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Background Alcohol use disorders (AUD) are prevalent and often go untreated. Patients are commonly screened for AUD in primary care, but existing treatment programs are failing to meet demand. Digital therapeutics include novel mobile app-based treatment approaches which may be cost-effective treatment options to help fill treatment gaps. The goal of this study was to identify implementation needs and workflow design considerations for integrating digital therapeutics for AUD into primary care. Methods We conducted qualitative interviews with clinicians, care delivery leaders, and implementation staff (n = 16) in an integrated healthcare delivery system in the United States. All participants had experience implementing digital therapeutics for depression or substance use disorders in primary care. Interviews were designed to gain insights into adaptations needed to optimize existing clinical processes, workflows, and implementation strategies for use with alcohol-focused digital therapeutics. Interviews were recorded and transcribed and then analyzed using a rapid analysis process and affinity diagramming. Results Qualitative themes were well represented across health system staff roles. Participants were enthusiastic about digital therapeutics for AUD, anticipated high patient demand for such a resource, and made suggestions for successful implementation. Key insights regarding the implementation of digital therapeutics for AUD and unhealthy alcohol use from our data include: (1) implementation strategy selection must be driven by digital therapeutic design and target population characteristics, (2) implementation strategies should seek to minimize burden on clinicians given the large numbers of patients with AUD who are likely to be interested in and eligible for digital therapeutics, and (3) digital therapeutics should be offered alongside many other treatment options to accommodate individual patients’ AUD severity and treatment goals. Participants also expressed confidence that previous implementation strategies used with other digital therapeutics such as clinician training, electronic health record supports, health coaching, and practice facilitation would be effective for the implementation of digital therapeutics for AUD. Conclusions The implementation of digital therapeutics for AUD would benefit from careful consideration of the target population. Optimal integration requires tailoring workflows to meet anticipated patient volume and designing workflow and implementation strategies to meet the unique needs of patients with varying AUD severity.

Background Most people with opioid use disorder (OUD) have co-occurring substance use, which is associated with lower receipt of OUD medications (MOUD). Expanding MOUD provision and care linkage outside of substance use disorder (SUD) specialty settings is a key strategy to increase access. Therefore, it is important to understand how MOUD providers in these settings approach care for patients with co-occurring substance use. This qualitative study of Veterans Health Administration (VA) clinicians providing buprenorphine care in primary care, mental health, and pain settings aimed to understand (1) their approach to addressing OUD in patients with co-occurring substance use, (2) perspectives on barriers/facilitators to MOUD receipt for this population, and (3) support needed to increase MOUD receipt for this population. Methods We interviewed a purposive sample of 27 clinicians (12 primary care, 7 mental health, 4 pain, 4 pharmacists) in the VA northwest network. The interview guide assessed domains of the Tailored Implementation for Chronic Diseases Checklist. Interviews were transcribed and qualitatively analyzed using inductive content analysis. Results Participants reported varied approaches to identifying co-occurring substance use and addressing OUD in this patient population. Although they reported that this topic was not clearly addressed in clinical guidelines or training, participants generally felt that patients with co-occurring substance use should receive MOUD. Some viewed their primary role as providing this care, others as facilitating linkage to OUD care in SUD specialty settings. Participants reported multiple barriers and facilitators to providing buprenorphine care to patients with co-occurring substance use and linking them to SUD specialty care, including provider, patient, organizational, and external factors. Conclusions Efforts are needed to support clinicians outside of SUD specialty settings in providing buprenorphine care to patients with co-occurring substance use. These could include clearer guidelines and policies, more specific training, and increased care integration or cross-disciplinary collaboration. Simultaneously, efforts are needed to improve linkage to specialty SUD care for patients who would benefit from and are willing to receive this care, which could include increased service availability and improved referral/hand-off processes. These efforts may increase MOUD receipt and improve OUD care quality for patients with co-occurring substance use.

Background Experts recommend that treatment for substance use disorder (SUD) be integrated into primary care. The Digital Therapeutics for Opioids and Other SUD (DIGITS) Trial tests strategies for implementing reSET® and reSET-O®, which are prescription digital therapeutics for SUD and opioid use disorder, respectively, that include the community reinforcement approach, contingency management, and fluency training to reinforce concept mastery. This purpose of this trial is to test whether two implementation strategies improve implementation success (Aim 1) and achieve better population-level cost effectiveness (Aim 2) over a standard implementation approach. Methods/Design The DIGITS Trial is a hybrid type III cluster-randomized trial. It examines outcomes of implementation strategies, rather than studying clinical outcomes of a digital therapeutic. It includes 22 primary care clinics from a healthcare system in Washington State and patients with unhealthy substance use who visit clinics during an active implementation period (up to one year). Primary care clinics implemented reSET and reSET-O using a multifaceted implementation strategy previously used by clinical leaders to roll-out smartphone apps (“standard implementation” including discrete strategies such as clinician training, electronic health record tools). Clinics were randomized as 21 sites in a 2x2 factorial design to receive up to two added implementation strategies: (1) practice facilitation, and/or (2) health coaching. Outcome data are derived from electronic health records and logs of digital therapeutic usage. Aim 1’s primary outcomes include reach of the digital therapeutics to patients and fidelity of patients’ use of the digital therapeutics to clinical recommendations. Substance use and engagement in SUD care are additional outcomes. In Aim 2, population-level cost effectiveness analysis will inform the economic benefit of the implementation strategies compared to standard implementation. Implementation is monitored using formative evaluation, and sustainment will be studied for up to one year using qualitative and quantitative research methods. Discussion The DIGITS Trial uses an experimental design to test whether implementation strategies increase and improve the delivery of digital therapeutics for SUDs when embedded in a large healthcare system. It will provide data on the potential benefits and cost-effectiveness of alternative implementation strategies. ClinicalTrials.gov Identifier: NCT05160233 (Submitted 12/3/2021). https://clinicaltrials.gov/ct2/show/NCT05160233

Extracellular vesicles and exomere nanoparticles are under intense investigation as sources of clinically relevant cargo. Here we report the discovery of a distinct extracellular nanoparticle, termed supermere. Supermeres are morphologically distinct from exomeres and display a markedly greater uptake in vivo compared with small extracellular vesicles and exomeres. The protein and RNA composition of supermeres differs from small extracellular vesicles and exomeres. Supermeres are highly enriched with cargo involved in multiple cancers (glycolytic enzymes, TGFBI, miR-1246, MET, GPC1 and AGO2), Alzheimer’s disease (APP) and cardiovascular disease (ACE2, ACE and PCSK9). The majority of extracellular RNA is associated with supermeres rather than small extracellular vesicles and exomeres. Cancer-derived supermeres increase lactate secretion, transfer cetuximab resistance and decrease hepatic lipids and glycogen in vivo. This study identifies a distinct functional nanoparticle replete with potential circulating biomarkers and therapeutic targets for a host of human diseases., Zhang et al. identify and characterize supermeres as extracellular nanoparticles that exhibit unique biological and functional properties with potential prognostic and therapeutic value across distinct diseases.

