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Ducted fuel injection (DFI) has been shown to be effective at attenuating soot emissions from mixing-controlled compression-ignition engines. Furthermore, simultaneously low soot and nitrogen oxide (NOx) emissions have been achieved when DFI is combined with simulated exhaust-gas recirculation. Whereas previous studies investigating the effects of duct length and diameter have been conducted in combustion vessels, this is the first such study conducted in an engine. The work presented here quantifies the effects of duct length and diameter using 2- and 3-mm ducts that are 8, 12, and 16 mm long with a four-orifice fuel injector. This study also employs a larger fuel-injector-orifice diameter than has been studied previously. A comparison of 0.110-mm and 0.175-mm fuel-injector-orifice diameters with a single duct geometry is also presented. This study finds that the larger fuel-injector-orifice diameter provides better soot attenuation when it is used with a larger-diameter duct. The purpose of the larger orifice was to achieve a higher load than has been reported in previous DFI studies, namely 13.4 bar gross indicated mean effective pressure.

Background: The impact of antegrade pulmonary blood flow (APBF) during single-ventricle (SV) palliation continues to be debated. We sought to assess its impact on the hemodynamic profile and the short- and long-term outcomes of patients progressing through stages of SV palliation., Methods: A retrospective single-center study was conducted of SV patients who underwent surgery between January 2010 and December 2020. Patients with APBF were matched to those with no APBF by a propensity score based on body surface area, sex, and type of systemic ventricle. Analysis was performed using appropriate statistics with a significance level of P = .05., Results: Sixty-three patients with APBF were matched with 95 patients with no APBF. At the pre-stage 2 catheterization, APBF patients had a larger left pulmonary artery diameter (z score, 0.1 vs -0.8; P < .042). Patients with APBF had shorter cardiopulmonary bypass time (57.0 vs 79.0 minutes), shorter duration of mechanical ventilation (14.1 vs 17.4 hours), and shorter hospital length of stay (5.0 vs 7.0 days) at stage 2 palliation (P < .05). In the multivariable Cox regression analysis, patients with hypoplastic pulmonary arteries (z scores < -2; adjusted hazard ratio, 9.17) and patients with chromosomal abnormalities/genetic syndrome (adjusted hazard ratio, 4.03) were at increased risk for poor outcomes (P < .05). During the follow-up period, there was no significant difference in risk of the composite poor outcome and long-term survival between groups., Conclusions: SV patients with APBF had shorter cardiopulmonary bypass time, duration of mechanical ventilation, and hospital length of stay after stage 2 palliation. Patients with hypoplastic pulmonary arteries or chromosomal abnormalities/genetic syndromes had increased risk for poor outcomes. Maintaining APBF has better short-term outcomes, but there are no long-term hemodynamic or survival benefits., (Copyright © 2024 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Atrial fibrillation (AF) is an established risk factor for acute ischemic stroke (AIS). It remains unclear if new-onset AF confers a higher risk of AIS than longer-standing AF., Methods: We retrospectively analyzed all stroke-free patients who underwent transthoracic echocardiography (TTE) in the Henry Ford Health System between March 6 and September 6, 2016. Incident AIS and new-onset AF were ascertained by the presence of new diagnostic codes in the electronic medical record over a follow-up period of up to 5 years. Cox proportional hazards regression was used to identify risk factors for new-onset AF or AIS., Results: Of 7310 patients who underwent baseline TTE the mean age was 65 years, 54% were female, 51% were Caucasian, and 46% had left atrial enlargement (LAE). Of at-risk patients, 10.9% developed new-onset AF and 2.9% experienced incident AIS. The risk of new-onset AF among at-risk patients was 3.1 times higher among patients with any degree of LAE compared to those with normal LA size (95% CI 2.6-3.6, P < 0.0001). New-onset AF, more than established AF, in turn had a powerful association with incident AIS. The cumulative 5-year risk of AIS was 3.5% in those without AF, 5.9% in those with established AF prior to TTE, and 20.1% in those with new-onset AF (P < 0.0001). In multivariable analysis new-onset AF had the strongest association with incident AIS (P < 0.0001), followed by increasing age (P = 0.0025), black race (P = 0.0032), and smoking (P = 0.0063)., Conclusions: New-onset AF has a strong relationship with incident AIS. LAE was present in nearly half of stroke-free patients undergoing TTE, and was associated with a significantly higher likelihood of new-onset AF during follow-up. Vigilant cardiac monitoring for AF in individuals with LAE, coupled with the timely initiation of anticoagulation, may be an important strategy for the primary prevention of AF-related stroke., Competing Interests: Declaration of Competing Interest Authors have no conflicts of interest to report., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Despite decades of research, human cytomegalovirus (CMV) continues to contribute to significant morbidity and mortality in transplant settings and remains the leading cause of viral congenital infections. Clinical diagnosis of CMV infection and/or reactivation under these settings is completed using real time quantitative polymerase chain reaction (RT-qPCR). This assay performs well but is hampered by poor sensitivity and a lack of standardization among testing facilities. A point-of-care rapid diagnostic to determine CMV viremia could address these issues and improve patient care. In this manuscript, we introduce clustered regularly interspaced short palindromic repeats (CRISPR)-Cas12a technology to design and validate a rapid diagnostic for CMV. This system was tested using CMV spiked human saliva and urine samples. Sensitivity of the assay was ∼10 infectious units (IU)/mL. Specificity of the assay was robust and failed to detect other herpesviruses. Collectively, we have designed and validated a rapid diagnostic for CMV that overcomes limitations of the current standard diagnostic. This assay has the potential to be used as a point-of-care screening tool in transplant and neonatal settings., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Way-a-linah, an alcoholic beverage produced from the fermented sap of Eucalyptus gunnii, and tuba, a fermented drink made from the syrup of Cocos nucifera fructifying bud, are two of several fermented beverages produced by Australian Aboriginal and Torres Strait people. Here we describe the characterisation of yeast isolates from samples associated with the fermentation of way-a-linah and tuba. Microbial isolates were obtained from two different geographical locations in Australia - the Central Plateau in Tasmania, and Erub Island in the Torres Strait. While Hanseniaspora species and Lachancea cidri were the most abundant species in Tasmania, Candida species were the most abundant in Erub Island. Isolates were screened for tolerance to stress conditions found during the production of fermented beverages and for enzyme activities relevant to the appearance, aroma and flavour of these beverages. Based on screening results, eight isolates were evaluated for their volatile profile during the fermentation of wort, apple juice and grape juice. Diverse volatile profiles were observed for beers, ciders and wines fermented with different isolates. These findings reveal the potential of these isolates to produce fermented beverages with unique aroma and flavour profiles and highlight the vast microbial diversity associated with fermented beverages produced by Australia's Indigenous peoples., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Magnitude-based PDFF (Proton Density Fat Fraction) and R 2 ∗ mapping with resolved water-fat ambiguity is extended to calculate field inhomogeneity (field map) using the phase images. The estimation is formulated in matrix form, resolving the field map in a least-squares sense. PDFF and R 2 ∗ from magnitude fitting may be updated using the estimated field maps. The limits of quantification of our voxel-independent implementation were assessed. Bland-Altman was used to compare PDFF and field maps from our method against a reference complex-based method on 152 UK Biobank subjects (1.5 T Siemens). A separate acquisition (3 T Siemens) presenting field inhomogeneities was also used. The proposed field mapping was accurate beyond double the complex-based limit range. High agreement was obtained between the proposed method and the reference in UK. Robust field mapping was observed at 3 T, for inhomogeneities over 400 Hz including rapid variation across edges. Field mapping following unambiguous magnitude-based water-fat separation was demonstrated in-vivo and showed potential at 3 T., Competing Interests: Declaration of Competing Interest ATB, DM, CH, AB, MLG, PA, MDR, MB are employees of Perspectum and hold shares and/or share options. DPB declares no potential conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Prior work documents that Veteran drug overdose mortality increased from 2010 to 2016. The present study assessed trends from 2010 to 2019, by drug type and recent receipt of Veterans Health Administration (VHA) services, and compared rates for Veteran and non-Veteran US adults., Methods: This retrospective cross-sectional study used data from Veterans Affairs (VA) medical records, the VA/Department of Defense Mortality Data Repository, and CDC WONDER. Trends were compared using Joinpoint regression., Results: From 2010-2019, age-adjusted overdose mortality rates increased 53.2% among Veterans and 79.0% among non-Veterans. Age-adjusted rates of overdose mortality among Veterans rose from 19.8/100,000 in 2010 to 32.6/100,000 in 2017, before falling to 30.3/100,000 in 2019. Despite the decrease from 2017 to 2019 in overall overdose mortality, rates of overdose deaths involving synthetic opioids other than methadone and involving psychostimulants continued to increase through 2019. In 2019, overdose mortality was lower for male Veterans than male non-Veterans (standardized rate ratio (SRR) = 0.81, 95% confidence interval (CI): 0.77-0.84). Among male Veterans, rates were higher in all years for those with recent VHA use than those without (2019: SRR=1.69, 95% CI: 1.56-1.83). From 2010-2019, overdose mortality rates increased faster among female Veterans without VHA use than those with VHA use., Conclusions: From 2015 onward, Veteran men experienced lower age-adjusted overdose rates than non-Veteran men. In all years, overdose rates were higher among male Veterans with recent VHA use than those without recent use. While overall rates of Veteran overdose deaths declined from 2017 to 2019, rates involving psychostimulants and synthetic opioids continued to rise., (Copyright © 2022. Published by Elsevier B.V.)

