisgender women with ≥ 3 behavioral risk-factors as "high-risk" for HIV acquisition; 26.9% (N = 387) met high-risk criterion. Among cisgender women in the high-risk sample, the majority were Black and single. Perceived risk of HIV acquisition was low and 13.7% reported intention to initiate PrEP. Positive attitudes toward PrEP, self-efficacy, perceived support from medical providers and social networks, and prior discussion about PrEP with medical providers were associated with intention to initiate PrEP; stigma was negatively associated. Background characteristics (other than age), risk factors for HIV acquisition, prior awareness of PrEP, and perceived risk of HIV were not associated with uptake intention. These findings support interventions that center on the role of providers in the provision of PrEP and on social networks in destigmatization of PrEP use., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

It is unknown whether antiretroviral (ARV) drugs in women living with HIV (WLHIV) are associated with mitochondrial toxicity and altered fat oxidation and branched-chain amino acid metabolism in the placenta and fetus. Immediately after delivery, we froze placental biopsies from 20 WLHIV and 20 matched uninfected women. We analyzed global biochemical profiles using high-performance liquid chromatography/tandem mass spectrometry and gas chromatography/mass spectrometry. We used t -tests, principle component analysis, hierarchical clustering, and random forest analysis (RFA) in our analysis. Twelve WLHIV were on protease inhibitors, six on non-nucleoside reverse inhibitors, and two on integrase strand inhibitors with optimized backbone. Mean birth weight of HIV-exposed neonates was significantly lower than unexposed neonates (3,075 g vs. 3,498 g, p  = .01) at similar gestational age. RFA identified 30 of 702 analytes that differentiated the placental profiles of WLHIV from uninfected women with 72.5% predictive accuracy. Placental profiles of non-nucleoside reverse transcriptase inhibitor (NNRTI)-treated WLHIV exhibited lower levels of amino acids, including essential and branched-chain amino acids, and some medium-chain acylcarnitines. Placental metabolism may be altered in WLHIV, possibly associated with ARV exposure. The lower birth weight among neonates of WLHIV suggests the need for further studies considering potential deleterious effects of altered placenta metabolism on fetal growth and development.

HIV prevention is critically important during pregnancy, however, pre-exposure prophylaxis (PrEP) is underutilized. We conducted a survey of pregnant and non-pregnant women in a high HIV prevalence community in Washington D.C. to evaluate determinants of PrEP initiation during pregnancy. 201 pregnant women and a reference population of 1103 non-pregnant women completed the survey. Among pregnant women, mean age was 26.9 years; the majority were Black with household-incomes below the federal poverty level. Despite low perceived risk of HIV acquisition and low prior awareness of PrEP, 10.5% of respondents planned to initiate PrEP during pregnancy. Pregnant women identified safety, efficacy, and social network and medical provider support as key factors in PrEP uptake intention. The belief that PrEP will "protect (their) baby from HIV" was associated with PrEP uptake intention during pregnancy. Concerns regarding maternal/fetal side effects, and safety in pregnancy or while breastfeeding were not identified as deterrents to uptake intention. When compared to a nonpregnant sample, there were no significant differences in uptake intention between the two samples. These findings support the need for prenatal educational interventions to promote HIV prevention during pregnancy, as well as interventions that center on the role of providers in the provision of PrEP.

