Search

Objectives The rapid expansion of biomedical literature necessitates automated techniques to discern relationships between biomedical concepts from extensive free text. Such techniques facilitate the development of detailed knowledge bases and highlight research deficiencies. The LitCoin Natural Language Processing (NLP) challenge, organized by the National Center for Advancing Translational Science, aims to evaluate such potential and provides a manually annotated corpus for methodology development and benchmarking. Materials and Methods For the named entity recognition (NER) task, we utilized ensemble learning to merge predictions from three domain-specific models, namely BioBERT, PubMedBERT, and BioM-ELECTRA, devised a rule-driven detection method for cell line and taxonomy names and annotated 70 more abstracts as additional corpus. We further finetuned the T0pp model, with 11 billion parameters, to boost the performance on relation extraction and leveraged entites' location information (eg, title, background) to enhance novelty prediction performance in relation extraction (RE). Results Our pioneering NLP system designed for this challenge secured first place in Phase I—NER and second place in Phase II—relation extraction and novelty prediction, outpacing over 200 teams. We tested OpenAI ChatGPT 3.5 and ChatGPT 4 in a Zero-Shot setting using the same test set, revealing that our finetuned model considerably surpasses these broad-spectrum large language models. Discussion and Conclusion Our outcomes depict a robust NLP system excelling in NER and RE across various biomedical entities, emphasizing that task-specific models remain superior to generic large ones. Such insights are valuable for endeavors like knowledge graph development and hypothesis formulation in biomedical research. [ABSTRACT FROM AUTHOR]

Dominance refers to the effect of a heterozygous genotype relative to that of the two homozygous genotypes. The degree of dominance of mutations for fitness can have a profound impact on how deleterious and beneficial mutations change in frequency over time as well as on the patterns of linked neutral genetic variation surrounding such selected alleles. Since dominance is such a fundamental concept, it has received immense attention throughout the history of population genetics. Early work from Fisher, Wright, and Haldane focused on understanding the conceptual basis for why dominance exists. More recent work has attempted to test these theories and conceptual models by estimating dominance effects of mutations. However, estimating dominance coefficients has been notoriously challenging and has only been done in a few species in a limited number of studies. In this review, we first describe some of the early theoretical and conceptual models for understanding the mechanisms for the existence of dominance. Second, we discuss several approaches used to estimate dominance coefficients and summarize estimates of dominance coefficients. We note trends that have been observed across species, types of mutations, and functional categories of genes. By comparing estimates of dominance coefficients for different types of genes, we test several hypotheses for the existence of dominance. Lastly, we discuss how dominance influences the dynamics of beneficial and deleterious mutations in populations and how the degree of dominance of deleterious mutations influences the impact of inbreeding on fitness. [ABSTRACT FROM AUTHOR]

The presence and impact of recessive lethal mutations have been widely documented in diploid outcrossing species. However, precise estimates of the proportion of new mutations that are recessive lethal remain limited. Here, we evaluate the performance of Fit∂a∂i, a commonly used method for inferring the distribution of fitness effects (DFE), in the presence of lethal mutations. Using simulations, we demonstrate that in both additive and recessive cases, inference of the deleterious nonlethal portion of the DFE is minimally affected by a small proportion (<10%) of lethal mutations. Additionally, we demonstrate that while Fit∂a∂i cannot estimate the fraction of recessive lethal mutations, Fit∂a∂i can accurately infer the fraction of additive lethal mutations. Finally, as an alternative approach to estimate the proportion of mutations that are recessive lethal, we employ models of mutation–selection–drift balance using existing genomic parameters and estimates of segregating recessive lethals for humans and Drosophila melanogaster. In both species, the segregating recessive lethal load can be explained by a very small fraction (<1%) of new nonsynonymous mutations being recessive lethal. Our results refute recent assertions of a much higher proportion of mutations being recessive lethal (4%–5%), while highlighting the need for additional information on the joint distribution of selection and dominance coefficients. [ABSTRACT FROM AUTHOR]

Island ecosystems provide natural laboratories to assess the impacts of isolation on population persistence. However, most studies of persistence have focused on a single species, without comparisons to other organisms they interact with in the ecosystem. The case study of moose and gray wolves on Isle Royale allows for a direct contrast of genetic variation in isolated populations that have experienced dramatically differing population trajectories over the past decade. Whereas the Isle Royale wolf population recently declined nearly to extinction due to severe inbreeding depression, the moose population has thrived and continues to persist, despite having low genetic diversity and being isolated for ∼120 years. Here, we examine the patterns of genomic variation underlying the continued persistence of the Isle Royale moose population. We document high levels of inbreeding in the population, roughly as high as the wolf population at the time of its decline. However, inbreeding in the moose population manifests in the form of intermediate-length runs of homozygosity suggestive of historical inbreeding and purging, contrasting with the long runs of homozygosity observed in the smaller wolf population. Using simulations, we confirm that substantial purging has likely occurred in the moose population. However, we also document notable increases in genetic load, which could eventually threaten population viability over the long term. Overall, our results demonstrate a complex relationship between inbreeding, genetic diversity, and population viability that highlights the use of genomic datasets and computational simulation tools for understanding the factors enabling persistence in isolated populations. [ABSTRACT FROM AUTHOR]

Adaptive introgression (AI) facilitates local adaptation in a wide range of species. Many state-of-the-art methods detect AI with ad-hoc approaches that identify summary statistic outliers or intersect scans for positive selection with scans for introgressed genomic regions. Although widely used, approaches intersecting outliers are vulnerable to a high false-negative rate as the power of different methods varies, especially for complex introgression events. Moreover, population genetic processes unrelated to AI, such as background selection or heterosis, may create similar genomic signals to AI, compromising the reliability of methods that rely on neutral null distributions. In recent years, machine learning (ML) methods have been increasingly applied to population genetic questions. Here, we present a ML-based method called MaLAdapt for identifying AI loci from genome-wide sequencing data. Using an Extra-Trees Classifier algorithm, our method combines information from a large number of biologically meaningful summary statistics to capture a powerful composite signature of AI across the genome. In contrast to existing methods, MaLAdapt is especially well-powered to detect AI with mild beneficial effects, including selection on standing archaic variation, and is robust to non-AI selective sweeps, heterosis from deleterious mutations, and demographic misspecification. Furthermore, MaLAdapt outperforms existing methods for detecting AI based on the analysis of simulated data and the validation of empirical signals through visual inspection of haplotype patterns. We apply MaLAdapt to the 1000 Genomes Project human genomic data and discover novel AI candidate regions in non-African populations, including genes that are enriched in functionally important biological pathways regulating metabolism and immune responses. [ABSTRACT FROM AUTHOR]

Ethiopian wolves, a canid species endemic to the Ethiopian Highlands, have been steadily declining in numbers for decades. Currently, out of 35 extant species, it is now one of the world's most endangered canids. Most conservation efforts have focused on preventing disease, monitoring movements and behavior, and assessing the geographic ranges of sub-populations. Here, we add an essential layer by determining the Ethiopian wolf's demographic and evolutionary history using high-coverage (∼40×) whole-genome sequencing from 10 Ethiopian wolves from the Bale Mountains. We observe exceptionally low diversity and enrichment of weakly deleterious variants in the Ethiopian wolves in comparison with two North American gray wolf populations and four dog breeds. These patterns are consequences of long-term small population size, rather than recent inbreeding. We infer the demographic history of the Ethiopian wolf and find it to be concordant with historic records and previous genetic analyses, suggesting Ethiopian wolves experienced a series of both ancient and recent bottlenecks, resulting in a census population size of fewer than 500 individuals and an estimated effective population size of approximately 100 individuals. Additionally, long-term small population size may have limited the accumulation of strongly deleterious recessive mutations. Finally, as the Ethiopian wolves have inhabited high-altitude areas for thousands of years, we searched for evidence of high-altitude adaptation, finding evidence of positive selection at a transcription factor in a hypoxia-response pathway [CREB-binding protein (CREBBP)]. Our findings are pertinent to continuing conservation efforts and understanding how demography influences the persistence of deleterious variation in small populations. [ABSTRACT FROM AUTHOR]