Objective: Helplines are generally a population-level resource for providing free, timely, easy-to-access, and anonymous counseling and/or information. Helplines have been developed and widely implemented for specific use by young people. The current study aimed to systematically review the literature to determine the status of research into the use of helplines among young people., Method: Following the PRISMA checklist, 5 electronic databases were searched using relevant terms for literature published until May 2020. The extracted studies were summarized with the intention of identifying key themes that highlighted common findings, key implications, and important gaps in understanding., Results: A total of 52 articles fitting study inclusion criteria were identified. Most studies were quantitative papers from the United States and Australia. The types of helpline interactions studied were a mixture of telephone-based and SMS/text-based interactions. Three major themes were identified: awareness of and engagement with helpline services, nature of problems faced by young people, and service-related factors. Subthemes were use and awareness, barriers to help seeking, psychosocial problems, suicidality, telephone- versus text-based interactions, counselor-caller interaction, and provision of services to historically and systemically marginalized groups., Conclusion: It appears that helplines may provide a beneficial service to youths, and that myriad psychosocial concerns provide the basis for calling. The literature is limited by a lack of controlled trials, on one hand, and complex methodological/ethical barriers preventing such trials, on the other hand. However, more research is needed before conclusions regarding effectiveness in youths can be made, particularly for services provided to systemically marginalized groups and using online text-based approaches., (Copyright © 2020 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Prospective cardiac gating during MRI is hampered by electromagnetic induction from the rapidly switched imaging gradients into the ECG detection circuit. This is particularly challenging in small animal MRI, as higher heart rates combined with a smaller myocardial mass render routine ECG detection challenging. We have developed an open-hardware system that enables continuously running MRI scans to be performed in conjunction with cardio-respiratory gating such that the relaxation-weighted steady state magnetisation is maintained throughout the scan. This requires that the R-wave must be detected reliably even in the presence of rapidly switching gradients, and that data previously acquired that were corrupted by respiratory motion re-acquired. The accurately maintained steady-state magnetisation leads to an improvement in image quality and removes alterations in intensity that may otherwise occur throughout the cardiac cycle and impact upon automated image analysis. We describe the hardware required to enable this and demonstrate its application and robust performance using prospectively cardio-respiratory gated CINE imaging that is operated at a single, constant TR. Schematics, technical drawings, component listing and assembly instructions are made publicly available., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

