Correction: Adam et al. Acetic Acid as Processing Aid Dramatically Improves Organic Solvent Solubility of Weakly Basic Drugs for Spray Dried Dispersion Manufacture. Pharmaceutics 2022, 14, 555.

Figure Legend [...].

Acetic Acid as Processing Aid Dramatically Improves Organic Solvent Solubility of Weakly Basic Drugs for Spray Dried Dispersion Manufacture.

Many active pharmaceutical ingredients (APIs) in the pharmaceutical pipeline require bioavailability enhancing formulations due to very low aqueous solubility. Although spray dried dispersions (SDDs) have demonstrated broad utility in enhancing the bioavailability of such APIs by trapping them in a high-energy amorphous form, many new chemical entities (NCEs) are poorly soluble not just in water, but in preferred organic spray drying solvents, e.g., methanol (MeOH) and acetone. Spraying poorly solvent soluble APIs from dilute solutions leads to low process throughput and small particles that challenge downstream processing. For APIs with basic pKa values, spray solvent solubility can be dramatically increased by using an acid to ionize the API. Specifically, we show that acetic acid can increase API solubility in MeOH:H2O by 10-fold for a weakly basic drug, gefitinib (GEF, pKa 7.2), by ionizing GEF to form the transient acetate salt. The acetic acid is removed during drying, resulting in a SDD of the original GEF free base having performance similar to SDDs sprayed from solvents without acetic acid. The increase in solvent solubility enables large scale manufacturing for these challenging APIs by significantly increasing the throughput and reducing the amount of solvent required.

Black-White Differences in Pregnancy Desire During the Transition to Adulthood.

This article explores race differences in the desire to avoid pregnancy or become pregnant using survey data from a random sample of 914 young women (ages 18-22) living in a Michigan county and semi-structured interviews with a subsample of 60 of the women. In the survey data, desire for pregnancy, indifference, and ambivalence are very rare but are more prevalent among Black women than White women. In the semi-structured interviews, although few women described fatalistic beliefs or lack of planning for future pregnancies, Black and White women did so equally often. Women more often described fatalistic beliefs and lack of planning when retrospectively describing their past than when prospectively describing their future. Using the survey data to compare prospective desires for a future pregnancy with women's recollections of those desires after they conceived, more Black women shifted positive than shifted negative, and Black women were more likely to shift positive than White women-that is, Black women do not differentially retrospectively overreport prospectively desired pregnancies as having been undesired before conception. Young women's consistent (over repeated interviews) prospective expression of strong desire to avoid pregnancy and correspondingly weak desire for pregnancy, along with the similarity of Black and White women's pregnancy plans, lead us to conclude that a "planning paradigm"-in which young women are encouraged and supported in implementing their pregnancy desires-is probably appropriate for the vast majority of young women and, most importantly, is similarly appropriate for Black and White young women.

Mechanisms of water permeation and diffusive API release from stearyl alcohol and glyceryl behenate modified release matrices.

This work aims to develop complimentary analytical tools for lipid formulation selection that offer insights into the mechanisms of in-vitro drug release for solid lipid modified release excipients. Such tools are envisioned to aide and expedite the time consuming process of formulation selection and development. Two pharmaceutically relevant solid lipid excipients are investigated, stearyl alcohol and glyceryl behenate, which are generally known to exhibit faster and slower relative release rates, respectively. Nuclear magnetic resonance spectroscopy and diffusometry are used, along with water uptake and dissolution experiments to help distinguish between two proposed in-vitro release mechanisms for crystalline caffeine from these matrices: 1) rate limiting movement of the wetting front through the particle, and 2) rate limiting diffusive release of the active from the wetted particle. Findings based on water permeation rates, API diffusion coefficients and kinetic modeling suggest that the rate limiting steps for caffeine release from these matrices are different, with stearyl alcohol being co-rate limited by movement of the wetting front and diffusive release of API, whereas glyceryl behenate is more strictly limited by diffusive release of API from the wetted matrix. A Peclet-like number is proposed to describe the different regimes of rate limitation for drug release. NMR spectroscopy and diffusometry are demonstrated to be useful tools for elucidating mechanisms of API release from crystalline drug/lipid mixtures and have significant potential value as screening tools in MR formulation development.