To evaluate factors associated with ICU delirium in patients who underwent damage control laparotomy (DCL), with the hypothesis that benzodiazepines and paralytic infusions would be associated with increased delirium risk. We also sought to evaluate the differences in sedation practices between trauma (T) and non-trauma (NT) patients. We reviewed retrospective data from 15 centers in the EAST SLEEP-TIME registry admitted from January 1, 2017 to December 31, 2018. We included all adults undergoing DCL, regardless of diagnosis, who had completed daily Richmond Agitation Sedation Score (RASS) and Confusion Assessment Method-ICU (CAM-ICU). We excluded patients younger than 18 years, pregnant women, prisoners and patients who died before the first re-laparotomy. Data collected included age, number of re-laparotomies after DCL, duration of paralytic infusion, duration and type of sedative and opioid infusions as well as daily CAM-ICU and RASS scores to analyze risk factors associated with the proportion of delirium-free/coma-free ICU days during the first 30 days (DF/CF-ICU-30) using multivariate linear regression. A 353 patient subset (73.2% trauma) from the overall 567-patient cohort had complete daily RASS and CAM-ICU data. NT patients were older (58.9 ± 16.0 years vs 40.5 ± 17.0 years [p

Background Möbius (Moebius) and Poland’s syndromes are two rare congenital syndromes characterized by non-progressive bilateral (and often asymmetric) dysfunction of the 6th and 7th cranial nerves and hypoplasia of the pectoral muscles associated with chest wall and upper limb anomalies respectively. Manifest simultaneously as Poland-Möbius (Poland-Moebius) syndrome, debate continues as to whether this is a distinct nosological entity or represents phenotypic variation as part of a spectrum of disorders of rhomboencephalic development. Etiological hypotheses implicate both genetic and environmental factors. The PLXND1 gene codes for a protein expressed in the fetal central nervous system and vascular endothelium and is thus involved in embryonic neurogenesis and vasculogenesis. It is located at chromosome region 3q21-q22, a locus of interest for Möbius syndrome. Case presentation We present the first report of a patient with Poland-Möbius syndrome and a mutation in the PLXND1 gene. A child with Poland-Möbius syndrome and a maternally inherited missense variant (NM_015103.2:ex14:c.2890G > Ap.V964M) in the PLXND1 gene is described. In order to contextualize these findings, the literature was examined to identify other confirmed cases of Poland-Möbius syndrome for which genetic data were available. Fourteen additional cases of Poland-Möbius syndrome with genetic studies are described in the literature. None implicated the PLXND1 gene which has previously been implicated in isolated Möbius syndrome. Conclusions This report provides further evidence in support of a role for PLXND1 mutations in Möbius syndrome and reasserts the nosological link between Möbius and Poland’s syndromes. Level of evidence Level V, Descriptive Study.

BACKGROUND: Hepatitis C and HIV are associated with opioid use disorders (OUD) and injection drug use. Medications for OUD can prevent the spread of HCV and HIV. OBJECTIVE: To describe the prevalence of documented OUD, as well as receipt of office-based medication treatment, among primary care patients with HCV or HIV. DESIGN: Retrospective observational cohort study using electronic health record and insurance data. PARTICIPANTS: Adults ≥ 18 years with ≥ 2 visits to primary care during the study (2014–2016) at 6 healthcare systems across five states (CO, CA, OR, WA, and MN). MAIN MEASURES: The primary outcome was the diagnosis of OUD; the secondary outcome was OUD treatment with buprenorphine or oral/injectable naltrexone. Prevalence of OUD and OUD treatment was calculated across four groups: HCV only; HIV only; HCV and HIV; and neither HCV nor HIV. In addition, adjusted odds ratios (AOR) of OUD treatment associated with HCV and HIV (separately) were estimated, adjusting for age, gender, race/ethnicity, and site. KEY RESULTS: The sample included 1,368,604 persons, of whom 10,042 had HCV, 5821 HIV, and 422 both. The prevalence of diagnosed OUD varied across groups: 11.9% (95% CI: 11.3%, 12.5%) for those with HCV; 1.6% (1.3%, 2.0%) for those with HIV; 8.8% (6.2%, 11.9%) for those with both; and 0.92% (0.91%, 0.94%) among those with neither. Among those with diagnosed OUD, the prevalence of OUD medication treatment was 20.9%, 16.0%, 10.8%, and 22.3%, for those with HCV, HIV, both, and neither, respectively. HCV was not associated with OUD treatment (AOR = 1.03; 0.88, 1.21), whereas patients with HIV had a lower probability of OUD treatment (AOR = 0.43; 0.26, 0.72). CONCLUSIONS: Among patients receiving primary care, those diagnosed with HCV and HIV were more likely to have documented OUD than those without. Patients with HIV were less likely to have documented medication treatment for OUD. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11606-020-06389-7.

We review the underappreciated problem of elder abuse with a focus on what trauma surgeons need to know. Because of its prevalence, it is important that clinicians understand types of elder abuse, risk factors in patient and perpetrator, prevention strategies, and the appropriate referral and treatment of potential victims of elder abuse. Elder abuse affects at least 10% of older individuals in the USA. Despite much effort to address the problem via legal and societal approaches, data to support particular programs are poor. And even with extensive efforts, the utility of established prevention strategies or existing screening tools to identify victims of elder abuse in the acute care setting has yet to be established. Elder abuse is a public health problem. As a society, we have only begun to define the extent of the problem. Healthcare systems have failed to effectively prevent or to accurately screen for, diagnose, and report elder abuse. The next steps include broader public awareness, educational initiatives, improved screening tools, and effective intervention strategies. In the meantime, we as trauma surgeons can be more diligent in reporting.

Background Epithelial-to-mesenchymal transition (EMT) is a process linked to metastasis and drug resistance with non-coding RNAs (ncRNAs) playing pivotal roles. We previously showed that miR-100 and miR-125b, embedded within the third intron of the ncRNA host gene MIR100HG, confer resistance to cetuximab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody, in colorectal cancer (CRC). However, whether the MIR100HG transcript itself has a role in cetuximab resistance or EMT is unknown. Methods The correlation between MIR100HG and EMT was analyzed by curating public CRC data repositories. The biological roles of MIR100HG in EMT, metastasis and cetuximab resistance in CRC were determined both in vitro and in vivo. The expression patterns of MIR100HG, hnRNPA2B1 and TCF7L2 in CRC specimens from patients who progressed on cetuximab and patients with metastatic disease were analyzed by RNAscope and immunohistochemical staining. Results The expression of MIR100HG was strongly correlated with EMT markers and acted as a positive regulator of EMT. MIR100HG sustained cetuximab resistance and facilitated invasion and metastasis in CRC cells both in vitro and in vivo. hnRNPA2B1 was identified as a binding partner of MIR100HG. Mechanistically, MIR100HG maintained mRNA stability of TCF7L2, a major transcriptional coactivator of the Wnt/β-catenin signaling, by interacting with hnRNPA2B1. hnRNPA2B1 recognized the N6-methyladenosine (m6A) site of TCF7L2 mRNA in the presence of MIR100HG. TCF7L2, in turn, activated MIR100HG transcription, forming a feed forward regulatory loop. The MIR100HG/hnRNPA2B1/TCF7L2 axis was augmented in specimens from CRC patients who either developed local or distant metastasis or had disease progression that was associated with cetuximab resistance. Conclusions MIR100HG and hnRNPA2B1 interact to control the transcriptional activity of Wnt signaling in CRC via regulation of TCF7L2 mRNA stability. Our findings identified MIR100HG as a potent EMT inducer in CRC that may contribute to cetuximab resistance and metastasis by activation of a MIR100HG/hnRNPA2B1/TCF7L2 feedback loop.