As both natural selection and population history can affect genome-wide patterns of variation, disentangling the contributions of each has remained as a major challenge in population genetics. We here discuss historical and recent progress towards this goal—highlighting theoretical and computational challenges that remain to be addressed, as well as inherent difficulties in dealing with model complexity and model violations—and offer thoughts on potentially fruitful next steps. [ABSTRACT FROM AUTHOR]

Recent genome sequencing studies with large sample sizes in humans have discovered a vast quantity of low-frequency variants, providing an important source of information to analyze how selection is acting on human genetic variation. In order to estimate the strength of natural selection acting on low-frequency variants, we have developed a likelihood-based method that uses the lengths of pairwise identity-bystate between haplotypes carrying low-frequency variants. We show that in some nonequilibrium populations (such as those that have had recent population expansions) it is possible to distinguish between positive or negative selection acting on a set of variants. With our new framework, one can infer a fixed selection intensity acting on a set of variants at a particular frequency, or a distribution of selection coefficients for standing variants and new mutations. We show an application of our method to the UK10K phased haplotype dataset of individuals. [ABSTRACT FROM AUTHOR]

Hypothesis generation is a critical, but challenging, step in a foodborne outbreak investigation. The pathogens that contaminate food have many diverse reservoirs, resulting in seemingly limitless potential vehicles. Identifying a vehicle is particularly challenging for clusters detected through national pathogen-specific surveillance, because cases can be geographically dispersed and lack an obvious epidemiologic link. Moreover, state and local health departments could have limited resources to dedicate to cluster and outbreak investigations. These challenges underscore the importance of hypothesis generation during an outbreak investigation. In this review, we present a framework for hypothesis generation focusing on 3 primary sources of information, typically used in combination: 1) known sources of the pathogen causing illness; 2) person, place, and time characteristics of cases associated with the outbreak (descriptive data); and 3) case exposure assessment. Hypothesis generation can narrow the list of potential food vehicles and focus subsequent epidemiologic, laboratory, environmental, and traceback efforts, ensuring that time and resources are used more efficiently and increasing the likelihood of rapidly and conclusively implicating the contaminated food vehicle. [ABSTRACT FROM AUTHOR]

Human‐driven habitat fragmentation and loss have led to a proliferation of small and isolated plant and animal populations with high risk of extinction. One of the main threats to extinction in these populations is inbreeding depression, which is primarily caused by recessive deleterious mutations becoming homozygous due to inbreeding. The typical approach for managing these populations is to maintain high genetic diversity, increasingly by translocating individuals from large populations to initiate a "genetic rescue." However, the limitations of this approach have recently been highlighted by the demise of the gray wolf population on Isle Royale, which declined to the brink of extinction soon after the arrival of a migrant from the large mainland wolf population. Here, we use a novel population genetic simulation framework to investigate the role of genetic diversity, deleterious variation, and demographic history in mediating extinction risk due to inbreeding depression in small populations. We show that, under realistic models of dominance, large populations harbor high levels of recessive strongly deleterious variation due to these mutations being hidden from selection in the heterozygous state. As a result, when large populations contract, they experience a substantially elevated risk of extinction after these strongly deleterious mutations are exposed by inbreeding. Moreover, we demonstrate that, although genetic rescue is broadly effective as a means to reduce extinction risk, its effectiveness can be greatly increased by drawing migrants from small or moderate‐sized source populations rather than large source populations due to smaller populations harboring lower levels of recessive strongly deleterious variation. Our findings challenge the traditional conservation paradigm that focuses on maximizing genetic diversity in small populations in favor of a view that emphasizes minimizing strongly deleterious variation. These insights have important implications for managing small and isolated populations in the increasingly fragmented landscape of the Anthropocene. [ABSTRACT FROM AUTHOR]

Objectives: To describe, for the first time (to the best of our knowledge), the genetic mechanisms of vancomycin resistance in clinical isolates of Clostridioides difficile ribotype 027.Methods: Clinical isolates and laboratory mutants were analysed: genomically to identify resistance mutations; by transcriptional analysis of vanGCd, the vancomycin resistance operon encoding lipid II d-alanine-d-serine that is less bound by vancomycin than native lipid II d-alanine-d-alanine; by imaging of vancomycin binding to cell walls; and for changes in vancomycin bactericidal activity and autolysis.Results: Vancomycin-resistant laboratory mutants and clinical isolates acquired mutations to the vanSR two-component system that regulates vanGCd. The substitutions impaired VanSR's function, resulting in constitutive transcription of vanGCd. Resistance was reversed by silencing vanG, encoding d-alanine-d-serine ligase in the vanGCd operon. In resistant cells, vancomycin was less bound to the cell wall septum, the site where vancomycin interacts with lipid II. Vancomycin's bactericidal activity was reduced against clinical isolates and laboratory mutants (64 and ≥1024 mg/L, respectively) compared with WT strains (4 mg/L). Truncation of the potassium transporter TrkA occurred in laboratory mutants, which were refractory to autolysis, accounting for their survival in high drug concentrations.Conclusions: Ribotype 027 evolved first-step resistance to vancomycin by constitutively expressing vanGCd, which is otherwise silent. Experimental evolutions and bactericidal assays show that ribotype 027 can acquire mutations to drastically enhance its tolerance to vancomycin. Thus, further epidemiological studies are warranted to examine the extent to which vancomycin resistance impacts clinical outcomes and the potential for these strains to evolve higher-level resistance, which would be devastating. [ABSTRACT FROM AUTHOR]

Despite its recent invasion into the marine realm, the sea otter (Enhydra lutris) has evolved a suite of adaptations for life in cold coastal waters, including limb modifications and dense insulating fur. This uniquely dense coat led to the near-extinction of sea otters during the 18th–20th century fur trade and an extreme population bottleneck. We used the de novo genome of the southern sea otter (E. l. nereis) to reconstruct its evolutionary history, identify genes influencing aquatic adaptation, and detect signals of population bottlenecks. We compared the genome of the southern sea otter with the tropical freshwater-living giant otter (Pteronura brasiliensis) to assess common and divergent genomic trends between otter species, and with the closely related northern sea otter (E. l. kenyoni) to uncover population-level trends. We found signals of positive selection in genes related to aquatic adaptations, particularly limb development and polygenic selection on genes related to hair follicle development. We found extensive pseudogenization of olfactory receptor genes in both the sea otter and giant otter lineages, consistent with patterns of sensory gene loss in other aquatic mammals. At the population level, the southern sea otter and the northern sea otter showed extremely low genomic diversity, signals of recent inbreeding, and demographic histories marked by population declines. These declines may predate the fur trade and appear to have resulted in an increase in putatively deleterious variants that could impact the future recovery of the sea otter. [ABSTRACT FROM AUTHOR]

The genetic consequences of population bottlenecks on patterns of deleterious genetic variation in human populations are of tremendous interest. Based on exome sequencing of 18 Greenlandic Inuit we show that the Inuit have undergone a severe ~ 20,000-year-long bottleneck. This has led to a markedly more extreme distribution of allele frequencies than seen for any other human population tested to date, making the Inuit the perfect population for investigating the effect of a bottleneck on patterns of deleterious variation. When comparing proxies for genetic load that assume an additive effect of deleterious alleles, the Inuit show, at most, a slight increase in load compared to European, East Asian, and African populations. Specifically, we observe, 4% increase in the number of derived deleterious alleles in the Inuit. In contrast, proxies for genetic load under a recessive model suggest that the Inuit have a significantly higher load (20% increase or more) compared to other less bottlenecked human populations. Forward simulations under realistic models of demography support our empirical findings, showing up to a 6% increase in the genetic load for the Inuit population across all models of dominance. Further, the Inuit population carries fewer deleterious variants than other human populations, but those that are present tend to be at higher frequency than in other populations. Overall, our results show how recent demographic history has affected patterns of deleterious variants in human populations. [ABSTRACT FROM AUTHOR]