Engaging with Indigenous Australian communities for a human papilloma virus and oropharyngeal cancer project; use of the CONSIDER statement.

BACKGROUND: The prevalence of oral HPV infection and HPV-related oropharyngeal squamous cell carcinoma (OPSCC) among Indigenous Australians is unknown. This paper outlines the engagement, consultation and recruitment strategies for a study involving investigation of HPV and OPSCC among Indigenous South Australians, based on the consolidated criteria for strengthening the reporting of health research involving Indigenous Peoples (CONSIDER) statement. METHODS: Initial consultations with all interested Aboriginal Community Controlled Health Organisations (ACCHOs) were done throughout 2014 and 2015. This resulted in a funding application submitted that reflected Indigenous community views and inputs in study design and methodology, and which included nine Indigenous investigators. Once funding was received, community consultation was again undertaken, with six ACCHOs providing structures, strategies and recommendations for how recruitment for participants taking part in the study should be undertaken. Staff were hired (n = 6), with non-Indigenous staff (n = 3) undertaking extensive cultural competency training. An Indigenous Reference Group was established to provide oversight and cultural guidance. Recruitment of Indigenous participants by trained field officers occurred between Feb 2018 and Dec 2018, with n = 1011 recruited. Qualitative records summarising research staff contact with ACCHOs and participants were documented. These records, together with field trip notes, key ACCHO stakeholder reflections and research staff comments, were reviewed to summarise the culturally sensitive strategies that appeared to work most successfully to facilitate ACCHO and participant buy-in. RESULTS: Findings were documented against the CONSIDER statement's research reporting framework of governance: relationships, prioritization, methodologies, participation, capacity, analysis and findings, and dissemination. The apparent success of the community engagement processes were then conceptualised into five domains: (1) engaging with ACCHOs as equal partners very early in the research process; (2) having an Indigenous Reference Group; (3) ACCHOs actively promoting the study; (4) having a flexible agenda responsive to broader environment demands and; (5) including Indigenous capacity building. CONCLUSIONS: Consultation and engagement with all sectors of the Indigenous community are essential in any research, especially a project involving HPV and OPSCC. Enabling local Indigenous staff to provide cultural guidance throughout the research process is helpful. Research that is culturally respectful and in partnership with Indigenous groups can be embraced when the research is collaborative and has clear translational benefits. The CONSIDER statement is a useful checklist against which to assess Indigenous health research processes. In future, the findings may be useful to yield important Aboriginal population estimates for both oral HPV infection and OPSCC. This may serve to convince funding bodies to provide health promotion personnel in the field of oral health, specifically OPSCC, in ACCHOs.

Intimate Relationship Dynamics and Changing Desire for Pregnancy Among Young Women.

CONTEXT: Although substantial research has focused on unintended pregnancy among young women, less is known about the circumstances under which pregnancy is desired. Whether a young woman's pregnancy desire changes across her different relationships, or over time within a relationship, has not been directly assessed. METHODS: Data on intimate relationships and pregnancy desire were assessed weekly for 895 women aged 18-22 who participated in the Relationship Dynamics and Social Life study in a county in Michigan (2008-2012). Within-between logistic regression models were used to examine within-cluster and between-cluster differences-comparisons of a woman's pregnancy desire within a relationship over time as well as across a woman's different relationships. RESULTS: Young women were more likely to desire pregnancy if they were in any relationship more intimate and committed than a casual relationship (odds ratios, 1.6-9.2); the odds of desiring pregnancy were also higher in long-term relationships rather than in short-term ones (2.1). In general, pregnancy desire increased over time as a relationship endured and became more serious. The odds of desiring pregnancy were lower among women with less educated, rather than equally educated, partners (0.7), while the odds were higher in nonmonogamous or violent relationships than in monogamous or nonviolent relationships (1.6 and 1.9, respectively). CONCLUSIONS: Young women's pregnancy desire changes depending on their intimate relationship context, across the range of relationships they experience during the transition to adulthood.