Background: Despite their disparately high HIV incidence and voiced willingness to use pre-exposure prophylaxis (PrEP), Black cisgender women's knowledge and uptake of PrEP are low, especially relative to White cisgender women and men who have sex with men. Mounting evidence demonstrates that health care provider recommendations are a critical factor in women's awareness, willingness, and ability to uptake PrEP. Health care providers may make clinical judgments about who is (not) a good candidate for PrEP based on unconscious and conscious stereotypes and prejudice., Setting: We conducted an online experiment among N = 160 health care providers with prescribing privileges in the 48 HIV hotspot counties., Method: Providers received 1 of 4 vignettes about a PrEP eligible woman. Vignettes varied by patient race and substance use status. Then, providers reported their willingness to discuss PrEP with the patient and willingness to prescribe PrEP to her., Results: We tested 2 models predicting providers (1) willingness to discuss and (2) willingness to prescribe PrEP, contingent on their racial attitudes. Providers who scored high on a modern racism measure were less willing to discuss and prescribe PrEP to the Black patient. These effects were mediated by provider perceptions of patients' abilities to adhere to PrEP, but not their expectations of risk compensatory behaviors., Conclusions: Our findings highlight the importance of applying an intersectional lens in documenting the processes that exacerbate inequities in PrEP use. This study provides evidence to support the development of interventions that address the mechanisms that work to thwart optimal care., Competing Interests: The authors gratefully acknowledge the contributions of the Center for AIDS Prevention Studies, University of California, San Francisco (NIH Grant R25 DA028567) in facilitating the completion of the work described in this manuscript. This research has also been facilitated by the services and resources provided by the District of Columbia Center for AIDS Research, an NIH funded program (P30AI117970), which is supported by the following NIH co-funding and participating institutes and centers: NIAID, NCI, NICHD, NHLBI, NIDA, NIMH, NIA, NIDDK, NIMHD, NIDCR, NINR, FIC, and OAR. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. S.J.H and R.K.S. recently completed an investigator initiated award from Gilead Sciences to study the PrEP cascade among cisgender women (ISR-US-17-10270). Hull received consulting renumeration from Gilead Sciences in 2018. The remaining authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Despite clinicians consistently advising against vaginal douching, 29-92% of women worldwide report douching. This review documents women's douching practices, motivations for douching, and specific associations (or absence of associations) between vaginal douche use and vaginal outcomes thought to be associated with douching. Understanding women's existing douching behaviors and vaginal health outcomes is critical for developing a safe vaginal microbicide douche that can be used as HIV pre-exposure prophylaxis (PrEP). A vaginal douche as PrEP could help prevent new HIV infections, since emerging evidence shows some women discontinue oral PrEP. We performed a systematic review of the literature using the guidelines for Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA). Articles included in the analysis (N = 48) were published 2009-2019 in English and focused on women's experiences with douching. Two trained independent reviewers assessed these articles for content on vaginal douching, including racial/ethnic focus of studies, study design, sampling, women's reasons for douching, contents of douche solutions, and associations between vaginal douching and vaginal health outcomes. Several studies focused on Black women (N = 12 studies) or had no racial/ethnic focus (N = 12). Just over half of all studies (N = 24) were cross-sectional and involved a self-reported questionnaire and lab samples. Studies sampled women from health clinics where they were (N = 13) or were not (N = 14) presenting for vaginal health complaints. Women's primary motivation for douching was for "general cleanliness" (N = 13), and most douche solutions contained water (N = 12). There was little empirical agreement between vaginal douche use and most vaginal health outcomes. Future studies of PrEP vaginal douches should be well controlled and prioritize safety to ensure positive vaginal health outcomes., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: We examined factors influencing end-of-life care preferences among persons living with HIV (PLWH)., Methods: 223 PLWH were enrolled from 5 hospital-based clinics in Washington, DC. They completed an end-of-life care survey at baseline of the FACE™-HIV Advance Care Planning clinical trial., Findings: The average age of patients was 51 years. 56% were male, 66% heterosexual, and 86% African American. Two distinct groups of patients were identified with respect to end-of-life care preferences: (1) a Relational class (75%) who prioritized family and friends, comfort from church services, and comfort from persons at the end-of-life; and (2) a Transactional/Self-Determination class (25%) who prioritized honest answers from their doctors, and advance care plans over relationships. African Americans had 3x the odds of being in the Relational class versus the Transactional/Self-determination class, Odds ratio = 3.30 (95% CI, 1.09, 10.03), p = 0.035. Males were significantly less likely to be in the relational latent class, Odds ratio = 0.38 (CI, 0.15, 0.98), p = 0.045. Compared to non-African-Americans, African-American PLWH rated the following as important: only taking pain medicines when pain is severe, p = 0.0113; saving larger doses for worse pain, p = 0.0067; and dying in the hospital, p = 0.0285. PLWH who were sexual minorities were more afraid of dying alone, p = 0.0397, and less likely to only take pain medicines when pain is severe, p = 0.0091., Conclusion: Integrating culturally-sensitive palliative care services as a component of the HIV care continuum may improve health equity and person-centered care.

