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Biostatisticians with advanced degrees are highly sought after. Employment opportunities in the fields of mathematics and statistics are expected to increase dramatically by 2028. Underrepresentation of minorities in biostatistics has been a persistent problem, yielding a demographic landscape that differs substantially from the general US population. In some instances, students may have the appropriate quantitative skills, but are unaware of biostatistics and in other instances, students may not yet have the appropriate quantitative background, but are intellectually capable and willing to shore up those skills once they learn about biostatistics as a viable, exciting career option. Therefore, in order to ensure robust scientific advancement, there must be a concerted effort to increase the pipeline of intellectually talented persons available with exposure to the appropriate quantitative skills who are interested in careers in biostatistics. The overarching goal of this paper is to discuss the development, implementation, and impact of a federally funded pipeline initiative aimed at increasing the number of underrepresented minorities successful in graduate training and professional careers in biostatistics as well as establishing effective mentoring and networking relationships. Our findings provide a roadmap for the development of sustainable initiatives to promote diversity in biostatistics and STEM fields more broadly.

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Primary graft dysfunction (PGD) is a major cause of early mortality after lung transplant. We aimed to define objective estimates of PGD risk based on readily available clinical variables, using a prospective study of 11 centers in the Lung Transplant Outcomes Group (LTOG). Derivation included 1255 subjects from 2002 to 2010; with separate validation in 382 subjects accrued from 2011 to 2012. We used logistic regression to identify predictors of grade 3 PGD at 48/72 h, and decision curve methods to assess impact on clinical decisions. 211/1255 subjects in the derivation and 56/382 subjects in the validation developed PGD. We developed three prediction models, where low-risk recipients had a normal BMI (18.5-25 kg/m(2) ), chronic obstructive pulmonary disease/cystic fibrosis, and absent or mild pulmonary hypertension (mPAP<40 mmHg). All others were considered higher-risk. Low-risk recipients had a predicted PGD risk of 4-7%, and high-risk a predicted PGD risk of 15-18%. Adding a donor-smoking lung to a higher-risk recipient significantly increased PGD risk, although risk did not change in low-risk recipients. Validation demonstrated that probability estimates were generally accurate and that models worked best at baseline PGD incidences between 5% and 25%. We conclude that valid estimates of PGD risk can be produced using readily available clinical variables.

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Early epithelial injury after lung transplantation may contribute to development of bronchiolitis obliterans syndrome (BOS). We evaluated the relationship between early postoperative soluble receptor for advanced glycation end-product (sRAGE) levels, a marker of type I alveolar cell injury and BOS. We performed a cohort study of 106 lung transplant recipients between 2002 and 2006 at the University of Pennsylvania with follow-up through 2010. Plasma sRAGE was measured 6 and 24 h after transplantation. Cox proportional hazards models were used to evaluate the association between sRAGE and time to BOS, defined according to ISHLT guidelines. Sixty (57%) subjects developed BOS. The average time to BOS was 3.4 years. sRAGE levels measured at 6 h (HR per SD of sRAGE: 1.69, 95% CI: 1.11, 2.57, p = 0.02) and 24 h (HR per SD of sRAGE: 1.74, 95% CI: 1.14, 2.65, p = 0.01) were associated with an increased hazard of BOS. Multivariable Cox regression indicated this relationship was independent of potential confounders. Elevated plasma sRAGE levels measured in the immediate postoperative period are associated with the development of BOS. Early epithelial injury after transplantation may contribute to the development of fibrosis in BOS.

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Primary graft dysfunction (PGD) after lung transplantation may result from ischemia reperfusion injury (IRI). The innate immune response to IRI may be mediated by Toll-like receptor and IL-1-induced long pentraxin-3 (PTX3) release. We hypothesized that elevated PTX3 levels were associated with PGD. We performed a nested case control study of lung transplant recipients with idiopathic pulmonary fibrosis (IPF) or chronic obstructive pulmonary disease (COPD) from the Lung Transplant Outcomes Group cohort. PTX3 levels were measured pretransplant, and 6 and 24 h postreperfusion. Cases were subjects with grade 3 PGD within 72 h of transplantation and controls were those without grade 3 PGD. Generalized estimating equations and multivariable logistic regression were used for analysis. We selected 40 PGD cases and 79 non-PGD controls. Plasma PTX3 level was associated with PGD in IPF but not COPD recipients (p for interaction < 0.03). Among patients with IPF, PTX3 levels at 6 and 24 h were associated with PGD (OR = 1.6, p = 0.02 at 6 h; OR = 1.4, p = 0.008 at 24 h). Elevated PTX3 levels were associated with the development of PGD after lung transplantation in IPF patients. Future studies evaluating the role of innate immune activation in IPF and PGD are warranted.