We introduce Region of Interest Contrast Enhancement (RICE) to identify focal densities in mammograms. It aims to help radiologists: 1) enhancing the contrast of mammographic images; and 2) detecting regions of interest (such as focal densities) that are candidate masses potentially masked behind dense parenchyma. Cancer masking is an unsolved issue, particularly in breast density categories BI-RADS C and D. RICE suppresses normal breast parenchyma in order to highlight focal densities. Unlike methods that enhance mammograms by modifying the dynamic range of an image; RICE relies on the actual tissue composition of the breast. It segments Volumetric Breast Density (VBD) maps into smaller regions and then applies a recursive mechanism to estimate the 'neighbourhood' for each segment. The method then subtracts and updates the neighbourhood, or the encompassing tissue, from each piecewise constant component of the breast image. This not only enhances the appearance of a candidate mass but also helps in estimating the mass density. In extensive experiments, RICE enhances focal densities in all breast density types including the most challenging category BI-RADS D. Suitably adapted, RICE can be used as a precursor to any computer-aided diagnostics and detection system., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Nicotine and varenicline (Chantix®; the leading non-nicotine cessation pharmacotherapy) can come to control appetitive behaviors such as goal-tracking. We tested rats (N = 48) in a drug-discriminated goal-tracking (DGT) task where each rat received daily subcutaneous injections of either nicotine (0.4 mg/kg) or saline (0.9% [w/v]) interspersed across the acquisition phase (Phase 1). On saline days, sucrose was intermittently available. On nicotine days, sucrose was withheld. All rats acquired the discrimination with increased goal-tracking rates on saline days relative to nicotine days. Following acquisition, rats were separated into four groups to assess drug-substitution and discrimination reversal in Phase 2. The first group maintained the stimulus-reinforcer relation from acquisition (NIC-). The reversal group was now given access to sucrose on nicotine days (NIC+). The substitution group replaced nicotine with varenicline (1 mg/kg) while maintaining the acquisition stimulus-reinforcer relation (VAR-). The substitution and reversal group had nicotine replaced by varenicline and the stimulus-reinforcer relation reversed (VAR+). Rats in all groups learned or maintained their Phase 1 discriminations. For Phase 2, the reversal groups (+ conditions) acquired their discriminations within 10 sessions. The VAR- group displayed a pattern of disrupted discrimination at the outset of Phase 2 but was reestablished after continued training. In substitution testing, VAR groups received nicotine and NIC groups received varenicline. The NIC- and VAR- groups displayed full substitution of the test stimulus whereas the NIC+ and VAR+ groups displayed partial substitution of the test stimulus. Rats underwent nicotine extinction in Phase 3. Initial responding for each group mimicked Phase 2 training (i.e., higher responding by the reversal groups). All rats maintained similarly low levels of responding after six sessions. In conclusion, initial learning history with nicotine (i.e., + or -) influenced drug-stimulus substitution and the rate at which new learning (e.g., reversal) occurs with the varenicline and nicotine interoceptive stimuli., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Adverse childhood experiences (ACEs) have been shown to be associated with increased risk of mortality. The biobehavioral mechanisms linking adverse events and survival in cancer patients remain unclear. The aims of the study were to: (1) examine the rates and types of early adverse events in patients diagnosed with cancer; (2) investigate the association of adverse events with circulating cytokines, representing immune status of the patient; and (3) test whether immune markers mediated the association between early adverse events and survival while adjusting for other factors that are associated with immunity (e.g., fatigue) and survival (e.g., depression)., Patients and Methods: The patients were recruited from an outpatient oncology clinic. Patients were administered a battery of questionnaires including the Traumatic Events Survey and the Center for Epidemiological Studies-Depression scale. Blood was collected and serum levels of cytokines were assessed to characterize immune status. Descriptive statistics, Mann-Whitney U tests and Cox regression were performed to address study aims., Results: Of the 408 patients, 66% reported at least one ACE. After adjusting for demographic, disease-specific factors, and psychological/behavioral factors; having had a major upheaval between parents during childhood or adolescence was associated with poorer survival [β = -0.702, HR = 0.496, p = 0.034]. Lower levels of interleukin-2 (IL-2) explained, in part, the link between this early adverse event and poorer survival as when IL-2 was entered into the model, a major upheaval between one's parents and survival was no longer significant [β = -0.612, HR = 0.542, p = 0.104]., Conclusion: Having experienced an ACE was associated with lower IL-2 levels-a growth factor for anti-inflammatory T-regulatory lymphocytes-central in contemporary immunotherapy, as well as poorer survival in those diagnosed with cancer. Since lower IL-2 levels also explained, in part, the link between the ACE involving parental upheaval and survival, there is support for a psychoneuroimmunological model of disease course in this vulnerable population., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

As new reproductive health products become available, women increasingly want to take a participatory role in their health. New developments and formulations of contraceptive products provide an opportunity to support this evolving trend toward self-care. Self-care, as defined by the World Health Organization (WHO), highlights the ability of individuals to promote health, prevent disease, and manage their own health with or without the support of a health care provider. The recently released WHO Guidelines on Self-Care Interventions for Health: Sexual and Reproductive Health and Rights included new self-care recommendations related to use of family planning, including self-injection of injectable contraceptives and over-the-counter provision of oral contraceptive pills. This paper focuses on the research evidence of self-administration (self-injection) of subcutaneous depot medroxyprogesterone acetate (DMPA-SC), and the practical experience of providers, women, and family planning programs adopting self-injection practices. We also explore the role of self-care in the provision of other contraceptives., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020. Published by Elsevier Ltd.)

