Human SNP links differential outcomes in inflammatory and infectious disease to a FOXO3-regulated pathway.

The clinical course and eventual outcome, or prognosis, of complex diseases varies enormously between affected individuals. This variability critically determines the impact a disease has on a patient's life but is very poorly understood. Here, we exploit existing genome-wide association study data to gain insight into the role of genetics in prognosis. We identify a noncoding polymorphism in FOXO3A (rs12212067: T > G) at which the minor (G) allele, despite not being associated with disease susceptibility, is associated with a milder course of Crohn's disease and rheumatoid arthritis and with increased risk of severe malaria. Minor allele carriage is shown to limit inflammatory responses in monocytes via a FOXO3-driven pathway, which through TGFß1 reduces production of proinflammatory cytokines, including TNFα, and increases production of anti-inflammatory cytokines, including IL-10. Thus, we uncover a shared genetic contribution to prognosis in distinct diseases that operates via a FOXO3-driven pathway modulating inflammatory responses.

Developmental changes in colour constancy in a naturalistic object selection task.

When the illumination falling on a surface change, so does the reflected light. Despite this, adult observers are good at perceiving surfaces as relatively unchanging-an ability termed colour constancy. Very few studies have investigated colour constancy in infants, and even fewer in children. Here we asked whether there is a difference in colour constancy between children and adults; what the developmental trajectory is between six and 11 years; and whether the pattern of constancy across illuminations and reflectances differs between adults and children. To this end, we developed a novel, child-friendly computer-based object selection task. In this, observers saw a dragon's favourite sweet under a neutral illumination and picked the matching sweet from an array of eight seen under a different illumination (blue, yellow, red, or green). This set contained a reflectance match (colour constant; perfect performance) and a tristimulus match (colour inconstant). We ran two experiments, with two-dimensional scenes in one and three-dimensional renderings in the other. Twenty-six adults and 33 children took part in the first experiment; 26 adults and 40 children took part in the second. Children performed better than adults on this task, and their performance decreased with age in both experiments. We found differences across illuminations and sweets, but a similar pattern across both age groups. This unexpected finding might reflect a real decrease in colour constancy from childhood to adulthood, explained by developmental changes in the perceptual and cognitive mechanisms underpinning colour constancy, or differences in task strategies between children and adults. HIGHLIGHTS: Six- to 11-year-old children demonstrated better performance than adults on a colour constancy object selection task. Performance decreased with age over childhood. These findings may indicate development of cognitive strategies used to overcome automatic colour constancy mechanisms.

One size does not fit all: Impact of hand size on ease of use of instruments for minimally invasive surgery.

BACKGROUND: Consideration of ergonomic factors is important for the practice of safe and efficient minimally invasive surgery (MIS). Surgeons with smaller glove sizes have previously been reported to have increased difficulties with some minimally invasive instruments. We aim to investigate hand anthropometrics and their relationship to surgeon comfort when using MIS instruments. METHODS: Male and female surgeons from two centres were surveyed on their experience of handling MIS instruments and images obtained of the dorsal and palmar aspects of their dominant hand. Photographs of hands were transformed to calibrated coordinates to enable anthropometric measurements of finger length and width as well as palm width and hand span photogrammetrically. Surgeon-perceived discomfort, fatigue, pressure points and techniques to mitigate difficulty handling instruments were compared to hand measurements. RESULTS: Questionnaires were completed by 58 surgeons; 20 (34%) were consultants, 17 (29%) were women. Glove size ranged from 6 to 8 (median 7.5). Male participants had significantly larger hands than females in all measured dimensions. Female surgeons and those with smaller finger and hand dimensions were significantly more likely to experience difficulty or discomfort across a range of variables when using MIS instruments. CONCLUSIONS: Surgeons with smaller hands reported increased problems handling MIS instruments. This represents an issue of equity in surgery, with women being more significantly affected than men. Hand size varies greatly between surgeons and anthropometric variability should be considered in design of MIS instruments.

Functional Evolution of a Bark Beetle Odorant Receptor Clade Detecting Monoterpenoids of Different Ecological Origins.

Insects detect odors using an array of odorant receptors (ORs), which may expand through gene duplication. How and which new functions may evolve among related ORs within a species remain poorly investigated. We addressed this question by functionally characterizing ORs from the Eurasian spruce bark beetle Ips typographus, in which physiological and behavioral responses to pheromones, volatiles from host and nonhost trees, and fungal symbionts are well described. In contrast, knowledge of OR function is restricted to two receptors detecting the pheromone compounds (S)-(-)-ipsenol (ItypOR46) and (R)-(-)-ipsdienol (ItypOR49). These receptors belong to an Ips-specific OR-lineage comprising seven ItypORs. To gain insight into the functional evolution of related ORs, we characterized the five remaining ORs in this clade using Xenopus oocytes. Two receptors responded primarily to the host tree monoterpenes (+)-3-carene (ItypOR25) and p-cymene (ItypOR27). Two receptors responded to oxygenated monoterpenoids produced in larger relative amounts by the beetle-associated fungi, with ItypOR23 specific for (+)-trans-(1R, 4S)-4-thujanol, and ItypOR29 responding to (+)-isopinocamphone and similar ketones. ItypOR28 responded to the pheromone E-myrcenol from the competitor Ips duplicatus. Overall, the OR responses match well with those of previously characterized olfactory sensory neuron classes except that neurons detecting E-myrcenol have not been identified. The characterized ORs are under strong purifying selection and demonstrate a shared functional property in that they all primarily respond to monoterpenoids. The variation in functional groups among OR ligands and their diverse ecological origins suggest that neofunctionalization has occurred early in the evolution of this OR-lineage following gene duplication.