We investigated a trichinellosis outbreak associated with wild boar consumption. The index patient sought healthcare multiple times before being diagnosed. Targeted education of hunters and consumers handling wild game or free-range pork, owners of game farms, and clinicians is warranted.Background. Rates of trichinellosis have declined significantly in the United States due to improved pork production practices and public awareness of the danger of eating raw or undercooked pork. In April 2011, the Minnesota Department of Health received a report of presumptive trichinellosis in a 50-year-old man with a history of wild boar consumption. A public health investigation was initiated.Methods. Medical record reviews and patient and family interviews were conducted. Trichinella species serology was performed on patient and family serum samples, and larval identification was attempted on clinical specimens and meat samples.Results. The index patient harvested a wild boar from an Iowa game farm; he processed the meat after returning home and developed gastrointestinal symptoms 2 days later. Four days after his illness onset, all 5 family members consumed a roast from the boar. The index patient sought healthcare 4 times after illness onset before being definitively diagnosed with trichinellosis. Following initiation of albendazole therapy, the index patient developed atrial fibrillation. One additional family member who processed the raw meat was diagnosed with trichinellosis. Trichinella spiralis larvae were identified in wild boar meat samples.Conclusions. Trichinellosis has long been recognized as a potential hazard of consuming undercooked wild carnivore meat, and historically has been associated with consumption of pork from domestic swine, but may be unfamiliar to practicing clinicians in the United States. Education of hunters and the broader population on the potential for trichinellosis and the importance of proper handling and cooking meat from wild or free-range animals needs to be reinforced. [ABSTRACT FROM AUTHOR]

STUDY QUESTION How does a protocol based on a single serum progesterone measurement perform as a triage tool in women with pregnancy of unknown location (PUL) in comparison to protocols based on serial hCG measurement? SUMMARY ANSWER Triage based on the logistic regression model M4 (using initial hCG and hCG ratio (48 h/0 h)) classifies the majority of PUL into low and high risk groups, in contrast to a progesterone protocol based on a serum level threshold of 10 nmol/l. WHAT IS KNOWN ALREADY Low progesterone has been shown to identify failing pregnancies and those at low risk of complications. A prediction model (M4) based on the initial hCG and the hCG ratio at 0 and 48 h can successfully classify PUL into low and high risk groups. STUDY DESIGN, SIZE AND DURATION A multi-centre diagnostic accuracy study of 1271 women was performed retrospectively on data from women at St. George's Hospital (SGH, London, UK) between February 2005 and 2006, Queen Charlottes & Chelsea Hospital (QCCH, London, UK) between April 2009 and August 2012, and the Royal Prince Alfred Hospital (RPAH, Sydney, Australia) between February 2008 and October 2011. The end-points were the final observed outcome for each pregnancy as a failed PUL (low risk), intrauterine pregnancy (IUP, low risk), or ectopic pregnancy (EP, high risk), and any interventions or complications for EP during the follow-up period. PARTICIPANTS/MATERIALS, SETTING AND METHODS Complete data were available for initial progesterone, 0/48 h hCG and final outcome in 431 of 534 women (81%) at SGH, 396/585 (68%) at QCCH and 96/152 (63%) at RPAH. Missing values were handled using multiple imputation. Three diagnostic approaches were used to classify PUL as high risk: a range of serum progesterone levels were evaluated (>10, 16 and 20 nmol/l) for the progesterone protocol, risk of EP given by the M4 model ≥5% for the M4-based protocol, and hCG ratio was between 0.87 and 1.66 for hCG cut-offs as previously published. Results were analysed using random intercept models or stratified analysis to account for variability between centres. MAIN RESULTS AND THE ROLE OF CHANCE The progesterone protocol based on levels of >10 nmol/l classified 24% (95% confidence interval 20–28%) of failed PUL, 95% (92–97%) of IUP and 76% (67–83%) of EP as high risk. The M4 protocol classified 14% (11–17%) of failed PUL, 37% (31–43%) of IUP and 84% (76–90%) of EP as high risk. The hCG ratio cut-offs classified 10% (8–12%) of failed PUL, 15% (11–20%) of IUP and 63% (53–71%) of EP as high risk. Using complete cases only, 67% of EP treated with methotrexate (n = 48) and 89% surgically managed (n = 37) were correctly classified by the progesterone protocol, 96 and 81% by M4 protocol and 75 and 65% by hCG ratio cut offs, respectively. LIMITATIONS, REASONS FOR CAUTION Data were incomplete for 103 (19%), 189 (32%) and 56 (37%) patients at SGH, QCCH and RPAH, respectively; however, we are reassured by the minimal differences seen between the results of complete cases and those following imputation of missing values. The variation in the inclusion criteria between the three centres is also a potential limitation of this study; however, it reflects real clinical practice. Furthermore, the hCG ratio cut-offs were not originally developed to optimize triage. WIDER IMPLICATIONS OF THE FINDINGS The results show that serum progesterone is less efficient for triage than serial hCG measurements assessed using the M4 model, the striking difference being serum progesterone places nearly all IUP in the high-risk category. A two-step strategy combining single-visit and two-visit approaches should be investigated. STUDY FUNDING/COMPETING INTERESTS Funding was from Research Foundation-Flanders (FWO). There are no competing interests. [ABSTRACT FROM AUTHOR]

BACKGROUND A diagnosis of ectopic pregnancy (EP) is primarily achieved using transvaginal ultrasonography (TVS). Pregnancy of unknown location (PUL) is the term used to categorize a pregnancy in a woman with a positive pregnancy test when no pregnancy has been visualized using TVS. This review appraises current tools for the diagnosis of EP, describes the diagnostic criteria for non-tubal EP and reviews the literature on the clinical management of PUL. METHODS We performed a targeted search using the PubMed database. All articles published in the English language from January 1984 to March 2013 were screened for eligibility. RESULTS Using TVS to diagnose EP is highly sensitive (87–99%) and specific (94–99.9%). Variations exist in the criteria used for ultrasound diagnosis. Studies report that between 5 and 42% of women seen for ultrasound assessment with a positive pregnancy test have a PUL. For PUL, measurements of serum human chorionic gonadotrophin (hCG) and progesterone are used to predict pregnancy viability and therefore give an indication of the risk of an EP. Only 6–20% of PUL are subsequently diagnosed with EP. Non-tubal EPs are relatively uncommon, difficult to diagnose and result in disproportionate morbidity and mortality. CONCLUSIONS Access to expertise and equipment for high-quality TVS means the majority of women with EP in developed countries can be diagnosed rapidly and accurately. Identifying PUL, which are low risk and therefore requiring less follow-up, finding better serum markers for EP and safely identifying women who do not require intervention for EP are the current diagnostic challenges. [ABSTRACT FROM AUTHOR]