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Primary graft dysfunction (PGD) is the leading cause of early posttransplant morbidity and mortality after lung transplantation. Clara cell secretory protein (CC16) is produced by the nonciliated lung epithelium and may serve as a plasma marker of epithelial cell injury. We hypothesized that elevated levels of CC16 would be associated with increased odds of PGD. We performed a prospective cohort study of 104 lung transplant recipients. Median plasma CC16 levels were determined at three time points: pretransplant and 6 and 24 h posttransplant. The primary outcome was the development of grade 3 PGD within the first 72 h after transplantation. Multivariable logistic regression was performed to evaluate for confounding by donor and recipient demographics and surgical characteristics. Twenty-nine patients (28%) developed grade 3 PGD within the first 72 h. The median CC16 level 6 h after transplant was significantly higher in patients with PGD [13.8 ng/mL (IQR 7.9, 30.4 ng/mL)] than in patients without PGD [8.2 ng/mL (IQR 4.5, 19.1 ng/mL)], p = 0.02. Elevated CC16 levels were associated with increased odds of PGD after lung transplantation. Damage to airway epithelium or altered alveolar permeability as a result of lung ischemia and reperfusion may explain this association.

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Primary graft dysfunction (PGD) after lung transplantation causes significant morbidity and mortality. We aimed to determine the role of cytokines and chemokines in PGD. This is a multicenter case-control study of PGD in humans. A Luminex analysis was performed to determine plasma levels of 25 chemokines and cytokines before and at 6, 24, 48 and 72 h following allograft reperfusion in 25 cases (grade 3 PGD) and 25 controls (grade 0 PGD). Biomarker profiles were evaluated using a multivariable logistic regression and generalized estimating equations. PGD cases had higher levels of monocyte chemotactic protein-1 (MCP-1)/chemokine CC motif ligand 2 (CCL2) and interferon (IFN)-inducible protein (IP-10)/chemokine CXC motif ligand 10 (CXCL10) (both p < 0.05), suggesting recruitment of monocytes and effector T cells in PGD. In addition, PGD cases had lower levels of interleukin (IL-13) (p = 0.05) and higher levels of IL-2R (p = 0.05). Proinflammatory cytokines, including tumor necrosis factor (TNF)-alpha, and IFN-gamma decreased to very low levels after transplant in both PGD cases and controls, exhibiting no differences between the two groups. These findings were independent of clinical variables including diagnosis in multivariable analyses, but may be affected by cardiopulmonary bypass. Profound injury in clinical PGD is distinguished by the upregulation of selected chemokine pathways, which may useful for the prediction or early detection of PGD if confirmed in future studies.

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Primary graft dysfunction (PGD), a form of acute lung injury occurring within 72 h following lung transplantation, is characterized by pulmonary edema and diffuse alveolar damage. We hypothesized that higher concentrations of intercellular adhesion molecule-1 (ICAM-1) and von Willebrand factor (vWF) would be associated with the occurrence of PGD. A total of 128 lung transplant recipients among 7 lung transplant centers were enrolled in a multicenter, prospective, cohort study. Blood specimens were collected preoperatively and at 6, 24, 48 and 72 h following lung transplantation. The primary outcome was Grade 3 PGD at 72 h after transplant. Logistic regression and generalized estimating equations (GEE) were used to analyze plasma ICAM-1 and vWF. At each postoperative timepoint, mean plasma ICAM-1 concentrations were higher for patients with PGD versus no PGD. The GEE contrast estimate for the association of plasma ICAM-1 with PGD was 107.5 ng/mL (95% CI 38.7, 176.3), p = 0.002. In the multivariate analyses, this finding was independent of all clinical variables except pulmonary artery pressures prior to transplant. There was no association between plasma vWF levels and PGD. We conclude that higher levels of plasma ICAM-1 are associated with PGD following lung transplantation.