OBJECTIVES. To examine factors that account for women veterans’ higher prevalence of past-year DSM-5 posttraumatic stress disorder (PTSD) compared to women civilians and men veterans. METHODS. Cross-sectional analyses of the 2012–2013 National Epidemiologic Survey on Alcohol and Related Conditions-III (NESARC-III). Face-to-face interviews with 379 women veterans, 20,007 women civilians, and 2,740 men veterans were conducted. Trauma type (child abuse, interpersonal violence, combat or war zone, and other), number of trauma types, past-year stressful life events, current social support, and DSM-5 PTSD were assessed using the Alcohol Use Disorder and Associated Disabilities Interview Schedule-5. Generalized linear models were used that accounted for the complex survey design. RESULTS. Women veterans had a higher unadjusted prevalence of past-year PTSD (11.40%) compared to their civilian (5.96%) and male (5.19%) counterparts. Individual predictor models indicated that the difference between women veterans’ and civilians’ prevalence of PTSD was attenuated when adjusting for number of trauma types, whereas the difference between men and women veterans was attenuated when adjusting for child abuse, interpersonal violence, and stressful life events. Nonetheless, while full adjustment in a multiple predictor model accounted for the difference in PTSD between women veterans and civilians, gender differences between men and women veterans remained. CONCLUSIONS. Number of trauma types, type of trauma, and social factors may together help explain women veterans’ higher PTSD prevalence compared to women civilians, but do not fully account for differences between men and women veterans. Results highlight a need to explore additional explanatory factors and evaluate associations with longitudinal data.

Some industry observers and medical professionals, and even the popular media, assert that pharmaceutical companies are conducting an increasing number of clinical trials in countries outside the more established geographies of North America and Western Europe as a way to minimize costs, speed clinical trial completion and reduce regulatory oversight. This raises a number of medical and ethical issues. We sought to establish the degree to which pharmaceutical companies, between 2008 and 2012, have moved phase 3 clinical trials from the traditional research geographies of North America and Europe to less economically developed geographies. We present descriptive summaries of our findings from ClinicalTrials.gov. To test the significance of our findings, we designed a mixed logistic regression analysis with the outcome variable designated as whether or not the site was a site within a traditional clinical trial market. The results demonstrate that there has been very little overall change between 2008 and 2012 where phase 3 studies are conducted. There is virtually no shift in the distribution of studies conducted in the traditional clinical trial areas of North America and Western Europe. Across the five-year window, the percentage of North American sites was 39 % while the percent of sites in Western Europe barely changed from 26 to 25 %. There was little change in the geographic distribution of phase 3 sites during the period covered by the analysis.

The name of author Hans Oh was presented incorrectly as “By Hans Oh” in this article as original published.

Since 2007, the US federal government has required that organizations sponsoring clinical trials with a least one site in the United States submit information on these clinical trials to an existing database: ClinicalTrials.gov . Over time, the number of mandatory variables has grown and will probably continue to grow. The database now represents an important source of descriptive information about the landscape for clinical trials. In addition, it constitutes a rich pool of data to test hypotheses-for instance, what variables are associated with an organization's ability to correctly estimate study completion times or complete those studies in as short a time frame as possible. This paper concludes that for mandated variables that the authors have labeled study identification, protocol and study design, and study execution, the data set constitutes a potentially very valuable research resource. With the exception of some site-related information, incomplete data did not exceed 3%. The incomplete site data are concentrated in several companies, so it is not unreasonable to assume that those data will also become more complete.

In 2016, the International Network on Brief Interventions for Alcohol & Other Drugs convened a meeting titled "Rethinking alcohol interventions in health care". The aims of the meeting were to synthesize recent evidence about screening and brief intervention and to set directions for research, practice, and policy in light of this evidence. Screening and brief intervention is efficacious in reducing self-reported alcohol consumption for some with unhealthy alcohol use, but there are gaps in evidence for its effectiveness. Because screening and brief intervention is not known to be efficacious for individuals with more severe unhealthy alcohol use, recent data showing the lack of evidence for referral to treatment as part of screening and brief intervention are alarming. While screening and brief intervention was designed to be a population-based approach, its reach is limited. Implementation in real world care also remains a challenge. This report summarizes practice, research, and policy recommendations and key research developments from our meeting. In order to move the field forward, a research agenda was proposed to (1) address evidence gaps in screening, brief intervention, and referral to treatment, (2) develop innovations to address severe unhealthy alcohol use within primary care, (3) describe the stigma of unhealthy alcohol use, which obstructs progress in prevention and treatment, (4) reconsider existing conceptualizations of unhealthy alcohol use that may influence health care, and (5) identify efforts needed to improve the capacity for addressing unhealthy alcohol consumption in all world regions.

Pelvic fractures can lead to life-threatening hemorrhage, particularly as they tend to occur in the setting of polytrauma. Several approaches to hemorrhage control have been employed in pelvic fracture patients over the years. This review describes the indications, operative technique, and outcomes for preperitoneal pelvic packing (PPP). Pelvic packing should be considered for every hemodynamically unstable patient with a significant pelvic fracture. We describe how this can be accomplished in coordination with other resuscitative efforts and operative needs.

We constructed a model to predict the potential distribution of Oligoryzomys longicaudatus, the reservoir of Andes virus (Genus: Hantavirus), in Argentina. We developed an extensive database of occurrence records from published studies and our own surveys and compared two methods to model the probability of O. longicaudatus presence; logistic regression and MaxEnt algorithm. The environmental variables used were tree, grass and bare soil cover from MODIS imagery and, altitude and 19 bioclimatic variables from WorldClim database. The models performances were evaluated and compared both by threshold dependent and independent measures. The best models included tree and grass cover, mean diurnal temperature range, and precipitation of the warmest and coldest seasons. The potential distribution maps for O. longicaudatus predicted the highest occurrence probabilities along the Andes range, from 32°S and narrowing southwards. They also predicted high probabilities for the south-central area of Argentina, reaching the Atlantic coast. The Hantavirus Pulmonary Syndrome cases coincided with mean occurrence probabilities of 95 and 77% for logistic and MaxEnt models, respectively. HPS transmission zones in Argentine Patagonia matched the areas with the highest probability of presence. Therefore, colilargos presence probability may provide an approximate risk of transmission and act as an early tool to guide control and prevention plans.