Foodborne transmission should be considered as a possible cause of clusters of group A Streptococcus (GAS) pharyngitis. When possible, strain typing should be employed in epidemiologic investigations of suspected GAS outbreaks to enhance understanding of the epidemiology of GAS disease.Background On 20 March 2012, the Minnesota Department of Health (MDH) was notified of multiple Facebook postings suggestive of a foodborne outbreak of Group A Streptococcus (GAS) pharyngitis occurring among attendees of a high school dance team banquet. An investigation was initiated. Methods Associations between GAS pharyngitis and specific food items were assessed among banquet attendees. Pharyngeal swabs were performed on attendees, household contacts, and food workers. Patient GAS isolates from clinical laboratories were also obtained. Pharyngeal and food specimens were cultured for GAS by the MDH Public Health Laboratory. Isolates were further characterized by pulsed-field gel electrophoresis (PFGE) and emm typing. Results Among 63 persons who consumed banquet food, 18 primary illnesses occurred, yielding an attack rate of 29%. Although no food or beverage items were significantly associated with illness, pasta consumption yielded the highest relative risk (risk ratio, 3.56; 95% confidence interval, .25–50.6). GAS colonies with indistinguishable PFGE patterns corresponding to emm subtype 1.0 were isolated from 5 patients and from leftover pasta. The pasta was prepared at home by a dance team member parent; both parent and child reported GAS pharyngitis episodes 3 weeks before the banquet. Conclusions In this foodborne outbreak of GAS pharyngitis, pasta was implicated as the vehicle. Recognition of foodborne GAS illness is challenging because transmission is typically assumed to occur by respiratory spread; foodborne transmission should be considered when clusters of GAS pharyngitis patients are encountered. DNA-based typing can reveal potentially epidemiologically related isolates during GAS disease outbreaks and facilitate understanding and control of GAS disease. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Can we accurately define a group of pregnancies of unknown location (PULs) as low risk in order to safely reduce follow-up for these pregnancies and allocate resources to pregnancies at an increased risk of being ectopic? SUMMARY ANSWER Prediction model M4 classified around 70% of PULs as low risk, of which around 97% were later characterized as failed PULs or intrauterine pregnancies (IUPs), while still classifying 88% of ectopic pregnancies as high risk. WHAT IS KNOWN ALREADY Depending on the level of suspicion of ectopic pregnancy (EP), women with a PUL receive a lengthy follow-up in order to confirm the location and viability of the pregnancy. STUDY DESIGN, SIZE, DURATION A multi-centre diagnostic accuracy study of 1962 patients was carried out between 2003 and 2007 for retrospective temporal validation and between 2009 and 2011 for prospective external validation. The reference standard is the final characterization of PUL as failed pregnancies or IUPs (low risk), or as ectopic pregnancies (high risk). M4 is a multinomial logistic regression model based on the serum human chorionic gonadotrophin (hCG) levels at presentation and 48 h later. PARTICIPANTS/MATERIALS, SETTING, METHODS Temporal validation data from 1341 PULs collected at St George's Hospital in London were available, of which 53% were failed, 39% were intrauterine and 8% were ectopic pregnancies. External validation data from 621 PULs collected at four other London-based teaching hospitals were available, of which 63% were failed, 22% were intrauterine and 15% were ectopic pregnancies. MAIN RESULTS AND THE ROLE OF CHANCE The EP rate varied between 8 and 16% across the five hospitals. At St George's, 980 [73.1%, 95% confidence interval (CI): 70.5–75.4] PULs were considered low risk. Of these, 963 were failed PULs or IUPs (98.3%, 95% CI: 97.2–98.9) and 17 were ectopic pregnancies. At the other four hospitals, 62–75% were considered low risk, with 96–98% of these turning out to be failed PUL or IUP. Eighty-five percent (95% CI: 76.8–90.2) of the ectopic pregnancies were considered high risk at St George's, compared with 80–92% in the other hospitals. LIMITATIONS, REASONS FOR CAUTION Of total, 120 patients had been excluded due to loss to follow-up, and a further 102 patients because of missing hCG levels due to differences in local clinical practice. There are variations in the definition of a PUL used in different countries. WIDER IMPLICATIONS OF THE FINDINGS The suggested protocol could safely reduce the follow-up in the majority of PUL such that units could increase the focus on women at a risk of complications. This would lead to a change in the management of the majority of women with a PUL and a more efficient use of resources. At the end of the manuscript, we provide a link to enable clinicians to use the protocol. STUDY FUNDING/COMPETING INTEREST(S) B.V.C. is supported by a postdoctoral fellowship from the Research Foundation Flanders (FWO). K.V.H. is supported by a fellowship from the Flanders' Agency for Innovation by Science and Technology (IWT-Vlaanderen), by the Research Council KU Leuven (GOA MaNet), by the Flemish Government (iMinds) and by the Belgian Federal Science Policy Office (IUAP P7/DYSCO). T.B. is supported by the Imperial Healthcare NHS Trust NIHR Biomedical Research Centre. No competing interests are declared. [ABSTRACT FROM AUTHOR]

Background. Primary amebic meningoencephalitis (PAM), caused by the free-living ameba Naegleria fowleri, has historically been associated with warm freshwater exposures at lower latitudes of the United States. In August 2010, a Minnesota resident, aged 7 years, died of rapidly progressive meningoencephalitis after local freshwater exposures, with no history of travel outside the state. PAM was suspected on the basis of amebae observed in cerebrospinal fluid. Methods. Water and sediment samples were collected at locations where the patient swam during the 2 weeks preceding illness onset. Patient and environmental samples were tested for N. fowleri with use of culture and realtime polymerase chain reaction (PCR); isolates were genotyped. Historic local ambient temperature data were obtained. Results. N. fowleri isolated from a specimen of the patient's brain and from water and sediment samples was confirmed using PCR as N. fowleri genotype 3. Surface water temperatures at the times of collection of the positive environmental samples ranged from 22.1°C to 24.5°C. August 2010 average air temperature near the exposure site was 25°C, 3.6°C above normal and the third warmest for August in the Minneapolis area since 1891. Conclusions. This first reported case of PAM acquired in Minnesota occurred 550 miles north of the previously reported northernmost case in the Americas. Clinicians should be aware that N. fowleri-associated PAM can occur in areas at much higher latitude than previously described. Local weather patterns and long-term climate change could impact the frequency of PAM. [ABSTRACT FROM AUTHOR]

We investigate the performance of tests of neutrality in admixed populations using plausible demographic models for African-American history as well as resequencing data from African and African-American populations. The analysis of both simulated and human resequencing data suggests that recent admixture does not result in an excess of false-positive results for neutrality tests based on the frequency spectrum after accounting for the population growth in the parental African population. Furthermore, when simulating positive selection, Tajima's D, Fu and Li's D, and haplotype homozygosity have lower power to detect population-specific selection using individuals sampled from the admixed population than from the nonadmixed population. Fay and Wu's H test, however, has more power to detect selection using individuals from the admixed population than from the nonadmixed population, especially when the selective sweep ended long ago. Our results have implications for interpreting recent genome-wide scans for positive selection in human populations. [ABSTRACT FROM AUTHOR]

Background: A logistic regression model (M4) was developed in the UK to predict the outcome for women with a pregnancy of unknown location (PUL) based on the initial two human chorionic gonadotrophin (hCG) values, 48 h apart. The purpose of this paper was to assess the utility of this model to predict the outcome for a woman (PUL) in a US population.Methods: Diagnostic variables included log-transformed serum hCG average of two measurements, and linear and quadratic hCG ratios. Outcomes modeled were failing PUL, intrauterine pregnancy (IUP) and ectopic pregnancy (EP). This model was applied to a US cohort of 604 women presenting with symptomatic first-trimester pregnancies, who were followed until a definitive diagnosis was made. The model was applied before and after correcting for differences in terminology and diagnostic criteria.Results: When retrospectively applied to the adjusted US population, the M4 model demonstrated lower areas under the curve compared with the UK population, 0.898 versus 0.988 for failing PUL/spontaneous miscarriage, 0.915 versus 0.981 for IUP and 0.831 versus 0.904 for EP. Whereas the model had 80% sensitivity for EP using UK data, this decreased to 49% for the US data, with similar specificities. Performance only improved slightly (55% sensitivity) when the US population was adjusted to better match the UK diagnostic criteria.Conclusions: A logistic regression model based on two hCG values performed with modest decreases in predictive ability in a US cohort for women at risk for EP compared with the original UK population. However, the sensitivity for EP was too low for the model to be used in clinical practice in its present form. Our data illustrate the difficulties of applying algorithms from one center to another, where the definitions of pathology may differ. [ABSTRACT FROM AUTHOR]

Despite the widespread study of genetic variation in admixed human populations, such as African- Americans, there has not been an evaluation of the effects of recent admixture on patterns of polymorphism or inferences about population demography. These issues are particularly relevant because estimates of the timing and magnitude of population growth in Africa have differed among previous studies, some of which examined African-American individuals. Here we use simulations and singlenucleotide polymorphism (SNP) data collected through direct resequencing and genotyping to investigate these issues. We find that when estimating the current population size and magnitude of recent growth in an ancestral population using the site frequency spectrum (SFS), it is possible to obtain reasonably accurate estimates of the parameters when using samples drawn from the admixed population under certain conditions. We also show that methods for demographic inference that use haplotype patterns are more sensitive to recent admixture than are methods based on the SFS. The analysis of human genetic variation data from the Yoruba people of Ibadan, Nigeria and African-Americans supports the predictions from the simulations. Our results have important implications for the evaluation of previous population genetic studies that have considered African-American individuals as a proxy for individuals from West Africa as well as for future population genetic studies of additional admixed populations. [ABSTRACT FROM AUTHOR]