Context: The effect of advance care planning (ACP) interventions on the trajectory of end-of-life treatment preference congruence between patients and surrogate decision-makers is unstudied., Objective: To identify unobserved distinctive patterns of congruence trajectories and examine how the typology of outcome development differed between ACP and controls., Methods: Multisite, assessor-blinded, intent-to-treat, randomized clinical trial enrolled participants between October 2013 to March 2017 from 5 hospital-based HIV clinics. Persons living with HIV(PLWH)/surrogate dyads were randomized to 2 weekly 60-minute sessions: ACP (1) ACP facilitated conversation, (2) advance directive completion; or Control (1) Developmental/relationship history, (2) Nutrition/Exercise. Growth Mixed Modeling was used for 18-month post-intervention analysis., Findings: 223 dyads (N = 449 participants) were enrolled. PLWH were 56% male, aged 22 to 77 years, and 86% African American. Surrogates were 56% female, aged 18 to 82 years, and 84% African American. Two latent classes (High vs. Low) of congruence growth trajectory were identified. ACP influenced the trajectory of outcome growth (congruence in all 5 AIDS related situations) by latent class. ACP dyads had a significantly higher probability of being in the High Congruence latent class compared to controls (52%, 75/144 dyads versus 27%, 17/62 dyads, p = 0.001). The probabilities of perfect congruence diminished at 3-months post-intervention but was then sustained. ACP had a significant effect (β = 1.92, p = 0.006, OR = 7.10, 95%C.I.: 1.729, 26.897) on the odds of being in the High Congruence class., Conclusion: ACP had a significant effect on the trajectory of congruence growth over time. ACP dyads had 7 times the odds of congruence, compared to controls. Three-months post-intervention is optimal for booster sessions.

Objective: To evaluate the uptake of perinatal HIV preventive interventions by the risk of perinatal HIV transmission in mother-infant pairs in a high-HIV prevalence area in the US., Study Design: This was a retrospective cohort study of mother-infant pairs with perinatal HIV exposure during 2013-2017 managed at a subspecialty pediatric HIV program in Washington, DC. We collected demographic data, maternal HIV history, delivery mode, maternal and infant antiretroviral drug (ARV) use, and infant HIV test results. We compared the uptake of recommended preventive interventions in low-risk (ie, mothers on antiretroviral therapy [ART] with viral suppression) and high-risk (mothers without ART or viral suppression) mother-infant pairs using the Pearson chi-square, Fisher exact, and Wilcoxon rank-sum tests and logistic regression., Results: We analyzed 551 HIV-exposed infants (HEIs) and 542 mothers living with HIV. The majority of mothers received ARVs (95.5%), had HIV RNA ≤1000 copies/mL before delivery (81.9%), and received intrapartum zidovudine (ZDV; 65.5%). The majority of all HEIs were low risk (82.6%) and received postpartum ARVs (98.9%). Among the low-risk infants, 53.2% were delivered via cesarean delivery (CD), and 62.9% and 96.5% were administered intrapartum and postpartum ZDV, respectively. Among high-risk infants, 84.4% were delivered via CD, 78.1% received intrapartum ZDV, and 62.5% received combination ART. Nine high-risk infants acquired HIV perinatally., Conclusion: In an area of high HIV prevalence in the US, a large proportion of low-risk HEIs received intrapartum ZDV and were delivered via CD. We also observed missed opportunities for the prevention of perinatal HIV transmission., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Trial tested effect of advance care planning on family/surrogates' understanding of patients' end-of-life treatment preferences longitudinally. A multisite, assessor-blinded, intent-to-treat, parallel-group, randomized controlled clinical trial in five hospital-based HIV clinics enrolled 449 participants aged 22 to 77 years during October 2013-March 2017. Patients living with HIV/family dyads were randomized at 2:1 ratio to 2 weekly ~ 60-min sessions either ACP (n = 155 dyads)-(1) ACP facilitated conversation, (2) Advance directive completion; or Control (n = 68 dyads)-(1) Developmental/relationship history, (2) Nutrition/exercise tips. ACP families/surrogates were more likely to accurately report patients' treatment preferences at Time 1 (T 1 ) and 12 months post-intervention (T 2 ) compared to controls, experiencing high congruence longitudinally (high→high transition), [63·6% vs 37·7% (difference = 25·9%, 95% CI: 11·3%, 40·4%, χ 2  = 11·52, p = 0·01)], even as patients' preferences changed over time. ACP families/surrogates had eight times the odds of controls of having an excellent understanding of patients' treatment preferences (Adjusted Odds Ratio 7.91, 95%CI: 3.08, 20.3). Conversations matter.