Background: Mycobacterium porcinum is a non-tuberculous mycobacterium (NTM) identified in potable water. The identification and clinical impact of M. porcinum in patients with cystic fibrosis (CF) has not been described. In our institution, M. porcinum was isolated exclusively during hospitalization in a cluster of patients with CF., Methods: Patients with CF who were hospitalized between September 2016 and September 2018 and could expectorate sputum were included, and samples were processed per institutional guidelines. Post-hospitalization and one-year clinical outcomes on those who isolated M. porcinum in respiratory cultures were reviewed. Whole genome sequencing was performed on M. porcinum isolates obtained from patients and environmental sources to identify source of acquisition., Results: Review of 14 CF patients with 16 M. porcinum isolates revealed rapid time to culture positivity within 0.8 (0.04-8.0) days after admission. M. porcinum was isolated in teenagers and adults irrespective of baseline pulmonary function, body mass index, or CF genotype. Whole genome sequencing suggested all isolates belong to the same M. porcinum strain and confirmed the source of acquisition to the ice machine. Review of patients' clinical course, including three patients who underwent lung transplantation, suggested a pseudo-outbreak with minimal clinical impact., Conclusions: NTM, including M. porcinum, are ubiquitous in potable water and institutional water reservoirs. Our findings suggest M. porcinum is a transient colonizer rather than a pathogen. Challenges exist in discerning the role of NTM as a contributor of pulmonary morbidity in patients with CF, and adherence to established guidelines regarding NTM related pulmonary disease remains important., Competing Interests: Declaration of Competing Interest None, (Copyright © 2020. Published by Elsevier B.V.)

Learning processes associated with nicotine influence the development of addiction to tobacco products. In the present report, we are interested in the interoceptive stimulus effects of nicotine acquiring control over appetitive behaviors - specifically, reward seeking. Also of interest is the current smoking cessation drug, varenicline (Chantix®). Varenicline, with its nicotine-like stimulus effects, can decrease withdrawal and cravings for a subset of individuals addicted to nicotine, though relapse is still common. We trained rats (N = 48) with nicotine (0.4 mg/kg, SC) as an excitatory stimulus (i.e., paired with sucrose) in a drug-discriminated goal-tracking (DGT) task. There was no access to sucrose on interspersed saline days. After acquisition of the initial nicotine-saline discrimination, rats were separated into four groups to test discrimination reversal and drug substitution. The control group maintained nicotine as the excitatory stimulus (NIC+). The substitution group had varenicline (1 mg/kg) replace nicotine as the stimulus paired with sucrose (VAR+). One reversal group had nicotine signal the absence of sucrose (i.e., now available on intermixed saline sessions; NIC-). The last group was similar to the NIC- group except varenicline replaced nicotine on non-reinforced sessions (VAR-). We found that varenicline fully substituted as the training stimulus when the drug-sucrose relation remained in place (VAR+). Both reversal groups acquired the new discrimination, albeit slowly and more variable for the VAR- group in comparison to NIC-. There was an effect of group during substitution testing. Specifically, nicotine fully substituted for varenicline regardless of condition. However, varenicline only partially substituted for the nicotine stimulus. At the start of extinction, responding mimicked that of the rats training condition. However, by extinction session 12, all groups maintained similarly low levels of responding. These findings show nicotine and varenicline share stimulus elements, yet the conclusion of partial to full substitution depends on the nature of the testing protocol., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Smoking constitutes a significant public health risk. Alcohol and methamphetamine use disorders are also highly co-morbid with smoking, further increasing negative health outcomes. An important question in determining the underlying neurobiology of nicotine poly-drug use is understanding whether having a positive history with nicotine effects alters later drug-taking behavior., Methods: The current experiments sought to elucidate whether having an appetitive nicotine conditioning history would affect later alcohol or methamphetamine self-administration. Adult male and female Long-Evans rats were first trained on a discriminated goal-tracking task in which the interoceptive effects of nicotine predicted sucrose reinforcement. As a control, pseudo-conditioned groups were included that had equated nicotine and sucrose experience. Rats were then shifted to either alcohol self-administration or methamphetamine self-administration., Results: Nicotine conditioning history had no effect on acquisition or maintenance of alcohol self-administration in males or females. In contrast, an appetitive nicotine conditioning history decreased methamphetamine self-administration in female rats, but not males., Conclusions: In female, but not male, rats, an appetitive conditioning history with nicotine decreases methamphetamine, but not alcohol, self-administration. This dissociation suggests that the effects may be due to a specific increase in the reinforcing value of methamphetamine. This may have implications for better understanding the progression of drug use from nicotine to methamphetamine., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: Cardiac and respiratory motion derived image artefacts are reduced when data are acquired with cardiac and respiratory synchronisation. Where steady state imaging techniques are required in small animals, synchronisation is most commonly performed using retrospective gating techniques but these invoke an inherent time penalty. This paper reports the development of prospective gating techniques for cardiac and respiratory motion desensitised MRI with significantly reduced minimum scan time compared to retrospective gating., Methods: Prospective gating incorporating the automatic reacquisition of data corrupted by motion at the entry to each breath was implemented in short TR 3D spoiled gradient echo imaging. Motion sensitivity was examined over the whole mouse body for scans performed without gating, with respiratory gating, and with cardio-respiratory gating. The gating methods were performed with and without automatic reacquisition of motion corrupted data immediately after completion of the same breath. Prospective cardio-respiratory gating, with acquisition of 64 k-space lines per cardiac R-wave, was used to enable whole body DCE-MRI in the mouse., Results: Prospective cardio-respiratory gating enabled high fidelity steady state imaging of physiologically mobile organs such as the heart and lung. The automatic reacquisition of data corrupted by motion at the entry to each breath minimised respiratory motion artefact and enabled a highly efficient data capture that was adaptive to changes in the inter-breath interval. Prospective cardio-respiratory gating control enabled DCE-MRI to be performed over the whole mouse body with the acquisition of successive image volumes every 12-15 s at 422 μm isotropic resolution., Conclusions: Highly efficient cardio-respiratory motion desensitised steady state MRI can be performed in small animals with prospective synchronisation, centre-out phase-encode ordering, and the automatic reacquisition of data corrupted by motion at the entry to each breath. The method presented is robust against spontaneous changes in the breathing rate. Steady state imaging with prospective cardio-respiratory gating is much more efficient than with retrospective gating, and enables the examination of rapidly changing systems such as those found when using DCE-MRI., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Increasing attention to adolescent girls has generated an abundance of programs and a growing body of research on adolescent girls in low- and middle-income countries. Despite this, questions remain about what implementation approaches in program design are most effective, hindering efficient resource allocation, program scale-up, and replication across settings. To address these questions, we conducted a systematic review to identify lessons learned and gaps in the evidence base. We searched four electronic databases to identify studies published between 1990 and 2014 that evaluated health, social, and/or economic development programs targeting adolescent girls in low- and middle-income countries. Seventy-seven (77) studies meeting specified criteria were identified, of which 19 presented results that allowed conclusions relevant to implementation science. Studies examining the following questions were assessed: To what extent, if any, do multicomponent interventions (as opposed to single-component interventions) improve outcomes for girls? What is the added value of involving actors in addition to the girl herself such as parents, guardians, husbands (i.e., multilevel interventions)? What is the threshold proportion of girls who need to participate in a program to bring about normative and behavior changes at the community level? Is a greater level of program exposure associated with greater programmatic benefit for girls? Can supplemental "booster" activities extend the benefits of a program after it ends? We found evidence to support associations between multicomponent (vs. single component) programs, and longer program exposure (vs. less program exposure), with more favorable outcomes for girls, although both conclusions include methodological limitations. Overall, few studies assessed boosters or program saturation, and evidence on multilevel versus single-level programs was inconclusive. Few studies assessed implementation science questions by design, exposing large gaps in the evidence base. We call for future research to explicitly test such implementation science questions to inform more effective use of resources and to improve outcomes for girls., (Copyright © 2017 The Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