MEDIATION MODELS OF PREGNANCY DESIRES AND UNPLANNED PREGNANCY IN YOUNG, UNMARRIED WOMEN.

This paper examines the proposition that sexual and contraceptive behaviours mediate the relationship between the pregnancy desires of young, unmarried women and their having an unplanned pregnancy. The sample consisted of 854 18- to 19-year-old women living in Michigan, USA. First, the positive and negative pregnancy desires of these women were measured, as were the women's perceptions of the positive and negative desires of their sexual partners. Then the extent to which these four types of desires, as well as several types of interactions between them, prospectively predicted the occurrence of subsequent pregnancies were tested with logistic regression analyses, initially alone and then after the addition of several types of sexual and contraceptive mediator variables. The results demonstrated that four of the ten significant motivational predictors became non-significant following the introduction of the contraceptive mediator variables and that the predictive strength of the other six significant motivational predictors was substantially reduced by their introduction. A number of factors that may account for only a partial mediational effect in some models are discussed.

Lipophilic salts of poorly soluble compounds to enable high-dose lipidic SEDDS formulations in drug discovery.

Self-emulsifying drug delivery systems (SEDDS) have been used to solubilize poorly water-soluble drugs to improve exposure in high-dose pharmacokinetic (PK) and toxicokinetic (TK) studies. However, the absorbable dose is often limited by drug solubility in the lipidic SEDDS vehicle. This study focuses on increasing solubility and drug loading of ionizable drugs in SEDDS vehicles using lipophilic counterions to prepare lipophilic salts of drugs. SEDDS formulations of two lipophilic salts-atazanavir-2-naphthalene sulfonic acid (ATV-2-NSA) and atazanavir-dioctyl sulfosuccinic acid (ATV-Doc)-were characterized and their performance compared to atazanavir (ATV) free base formulated as an aqueous crystalline suspension, an organic solution, and a SEDDS suspension, using in vitro, in vivo, and in silico methods. ATV-2-NSA exhibited ∼6-fold increased solubility in a SEDDS vehicle, allowing emulsion dosing at 12mg/mL. In rat PK studies at 60mg/kg, the ATV-2-NSA SEDDS emulsion had comparable exposure to the free-base solution, but with less variability, and had better exposure at high dose than aqueous suspensions of ATV free base. Trends in dose-dependent exposure for various formulations were consistent with GastroPlus™ modeling. Results suggest use of lipophilic salts is a valuable approach for delivering poorly soluble compounds at high doses in Discovery.

Do perceptions of their partners' childbearing desires affect young women's pregnancy risk? Further study of ambivalence.

We explore whether young women's perceptions of their sexual partners' childbearing desires contribute to their risk of pregnancy. We used weekly journal data collected from 787 young women to measure their childbearing desires and their perceptions of their partners' childbearing desires. We then conducted hazard modelling to predict pregnancy risk with variables based on interactions between the women's desires and their perceived partners' desires. Models that include perceived partners' desires perform better than one based on women's desires alone. The best model contains three significant predictors: one confirms the importance of pronatal, ambivalent, and indifferent desires for pregnancy risk; one indicates that the perceived partners' antinatal desires reduce women's pregnancy risk; and one suggests that women who both perceive their partners accurately and are in agreement with them have a lower pregnancy risk. The results indicate that perceived partner data can improve prediction and enhance our understanding of pregnancy risk.

The NLSY Kinship Links: Using the NLSY79 and NLSY-Children Data to Conduct Genetically-Informed and Family-Oriented Research.