We aimed to systematically evaluate the feasibility of integrating HIV prevention services, including pre-exposure prophylaxis (PrEP), into a family planning setting in a high-prevalence community. We used the RE-AIM Framework (Reach, Efficacy, Adoption, Implementation, Maintenance) to evaluate the integration of HIV prevention services into a family planning clinic over 6 months. Before the integration, PrEP was not offered. We implemented a staff training program on HIV PrEP. We determined the proportion of women presenting to the clinic who were screened, eligible for, and initiated PrEP through chart review. We assessed staff comfort with PrEP pre- and post-integration. We compared planned and actual implementation, interviewed staff to determine barriers and facilitators, and tracked systems adaptations. We assessed maintenance of PrEP after the study concluded. There were 640 clinical encounters for 515 patients; the rate of HIV counseling and PrEP screening was 50%. The rate was 10% in month 1 and peaked to 65% in month 3. Nearly all screened patients were eligible for PrEP (98.4%) and 15 patients (6%) initiated PrEP. Staff knowledge and comfort discussing PrEP improved after education. Facilitators included partnering with local experts, continuing education, clinical tools for providers, and patient education materials. Barriers included competing priorities during clinical encounters, limited woman-centered patient education materials, and insurance-related barriers. Embedding HIV prevention services in the family planning setting was feasible in this pilot. The proportion of women screened for PrEP rapidly increased. In this high HIV prevalence community, nearly all screened women were eligible and 6% initiated PrEP.

Context: No prospective studies address disease-specific advance care planning (ACP) for adults living with HIV/AIDS., Objective: To examine the efficacy of FAmily-CEntered (FACE) ACP in increasing ACP and advance directive documentation in the medical record., Methods: Longitudinal, two-arm, randomized controlled trial with intent-to-treat design recruited from five hospital-based outpatient HIV clinics in Washington, DC. Adults living with HIV and their surrogate decision-makers (N = 233 dyads) were randomized to either an intensive facilitated two-session FACE ACP (Next Steps: Respecting Choices goals of care conversation and Five Wishes advance directive) or healthy living control (conversations about developmental/relationship history and nutrition)., Results: Patients (n = 223) mean age: 51 years, 56% male, 86% African-American. One hundred ninety-nine dyads participated in the intervention. At baseline, only 13% of patients had an advance directive. Three months after intervention, this increased to 59% for the FACE ACP group versus 17% in the control group (P < 0.0001). Controlling for race, the odds of having an advance directive in the medical record in the FACE ACP group was approximately seven times greater than controls (adjusted odds ratio = 6.58, 95% CI: 3.21-13.51, P < 0.0001). Among African-Americans randomized to FACE, 58% had completed/documented advance directives versus 20% of controls (P < 0.0001)., Conclusions: The FACE ACP intervention significantly improved ACP completion and advance directive documentation in the medical record among both African-American and non-African-American adults living with HIV in Washington, DC, providing health equity in ACP, which can inform best practices., (Copyright © 2018 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Purpose: Physicians and caregivers rate patient quality of life (QOL) lower than patients rate their own QOL. This study investigated discrepancies between self-assessments of patient QOL by adults with HIV and their surrogate decision-makers., Methods: We collected baseline data from 223 adult dyads in the FAmily-CEntered (FACE) Advance Care Planning (ACP) clinical trial, consisting of HIV positive patients and their chosen surrogates. Participants independently completed the Medical Outcome Study-HIV Survey (MOS-HIV) and the Palliative care Outcome Scale (POS). We used Wilcoxon Signed-Rank Test to assess differences in overall patient-surrogate means. We used Prevalence Adjusted Bias Adjusted Kappa (PABAK) statistics to assess dyadic agreement, with surrogate HIV status and cohabitation status as grouping variables., Results: Patients were 56.1% male, 86.1% Black/African-American, aged 22-77 (mean = 50.83, SD = ± 12.33). Surrogates were 43.8% male, 84.1% Black/African-American, aged 18-82 (mean = 49.73, SD = ± 14.22). 46.2% of surrogates lived with the patient. 64.6% of surrogates reported negative HIV status. Surrogates were more likely to state patients were ill, p = 0.032. Among patient-surrogate dyads, most QOL assessments showed poor (0.00-0.39) or fair (0.40-0.59) agreement and agreement tended to be even poorer among patient-surrogate dyads where the surrogate had a shared HIV diagnosis., Conclusions: QOL discrepancies are said to arise from healthy surrogates overestimating the effects of chronic illness. In this novel assessment, many surrogates had a shared HIV diagnosis, without increased agreement. These findings highlight the challenge of accurately assessing patient QOL by surrogates, even when there is a shared HIV diagnosis. Improved communication is needed between patients and surrogates about the patients' representation of illness. National Clinical Trial Number: NCT01775436.