Background: A phase 2, randomized, placebo-controlled trial was conducted in women with recurrent epithelial ovarian carcinoma to evaluate the efficacy and safety of motolimod-a Toll-like receptor 8 (TLR8) agonist that stimulates robust innate immune responses-combined with pegylated liposomal doxorubicin (PLD), a chemotherapeutic that induces immunogenic cell death., Patients and Methods: Women with ovarian, fallopian tube, or primary peritoneal carcinoma were randomized 1 : 1 to receive PLD in combination with blinded motolimod or placebo. Randomization was stratified by platinum-free interval (≤6 versus >6-12 months) and Gynecologic Oncology Group (GOG) performance status (0 versus 1). Treatment cycles were repeated every 28 days until disease progression., Results: The addition of motolimod to PLD did not significantly improve overall survival (OS; log rank one-sided P = 0.923, HR = 1.22) or progression-free survival (PFS; log rank one-sided P = 0.943, HR = 1.21). The combination was well tolerated, with no synergistic or unexpected serious toxicity. Most patients experienced adverse events of fatigue, anemia, nausea, decreased white blood cells, and constipation. In pre-specified subgroup analyses, motolimod-treated patients who experienced injection site reactions (ISR) had a lower risk of death compared with those who did not experience ISR. Additionally, pre-treatment in vitro responses of immune biomarkers to TLR8 stimulation predicted OS outcomes in patients receiving motolimod on study. Immune score (tumor infiltrating lymphocytes; TIL), TLR8 single-nucleotide polymorphisms, mutational status in BRCA and other DNA repair genes, and autoantibody biomarkers did not correlate with OS or PFS., Conclusions: The addition of motolimod to PLD did not improve clinical outcomes compared with placebo. However, subset analyses identified statistically significant differences in the OS of motolimod-treated patients on the basis of ISR and in vitro immune responses. Collectively, these data may provide important clues for identifying patients for treatment with immunomodulatory agents in novel combinations and/or delivery approaches., Trial Registration: Clinicaltrials.gov, NCT 01666444., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