Introduction: Latin America currently represents a relatively small but constant number of clinical sites for commercially funded studies. This article describes the profiles of sites and investigators involved in commercial clinical research and compares the results with published results of similar US investigators. In addition, the research examines investigators’ motives for taking part in clinical research and the concerns these investigators have with the operational challenge of conducting these studies. Methods: The data were drawn from a survey of investigators involved in commercially funded clinical trials in Argentina, Brazil, Chile, Colombia, Ecuador, El Salvador, Guatemala, Honduras, Mexico, Peru and Venezuela. The questionnaire comprised a list of 12 reasons related to why an investigator might participate in a phase III clinical trial of a new compound being tested by a pharmaceutical company, and respondents were asked to rate the importance of each reason on a scale of 12–10, with 1 being not important at all and 10 being very important. Surveys were conducted in 2008–9 and data were compared with a published analysis of US clinical investigators. Factor analysis, ANOVA, chi-square, gamma statistics and approximate significance measures were used to analyse the survey responses. All analyses were conducted using SPSS version 17. Results: The clinical experience of Latin American investigators is generally somewhat less than that of US investigators. Among other things, Latin America conducts a vastly greater portion of its research in hospitals compared with the US; few investigators work in private practice, in contrast to the US pattern. In addition, a far larger percentage of clinical research is conducted at dedicated sites than is the case in the US. Latin American investigators, along with their US counterparts, stress the importance of taking part in medical innovation as the primary reason for their involvement in commercially funded clinical research. Latin American investigators especially value the opportunity to work with other physicians on the study. Financial considerations, while not unimportant in Latin America, are secondary to this desire to be a part of medical innovation. Latin American investigators do differ somewhat from the US respondents in the importance they place on certain operational aspects of a clinical study. For instance, Latin American investigators are distinctly more concerned that a major pharmaceutical company sponsors the study than is the case with US investigators. In general, with the one noteworthy exception of serious adverse event reporting, Latin American and US investigators seem to have fairly comparable areas of dissatisfaction in the conduct of clinical trials. Conclusions: Latin America represents a particularly attractive growth market for pharmaceutical products. With a population in the hundreds of millions the demand for prescription drugs will make the need to conduct clinical research there essential for global pharmaceutical companies. Understanding the motivation of Latin American investigators should be valuable in helping such companies develop their clinical trial strategies and tactics.

In this study, we evaluated the peri-operative abdominal drain volumes and length of hospital admission between our superficial inferior epigastric artery (SIEA) and deep inferior epigastric artery perforator (DIEP) patients to determine whether SIEA flaps were associated with increased post-operative abdominal drainage and length of hospital stay. We studied consecutive patients who had breast reconstruction using either a free SIEA (seven) or DIEP (28) flaps. All patients had abdominal drains inserted, and cumulative drainage measurements were taken every 24 h. Data on patient's age, BMI, length of hospital stay, smoking history, and abdominal fluid drainage were collected. Statistical analyses were performed using a t test (Mann–Whitney). A statistically significant difference (P = 0.029) was observed in the total abdominal drainage between the two groups. The mean drainage volume in the SIEA group was 2,248 ml and 531 ml in the DIEP group. No association was observed between smoking and drainage volume in the DIEP group. Similarly, obesity did not appear to influence drainage volumes in either the SIEA or the DIEP groups. The average length of stay for the SIEA group was 10.4 days and 9.1 days in the DIEP group, although this was not statistically significant (P = 0.351). While abdominal wall morbidity is reduced in patients undergoing an SIEA flap for breast reconstruction, in our series, we found that the SIEA flap was associated with a significant increase in abdominal drain volume relative to the DIEP flap, which translated to an extra day in hospital.

Background: Studies managed by contract research organizations (CROs) make up a significant portion of all clinical research activities. Despite this, there have been few analyses of investigator attitudes about the type of organization (i.e. CRO or sponsor company) that directly manages the investigator’s clinical trial. Methods:Utilizing a random sample of 5000 US investigators from the US Food and Drug Administration (FDA) 1572 database, the University of the Sciences in Philadelphia and TTC llc conducted a questionnairebased mail survey. Results:A total of 762 US investigators responded to the questionnaire. Investigators returning a completed questionnaire were more likely to come from an academic medical centre, be involved in teaching or be located at a research centre than non-respondents. They also had more 1572 records on file with the FDA, were older, but did not differ by sex. Nearly one-third of investigators preferred working directly with sponsor companies; two-thirds had no preference or actually preferred a CRO. These three types of investigators differed little in their reasons for participating in clinical trials. Each group cited the opportunity to participate in the research of innovative medical treatments as their primary motivation. Conclusions: Older investigators with more research experience do somewhat prefer a sponsor company to manage the clinical trial, although this group participates in a high percentage of CRO-managed studies.

Modeling mosquito population dynamics has become an important part of understanding the transmission of mosquito-borne arboviruses. Of these models, those including meteorological variables have mainly focused on conditions during or immediately preceding the mosquito breeding season. While these conditions are clearly critical biologically and statistically, it is also biologically plausible that conditions during the off-season may contribute to interannual variation in mosquito population size. To examine the effect of off-season factors, we develop a pair of Poisson regression models for July captures of Aedes sollicitans and Culex salinarius, two East Coast vector species of arboviruses including Eastern equine encephalitis virus and West Nile virus. Model results indicate that average maximum temperature, total heating degree-days, and the total number of days with a minimum temperature below freezing during the winter months was predictive of mosquito populations. In addition, the average maximum relative humidity from the preceding fall and total rainfall and total heating degree-days during the preceding spring were also associated with vector population dynamics. The descriptive and predictive power of these models is discussed.

This article examines the demographic, practice, and prescribing behavior of US principal investigators, especially those conducting outpatient clinical trials. US investigators are predominantly office based but are more likely than the general US physician population to be teaching, conducting research, or working at academic medical centers. When compared with the US physician population, investigators are somewhat older, more likely to be male, prescribe at levels comparable to their practice peers, and more likely to be board certified. However, there appear to be few demographic, practice, or prescribing differences between physicians who conduct numerous clinical trials and those who conduct few trials. For the many physicians who only participate in one or two clinical trials, the reasons for this limited participation must be due to factors other than these investigators' demographic, practice and prescribing characteristics.