Objective: To determine the cost-effectiveness of universal maternal HIV screening at time of delivery to decrease mother-to-child transmission (MTCT), by comparing the cost and quality-adjusted life years (QALYs) of universal rapid HIV screening at time of delivery to two current standards of care for prenatal HIV screening in the United States., Study Design: We conducted a cost-effectiveness analysis to compare the cost and QALY of universal intrapartum rapid HIV screening with two current standards of care: (I) opt-out rapid HIV testing limited to patients without previous third-trimester screening and (II) opt-out rapid HIV testing limited to patients without any prenatal screening. We developed a decision-tree model and performed sensitivity analyses to estimate the impact of variances in QALY, estimated lifetime medical costs, HIV prevalence, and cumulative incidence., Results: The incremental cost-effectiveness ratio for universal screening was $7,973.45/QALY. The results remained robust to sensitivity analysis, except for annual cumulative incidence. In areas with an annual cumulative incidence rate of <0.02% for reproductive-age women, the incremental cost-effectiveness ratio for the expanded program would exceed $89,926.94/QALY, approaching the commonly applied cost-effectiveness thresholds ($100,000/QALY)., Conclusions: Intrapartum universal rapid HIV screening to decrease MTCT appears cost-effective in populations with high HIV incidence in the United States.

Background: A case of mother to child transmission (MTCT) of HIV at a medical center in Washington, DC, resulted in the implementation of universal opt-out rapid testing of patients admitted for delivery. This article evaluates the policy's efficacy and implementation., Methods: We evaluated the implementation using the Reach, Efficacy, Adoption, Implementation, and Maintenance (RE-AIM) framework., Results: We could not evaluate decrease in MTCT rate secondary to low sample size ( n  = 3324) and no true-positive results. Patients not tested ( n  = 458) were predominately secondary to physician omission (93.7%) and were more likely to be White ( p  < 0.01) and older ( p  < 0.01). There was a negative relationship with physician omission over time., Conclusion: The policy was successfully implemented with decreasing proportions of patients not tested. Earlier inclusion of testing into standard admission orders and nurse-based approach may have expedited adoption. Given the low incidence of new HIV diagnosis in labor, we were unable to assess decrease in MTCT., Competing Interests: Conflict of interest statement: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: To evaluate whether there is increased mother-to-child transmission of human immunodeficiency virus (HIV)-1 associated with deliveries at 40 weeks of estimated gestational age (EGA) or greater in pregnant women with HIV-1 viral loads of 1,000 copies/mL or less., Methods: We performed a secondary analysis of the Eunice Kennedy Shriver National Institute of Child Health and Human Development International Site Development Initiative Perinatal and Longitudinal Study in Latin American Countries and International Maternal Pediatric Adolescent AIDS Clinical Trials P1025 cohorts. We included pregnant women with HIV-1 with recent viral loads of 1,000 copies/mL or less at the time of delivery and compared delivery outcomes at between 38 and less than 40 weeks EGA with delivery outcomes at 40 weeks EGA or greater, the exposure of interest. Our primary outcome of interest was mother-to-child transmission, and secondary outcomes included indicators of maternal and neonatal morbidity. We examined the association between EGA and mother-to-child transmission using Poisson distribution. Associations between EGA and secondary outcomes were examined through bivariate analyses using Pearson χ and Fisher exact test or the nonparametric Mann-Whitney U test., Results: Among the 2,250 eligible neonates, eight neonates were infected with HIV-1 (overall transmission rate 0.4%, 95% CI 0.2-8.1%, 40 weeks EGA or greater 0.5% [3/621, 95% CI 0.2-1.4%], less than 40 weeks EGA 0.3% [5/1,629, 95% CI 0.1-0.7%]); there was no significant difference in transmission by EGA (rate ratio 1.57, 95% CI 0.24-8.09, P=.77). There was no difference in maternal viral load between the two groups nor was there a difference in timing of transmission among neonates born with HIV-1., Conclusion: In pregnant women with well-controlled HIV-1, the risk of mother-to-child transmission did not differ significantly by EGA at delivery, although we were not powered to demonstrate equivalence of proportions of mother-to-child transmission between EGA groups.