The National Longitudinal Survey of Youth datasets (NLSY79; NLSY-Children/Young Adults; NLSY97) have extensive family pedigree information contained within them. These data sources are based on probability sampling, a longitudinal design, and a cross-generational and within-family data structure, with hundreds of phenotypes relevant to behavior genetic (BG) researchers, as well as to other developmental and family researchers. These datasets provide a unique and powerful source of information for BG researchers. But much of the information required for biometrical modeling has been hidden, and has required substantial programming effort to uncover-until recently. Our research team has spent over 20 years developing kinship links to genetically inform biometrical modeling. In the most recent release of kinship links from two of the NLSY datasets, the direct kinship indicators included in the 2006 surveys allowed successful and unambiguous linking of over 94 % of the potential pairs. In this paper, we provide details for research teams interested in using the NLSY data portfolio to conduct BG (and other family-oriented) research.

Fast-tracking ambulatory surgery patients following anesthesia.

PURPOSE: The purpose of this process improvement project was to introduce and evaluate the efficacy of fast-tracking ambulatory surgical patients in a community hospital. DESIGN: An observational pre-post design was used, in which patient data from a reference period (pre-fast-tracking) was compared with patient data collected during an implementation period (post-fast-tracking). METHODS: Anesthesia providers were trained to use a tool to assess patients for eligibility to bypass the postanesthesia care unit (PACU). Fifty-nine patients met the fast-track criteria during the implementation period and were transferred directly to the ambulatory care unit from the operating room. FINDING: During the fast-track implementation period, a PACU-bypass rate of 79% was achieved, and a significant decrease in the total number of patients held in the operating room and in total length of stay was noted. CONCLUSIONS: Results suggest that fast-tracking is a suitable intervention to increase work flow efficiency and decrease both patient and hospital costs while promoting a more rapid discharge from the facility.

Harmonization of quality indicators in laboratory medicine. A preliminary consensus.

Quality indicators (QIs) are fundamental tools for enabling users to quantify the quality of all operational processes by comparing it against a defined criterion. QIs data should be collected over time to identify, correct, and continuously monitor defects and improve performance and patient safety by identifying and implementing effective interventions. According to the international standard for medical laboratories accreditation, the laboratory shall establish and periodically review QIs to monitor and evaluate performance throughout critical aspects of pre-, intra-, and post-analytical processes. However, while some interesting programs on indicators in the total testing process have been developed in some countries, there is no consensus for the production of joint recommendations focusing on the adoption of universal QIs and common terminology in the total testing process. A preliminary agreement has been achieved in a Consensus Conference organized in Padua in 2013, after revising the model of quality indicators (MQI) developed by the Working Group on "Laboratory Errors and Patient Safety" of the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC). The consensually accepted list of QIs, which takes into consideration both their importance and applicability, should be tested by all potentially interested clinical laboratories to identify further steps in the harmonization project.

Nanoparticles for improved local retention after intra-articular injection into the knee joint.

PURPOSE: To evaluate using cationic polymeric nanoparticles that interact with hyaluronate to form ionically cross-linked hydrogels to increase the intra-articular retention time of osteoarthritis drugs in the synovial cavity. METHODS: In vitro tests included nanoparticle release from cross-linked hydrogels using syringe and membrane dissolution tests, viscosity measurement of synovial fluid containing hydrogels, and release-rate measurement for a model active conjugated to a cationically substituted dextran using a hydrolyzable ester linkage in a sink dissolution test. Nanoparticle retention after intra-articular injection into rat knees was measured in vivo using fluorescence molecular tomography. RESULTS: Diffusional and convective transport of cationic nanoparticles from ionically cross-linked hydrogels formed in synovial fluid was slower in vitro than for uncharged nanoparticles. Hydrogels formed after the nanoparticles were mixed with synovial fluid did not appreciably alter the viscosity of the synovial fluid in vitro. In vitro release of a conjugated peptide from the cationic nanoparticles was approximately 20% per week. After intra-articular injection in rat knees, 70% of the nanoparticles were retained in the joint for 1 week. CONCLUSIONS: This study demonstrates the feasibility of using cationic polymeric nanoparticles to increase the retention of therapeutic agents in articular joints for indications such as osteoarthritis.

The effects of ambivalent fertility desires on pregnancy risk in young women in the USA.