This paper addresses the problem of classifying materials from microspectroscopy at a pixel level. The challenges lie in identifying discriminatory spectral features and obtaining accurate and interpretable models relating spectra and class labels. We approach the problem by designing a supervised classifier from a tandem of Artificial Neural Network (ANN) models that identify relevant features in raw spectra and achieve high classification accuracy. The tandem of ANN models is meshed with classification rule extraction methods to lower the model complexity and to achieve interpretability of the resulting model. The contribution of the work is in designing each ANN model based on the microspectroscopy hypothesis about a discriminatory feature of a certain target class being composed of a linear combination of spectra. The novelty lies in meshing ANN and decision rule models into a tandem configuration to achieve accurate and interpretable classification results. The proposed method was evaluated using a set of broadband coherent anti-Stokes Raman scattering (BCARS) microscopy cell images (600 000  pixel-level spectra) and a reference four-class rule-based model previously created by biochemical experts. The generated classification rule-based model was on average 85% accurate measured by the DICE pixel label similarity metric, and on average 96% similar to the reference rules measured by the vector cosine metric., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Randomised placebo-controlled trials have shown that daily oral pre-exposure prophylaxis (PrEP) with tenofovir-emtricitabine reduces the risk of HIV infection. However, this benefit could be counteracted by risk compensation in users of PrEP. We did the PROUD study to assess this effect., Methods: PROUD is an open-label randomised trial done at 13 sexual health clinics in England. We enrolled HIV-negative gay and other men who have sex with men who had had anal intercourse without a condom in the previous 90 days. Participants were randomly assigned (1:1) to receive daily combined tenofovir disoproxil fumarate (245 mg) and emtricitabine (200 mg) either immediately or after a deferral period of 1 year. Randomisation was done via web-based access to a central computer-generated list with variable block sizes (stratified by clinical site). Follow-up was quarterly. The primary outcomes for the pilot phase were time to accrue 500 participants and retention; secondary outcomes included incident HIV infection during the deferral period, safety, adherence, and risk compensation. The trial is registered with ISRCTN (number ISRCTN94465371) and ClinicalTrials.gov (NCT02065986)., Findings: We enrolled 544 participants (275 in the immediate group, 269 in the deferred group) between Nov 29, 2012, and April 30, 2014. Based on early evidence of effectiveness, the trial steering committee recommended on Oct 13, 2014, that all deferred participants be offered PrEP. Follow-up for HIV incidence was complete for 243 (94%) of 259 patient-years in the immediate group versus 222 (90%) of 245 patient-years in the deferred group. Three HIV infections occurred in the immediate group (1·2/100 person-years) versus 20 in the deferred group (9·0/100 person-years) despite 174 prescriptions of post-exposure prophylaxis in the deferred group (relative reduction 86%, 90% CI 64-96, p=0·0001; absolute difference 7·8/100 person-years, 90% CI 4·3-11·3). 13 men (90% CI 9-23) in a similar population would need access to 1 year of PrEP to avert one HIV infection. We recorded no serious adverse drug reactions; 28 adverse events, most commonly nausea, headache, and arthralgia, resulted in interruption of PrEp. We detected no difference in the occurrence of sexually transmitted infections, including rectal gonorrhoea and chlamydia, between groups, despite a suggestion of risk compensation among some PrEP recipients., Interpretation: In this high incidence population, daily tenofovir-emtricitabine conferred even higher protection against HIV than in placebo-controlled trials, refuting concerns that effectiveness would be less in a real-world setting. There was no evidence of an increase in other sexually transmitted infections. Our findings strongly support the addition of PrEP to the standard of prevention for men who have sex with men at risk of HIV infection., Funding: MRC Clinical Trials Unit at UCL, Public Health England, and Gilead Sciences., (Copyright © 2016 McCormack et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.)

This paper describes our on-going work to accelerate ZENO, a software tool based on Monte Carlo methods (MCMs), used for computing material properties at nanoscale. ZENO employs three main algorithms: (1) Walk on Spheres (WoS), (2) interior sampling, and (3) surface sampling. We have accelerated the first two algorithms. For the sake of brevity, the paper will discuss our work on the first one only as it is the most commonly used and the acceleration techniques were similar in both cases. WoS is a Brownian motion MCM for solving a class of partial differential equations (PDEs). It provides a stochastic solution to a PDE by estimating the probability that a random walk, which started at infinity, will hit the surface of the material under consideration. WoS is highly effective when the problem's geometry is additive, as this greatly reduces the number of walk steps needed to achieve accurate results. The walks start on the surface of an enclosing sphere and can make much larger jumps than in a direct simulation of Brownian motion. Our current implementation represents the molecular structure of nanomaterials as a union of possibly overlapping spheres. The core processing bottleneck in WoS is a Computational Geometry one, as the algorithm repeatedly determines the distance from query point to the material surface in each step of the random walk. In this paper, we present results from benchmarking spatial data structures, including several open-source implementations of k -D trees, for accelerating WoS algorithmically. The paper also presents results from our multicore and cluster parallel implementation to show that it exhibits linear strong scaling with the number of cores and compute nodes; this implementation delivers up to 4 orders of magnitude speedup compared to the original FORTRAN code when run on 8 nodes (each with dual 6-core Intel Xeon CPUs) with 24 threads per node.

Unlabelled: This paper presents the public health rationale for multipurpose prevention technologies (MPTs) for sexual and reproductive health (SRH) based on regional trends in demographic and SRH indicators. It then distils important lessons gleaned from the introduction of contraceptive and reproductive health products over the past several decades in order to inform the development and future introduction of MPTs for SRH., Principal Results: A comparison of current demographic and public health regional data clearly revealed that the greatest confluence of women's SRH concerns occurs in sub-Saharan Africa and South/West Asia. These regional overlaps of SRH risks and outcomes present a strong rationale for developing MPTs designed to simultaneously protect against unintended pregnancy, HIV and other STIs. Information from acceptability, marketing, and operations research on the female condom, emergency contraception, pills and intravaginal rings identified key product characteristics and socio-behavioral issues to be considered in the development and introduction of MPTs. Product characteristics such as formulation, duration of action, presence and magnitude of side effects, prescription status (over-the-counter vs. prescribed), provider type and training and user perspectives, all contributed in varying degrees to both provider and user bias, and subsequent uptake of these family planning methods. Underlying socio-behavioral issues, including risk perception, ambivalence, and social costs also contributed to demand and use. Early identification of target populations will be critical to market shaping, demand creation and defining appropriate service delivery channels for MPTs. Ultimately, knowledge, attitudes, perceptions and practices of users (and their partners) will drive the success- or failure- of product introduction., Conclusions: MPTs provide a compelling response to the multiple and reinforcing SRH risks faced by women in key regions of the world, but specific product characteristics and their socio-behavioral correlates must be taken into account early in the development process. Successful introduction of new MPTs will require solid understanding of socio-behavioral correlates, effective demand generation, appropriate integration into health service delivery systems, quality counseling for proper use and active engagement of both public and private sectors. This article is based on a presentation at the "Product Development Workshop 2013: HIV and Multipurpose Prevention Technologies," held in Arlington, Virginia on February 21-22, 2013. It forms part of a special supplement to Antiviral Research., (Copyright © 2013 Elsevier B.V. All rights reserved.)