Although the human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) has become a chronic illness, disease-specific advance care planning has not yet been evaluated for the palliative care needs of adults with HIV/AIDS. This prospective, longitudinal, randomized, two-arm controlled clinical trial aims to test the efficacy of FAmily CEntered advance care planning among adults living with AIDS and/or HIV with co-morbidities on congruence in treatment preferences, healthcare utilization, and quality of life. The FAmily CEntered intervention arm is two face-to-face sessions with a trained, certified facilitator: Session 1) Disease-Specific Advance Care Planning Respecting Choices Interview; Session 2) Completion of advance directive. The Healthy Living Control arm is: Session 1) Developmental/Relationship History; Session 2) Nutrition. Follow-up data will be collected at 3, 6, 12, and 18 months post-intervention. A total of 288 patient/surrogate dyads will be enrolled from five hospital-based, out-patient clinics in Washington, District of Columbia. Participants will be HIV positive and ≥ 21 years of age; surrogates will be ≥ 18 years of age. Exclusion criteria are homicidality, suicidality, psychosis, and impaired cognitive functioning. We hypothesize that this intervention will enhance patient-centered communication with a surrogate decision-maker about end of life treatment preferences over time, enhance patient quality of life and decrease health care utilization. We further hypothesize that this intervention will decrease health disparities for Blacks in completion of advance directives. If proposed aims are achieved, the benefits of palliative care, particularly increased treatment preferences about end-of-life care and enhanced quality of life, will be extended to people living with AIDS., (Copyright © 2015 Elsevier Inc. All rights reserved.)

We provide numerical evidence for the existence of a cascade of filament instabilities in the surface quasigeostrophic system for rotating, stratified flow near a horizontal boundary. The cascade involves geometrically shrinking spatial and temporal scales and implies the singular collapse of the filament width to zero in a finite time. The numerical method is both spatially and temporally adaptive, permitting the accurate simulation of the evolution over an unprecedented range of spatial scales spanning over ten orders of magnitude. It provides the first convincing demonstration of the cascade, in which the large separation of scales between subsequent instabilities has made previous numerical simulation difficult.

Jets or localized strong currents in planetary atmospheres, as well as in the Earth's oceans, are often associated with sharp potential-vorticity gradients owing to the inherent balance exhibited by these flows. Here, we explore and quantify jet sharpening in a simple idealized single-layer quasi-geostrophic model on a mid-latitude β-plane. The advantages of this idealization are that just two parameters control the flow development (the Rossby deformation length and the amplitude of the initial random flow perturbation), and that numerical experiments can comprehensively and accurately cover the parameter space. These experiments, carried out at unprecedented numerical resolution, reveal how an initially broad jet is sharpened, and the role played by coherent vortices in the vicinity of jets.