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Vaginal complaints compel an evaluation of bacterial vaginosis (BV), however, many cases of BV are asymptomatic. We evaluated the sensitivity and specificity of vaginal symptoms in the diagnosis of BV and examined the utility of creating a BV screening tool using clinical, behavioural and demographic characteristics. A total of 1916 pregnant women were included in this analysis. In total, 757 women screened positive for BV and over one third of BV-positive women presented without any lower genital tract symptoms (39.4%). African American race, abnormal vaginal odour, and smoking were independently related to BV positivity. A BV screening tool including these three factors was fairly predictive of BV status with the area under the ROC curve equal to 0.669. This three-item prediction rule may be useful in identifying high- risk pregnant women in need of BV screening and, given the high specificity, accurately identify the group of BV-negative pregnant women.

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Traditionally, enzyme transient kinetics have been studied by the stopped-flow and rapid quench-flow (QF) methods. Whereas stopped-flow is the more convenient, it suffers from two weaknesses: optically silent systems cannot be studied, and when there is a signal it cannot always be assigned to a particular step in the reaction pathway. QF is a chemical sampling method; reaction mixtures are aged for a few milliseconds or longer, 'stopped' by a quenching agent and the product or the intermediate is measured by a specific analytical method. Here we show that by exploiting the array of current analytical methods and different quenching agents, the QF method is a key technique for identifying, and for characterising kinetically, intermediates in enzyme reaction pathways and for determining the order by which bonds are formed or cleaved by enzymes acting on polymer substrates such as DNA.

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Uracil-DNA glycosylase (UDG) is responsible for the removal of uracil from DNA. It has previously been demonstrated that UDG exhibits some sequence dependence in its activity, although this has not been well characterised. This study has investigated the sequence-dependent activity of UDG from herpes simplex virus type-1 (HSV-1). A more detailed analysis has been possible by using both kinetic and binding assays with a variety of different oligonucleotide substrates. The target uracil has been placed in substrates with either A-T-rich or G-C-rich flanking sequences and analyses have been performed on both the single- and double-stranded forms of each substrate. In the latter the uracil has been placed in both a U.A base pair and a U.G mismatch. It is observed that the sequences flanking the target uracil have a greater effect on UDG activity than the partner base of the uracil. Furthermore, the sequence context effects extend to single-stranded DNA. Systematic examination of the kinetics and binding of UDG with these different substrates has enabled us to examine the origin of the sequence preferences. We conclude that the damage recognition step in the HSV-1 UDG reaction pathway is modulated by local DNA sequence.

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Community intervention trials are becoming increasingly popular as a tool for evaluating the effectiveness of health education and intervention strategies. Typically, units such as households, schools, towns, counties, are randomized to receive either intervention or control, then outcomes are measured on individuals within each of the units of randomization. It is well recognized that the design and analysis of such studies must account for the clustering of subjects within the units of randomization. Furthermore, there are usually both subject level and cluster level covariates that must be considered in the modelling process. While suitable methods are available for continuous outcomes, data analysis is more complicated when dichotomous outcomes are measured on each subject. This paper will compare and contrast several of the available methods that can be applied in such settings, including random effects models, generalized estimating equations and methods based on the calculation of 'design effects', as implemented in the computer package SUDAAN. For completeness, the paper will also compare these methods of analysis with more simplistic approaches based on the summary statistics. All the methods will be applied to a case study based on an adolescent anti-smoking intervention in Australia. The paper concludes with some general discussion and recommendations for routine design and analysis.