We investigated the potential for gene flow in a dependent lineage (DL) system of the harvester ant Pogonomyrmex. Each DL system is composed of 2 reproductively isolated lineages that are locked in an obligate mutualism. The genetic components that produce the worker phenotype are acquired by hybridizing with the partner lineage. In the mating flight, queens of both lineages mate with multiple males from each lineage. During colony growth and reproduction, eggs fertilized by partner-lineage sperm produce F1 hybrid workers with interlineage genomes, whereas eggs fertilized by same-lineage sperm result in the development of new queens with intralineage genomes. New males are typically produced from unfertilized eggs laid by the pure-lineage queen but in her absence may be produced by interlineage F1 workers. We investigated the potential for interlineage gene flow in this system using 2 classes of lineage-specific nuclear markers to identify hybrid genome combinations. We confirmed the production of viable interlineage F1 reproductive females in field colonies, the occurrence of which is associated with the relative frequencies of each lineage in the population: interlineage F1 queens occurred only in the rare lineage of the population with dramatically skewed lineage frequencies. In laboratory colonies, we detected fair meiosis in interlineage F1 workers leading to the production of viable and haploid interlineage F2 males. We conclude that the genomes of each lineage recombine freely, suggesting that extrinsic postzygotic selection maintains the integrity of each lineage genome. We compare our findings with those of the H1/H2 DL system. [ABSTRACT FROM PUBLISHER]

Summary: The Poisson Random Field (PRF) model has become an important tool in population genetics to study weakly deleterious genetic variation under complicated demographic scenarios. Currently, there are no freely available software applications that allow simulation of genetic variation data under this model. Here we present PReFerSim, an ANSI C program that performs forward simulations under the PRF model. PReFerSim models changes in population size, arbitrary amounts of inbreeding, dominance and distributions of selective effects. Users can track summaries of genetic variation over time and output trajectories of selected alleles. Availability and Implementation: PReFerSim is freely available at: https://github.com/LohmuellerLab/PReFerSim. [ABSTRACT FROM AUTHOR]

Two experiments were conducted to evaluate reproductive responses to supplemental high-linoleate safflower seeds in postpartum beef cows. In Exp. 1, 18 primiparous, crossbred beef cows (411 ± 24.3 kg of BW) were fed Foxtail millet hay starting 1 d postpartum at 1.68% of BW (DM basis) and a low-fat control (control: 63.7% cracked corn, 33.4% saf-flower seed meal, and 2.9% liquid molasses; DM basis) at 0.35% of BW (n = 9) or a supplement (linoleate) containing 95.3% cracked high-linoleate (79% 18:2n-6) safflower seeds and 4.7% liquid molasses (DM basis) at 0.23% of BW (n = 9). Beginning 1 d postpartum, blood was collected every 3 d for sera. Cows were slaughtered at 37 ± 3 d postpartum for collection of hypothalami, anterior pituitary glands, liver, ovarian follicles, and uterine tissue. By 37 ± 3 d postpartum, dietary treatment did not influence ovarian follicular development (P ≥ 0.17), hypophyseal concentrations of LH (P = 0.14), or concentrations of IGF-I in liver (P = 0.15). In contrast, anterior pituitary glands from linoleate cows contained more FSH (P = 0.02) than control cows and linoleate cows had less IGF-I in the medial basal hypo- thalamus (P = 0.05), preoptic area (P = 0.06), and in follicular fluid (P ≤ 0.03) from follicles less than 15 mm in diameter. In Exp. 2, twenty-four 3-yr-old multiparous beef cows (initial BW 473.9 ± 9.2 kg) were fed chopped bromegrass hay at 2.1% of initial BW starting 1 d post-partum and a low-fat supplement (control) fed at 0.6% of initial BW or a high-linoleate supplement (linoleate) fed at 0.4% of initial BW until 80 d postpartum. Cows were observed for estrus twice daily from d 30 to 80 postpartum and treated with GnRH between 40 and 45 d postpartum. Seven days after GnRH administration cows were given PGF2α, and were checked for estrus and artificially inseminated until 80 d postpartum. The magnitude of GnRH-induced release of LH (P = 0.82) or FSH (P = 0.86) did not differ between treatments. However, peak serum concentrations of estradiol during proestrus after treatment with PGF2α were less (P = 0.04) in linoleate than control cows. In conclusion, fat supplementation with high-linoleate safflower seeds did not improve the development of ovarian follicles and detrimentally affected early postpartum fertility possibly because of a reduction in IGF-I concentrations in tissues essential to reproduction. [ABSTRACT FROM AUTHOR]

In insect societies, worker versus queen development (reproductive caste) is typically governed by environmental factors, but some Pogonomyrmex seed-harvester ants exhibit strict genetic caste determination, resulting in an obligate mutualism between two reproductively isolated lineages. Queens mate randomly with multiple males from each lineage and intralineage crosses produce new queens, whereas interlineage crosses produce workers. Early colony survival is negatively frequency dependent; when lineage frequencies are unequal, queens from the rarer lineage benefit because they acquire more interlineage sperm, and produce more workers. Here we examine theoretically and empirically the effect of relative lineage frequency on sex ratio. We predict that the ratio of inter- to intralineage sperm acquired by queens of each lineage will affect the sex ratio produced at colony maturity. Consistent with model predictions, we found that gyne production in mature colonies was positively frequency dependent, increasing significantly with increasing lineage frequency across 15 populations. Unequal lineage frequencies are common and likely maintained by a complex interplay between an ecological advantage specific to one lineage, and opposing frequency-dependent selection pressures experienced throughout the colonies life-cycle; rare lineage colonies benefit during early colony growth, and common lineage colonies benefit at reproductive maturity. [ABSTRACT FROM AUTHOR]

Background: The objective of this study was to determine the optimal gestational age at which to establish the location and viability of an early pregnancy using transvaginal ultrasonography (TVS). Methods: This was a prospective study of 1442 women undergoing initial TVS at no more than 84 days gestation. Logistic regression analysis was performed to determine the relationship between gestational age and the ability to confirm viability or non-viability, in women with and without symptoms of pain and bleeding. Results: The commonest TVS finding prior to 35 days was a pregnancy of unknown location, from 35 to 41 days an early intrauterine pregnancy of uncertain viability and from 42 days a viable intrauterine pregnancy. Miscarriage could only be diagnosed on initial TVS after 35 days. There was no difference between the ability to make a diagnosis for women with certain or uncertain dates (P = 0.719). The chance of confirming viability increased rapidly per day of gestation until 49 days and thereafter plateaued. Of the 29 ectopic pregnancies diagnosed, 72% presented prior to 49 days gestation and all of these women presented with pain, bleeding or a previous ectopic pregnancy history. Conclusions: The ability to confirm viability or non-viability is significantly related to gestational age. In asymptomatic women with no previous ectopic pregnancy TVS should be delayed until 49 days. Our data suggest that this would reduce the number of inconclusive scans, without an associated increase in morbidity from missed ectopic pregnancies. [ABSTRACT FROM AUTHOR]

Background. Escherichia coli O157:H7 (O157) is the Shiga toxin-producing E. coli (STEC) serotype most frequently isolated and most often associated with hemolytic uremic syndrome (HUS) in the United States. Non- O157 STEC serotypes can also cause serious illness, but their impact as pathogens remains undefined.We compared characteristics of non-O157 and O157 STEC infections identified through sentinel surveillance. Methods. Sentinel sites included a metropolitan health maintenance organization laboratory and a hospital laboratory serving a small city and rural area. We received sorbitol-MacConkey agar plates from every stool culture performed at both sites during 2000-2006. Colony sweeps were screened for stx1 and stx2 by polymerase chain reaction. E. coli identity, serotype, and presence of stx1 and/or stx2 were confirmed on individual isolates. Results. Two hundred six STEC isolates were identified: 108 (52%) were non-O157 serotypes, and 98 (48%) were O157. Of non-O157 cases, 54% involved bloody diarrhea, and 8% involved hospitalization. Non-O157 isolates with at least stx2 were not more likely to cause severe illness (bloody diarrhea, hospitalization, or HUS) than were non-O157 isolates with only stx1. O157 cases were more likely than non-O157 cases to involve bloody diarrhea (78% vs 54%; ), hospitalization P <.001 (34% vs 8%; P<.001), and HUS (7% vs 0%; P=.005). When including only isolates with at least stx2, O157 cases were still more likely to involve bloody diarrhea (78% vs 56%; P=.02) and hospitalization (33% vs 12%; P=.01) than non-O157 cases. Conclusions. Differences in severity among STEC infections could not be explained by stx2, suggesting that additional factors are important in STEC virulence. [ABSTRACT FROM AUTHOR]