We study the small-scale behavior of generalized two-dimensional turbulence governed by a family of model equations, in which the active scalar theta=(-Delta)(alpha/2)psi is advected by the incompressible flow u=(-psi(y),psi(x)). Here psi is the stream function, Delta is the Laplace operator, and alpha is a positive number. The dynamics of this family are characterized by the material conservation of theta, whose variance theta2 is preferentially transferred to high wave numbers (direct transfer). As this transfer proceeds to ever-smaller scales, the gradient nublatheta grows without bound. This growth is due to the stretching term (nablatheta.nabla)u whose "effective degree of nonlinearity" differs from one member of the family to another. This degree depends on the relation between the advecting flow u and the active scalar theta (i.e., on alpha) and is wide ranging, from approximately linear to highly superlinear. Linear dynamics are realized when nablau is a quantity of no smaller scales than theta, so that it is insensitive to the direct transfer of the variance of theta, which is nearly passively advected. This case corresponds to alpha>or=2 , for which the growth of nablatheta is approximately exponential in time and nonaccelerated. For alpha<2, superlinear dynamics are realized as the direct transfer of theta2 entails a growth in nablau, thereby, enhancing the production of nablatheta. This superlinearity reaches the familiar quadratic nonlinearity of three-dimensional turbulence at alpha=1 and surpasses that for alpha<1. The usual vorticity equation (alpha=2) is the border line, where nablau and theta are of the same scale, separating the linear and nonlinear regimes of the small-scale dynamics. We discuss these regimes in detail, with an emphasis on the locality of the direct transfer.

We present a scaling theory for unforced inviscid two-dimensional turbulence. Our model unifies existing spatial and temporal scaling theories. The theory is based on a self-similar distribution of vortices of different sizes A. Our model uniquely determines the spatial and temporal scaling of the associated vortex number density which allows the determination of the energy spectra and the vortex distributions. We find that the vortex number density scales as n(A,t)-t(-2/3)/A, which implies an energy spectrum E-k(-5), significantly steeper than the classical Batchelor-Kraichnan scaling. High-resolution numerical simulations corroborate the model.

The inverse energy cascade in two-dimensional Navier-Stokes turbulence is examined in the quasisteady regime, with small-scale, band-limited forcing at scale kf-1, with particular attention to the influence of forcing Reynolds number Re on the energy distribution at large scales. The strength of the inverse energy cascade, or fraction of energy input that is transferred to larger scales, increases monotonically toward unity with increasing Re proportional, variantkmax2kf2, where kmax is the maximum resolved wave number. Moreover, as Re increases beyond a critical value, for which a direct enstrophy cascade to small scales is first realized, the energy spectrum in the energy-cascading range steepens from a k-53 to k-2 dependence. The steepening is interpreted as the result of a greater tendency for coherent vortex formation in cases when forcing scales are adequately resolved. In spectral space, it is associated with nonlocality of the inverse energy transfer.

While the life sciences industry is still coming to terms with the consequences of the Human Genome Project, the market place is forcing businesses to streamline, re-focus and even merge with or acquire businesses across the entire sector. In these troubled times, is there a place for knowledge management in research and development and drug discovery? This article reviews some of the major challenges in realizing the value of information and asks if knowledge management has made a significant impact in drug discovery.

Objective: To examine the relationship between the mean daily concentration of respirable particles arising from bushfire smoke and hospital presentations for asthma., Design and Setting: An ecological study conducted in Darwin (Northern Territory, Australia) from 1 April - 31 October 2000, a period characterised by minimal rainfall and almost continuous bushfire activity in the proximate bushland. The exposure variable was the mean atmospheric concentration of particles of 10 microns or less in aerodynamic diameter (PM(10)) per cubic metre per 24-hour period., Outcome Measure: The daily number of presentations for asthma to the Emergency Department of Royal Darwin Hospital., Results: There was a significant increase in asthma presentations with each 10-microg/m(3) increase in PM(10) concentration, even after adjusting for weekly rates of influenza and for weekend or weekday (adjusted rate ratio, 1.20; 95% CI, 1.09-1.34; P < 0.001). The strongest effect was seen on days when the PM(10) was above 40 microg/m(3) (adjusted rate ratio, 2.39; 95% CI, 1.46-3.90), compared with days when PM(10) levels were less than 10 microg/m(3)., Conclusion: Airborne particulates from bushfires should be considered as injurious to human health as those from other sources. Thus, the control of smoke pollution from bushfires in urban areas presents an additional challenge for managers of fireprone landscapes.