Many different definitions of the construct of motivational ambivalence have appeared in the literature on reproductive health. Using a theoretical framework in which motivational ambivalence is defined as an interaction between positive and negative pregnancy desires, we propose two hypotheses. The first is that positive and negative pregnancy desires independently predict the risk of an unplanned pregnancy. The second is that ambivalence and three related constructs that are also based on the interaction between positive and negative desires are each important predictors of pregnancy risk. We use weekly journal data collected from a US sample of 1,003 women aged 18-19 years and conduct hazard model analysis to test our hypotheses. Using both dummy and continuous predictors, we report results that confirm both hypotheses. The proposed interaction framework has demonstrated validity, compares favourably with previously reported alternative approaches, and incorporates a set of constructs that have potential importance for further research directed at the prevention of unplanned pregnancy.

SAR studies around a series of triazolopyridines as potent and selective PI3Kγ inhibitors.

Herein we describe the SAR of a novel series of 6-aryl-2-amino-triazolopyridines as potent and selective PI3Kγ inhibitors. The 6-aryl-triazolopyridine core was identified by chemoproteomic screening of a kinase focused library. Rapid chemical expansion around a bi-functional core identified the key features required for PI3Kγ activity and selectivity. The series was optimized to afford 43 (CZC19945), a potent PI3Kγ inhibitor with high oral bioavailability and selectivity over PI3Kα and PI3Kδ. Modification to the core afforded 53 (CZC24832) which showed increased selectivity over the entire kinome in particular over PI3Kß.

Biodemographic modeling of the links between fertility motivation and fertility outcomes in the NLSY79.

In spite of long-held beliefs that traits related to reproductive success tend to become fixed by evolution with little or no genetic variation, there is now considerable evidence that the natural variation of fertility within populations is genetically influenced and that a portion of that influence is related to the motivational precursors to fertility. We conduct a two-stage analysis to examine these inferences in a time-ordered multivariate context. First, using data from the National Longitudinal Survey of Youth, 1979, and LISREL analysis, we develop a structural equation model in which five hypothesized motivational precursors to fertility, measured in 1979-1982, predict both a child-timing and a child-number outcome, measured in 2002. Second, having chosen two time-ordered sequences of six variables from the SEM to represent our phenotypic models, we use Mx to conduct both univariate and multivariate behavioral genetic analyses with the selected variables. Our results indicate that one or more genes acting within a gene network have additive effects that operate through child-number desires to affect both the timing of the next child born and the final number of children born, that one or more genes acting through a separate network may have additive effects operating through gender role attitudes to produce downstream effects on the two fertility outcomes, and that no genetic variance is associated with either child-timing intentions or educational intentions.

Fertility motivations of youth predict later fertility outcomes: a prospective analysis of national longitudinal survey of youth data.

We examine how the motivational sequence that leads to childbearing predicts fertility outcomes across reproductive careers. Using a motivational traits-desires-intentions theoretical framework, we test a structural equation model using prospective male and female data from the National Longitudinal Survey of Youth. Specifically, we take motivational data collected during the 1979-1982 period, when the youths were in their teens and early twenties, to predict the timing of the next child born after 1982 and the total number of children born by 2002. Separate models were estimated for males and females but ivith equality constraints imposed unless relaxing these constraints improved the overall model fit. The results indicate substantial explanatory power of fertility motivations for both short-term and long-term fertility outcomes. They also reveal the effects of both gender role attitude and educational intentions on these outcomes. Although some gender differences in model pathways occurred, the primary hypothesized pathways were essentially the same across the genders. Two validity substudies support the soundness of the results. A third sub-study comparing the male and female models across the sample split on the basis of previous childbearing revealed a number of pattern differences within the four gender-by-previous childbearing groups. Several of the more robust of these pattern differences offer interesting insights and support the validity and usefulness of our theoretical framework.

The cross-generational mother-daughter-aunt-niece design: establishing validity of the MDAN design with NLSY fertility variables.