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PIP: The increased use of ovulation induction and of medically assisted fertilization procedures involving transfer of 3 or more ova has resulted in an increased frequency of multiple pregnancies. This paper describes 6 cases in which the number of embryos was reduced by a transvaginal transuterine route guided by sonography. 3 women with multiple pregnancies resulting from in vitro fertilization (IVF) in a fertility clinic in France and 3 patients referred to the clinic with multiple pregnancies after ovulation induction elsewhere underwent the procedure under general anesthesia in 1989-90. A needle was introduced through the vagina and the uterine wall and into the nearest gestational sac. A hypertonic solution of potassium chloride was injected into or neat the heart. The needle was withdrawn after verification that cardiac activity had ceased and that the remaining embryos were healthy. A follow-up sonography was done 24 hours later and the procedure repeated if necessary. The 3 IVF patients ranged in age from 26-37 years. The 2 triplet and 1 quadruple pregnancies were reduced to twin pregnancies and all resulted in births of healthy twins at between 36 weeks and term. The 3 patients in whom ovulation was induced ranged in age from 18-26 years. 1 had a miscarriage of undetermined etiology at 20 weeks and the other 2 pregnancies were still in progress after reduction to 2. The literature on the progress of multiple pregnancies is relatively limited. It is recognized however the multiple pregnancy increased the rate of prematurity, of low birth weight, and of intrauterine and perinatal mortality, with the risk increasing as the pregnancy order increases. It is generally advised that pregnancies of orders higher than 3 be reduced, but opinions are divided for triple pregnancies. Selective reduction represents a partial solution to the problem of multiple pregnancies, at the cost of psychological suffering for the parents and an increased risk of abortion with embryonic reduction by different existing techniques. All the series are small and the cases very greatly. It is difficult to compare a reduction from 3 to 2 to a reduction from 6 to 2. A truly comparative study of the different techniques has not been done, but operator experience seems to be a crucial factor. Triplet or higher order pregnancies should become increasingly rare after ovulation induction because of the improving possibilities of rapid assessment of serum hormonal levels and use of sonography. Complete prevention of such pregnancies is much more difficult in the case of IVF. The number of embryos to transfer should be individually decided for each woman as a function of risk factors, taking into account her age, the rate of cleavage, the appearance of the embryos, the indication for the IVF, the couple's feelings about multiple pregnancies, the number of IVF attempts made, and the number of embryos potentially available for freezing and future use.^ieng

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The ductuli efferentes of male common starlings (Sturnus vulgaris) were prepared for light and electron microscopy. The epithelium of breeding birds was pseudostratified, consisting of ciliated cells, which were of the same type throughout the ductules, and of two types of non-ciliated cells: an electron-dense form with complex lateral invaginations, long microvilli and apical invaginations found in proximal ductuli efferentes (Type 1 a) and a less dense, taller, seemingly more secretory cell found distally (Type 1 b). Both types contained crystal-like structures in granular and transitional endoplasmic reticulum, which were occasionally seen in ciliated cells and not elsewhere. These 'intracisternal bodies' were probably proteinaceous in nature. The ciliated cells were typically more electron-lucent than the non-ciliated cells. They adopted the height and interdigitation characteristics of the surrounding epithelium. Occasional annulate lamellae were encountered. Intraepithelial lymphocytes were seen occasionally, notably in non-breeding birds. The epithelial morphology of the non-breeding common starling is briefly mentioned. The tubules were collapsed and apparently inactive, although signs of proliferative activity were seen in birds killed in February. The distinction of the epithelial cells into one ciliated and two non-ciliated types in this study is discussed in the light of previous work, as differences were found to exist. It is suggested that care should be taken in the use of mammalian tubule nomenclature when it is applied to birds.

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The Morinaga illusion is the apparent misalignment of the aligned apexes of oppositely facing angles. It is also called the Morinaga paradox because its direction is opposite to that intuitively expected from the Müller-Lyer illusion. Six experiments are reported. The first showed that the illusion is greater when the apexes are aligned obliquely than when aligned vertically or horizontally (the oblique effect); the second showed that the illusion is undiminished when the two outer angles are replaced with single lines coincident with the arms of the angles; and the third showed that the illusion is undiminished when the central apex is replaced by a dot but diminished by about half when the two outer apexes are each replaced by dots. The fourth experiment showed that the illusion also occurs with the aligned ends of parallel lines and edges of squares but not with the aligned tangential points of circles of about the same size. Experiments 5 and 6 showed that the effect is markedly greater with small, widely spaced elements. Explanations in terms of perceptual normalization to a line and perceptual assimilation have been considered. The latter explanation is the more plausible of the two, although it is conceivable that both processes contribute to the effect.

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