ABSTRACT A set of hypothetical steps has been defined, which links fungicide dose to marketable yield, whereby (i) increasing dose decreases symptom area, according to a dose-response curve, (ii) decreased symptom area increases crop green area index (GAI), (iii) increasing GAI increases fractional interception of photosynthetically active radiation, (iv) increased fractional interception increases crop dry matter accumulation, and (v) yield increases, depending on the partitioning of dry matter to the marketable fraction. One equation represented all five steps. By integrating this equation for light interception during the yield forming period and differentiating with respect to the ratio of fungicide cost over yield value, an analytical solution was obtained for the economic optimum dose. Taking published ranges of parameter values for the Septoria tritici wheat pathosystem as an example, yield-response curves and optimum doses were biologically plausible when compared with data from four field experiments. The analytical and empirical results imply that the dose required to optimize economic return will vary substantially between sites, seasons, and cultivars. Sensitivity analyses identified parameters describing specific facets of disease severity, fungicide efficacy, and assimilate partitioning as most influential in determining the dose optimum.

The crystal structure of the kinase domain of C-terminal Src kinase (CSK) has been determined by molecular replacement, co-complexed with the protein kinase inhibitor staurosporine (crystals belong to the space group P21212 with a=44.5 A, b=120.6 A, c=48.3 A). The final model of CSK has been refined to an R-factor of 19.9 % (Rfree=28.7 %) at 2.4 A resolution. The structure consists of a small, N-terminal lobe made up mostly of a beta-sheet, and a larger C-terminal lobe made up mostly of alpha-helices. The structure reveals atomic details of interactions with staurosporine, which binds in a deep cleft between the lobes. The polypeptide chain fold of CSK is most similar to c-Src, Hck and fibroblast growth factor receptor 1 kinase (FGFR1K) and most dissimilar to insulin receptor kinase (IRK). Interactions between the N and C-terminal lobe are mediated by the bound staurosporine molecule and by hydrogen bonds. In addition, there are several water molecules forming lobe-bridging hydrogen bonds, which may be important for maintaining the catalytic integrity of the kinase. Furthermore, the conserved Lys328 and Glu267 residues utilise water in the formation of a molecular pivot which is essential in allowing relative movement of the N and C-terminal lobes. An analysis of the residues around the ATP-binding site reveals structural differences with other protein tyrosine kinases. Most notable of these are different orientations of the conserved residues Asp332 and Phe333, suggesting that inhibitor binding proceeds via an induced fit. These structural observations have implications for understanding protein tyrosine kinase catalytic mechanisms and for the design of ATP-mimicking inhibitors of protein kinases., (Copyright 1999 Academic Press.)

A model of the wheat canopy/root/soil system has been developed, which calculates the risk of stem and root lodging from crop parameters and soil characteristics. For a large number of wind speed and rainfall realisations the model determines whether or not stem lodging will occur by comparing the wind induced bending moment at the base of an individual shoot with the stem base failure moment. Similarly, whether or not root lodging will occur is ascertained by comparing the wind induced base bending moment of the whole plant with the plant's root failure moment. The overall probability of lodging is determined from the proportion of wind speed and rainfall realisations for which lodging is predicted to occur. For differently managed wheat crops the model correctly predicted lodging in 21 of the 30 lodged crops and nil lodging for 38 of the 42 standing crops. The model showed that both stem and root lodging may occur given suitable circumstances. The state of the crop was as important as the prevailing weather for influencing lodging risk. A relatively small number of crop parameters were of major importance in the lodging process. These include the shoot's centre of gravity height, natural frequency, stem base radius and failure yield stress, and the plant's shoot number, root plate diameter and structural rooting depth. In addition, the importance of soil, particulary clay content, in influencing anchorage was illustrated. Recommendations for further improvement of the model include improvement of the soil strength calculation. Copyright 1998 Academic Press

Prototype irreversible inhibitors of the cysteinyl protease Der p I were designed, synthesised and evaluated in vitro. Candidates were designed using a modular approach, whereby a peptide sequence was appended with known thiophilic moieties. This hinged on utilizing peptide sequences from substrate specificity data compiled using proprietary RAPiD technology.