Using National Longitudinal Survey of Youth (NLSY) fertility variables, we introduce and illustrate a new genetically-informative design. First, we develop a kinship linking algorithm, using the NLSY79 and the NLSY-Children data to link mothers to daughters and aunts to nieces. Then we construct mother-daughter correlations to compare to aunt-niece correlations, an MDAN design, within the context of the quantitative genetic model. The results of our empirical illustration, which uses DF Analysis and generalized estimation equations (GEE) to estimate biometrical parameters from NLSY79 sister-sister pairs and their children in the NLSY-Children dataset, provide both face validity and concurrent validity in support of the efficacy of the design. We describe extensions of the MDAN design. Compared to the typical within-generational design used in most behavior genetic research, the cross-generational feature of this design has certain advantages and interesting features. In particular, we note that the equal environment assumption of the traditional biometrical model shifts in the context of a cross-generational design. These shifts raise questions and provide motivation for future research using the MDAN and other cross-generational designs.

The influence of depression on sexual risk reduction and STD infection in a controlled, randomized intervention trial.

BACKGROUND: A randomized controlled trial of SAFE, a cognitive/behavioral intervention, revealed that it significantly reduces reinfection and behavioral risks among participants compared with controls. However, studies suggest that depression may moderate intervention efficacy among affected persons because of impaired information processing, failure to recognize risk, or inability to change behavior. GOAL: We evaluated SAFE efficacy among depressed and nondepressed Mexican- and African American women after comparing initial risk factors by depression status. We further explored intervention effects in moderately and severely depressed women. STUDY DESIGN: We stratified 477 participants (249 intervention, 228 controls) according to their depression status at baseline determined by CES-D scores. Using chi and multivariate logistic regression, we evaluated differences in reinfection and behavioral risk at 6-month, 12-month, and 1-year cumulative follow-ups between groups within baseline depression strata. RESULTS: : At baseline, 74.4% of women were depressed and had significantly greater levels of behavioral risks than nondepressed women. At follow-up intervals, behavioral risks and reinfection rates were lower among intervention women compared with controls regardless of depression status. For example, at 1-year follow-up reinfection rates were 15.2% in nondepressed intervention women versus 21.4% in nondepressed controls (AOR = 0.6), and 18.6% in depressed intervention women versus 27.3% in depressed controls (AOR = 0.6). Moreover, reinfection was consistently lower among moderately and severely depressed intervention women than controls (moderately depressed: 19.3% vs. 27.2%, AOR = 0.6; severely depressed: 17.9% vs. 27.5%, AOR = 0.6). CONCLUSIONS: Despite significantly greater behavioral risk among depressed women at baseline, SAFE was equally successful in reducing reinfection and high-risk behavior among depressed and nondepressed participants.

The measurement of childbearing motivation in couples considering the use of assisted reproductive technology.

Relatively little is known about the motivational antecedents to the use of assisted reproductive technology (ART). In this paper we measure the fertility motivations of infertile couples who are considering the use of ART, using an established instrument, the Childbearing Questionnaire (CBQ). Our sample consists of 214 men and 216 women who were interviewed at home after an initial screening for ART but before making a final decision. We conducted two sets of analyses with the obtained data. In one set, we compared the scores on scales and subscales of the CBQ for the males and females in our sample with the scores for males and females from a comparable normative sample. For these analyses we first examined sample and gender differences with a four-group analysis of variance. We then conducted a series of linear models that included background characteristics as covariates and interactions between sample, gender, and age and between those three variables and the background characteristics. The results showed the expected higher positive and lower negative motivations in the ART sample and a significant effect on positive motivations of the interaction between sample and age. In the second set of analyses, we developed several new subscales relevant to facets of the desire for a child that appear to be important in ART decision-making. These facets include the desire to be genetically related to the child and the desire to experience pregnancy and childbirth. A third facet, the desire for parenthood, is already well covered by the existing subscales. The results showed the new subscales to have satisfactory reliability and validity. The results also showed that the original and new subscales predicted the three facets of the desire for a child in a multivariate context. We conclude with a general discussion of the way our findings relate both to ART decision-making and to further research on the motivations that drive it.