We propose a novel approximate-likelihood method to fit demographic models to human genomewide single-nucleotide polymorphism (SNP) data. We divide the genome into windows of constant genetic map width and then tabulate the number of distinct haplotypes and the frequency of the most common haplotype for each window. We summarize the data by the genomewide joint distribution of these two statistics-termed the HCN statistic. Coalescent simulations are used to generate the expected HCN statistic for different demographic parameters. The HCN statistic provides additional information for disentangling complex demography beyond statistics based on single-SNP frequencies. Application of our method to simulated data shows it can reliably infer parameters from growth and bottleneck models, even in the presence of recombination hotspots when properly modeled. We also examined how practical problems with genomewide data sets, such as errors in the genetic map, haplotype phase uncertainty, and SNP ascertainment bias, affect our method. Several modifications of our method served to make it robust to these problems. We have applied our method to data collected by Perlegen Sciences and find evidence for a severe population size reduction in northwestern Europe starting 32,500-47,500 years ago. [ABSTRACT FROM AUTHOR]

In eusocial Hymenoptera, haplodiploid life cycles, obligate sterile castes, and polyandry may facilitate selection for hybridization. We analyzed a broad hybrid zone between the ecologically distinct seed-harvester ants Pogonomyrmex occidentalis (Cresson) and Pogonomyrmex maricopa (Wheeler) using mitochondrial (mt)DNA sequence data, eight morphological markers, and 14 random amplified polymorphic DNA (RAPD) markers. Average mtDNA sequence divergence among parental species was 11.34%, indicating secondary contact. RAPD markers were significantly correlated with morphological variation, confirming the interspecific hybrid origin of all morphologically putative hybrid colonies. A morphological hybrid index indicates an abundance of both F1 hybrids and parental morphotypes within colonies. Individual character frequencies plotted against distance show coincident and concordant clines, suggesting little to no introgression. The structure of the hybrid zone is two-fold. Within the western region, stark reversals in character frequencies coincide with overt soil differences, indicating a mosaic hybrid zone structure. The eastern region is a riparian habitat where four adjacent populations were composed entirely of hybrid colonies. These habitat associations suggest that hybrid worker genomes permit dispersal into intermediate environments that select against one or both parental species. The present study suggests that, in addition to retaining reproductive compatibility, ecologically distinct species of ants may generate hybrid colonies maintained by environmental selection. © 2008 The Linnean Society of London, Biological Journal of the Linnean Society, 2008, 95, 320–336. [ABSTRACT FROM AUTHOR]

The expansion of Africanized honeybees (AHB) through the Americas has been one of the most spectacular and best-studied invasions by a biotype. African and European honeybees (EHB) hybridize, but with time, tropical and subtropical American environments have become dominated by AHB that exhibit only 20-35% genetic contribution from western European bees, and a predominance of African behavioral and physiological traits. EHB persist in temperate environments. Clines between AHB and EHB exist in ecotones of South and Central America, and are forming in North America. What individual-level genetic, behavioral and physiological traits determine the relative success of the AHB as an invader in the neotropics, and of the EHB in temperate areas? Preference for pollen versus nectar may be an important trait mediating these ecological trade-offs, as preference for pollen enhances nutrient intake and brood production for the AHB in the tropics, while a relative preference for nectar enhances honey stores and winter survival for EHB. AHB exhibit morphological (higher thorax-to-body mass ratios) and physiological (higher thorax-specific metabolic rates) traits that may improve flight capacity, dispersal, mating success and foraging intake. Enhanced winter longevity, linked with higher hemolymph vitellogenin levels, may be a key factor improving winter survival of EHB. Data from South America and distributions of AHB in the southwestern United States suggest that AHB-EHB hybrids will extend 200 km north of regions with a January maximal temperatures of 15-16°C. The formation of biotypic clines between AHB and EHB represents a unique opportunity to examine mechanisms responsible for the range limit of invaders. [ABSTRACT FROM AUTHOR]

Arabidopsis (Arabidopsis thaliana) QUARTET (QRT) genes are required for pollen separation during normal floral development. In qrt mutants, the four products of microsporogenesis remain fused and pollen grains are released as tetrad's. hi Arabidopsis, tetrad analysis m qrt mutants has been used to map all five centromeres, easily distinguish sporophytic from gametophytic mutations, and accurately assess crossover interference. Using a combination of forward and reverse genetics, we have identified the gene responsible for the qrt1 phenotype. Annotation predicts that QRT1 encodes a pectin methylesterase (PME), and enzymatic assays of QRT1 expressed in Escherichia coil indicate that QRT1 has PME activity. Promoter and transcription analysis demonstrate QRT1 is expressed in anther tissues shortly after meiosis is complete. Unexpectedly, the QRT1 promoter is also active in a variety of developmentally unrelated tissues, including developing guard cells, the hypocotyl-root transition zone, areas of lateral root emergence, and floral nectaries. PMEs constitute a large gene family in Arabidopsis, are involved in cell wall loosening, and have been implicated in various aspects of floral development and pollen tube elongation. The identification of QRT1 as a PME contributes to our understanding of pollen development and may help to provide valuable genetic tools in other plant species. [ABSTRACT FROM AUTHOR]

Background. Virginiamycin use in poultry selects for Enterococcus faecium with cross-resistance to quinupristindalfopristin, a drug for vancomycin-resistant E. faecium in humans. We conducted an epidemiologic study of poultry exposures as risk factors for human carriage of quinupristin-dalfopristin—resistant E. faecium. Methods. Rectal or fecal samples for E. faecium testing were obtained from 567 newly admitted hospital patients and 100 healthy vegetarians. Participants were interviewed regarding poultry exposure. Retail poultry washes (160 conventional and 26 antibiotic free) were also tested for the presence of E. faecium. Constitutive and inducible quinupristin-dalfopristin resistance were assessed in E. faecium isolates, and resistance genes were identified by polymerase chain reaction. Results. E. faecium was isolated from 105 patients, 65 vegetarians, and 77 conventional and 23 antibiotic-free poultry washes. Constitutive quinupristin-dalfopristin resistance was absent in human E. faecium, but 56% of conventional poultry isolates were quinupristin-dalfopristin resistant. Inducible quinupristin-dalfopristin resistance was more common in samples from patients than in those from vegetarians and in washes of conventional than antibiotic-free poultry. Higher poultry consumption was associated with inducible quinupristin-dalfopristin resistance. vatE was present in 38% of E. faecium isolates from patients and none from vegetarians. Touching raw poultry was associated with the presence of vatE. Conclusions. Poultry exposure is associated with a quinupristin-dalfopristin resistance gene and inducible quinupristin-dalfopristin resistance in human fecal E. faecium. The continued use of virginiamycin may increase the potential for streptogramin-resistant E. faecium infection in humans. [ABSTRACT FROM AUTHOR]

We report a concurrent increase in the number of isolates of Salmonella enterica serotype Newport and the rate of multidrug resistance in S. Newport isolates from animal and human populations in Minnesota. Antimicrobial susceptibility and pulsed-field gel electrophoresis analysis demonstrated heterogeneity of isolates and showed that 1 pulsed-field gel electrophoresis cluster contained most of the multidrug-resistant isolates with a resistance pattern and most class 1 integron isolates, implying the clonal origin of the isolates. [ABSTRACT FROM AUTHOR]