This paper explores the impact of various factors on completion times in phase III clinical trials; specifically, why some sites are able to complete more patients during the course of the clinical trial than other sites, including those within the same trial. Seven companies provided research data for inclusion in this analysis. The study sample inclusion criteria were the indications of asthma, chronic obstructive pulmonary disease, depression, schizophrenia, bipolar disorder, hypertension, type 2 diabetes mellitus or menopausal syndrome; phase III; study completion between 2002 and 2005; a New Chemical Entity for an initial (primary) indication and formulation; adult outpatient subjects; and multinational design, with sites in the US, at least one Western European country, and at least one Eastern or Central European country. The analysis assessed both study-level and site-level variables. This paper analyses the results from 262 phase III studies, involving 2047 sites, meeting the stated inclusion criteria. Unsurprisingly, the number of enrolled patients is a clear predictor of the number of completed patients (standardised beta coefficient 0.877; p=0.001). Better performing sites started enrolling patients earlier than other sites and continued to enrol patients over a longer period of time. The time between when a site enrols its first patient and the time the first site in that study enrols its first patient, is a specific predictor of how well a given site will perform; indeed the relationship is inverse so that the greater the time difference, the poorer the performance. Sites involved in studies using competitive enrolment and milestone payments generally complete a higher number of patients. The same holds for sites in clinical trials using upfront, nonrefundable start-up payments, although the relationship is weaker. Interestingly, higher grant payment levels do not translate into better site performance. Site level variables were consistent with study level variables. In addition, investigators with more recent clinical research experience with that sponsor company perform better and sites using a central institutional review board (IRB) outperform sites using local IRBs or a combination of central and local IRBs. Three major conclusions emerge from the analysis. First, better performing sites begin enrolling quickly, providing more time to enrol patients, and these sites continue to enrol and complete patients over that extended period of time. Second, investigators with overall clinical experience, especially with the sponsor company, are usually the better performers. Third, how much an investigator is paid seems less important than how that investigator is paid. Higher payment levels are not associated with improved site performance. In contrast, the use of competitive enrolment and milestone payments does seem to positively affect performance.

Background: Clinical investigator physicians who take part in clinical trials influence how other doctors adopt new drugs; however, not much is known about the attributes of these investigators (usually with office-based practices and a smaller number working in hospitals or academic medical centres) who tend to prescribe more of the study drug once it gets to the market.

Geostatistics is a set of statistical techniques used in the analysis of georeferenced data that can be applied to environmental contamination and remediation studies. In this study, the 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE) contamination at a Superfund site in western Maryland is evaluated. Concern about the site and its future clean up has triggered interest within the community because residential development surrounds the area. Spatial statistical methods, of which geostatistics is a subset, are becoming increasingly popular, in part due to the availability of geographic information system (GIS) software in a variety of application packages. In this article, the joint use of ArcGIS software and the R statistical computing environment are demonstrated as an approach for comprehensive geostatistical analyses. The spatial regression method, kriging, is used to provide predictions of DDE levels at unsampled locations both within the site and the surrounding areas where residential development is ongoing.

Given the important role of contract research organizations (CROs) in conducting market support clinical trials, this analysis sought to answer the question of whether clinical investigators who participate in CRO-run market support studies subsequently prescribe the study drug differently than investigators in studies directly managed by sponsor companies. The phase 3b sample of investigator cases consisted of 679 randomly drawn clinical study sites, totaling 450 unique physicians. An additional 488 unique physicians, who had been involved as principle investigators at 534 phase 4 clinical trials sites, were randomly selected. Approximately 75% of the investigators came from sponsor company-run clinical trials, with the remaining 25% from CRO-run clinical trials. An analysis of covariance indicates that investigators in sponsor company-run clinical trials subsequently prescribe significantly more of the study drug, particularly in phase 3b trials.

The objective of this research is to explore what would happen if the Hong Kong influenza pandemic strain of 1968-1969 returned in 2000. We report the results of a series of simulations of an SEIR epidemic model coupled with air transportation data for 52 global cities. Preliminary results suggest that if the 1968-1969 pandemic strain returned, it would spread concurrently to cities in both the northern and southern hemispheres thereby exhibiting less of the characteristic seasonal swing. In addition, after recognition of pandemic onset in the focal city, the time lag for public health intervention is very short. These findings highlight the importance of coordinated global surveillance and pandemic planning.

Although the immunologic effects of endogenous and synthetic estrogens are well studied, few studies have examined the hormonal effects of phytoestrogens (i.e., plant-derived estrogens) on the immune system. The primary goal of this study was to compare the effects of perinatal exposure with life-long exposure to genistein, an estrogenic compound in soy, on the endocrine and immune system in adulthood. Pregnant female rats were exposed to no, low (5 mg/kg diet), or high (300 mg/kg diet) genistein diets throughout gestation and lactation. At weaning, male offspring exposed to genistein perinatally were either switched to the genistein-free diet or remained on the genistein-dosed diets. At 70 days of age, immune organ masses, lymphocyte subpopulations, cytokine concentrations, and testosterone concentrations were assessed in male offspring. Data were analyzed based on the diets that males were exposed to during gestation and lactation because life-long exposure to genistein had no additional effect on any of the dependent measures. Relative thymus masses were greater among males exposed to the high genistein diet than among males exposed to no genistein. Although the proportions of splenic and thymic CD4+ T cells were not altered by genistein, the percentages of CD4+CD8+ thymocytes, CD8+ splenocytes, and total T cells in the spleen were higher and the percentages of CD4−CD8− thymocytes were lower among males exposed to genistein than among males not exposed to genistein. Synthesis of interferon-γ (IFN-γ) was marginally higher and testosterone concentrations were lower among genistein-exposed than genisteinfree males. These data illustrate that exposure to genistein during pregnancy and lactation exerts long-lasting effects on the endocrine and immune systems in adulthood. Whether exposure to phytoestrogens during early development affects responses to infectious or autoimmune diseases, as well as cancers, later in life requires investigation.

Background Francisella tularensis, the causative agent of tularemia, is a zoonotic agent that remains across much of the northern hemisphere, where it exists in enzootic cycles. In Ukraine, tularemia has a long history that suggests a need for sustained surveillance in natural foci. To better characterize the host-vector diversity and spatial distribution of tularemia, we analyzed historical data from field collections carried out from 1941 to 2008. Findings We analyzed the spatial-temporal distribution of bacterial isolates collected from field samples. Isolates were characterized by source and dominant land cover type. To identify environmental persistence and spatial variation in the source of isolation, we used the space-time permutation and multinomial models in SaTScan. A total of 3,086 positive isolates were taken from 1,084 geographic locations. Isolation of F. tularensis was more frequent among arthropods [n = 2,045 (66.3%)] followed by mammals [n = 619 (20.1%)], water [n = 393 (12.7%)], and farm produce [n = 29 (0.94%)], respectively. Four areas of persistent bacterial isolation were identified. Water and farm produce as sources of bacterial isolation were clustered. Conclusions Our findings confirm the presence of long-standing natural foci of F. tularensis in Ukraine. Given the history of tularemia as well as its environmental persistence there exists a possibility of (re)emergence in human populations. Heterogeneity in the distribution of tularemia isolate recovery related to land cover type supports the theory of natural nidality and clusters identify areas to target potential sources of the pathogen and improve surveillance. Electronic supplementary material The online version of this article (doi:10.1186/s13071-014-0453-2) contains supplementary material, which is available to authorized users.