This paper is concerned with limited view tomography. Inspired by the application of digital breast tomosynthesis (DBT), which is but one of an increasing number of applications of limited view tomography, we concentrate primarily on cases where the angular range is restricted to a narrow wedge of approximately ±30°, and the number of views is restricted to 10-30. The main challenge posed by these conditions is undersampling, also known as the null space problem. As a consequence of the Fourier Slice Theorem, a limited angular range leaves large swathes of the object's Fourier space unsampled, leaving a large space of possible solutions, reconstructed volumes, for a given set of inputs. We explore the feasibility of using same- or different-modality images as anatomical priors to constrain the null space, hence the solution. To allow for different-modality priors, we choose information theoretic measures to quantify the similarity between reconstructions and their priors. We demonstrate the limitations of two popular choices, namely mutual information and joint entropy, and propose robust alternatives that overcome their limitations. One of these alternatives is essentially a joint mixture model of the image and its prior. Promising mitigation of the data insufficiency problem is demonstrated using 2D synthetic as well as clinical phantoms. This work initially assumes a priori registered priors, and is then extended to allow for the registration to be performed simultaneously with the reconstruction., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Objective: To identify characteristics associated with abnormal blood glucose readings among African Americans and to determine the potential value of a more targeted approach to community-based screenings for type 2 diabetes., Methods: Data were collected from 7113 participants with no previous diagnosis of diabetes at mobile screening events in Detroit, Michigan. Data collected included gender, race, age, self-reported height and weight, total diabetes risk score, blood pressure, and random capillary blood glucose., Results: Nearly 9% of participants had abnormal random plasma glucose readings (RPG>or=160 mg/dL). Results indicated that higher age, elevated blood pressure, and body mass index (BMI) were significantly associated with abnormal glucose readings., Conclusion: These findings suggest that community-based screenings for diabetes that are targeted to adults aged more than 50 years who have high blood pressure or a BMI of at least 25 may enhance detection of abnormal glucose levels among African Americans.

Background: We treated melanoma patients with temozolomide (TMZ) in the neoadjuvant setting and collected cryopreserved tumor samples before and after treatment. The primary objective was to determine whether the response proportion was higher than previously reported in widely metastatic patients. A secondary objective was to test the feasibility of obtaining adequate tissue before and after treatment for genetic testing., Materials and Methods: Chemotherapy-naive melanoma patients who were candidates for surgical resection were eligible. TMZ was administered orally at 75 mg/m(2)/day for 6 weeks of every 8-week cycle. Cycles were repeated until complete response (CR), progression, or stable disease (SD) for two cycles., Results: Of 19 assessable patients, 2 had CRs and 1 had partial response. Four patients had SD; 12 progressed. Tumor O-6-methylguanine-DNA methyltransferase (MGMT) promoter was unmethylated in all nine patients analyzed including from the two CR patients. Pretreatment tumor microarray results were obtained in 16 of 19 patients., Conclusions: The response proportion to TMZ in the neoadjuvant setting was 16%, not different than in the metastatic setting. Responses were seen even in tumors with a methylated MGMT promoter. Pretreatment cryopreserved tumor adequate for microarray analysis could be obtained in most, but not all, patients. Post-treatment tumor was unavailable in complete responders.

One of the key criteria that informs patient management decisions for colorectal cancer is the extent of the shortest distance from the edge of the primary tumour to the edge of the mesorectum, also referred to as circumferential resection margin (CRM). This region is resected during surgery. The CRM is difficult for clinicians to measure accurately, particularly from 2D slice data. We present a method for automatically calculating and visualising the CRM distances in colorectal cancer MR images. We use local phase of the monogenic signal calculated from the MR image intensities to find edge and ridge features within the data. A non-parametric mixture model is then used to describe image intensity values within level set framework in order to segment the mesorectal fascia and the corresponding tumour and lymph nodes, as distinct regions. This segmentation is used to provide an automatic analysis of the shortest distance resection margin, and we show that this is consistent with that of the clinically accepted MERCURY method. We use the segmentation to provide a 3D visualisation of where the resection margin is smallest. Finally, we reconstruct a 3D map of the segmented anatomy. Both the visualisation methods provide a useful tool to aid surgeons in their treatment planning., (Copyright 2010 Elsevier B.V. All rights reserved.)

gamma-Glutamyl transferase (GGT) regulates glutathione metabolism and cysteine supply. GGT inactivation in GGT(enu1) mice limits cysteine availability causing cellular glutathione deficiency. In lung, the resultant oxidant burden is associated with increased nitric oxide (NO) production, yet GGT(enu1) mice still exhibit higher mortality in hyperoxia. We hypothesized that NO metabolism is altered under severe oxidant stress and contributes to lung cellular injury and death. We compared lung injury, NO synthase (NOS) expression, nitrate/nitrite production, nitroso product formation, peroxynitrite accumulation, and cell death in wild-type and GGT(enu1) mice in normoxia and hyperoxia. The role of NOS activity in cell death was determined by NOS inhibition. Exposure of wild-type mice to hyperoxia caused increased lung injury, altered NO metabolism, and induction of cell death compared with normoxia, which was attenuated by NOS inhibition. Each of these lung injury indices were magnified in hyperoxia-exposed GGT(enu1) mice except nitrosation, which showed a diminished decrease compared with wild-type mice. NOS inhibition attenuated cell death only slightly, likely due to further exacerbation of oxidant stress. Taken together, these data suggest that apoptosis in hyperoxia is partially NO-dependent and reiterate the importance of cellular glutathione in lung antioxidant defense. Therefore, reduced denitrosylation of proteins, possibly resulting in impaired cellular repair, and excessive apoptotic cell death likely contribute to increased lung injury and mortality of GGT(enu1) mice in hyperoxia.