Background and Purpose. Total-contact inserts (TCIs) and metatarsal pads (MPs) frequently are prescribed to reduce excessive plantar stresses to help prevent skin breakdown in people with diabetes mellitus (DM) and peripheral neuropathy. The first purpose of this study was to determine the effect of a TCI and an MP on metatarsal head peak plantar pressures (PPP) and pressure-time integrals (PTI). The second purpose of this study was to determine a possible mechanism of pressure reduction by measuring contact area and loaded soft-tissue thickness (STT) under the metatarsal heads and second metatarsal shaft. Subjects. Twenty subjects (12 men and 8 women; age [mean±SD]=57-9 years) with DM (duration [mean±SD]=16±11 years), peripheral neuropathy, and a history of plantar ulcers participated. Methods. A repeated-measures research design was used, and outcome measures are reported for 3 footwear conditions: shoe, shoe with TCI, and shoe with TCI and MP. In-shoe plantar pressures were collected during walking and during spiral x-ray computed tomography (SXCT). The STT and identification of the pressure sensor and location of the MP in relationship to the metatarsal heads were determined by use of SXCT. Results. The PPP and the PTI were 16% to 24% lower at the metatarsal heads in the TCI condition than in the shoe condition. The PPP and the PTI decreased an additional 15% to 28% (for a total reduction of 29% to 47%) with the addition of the MP. The contact area increased 27% with the TCI but not with the MP. The STT did not increase under the metatarsal heads in the TCI condition (compared with the shoe condition) but did increase 8% to 22% at metatarsal heads 2 to 5 with the addition of the MP. The PPP increased substantially (308%) and the STT decreased 14% under the shaft of the second metatarsal with the addition of the MP to the TCI-plus-shoe condition. Discussion and Conclusion. The TCI and the MP caused substantial and additive reductions of pressures under the metatarsal heads. The TCI reduces excessive pressures at the metatarsal heads by increasing the contact area of weight-bearing forces. Conversely, the MP acts by compressing the soft tissues proximal to the metatarsal heads and relieving compression at the metatarsal heads. These findings can assist in the design of effective orthotic devices to relieve excessive plantar stresses that contribute to skin breakdown and subsequent amputation in people with DM and peripheral neuropathy. [ABSTRACT FROM AUTHOR]

Background. In August 2000, the Minnesota Department of Health was notified of and investigated an outbreak of febrile respiratory illness among workers at a sugar-beet processing plant. Methods. A case was defined as fever and respiratory symptoms occurring in a worker at the sugar-beet plant on or after 31 July 2000. Case patients were interviewed, medical and work records were reviewed, and clinical samples were obtained. The plant was inspected, and environmental samples were collected. Results. Fourteen of 15 case patients performed high-pressure water cleaning in the confined space of an evaporator vessel. Symptoms included fever and chills (100%), chest tightness (93%), cough (80%), and shortness of breath (73%). In case patients, median temperature was 39.4°C, median oxygen saturation was 93%, and median white blood cell count was 12 × 103 cells/μL. Four (29%) of 14 case patients showed evidence of Legionella pneumophila exposure, according to serologic testing. Water sources contained up to 105 cfu/mL of L. pneumophila and 22,200 endotoxin units/mL. Conclusions. Outbreak features were consistent with Pontiac fever. Respiratory symptoms, which are atypical for Pontiac fever, could be attributed to a high exposure dose of L. pneumophila from confined-space aerosolization or to endotoxin exposure. This outbreak demonstrates the potential occupational hazards for those performing high-pressure cleaning in confined spaces. [ABSTRACT FROM AUTHOR]

Background. Nontyphoidal Salmonella is a leading cause of foodborne illness. Few studies have explored the health consequences of antimicrobial-resistant Salmonella. Methods. The National Antimicrobial Resistance Monitoring System (NARMS) performs susceptibility testing on nontyphoidal Salmonella isolates. The Foodborne Diseases Active Surveillance Network (FoodNet) ascertains outcomes for patients with culture-confirmed Salmonella infection, in 9 states, each of which participates in NARMS. We analyzed the frequency of bloodstream infection and hospitalization among patients with resistant infections. Isolates defined as resistant to a clinically important agent were resistant to 1 or more of the following agents: ampicillin, ceftriaxone, ciprofloxacin, gentamicin, and/or trimethoprim-sulfamethoxazole. Results. During 1996-2001, NARMS received 7370 serotyped, nontyphoidal Salmonella isolates from blood or stool. Bloodstream infection occurred more frequently among patients infected with an isolate resistant to 1 clinically important agent (adjusted odds ratio [OR], 1.6; 95% confidence interval [CI], 1.2-2.1), compared with patients with pansusceptible infection. During 1996-2001, Food Net staff ascertained outcomes for 1415 patients who had isolates tested in NARMS. Hospitalization with bloodstream infection occurred more frequently among patients infected with an isolate resistant to 1 clinically important agent (adjusted OR, 3.1; 95% CI, 1.4-6.6), compared with patients with pansusceptible infection. Conclusions. Patients with antimicrobial-resistant nontyphoidal Salmonella infection were more likely to have bloodstream infection and to be hospitalized than were patients with pansusceptible infection. Mitigation of antimicrobial resistance in Salmonella will likely benefit human health. [ABSTRACT FROM AUTHOR]

Background. Campylobacter causes >1 million infections annually in the United States. Fluoroquinolones (e.g., ciprofloxacin) are used to treat Campylobacter infections in adults. Although human infections with ciprofloxacin-resistant Campylobacter have become increasingly common, the human health consequences of such infections are not well described. Methods. A case-control study of persons with sporadic Campylobacter infection was conducted within 7 FoodNet sites during 1998–1999. The E-test system (AB Biodisk) was used to test for antimicrobial susceptibility to ciprofloxacin; ciprofloxacin resistance was defined as a ciprofloxacin minimum inhibitory concentration of ≥4 μg/mL. We conducted a case-comparison study of interviewed persons who had an isolate tested. Results. Of 858 isolates tested, 94 (11%) were ciprofloxacin resistant. Among 290 persons with Campylobacter infection who did not take antidiarrheal medications, persons with ciprofloxacin-resistant infection had a longer mean duration of diarrhea than did persons with ciprofloxacin-susceptible infection (9 vs. 7 days [P = .04]). This difference was even more pronounced among the 63 persons who did not take antidiarrheal medications or antimicrobial agents (12 vs. 6 days [P = .04]). In a multivariable analysis-of-variance model, the persons with ciprofloxacin-resistant infection had a longer mean duration of diarrhea than did the persons with ciprofloxacin-susceptible infection (P = .01); this effect was independent of foreign travel. The association between ciprofloxacin resistance and prolonged diarrhea is consistent across a variety of analytical approaches. Conclusions. Persons with ciprofloxacin-resistant Campylobacter infection have a longer duration of diarrhea than do persons with ciprofloxacin-susceptible Campylobacter infection. Additional efforts are needed to preserve the efficacy of fluoroquinolones. [ABSTRACT FROM AUTHOR]