Healthcare reform in the United States is encouraging Federally Qualified Health Centers and other primary-care practices to integrate treatment for addiction and other behavioral health conditions into their practices. The potential of mobile health technologies to manage addiction and comorbidities such as HIV in these settings is substantial but largely untested. This paper describes a protocol to evaluate the implementation of an E-Health integrated communication technology delivered via mobile phones, called Seva, into primary-care settings. Seva is an evidence-based system of addiction treatment and recovery support for patients and real-time caseload monitoring for clinicians. Our implementation strategy uses three models of organizational change: the Program Planning Model to promote acceptance and sustainability, the NIATx quality improvement model to create a welcoming environment for change, and Rogers’s diffusion of innovations research, which facilitates adaptations of innovations to maximize their adoption potential. We will implement Seva and conduct an intensive, mixed-methods assessment at three diverse Federally Qualified Healthcare Centers in the United States. Our non-concurrent multiple-baseline design includes three periods — pretest (ending in four months of implementation preparation), active Seva implementation, and maintenance — with implementation staggered at six-month intervals across sites. The first site will serve as a pilot clinic. We will track the timing of intervention elements and assess study outcomes within each dimension of the Reach, Effectiveness, Adoption, Implementation, and Maintenance framework, including effects on clinicians, patients, and practices. Our mixed-methods approach will include quantitative (e.g., interrupted time-series analysis of treatment attendance, with clinics as the unit of analysis) and qualitative (e.g., staff interviews regarding adaptations to implementation protocol) methods, and assessment of implementation costs. If implementation is successful, the field will have a proven technology that helps Federally Qualified Health Centers and affiliated organizations provide addiction treatment and recovery support, as well as a proven strategy for implementing the technology. Seva also has the potential to improve core elements of addiction treatment, such as referral and treatment processes. A mobile technology for addiction treatment and accompanying implementation model could provide a cost-effective means to improve the lives of patients with drug and alcohol problems. ClinicalTrials.gov ( NCT01963234 ).

Background: Malaria control interventions have been scaled-up in Zambia in conjunction with a malaria surveillance system. Although substantial progress has been achieved in reducing morbidity and mortality, national and local information demonstrated marked heterogeneity in the impact of malaria control across the country. This study reports the high burden of malaria in Nchelenge District, Luapula Province, Zambia from 2006 to 2012 after seven years of control measures. Methods: Yearly aggregated information on cases of malaria, malaria deaths, use of malaria diagnostics, and malaria control interventions from 2006 to 2012 were obtained from the Nchelenge District Health Office. Trends in the number of malaria cases, methods of diagnosis, malaria positivity rate among pregnant women, and intervention coverage were analysed using descriptive statistics. Results: Malaria prevalence remained high, increasing from 38% in 2006 to 53% in 2012. Increasing numbers of cases of severe malaria were reported until 2010. Intense seasonal malaria transmission was observed with seasonal declines in the number of cases between April and August, although malaria transmission continued throughout the year. Clinical diagnosis without accompanying confirmation declined from 95% in 2006 to 35% in 2012. Intervention coverage with long-lasting insecticide-treated nets and indoor residual spraying increased from 2006 to 2012. Conclusions: Despite high coverage with vector control interventions, the burden of malaria in Nchelenge District, Zambia remained high. The high parasite prevalence could accurately reflect the true burden, perhaps in part as a consequence of population movement, or improved access to care and case reporting. Quality information at fine spatial scales will be critical for targeting effective interventions and measurement of progress.

Inorganic-organic hybrid materials were prepared by hydrolysis and condensation of triethoxysilylated diethylenetriamine (f-DETA) and tetramethoxysilane (TMOS). The prehydrolysis stage of this f-DETA/TMOS system was monitored by 29Si NMR spectroscopy. The NMR experiments indicated that f-DETA hydrolyzes and condenses nearly as fast as TMOS at pH 0–1, but lags far behind the latter at pH~4.2. Gels derived from f-DETA and TMOS were studied using 13C or 29Si solid state NMR spectroscopy. The concentration of the alkoxy groups and the extent of condensation of the T & Q species in the cured gels were estimated. The contents of the Si–OMe group and Si–OEt group were barely detectable in most water-abundant systems (equivalent ratio of water to alkoxysilane ~4.0). However, a significant amount of Si–O i Pr groups was found if the reactant f-DETA was stored at room temperature in solvent 2-propanol for three weeks or longer. The relative composition of each Tz or Qz species was estimated for gels prepared in media of different acidity levels and water concentrations and then cured at 125–130°C for 4 h. As the acidity of the medium increased from pH 0–2 to pH 4–5, the extent of condensation of the T species decreased but that of the Q species increased. The hydrolysis of urea groups in f-DETA during the sol-gel process was also evaluated by 13C solid state NMR spectroscopy. The results indicated that only a very small fraction of urea groups was hydrolyzed during the sol-gel process.

Polydactyly is one of the most common congenital deformities with an incidence of between 5 and 17 per 10,000 live births. Super-numerary digits of the foot present most commonly at the fibular border. A super-numerary digit arising from the dorsum of the foot has only been described on two occasions. In one case, the digit was thought to be a skin appendage. In the other, the digit shared morphological features with its neighbours but was relatively hypo-plastic and was incapable of active movement. The child was non-syndromic. We present a case of a mobile, active super-numerary digit arising from the dorsum of the foot, the first of its kind to be described in the literature. The child had the rare congenital disorder Kabuki syndrome.

We describe an unusual case of cutaneous necrosis of the nasal tip presenting to a facial reconstructive surgeon. The patient had developed this painless necrosis over a period of about 10 days. Her past medical history included rheumatoid arthritis. She described an exacerbation of her arthritic symptoms in the weeks preceding the development of the nasal tip necrosis. Her rheumatoid arthritis had been managed with corticosteroid and immunosuppressive therapy for more than 3 years. She had not previously experienced extra-articular manifestations (EAMs). A biopsy was taken and histological analysis identified a lymphocytic vasculitis. She was referred to her rheumatologist, and surgical management of her necrotic nasal tip commenced.

Background Malaria control was strengthened in Zambia over the past decade. The two primary interventions for vector control are indoor residual spraying (IRS) and long-lasting insecticide-treated nets (LLINs). Using passive malaria surveillance data collected from 2006 to 2011 through the Zambian District Health Information System, the associations between increased coverage with LLINs and IRS and the burden of malaria in Zambia were evaluated. Methods National passive malaria surveillance data from 2006 to 2011 were analysed. A district-level, random-effects model with Poisson regression was used to explore the association between malaria cases and coverage with LLINs and IRS. Malaria cases and LLINs and IRS coverage were mapped to visualize spatiotemporal variation in malaria for each year. Results From 2006–2011, 24.6 million LLINs were distributed and 6.4 million houses were sprayed with insecticide. Coverage with LLINs was not uniformly distributed over the study period and IRS was targeted to central and southern districts where malaria transmission was low. LLIN coverage was associated with a reduction in malaria cases, although an increase in the number of malaria cases was reported in some districts over the study period. A high burden of malaria persisted in north-eastern Zambia, whereas a reduction in the number of reported malaria cases was observed in western and southern Zambia. Conclusion Enhanced and targeted interventions in north-eastern Zambia where the burden of malaria remains high, as well as efforts to sustain low malaria transmission in the south-west, will be necessary for Zambia to achieve the national goal of being malaria free by 2030.