We present a model for tumour metabolism that incorporates both microenvironmental (extracellular) and oncogenic (intracellular) influences. We explore the effects of the interaction between the hypoxic microenvironment and intracellular signalling on the glycolytic response of tumour tissue, finding that the glycolytic state is dependent on a delicately balanced interplay between the cellular hypoxic response, mediated by hypoxia-inducible factor-1alpha (HIF-1alpha), and growth-factor signalling cascades, which are frequently mutated in cancers. Our findings demonstrate the importance of considering both environmental and intracellular regulation when interpreting tumour metabolism for diagnostic or prognostic purposes. To illustrate this, we demonstrate the potential impact of this multi-factorial regulation on the kinetics of radiolabelled glucose analogues, used in positron emission tomography (PET).

The early detection of breast cancer greatly improves prognosis. One of the earliest signs of cancer is the formation of clusters of microcalcifications. We introduce a novel method for microcalcification detection based on a biologically inspired adaptive model of contrast detection. This model is used in conjunction with image filtering based on anisotropic diffusion and curvilinear structure removal using local energy and phase congruency. An important practical issue in automatic detection methods is the selection of parameters: we show that the parameter values for our algorithm can be estimated automatically from the image. This way, the method is made robust and essentially free of parameter tuning. We report results on mammograms from two databases and show that the detection performance can be improved by first including a normalisation scheme.

The endothelial cell protein C receptor (EPCR) augments protein C activation by the thrombin-thrombomodulin complex. Deletion of the EPCR gene (Procr) in mice leads to embryonic lethality before embryonic day 10 (E10.0). EPCR is detected in the giant trophoblast cells at the feto-maternal boundary from E7.5 and weakly in embryonic aortic endothelial cells from E13.5, suggesting that extraembryonic EPCR expression may be essential for embryonic viability. Using conditional knock-out strategies, we demonstrate that Procr-deficient embryos with EPCR expression on placenta giant trophoblasts can be carried to term and then develop normally. Conversely, EPCR expression in the embryo, without expression in the giant trophoblast cells, does not rescue the mice. In genetically modified mice with low tissue factor activity, Procr deficiency is not lethal to the embryo. As adults, Procr-deficient mice generate more thrombin and activate less protein C in response to procoagulant stimuli. Spontaneous thrombin formation in the deficient animals increases with age. These findings show that extraembryonic EPCR expression is critical for embryo development.

An analysis procedure is presented that enables the acquisition and visualization of physiologically relevant parameters using dynamic contrast-enhanced magnetic resonance imaging. The first stage of the process involves the use of a signal model that relates the measured magnetic resonance signal to the contrast agent concentration. Since the model requires knowledge of the longitudinal relaxation time T(1), a novel optimization scheme is presented which ensures a reliable measurement. Pharmacokinetic modelling of the observed contrast agent uptake is then performed to obtain physiological parameters relating to microvessel leakage permeability and volume fraction and the assumptions made in the derivation of these parameters are discussed. A simple colour representation is utilized that enables the relevant physiological information to be conveyed to the clinician in a visually efficient and meaningful manner. A second representation, based on vector maps, is also devised and it is demonstrated how this can be used for malignant tumour segmentation. Finally, the procedure is applied to 14 pre- and post-chemotherapy breast cases to demonstrate the clinical value of the technique. In particular, the apparent improved representation of tissue vascularity when compared to conventional methods and the implications for this in treatment assessment are discussed.

This article describes a new method for non-rigid alignment of multimodal images. Multimodal image registration is most often accomplished by modelling, in some sense, an intensity mapping between the images. Here, the alternative strategy of modelling a relationship between local image phase is introduced. This method is intrinsically image feature based, and searches for relationships between feature appearances, rather than tissue class intensity. This enables registration of modalities for which image intensity is not a simple function of tissue class, for example ultrasound. It is also demonstrated that this method performs comparably to an intensity method even when the images are related by a simple intensity transform, but that the phase method is significantly more robust to image artifacts which corrupt the ideal intensity mapping.

Background: Amelogenesis imperfecta (AI) is a hereditary dental condition with poor esthetics and dental sensitivity that frequently requires extensive dental treatment. The authors hypothesized that AI is associated with a negative psychosocial outcome., Methods: Family members with and without AI completed a questionnaire including demographic and dental history questions, as well as a number of psychometric scales. The authors investigated the effects of AI status (with versus without), sex and age on each of the psychosocial outcomes using a generalized linear model., Results: Subjects with AI (n = 30) had higher levels of social avoidance and distress, as well as higher levels of dysfunction, discomfort and disability attributable to their oral condition compared with subjects without AI (n = 29). The relationship of AI status to fear of negative evaluation, mastery and self-esteem was age-dependent. Younger subjects with AI tended to have higher fear of negative evaluation scores, while older subjects without AI tended to have higher fear of negative evaluation scores. Additionally, subjects without AI showed a definite decrease in mastery and self-esteem scores with age, while subjects with AI tended to show an increase in mastery and self-esteem scores with age., Conclusions: These results indicate that having AI has a marked impact on the psychosocial health of affected people comparable with the impact of systemic health conditions, especially at younger ages., Clinical Implications: Dental coverage for AI traditionally is excluded by third-party payers as being solely for esthetic reasons. The authors' study shows that AI has marked psychosocial effects, which suggests that dental treatment could be medically necessary and has far-reaching implications for the affected person's overall health.