The goal of this study was to determine the effects of short-term feed withdrawal on reproductive and metabolic hormones during the luteal phase of the estrous cycle in mature ewes. Mature ewes observed in estrus were assigned randomly to control and fasted groups (n = 10 per group Trials 1 and 2). For Trials 1 and 2, control ewes had ad libitum access to feed, whereas fasted ewes were not fed from d 7 through 11 of their estrous cycle; on d 12, all ewes were treated with 10 mg of PGF2α, and fasted ewes were given ad libitum access to feed. For Trial 1, blood samples were collected daily through fasting and at 2-h intervals following PGF2α, for 72 h. Serum concentrations of insulin (P ≤ 0.002) and IGF-I (P ≤ 0.01), but not GH (P ≥ 0.60), were decreased during fasting compared with fed ewes. Serum concentrations of 29 (P = 0.02) and 34 kDa (P = 0.04) IGFBP were greater in fasted ewes at 96 h after initiation of fasting than in control ewes. Two control and four fasted ewes in Trial 1 did not exhibit a preovulatory surge release of LH by 72 h. Therefore, Trial 2 was conducted so that the timing of the LH surge could be predicted following the collection of blood samples at 2-h intervals for 112 h and then at 6-h intervals until 178 h following PGF2α administration and realimentation. The magnitude of the preovulatory LH surge in Trial 2 was decreased (P = 0.009) and delayed (P = 0.04), and serum concentrations of estradiol were diminished (P ≤ 0.03) 12 h before the LH surge in fasted ewes. Ovulation rates were not influenced (P ≥ 0.32) by fasting in Trials 1 and 2. Serum concentrations of progesterone in both Trials 1 and 2 were, however, greater (P < 0.001) in fasted than in control ewes. A third trial with ovariectomized ewes was conducted to determine whether the increased serum concentrations of progesterone observed in fasted ewes during Trials 1 and 2 were ovarian-derived. Ovariectomized ewes were implanted with progesterone-containing intravaginal implants and allotted to control (n = 5) or fasted (n = 5) treatment groups and fed as described for Trials 1 and 2. Similar to intact ewes, serum concentrations of progesterone were approximately twofold greater (P < 0.001) in fasted than in control implanted ovariectomized ewes. In summary, feed withdrawal for 5 d during the luteal phase of the estrous cycle increased serum concentrations of progesterone and evoked endocrine changes that could perturb the subsequent estrous cycle. [ABSTRACT FROM AUTHOR]

A 12-month, population-based, case-control study of Campylobacter infections was conducted at Foodborne Disease Active Surveillance Network surveillance areas during 1998-1999. Of 858 Campylobacter isolates tested for antimicrobial susceptibility to the fluoroquinolone ciprofloxacin, 94 (11%) were resistant. Travel outside of the United States was reported by 27 (42%) of 64 patients with fluoroquinolone-resistant Campylobacter infection and by 51 (9%) of 582 patients with fluoroquinolone-susceptible Campylobacter infection (odds ratio [ORb 7.6; 95% confidence interval [CII, 4.3-13.4). When patients with domestically acquired fluoroquinolone- resistant Campylobacter infection were compared with matched healthy control subjects in a multivariate analysis, those infected were 10 times more likely to have eaten chicken or turkey cooked at a commercial establishment (18 [55%I of 33 case patients vs. 7 [21%I of 33 controls; matched OR, 10.0; 95% CI, 1.3-78). Although travel outside of the United States was associated with fluoroquinolone-resistant Campylobacter infection, most infections among study participants were domestically acquired. This study provides additional evidence that poultry is an important source of domestically acquired fluoroquinolone-resistant Campylobacter infection. Control measures should include efforts to improve food handling in commercial establishments. [ABSTRACT FROM AUTHOR]

To determine the burden of illness caused by Escherichia coil 0157 infections in populations in Foodborne Diseases Active Surveillance Network (FoodNet) surveillance areas, we initiated active, laboratory-based surveillance and surveyed laboratories, physicians, and the general public regarding the factors associated with the diagnosis and surveillance of infection with E. coil 0157. We evaluated survey responses and site-specific incidence, outbreak, and demographic data during 1996-1999. A total of 1425 laboratory-confirmed cases of E. coil 0157 infection and 32 outbreaks were reported from the 5 original FoodNet sites. The average annual incidence ranged from 0.5 cases/100,000 population in Georgia to 4.4 cases/100,000 population in Minnesota. After excluding outbreak-associated cases, the annual incidence of sporadic, laboratory-confirmed E. coil 0157 infections remained relatively stable during 1996-1999, with a range of 1.9-2.3 cases/100,000 population. Regional differences in incidence partly resulted from differing physician and laboratory practices and from site-specific exposure factors (e.g., living on or visiting farms). [ABSTRACT FROM AUTHOR]

Methicillin-resistant Staphylococcus aureus (MRSA) has emerged among patients in the general population who do not have established risk factors for MRSA. Records from 10 Minnesota health facilities were reviewed to identify cases of MRSA infection that occurred during 1996--1998 and to identify which cases were community acquired. Susceptibility testing and pulsed-field gel electrophoresis (PFGE) subtyping were performed on available isolates. A total of 354 patients (median age, 16 years) with community-acquired MRSA (CAMRSA) infection were identified. Most case patients (299 [84%]) had skin infections, and 103 (29%) were hospitalized. More than 90% of isolates were susceptible to all antimicrobial agents tested, with the exception of beta-lactams and erythromycin. Of 334 patients treated with antimicrobial agents, 282 (84%) initially were treated with agents to which their isolates were nonsusceptible. Of 174 Minnesota isolates tested, 150 (86%) belonged to 1 PFGE clonal group. CAMRSA infections were identified throughout Minnesota; although most isolates were genetically related and susceptible to multiple antimicrobials, they were generally nonsusceptible to initial empirical therapy. [ABSTRACT FROM AUTHOR]

Presents information on a case report which described how data from plantar pressure measurement and spiral x-ray tomography (SXCT) were used to manage a diabetic patient suffering from recurring plantar ulcers. Beneficial effects of using the technology for the management of ulcers; Traditional treatment given to patients with plantar ulcers; Implications of SXCT technology for the treatment of the patient.

Antimicrobial and antimotility agents are not recommended for the treatment of Shiga toxin–producing Escherichia coli O157 infection. In our study, many persons with Shiga toxin–producing E. coli O157 infection took antimicrobial (62%) and antimotility agents (32%); 43 (29%) of 146 reported commencing antimicrobial treatment after laboratory confirmation. Efforts are needed to promote practice guidelines. [ABSTRACT FROM AUTHOR]

We evaluated the positive predictive value (PPV) of rapid assays used by clinical laboratories in Minnesota to diagnose cryptosporidiosis. The overall PPV was 56% for rapid assays versus 97% for nonrapid assays; clinicians and laboratorians need to be aware of the low PPV of rapid assays when diagnosing cryptosporidiosis. [ABSTRACT FROM AUTHOR]

Metatarsals are frequent sites of stress and fragility fractures in younger athletic populations and aging older adults. Metatarsal fractures are particularly common in Charcot neuroarthropathy (CN), a complication of diabetes mellitus (DM) and peripheral neuropathy (PN). Neuropathic metatarsal fractures may be caused by an accelerated cortical bone osteolysis and may be reflected as geometric‐derived strength estimates from standard foot radiographs. The purpose of this cross‐sectional study was to determine geometry and strength‐derived estimates of the metatarsals in individuals with DM, PN, and CN compared with younger and older adult controls who were nondiabetic and nonneuropathic. We studied 62 participants: 20 young adult controls (YACs), 22 older adult controls (OACs), and 20 diagnosed with DMPN&CN. From weight‐bearing radiographs, we measured the outer diaphysis diameter and inner marrow diameter at the distal, middle, and proximal diaphysis sites of the second and fifth metatarsal. From these diameters, we derived strength estimates of combined cortical width (CCt.Wi), percent cortical area (%Ct.rA), buckling ratio (BR), moment of inertia (MOI), and section modulus (SM) at each site in both metatarsals. DMPN&CN participants had an accelerated cortical thinning, decreased %Ct.Ar, increased BR, and lower MOI and SM compared with OACs and YACs. The OACs showed age‐related decreases in CCt.Wi and % Ct.Ar, and increased BR. The BR demonstrated significant group × bone × site interaction with the distal fifth metatarsal in the DMPN&CN group having the lowest bone strength. The BR in the distal fifth metatarsal of DMPN&CN participants was 36% and 49% greater than in the OAC and YAC groups, respectively. DMPN&CN participants have lower metatarsal bone strength estimates compared with younger and older adult controls. Standard foot radiographs demonstrate an accelerated cortical osteolysis in DMPN&CN individuals, particularly in the distal fifth metatarsal diaphysis. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

The article discusses the implementation of The Indiana Pharmacy Teaching Certificate (IPTeC) mentoring program for the standardization of postgraduate pharmacy experiences in education as of June 2015. Topics covered include the mechanics of the mentor-mentee relationship, the benefits of the program to pharmacy residents, and the logistic impediments in facilitating the relationship. Also noted is the challenge of matching mentors with residents.