A 3'-terminal mutation of the gene encoding the beta subunit of Escherichia coli RNA polymerase was isolated using an in vivo polA(Ts) technique. Cloning of the allele was monitored by virtue of the fact that the deletion delta(rpoB)1570-1 resulted in an altered-size restriction fragment. DNA sequencing confirmed the predicted nature and location of the mutation: delta(rpoB)1570-1 involved an in-frame deletion of 186 bp (62 codons) encoding amino acid residues 967-1028. The phenotype conferred by delta(rpoB)1570-1 is discussed with respect to conserved domains within the beta polypeptide.

As the costs of developing drugs continue to soar, pharmaceutical companies are looking to manage these costs more effectively. One of the largest single cost items in drug development is the cost of outside investigators to test new compounds and marketed drugs. Speed, quality, and safety are the most important considerations in conducting a clinical trial. Recently, companies have begun to place a greater emphasis on managing the costs of conducting these clinical trials. One significant way companies are managing investigator grant costs is by shifting studies away from investigators affiliated with hospitals and other medical institutions to independent, or unaffiliated, investigators. The comparable grant costs of these unaffiliated investigators are substantially less on a per patient basis.

Background Critical to sustaining progress in malaria control is comprehensive surveillance to identify outbreaks and prevent resurgence. Serologic responses to Plasmodium falciparum antigens can serve as a marker of recent transmission and serosurveillance may be feasible on a large scale. Methods Satellite images were used to construct a sampling frame for the random selection of households enrolled in prospective longitudinal and cross-sectional surveys in two study areas in Southern Province, Zambia, one in 2007 and the other in 2008 and 2009. Blood was collected and stored as dried spots from participating household members. A malaria rapid diagnostic test (RDT) was used to diagnose malaria. An enzyme immunoassay (EIA) was used to detect IgG antibodies to asexual stage P. falciparum whole parasite lysate using serum eluted from dried blood spots. The expected mean annual increase in optical density (OD) value for individuals with a documented prior history of recent malaria was determined using mixed models. SatScan was used to determine the spatial clustering of households with individuals with serological evidence of recent malaria, and these households were plotted on a malaria risk map. Results RDT positivity differed markedly between the study areas and years: 28% of participants for whom serologic data were available were RDT positive in the 2007 study area, compared to 8.1% and 1.4% in the 2008 and 2009 study area, respectively. Baseline antibody levels were measured in 234 participants between April and July 2007, 435 participants between February and December 2008, and 855 participants between January and December 2009. As expected, the proportion of seropositive individuals increased with age in each year. In a subset of participants followed longitudinally, RDT positivity at the prior visit was positively correlated with an increase in EIA OD values after adjusting for age in 2007 (0.261, p = 0.003) and in 2008 (0.116, p = 0.03). RDT positivity at the concurrent visit also was associated with an increase in EIA OD value in 2007 (mean increase 0.177, p = 0.002) but not in 2008 (−0.063, p =0.50). Households comprised of individuals with serologic evidence of recent malaria overlapped areas of high malaria risk for serologic data from 2009, when parasite prevalence was lowest. Conclusions Serological surveys to whole asexual P. falciparum antigens using blood collected as dried blood spots can be used to detect temporal and spatial patterns of malaria transmission in a region of declining malaria burden, and have the potential to identify focal areas of recent transmission.

Background Historically, the Chittagong Hill Tracts (CHT) of Bangladesh was considered hyperendemic for malaria. To better understand the contemporary malaria epidemiology and to develop new and innovative control strategies, comprehensive epidemiologic studies are ongoing in two endemic unions of Bandarban district of CHT. Within these studies entomological surveillance has been undertaken to study the role of the existing anopheline species involved in the malaria transmission cycle throughout the year. Methods CDC miniature light traps were deployed to collect anopheline mosquitoes from the sleeping room of the selected houses each month in a single union (Kuhalong). Molecular identification was carried out for available Anopheles species complexes. Circumsporozoite proteins (CSP) for Plasmodium falciparum, Plasmodium vivax-210 (Pv-210) and Plasmodium vivax-247(Pv-247) were detected by Enzyme-linked immunosorbent assay (ELISA) from the female anopheline mosquitoes. To confirm CSP-ELISA results, polymerase chain reaction (PCR) was also performed. Results A total of 2,837 anopheline mosquitoes, of which 2,576 were female, belonging to 20 species were collected from July 2009 -June 2010. Anopheles jeyporiensis was the most abundant species (18.9%), followed by An. vagus (16.8%) and An. kochi (14.4%). ELISA was performed on 2,467 female mosquitoes of 19 species. 15 (0.6%) female anophelines belonging to eight species were found to be positive for Plasmodium infection by CSP-ELISA. Of those, 11 (0.4%) mosquitoes were positive for P. falciparum and four (0.2%) for Pv-210. No mosquito was found positive for Pv-247. An. maculatus (2.1%, 2/97) had the highest infection rate followed by An. umbrosus (1.7%, 2/115) and An. barbirostris (1.1%, 2/186). Other infected species were An. nigerrimus, An. nivipes, An. jeyporiensis, An. kochi, and An. vagus. Out of 11 P. falciparum CSP positive samples, seven turned out to be positive by PCR. None of the samples positive for Pv-210 was positive by PCR. In terms of abundance and incrimination, the results suggest that An. maculatus, An. jeyporiensis and An. nivipes play important roles in malaria transmission in Kuhalong. Conclusion The findings of this study suggest that even in the presence of an insecticide impregnated bed-net intervention, a number of Anopheles species still play a role in the transmission of malaria. Further investigations are required to reveal the detailed biology and insecticide resistance patterns of the vector mosquito species in endemic areas in Bangladesh in order to assist with the planning and implementation of improved malaria control strategies.

Background The burden of malaria has decreased dramatically within the past several years in parts of sub-Saharan Africa. Further malaria control will require targeted control strategies based on evidence of risk. The objective of this study was to identify environmental risk factors for malaria transmission using remote sensing technologies to guide malaria control interventions in a region of declining burden of malaria. Methods Satellite images were used to construct a sampling frame for the random selection of households enrolled in prospective longitudinal and cross-sectional surveys of malaria parasitaemia in Southern Province, Zambia. A digital elevation model (DEM) was derived from the Shuttle Radar Topography Mission version 3 DEM and used for landscape characterization, including landforms, elevation, aspect, slope, topographic wetness, topographic position index and hydrological models of stream networks. Results A total of 768 individuals from 128 randomly selected households were enrolled over 21 months, from the end of the rainy season in April 2007 through December 2008. Of the 768 individuals tested, 117 (15.2%) were positive by malaria rapid diagnostic test (RDT). Individuals residing within 3.75 km of a third order stream were at increased risk of malaria. Households at elevations above the baseline elevation for the region were at decreasing risk of having RDT-positive residents. Households where new infections occurred were overlaid on a risk map of RDT positive households and incident infections were more likely to be located in high-risk areas derived from prevalence data. Based on the spatial risk map, targeting households in the top 80th percentile of malaria risk would require malaria control interventions directed to only 24% of the households. Conclusions Remote sensing technologies can be used to target malaria control interventions in a region of declining malaria transmission in southern Zambia, enabling a more efficient use of resources for malaria elimination.

The essential role of DNA-dependent RNA polymerases in gene expression and the fact that the multimeric species are highly conserved throughout nature makes these enzymes a particular fascinating area of study. Here we shall review the conservation of structures and their relationship to function, especially in the multimeric eubacterial RNA polymerases, paying particular attention to the β core subunit and to recent studies of σ-factors of both the σ (70) and σ (54) families. We shall conclude with a brief consideration of phage-encoded RNA polymerases and phage-mediated modification of the host enzyme, and of the evolution of RNA-synthesising enzymes.

Mercury concentrations and depositions for northeastern Minnesota were measured in precipitation to investigate depositional trends, relationships with major cations and anions, and possible source emission regions. Results for 1987–1990 showed that environmentally significant amounts of Hg are present in precipitation and air and are subsequently deposited to remote lake watersheds. Volume-weighted concentrations of total Hg in precipitation averaged about 18 ng Hg L−1 with calculated annual depositions near 15 μg Hg m−2. Mercury concentrations in precipitation are positively correlated with the major ions, conductivity, and pH, and are negatively correlated with precipitation volume. The best predictor equation from stepwise regression has an r2 of 0.65 with Mg and chloride concentrations as predictor variables. From measurements of Hg in rain concentrations as a function of time within events, scavenging ratios for “washable” Hg were calculated to be 140 ± 80 (mass based at a 1 mm hr −1 precipitation rate). Up to about 10% of the total Hg in air is subject to washout by precipitation for a given event. Air parcel back-trajectories indicate that possible source regions within 72-hr travel time were located mostly to the south, southeast, and southwest, up to 2500 km distance away but local sources may also be important.

In this study,1H and13C dynamic nuclear polarization (DNP) was generated at a magnetic field strength of 0.33 T utilizing silica phase immobilized nitroxide (SPIN) samples. The polarization was subsequently transferred to flowing liquids and monitored at a magnetic field strength of 4.7 T. These solid/liquid intermolecular transfer (SLIT) experiments provide efficient polarization transfer without the necessity of the free radical system present in the monitoring fluid. Specifically, ultimate1H SLIT DNP Overhauser enhancements of −56 and −110 have been observed for benzene and chloroform in the presence of SPIN system 2, respectively.

The idea1 that fullerenes might be able to encapsulate atoms and molecules has been verified by the successful synthesis of a range of endohedral fullerenes, in which metallic or non-metallic species are trapped inside the carbon cage2,3,4,5,6,7,8,9,10,11,12,13. Metal-containing endohedral fullerenes have attracted particular interest as they might exhibit unusual material properties associated with charge transfer from the metal to the carbon shell. However, current synthesis methods have typical yields of less than 0.5%, and produce multiple endohedral fullerene isomers, which makes it difficult to perform detailed studies of their properties. Here we show that the introduction of small amounts of nitrogen into an electric-arc reactor allows for the efficient production of a new family of stable endohedral fullerenes encapsulating trimetallic nitride clusters, ErxSc3-xN@C80 (x = 0–3). This ‘trimetallic nitride template’ process generates milligram quantities of product containing 3–5% Sc3N@C80, which allows us to isolate the material and determine its crystal structure, and its optical and electronic properties. We find that the Sc3N moiety is encapsulated in a highly symmetric, icosahedral C80 cage, which is stabilized as a result of charge transfer between the nitride cluster and the fullerene cage. We expect that our method will provide access to a range of small-bandgap fullerene materials, whose electronic properties can be tuned by encapsulating nitride clusters containing different metals and metal mixtures.

The synthesis of soluble imide oligomers of controlled molecular weight endcapped with the 3-phenylethynyl aniline endcapping agent is described. The 3-phenylethynyl aniline was employed to afford a higher curing temperature (380–420°C) which widens the processing window compared to commercially available acetylene endcapped polyimides. The polyimides were synthesized via solution imidization techniques, using the ester-acid of various dianhydrides and various aromatic diamines. The “one pot” procedure utilizes NMP as the solvent and o-dichlorobenzene as the azeotroping agent, and reproducibly exhibit fully imidized soluble polyimides with % MathType!MTEF!2!1!+- % feaagKart1ev2aaatCvAUfeBSjuyZL2yd9gzLbvyNv2CaerbuLwBLn % hiov2DGi1BTfMBaeXatLxBI9gBaerbd9wDYLwzYbItLDharqqr1ngB % PrgifHhDYfgasaacH8srps0lbbf9q8WrFfeuY-Hhbbf9v8qqaqFr0x % c9pk0xbba9q8WqFfea0-yr0RYxir-Jbba9q8aq0-yq-He9q8qqQ8fr % Fve9Fve9Ff0dmeaabaqaciGacaGaaeqabaWaaeaaeaaakeaadaWcga % qaamaanaaabaGaaeytaiaabEhaaaaabaWaa0aaaeaacaqGnbGaaeOB % aaaaaaaaaa!3B6E! $${{\overline {{\text{Mw}}} } \mathord{\left/ {\vphantom {{\overline {{\text{Mw}}} } {\overline {{\text{Mn}}} }}} \right. \kern-\nulldelimiterspace} {\overline {{\text{Mn}}} }}$$ values of ~2.0 determined by gel permeation chromatography. Thermally cured samples display good solvent resistance and exhibit glass transition temperatures comparable to their high molecular weight linear analogs. These polyimides show excellent thermal stability at 700°F aged in air up to 100 hours. Mechanical testing has been performed on a pyromellitic dianhydride (PMDA) and a phosphine oxide-based system. The flow properties have been studied by parallel plate rheology and the cure cycle has been monitored using 13C NMR.

Nature 401, 55–57; 1999 In the second paragraph on page 55, the third sentence is misleading and should read “The yields even exceed those of the empty-cage C84” (without the erroneously inserted text “…the usually most abundant species…”).

We have previously isolated an E. coli derivative carrying a small internal deletion (delta(rpoB)1570-1) of the beta structural gene. This RNA polymerase deletion mutant has no noticeable phenotype other than a slightly increased generation time in minimal medium. The deletion, which removes about 165 bp, has been localised to between codons 965 and 1,083, indicating it excises part of a tandem repeat structure present in the C-terminal region of beta. Analysis in vitro of purified RNA polymerase from the deletion mutant indicates that this enzyme has an altered promoter selectivity. These observations allow localisation of a site on the beta polypeptide of E. coli RNA polymerase involved in transcriptional initiation.