Odorant receptor orthologues in conifer-feeding beetles display conserved responses to ecologically relevant odours.

Insects are able to detect a plethora of olfactory cues using a divergent family of odorant receptors (ORs). Despite the divergent nature of this family, related species frequently express several evolutionarily conserved OR orthologues. In the largest order of insects, Coleoptera, it remains unknown whether OR orthologues have conserved or divergent functions in different species. Using HEK293 cells, we addressed this question through functional characterization of two groups of OR orthologues in three species of the Curculionidae (weevil) family, the conifer-feeding bark beetles Ips typographus L. ("Ityp") and Dendroctonus ponderosae Hopkins ("Dpon") (Scolytinae), and the pine weevil Hylobius abietis L. ("Habi"; Molytinae). The ORs of H. abietis were annotated from antennal transcriptomes. The results show highly conserved response specificities, with one group of orthologues (HabiOR3/DponOR8/ItypOR6) responding exclusively to 2-phenylethanol (2-PE), and the other group (HabiOR4/DponOR9/ItypOR5) responding to angiosperm green leaf volatiles (GLVs). Both groups of orthologues belong to the coleopteran OR subfamily 2B, and share a common ancestor with OR5 in the cerambycid Megacyllene caryae, also tuned to 2-PE, suggesting a shared evolutionary history of 2-PE receptors across two beetle superfamilies. The detected compounds are ecologically relevant for conifer-feeding curculionids, and are probably linked to fitness, with GLVs being used to avoid angiosperm nonhost plants, and 2-PE being important for intraspecific communication and/or playing a putative role in beetle-microbe symbioses. To our knowledge, this study is the first to reveal evolutionary conservation of OR functions across several beetle species and hence sheds new light on the functional evolution of insect ORs.

Putative ligand binding sites of two functionally characterized bark beetle odorant receptors.

BACKGROUND: Bark beetles are major pests of conifer forests, and their behavior is primarily mediated via olfaction. Targeting the odorant receptors (ORs) may thus provide avenues towards improved pest control. Such an approach requires information on the function of ORs and their interactions with ligands, which is also essential for understanding the functional evolution of these receptors. Hence, we aimed to identify a high-quality complement of ORs from the destructive spruce bark beetle Ips typographus (Coleoptera, Curculionidae, Scolytinae) and analyze their antennal expression and phylogenetic relationships with ORs from other beetles. Using 68 biologically relevant test compounds, we next aimed to functionally characterize ecologically important ORs, using two systems for heterologous expression. Our final aim was to gain insight into the ligand-OR interaction of the functionally characterized ORs, using a combination of computational and experimental methods. RESULTS: We annotated 73 ORs from an antennal transcriptome of I. typographus and report the functional characterization of two ORs (ItypOR46 and ItypOR49), which are responsive to single enantiomers of the common bark beetle pheromone compounds ipsenol and ipsdienol, respectively. Their responses and antennal expression correlate with the specificities, localizations, and/or abundances of olfactory sensory neurons detecting these enantiomers. We use homology modeling and molecular docking to predict their binding sites. Our models reveal a likely binding cleft lined with residues that previously have been shown to affect the responses of insect ORs. Within this cleft, the active ligands are predicted to specifically interact with residues Tyr84 and Thr205 in ItypOR46. The suggested importance of these residues in the activation by ipsenol is experimentally supported through site-directed mutagenesis and functional testing, and hydrogen bonding appears key in pheromone binding. CONCLUSIONS: The emerging insight into ligand binding in the two characterized ItypORs has a general importance for our understanding of the molecular and functional evolution of the insect OR gene family. Due to the ecological importance of the characterized receptors and widespread use of ipsenol and ipsdienol in bark beetle chemical communication, these ORs should be evaluated for their potential use in pest control and biosensors to detect bark beetle infestations.

The myometrial-cervical ratio (MCR): Assessing the diagnostic accuracy of a novel ultrasound measurement in the diagnosis of adenomyosis.

BACKGROUND: Adenomyosis is histologically defined by the presence of endometrial glands and stroma in the myometrium. To date, there are no standardised ultrasound findings that reliably predict histological adenomyosis. AIMS: This study aimed to determine the diagnostic accuracy of a novel sonographic measurement for adenomyosis, the myometrial-cervical ratio (MCR), when compared with histopathological diagnosis. MATERIALS AND METHODS: A single-centre retrospective study was performed. The MCR was calculated from the pre-operative ultrasound, and histopathology reviewed for each case. Accuracy data were analysed in the form of 2 × 2 tables. The discriminative value of the MCR was summarised with a receiver operator characteristic (ROC) curve. Sub-analysis examined the impact of fibroids, hormonal suppression, menopausal status, parity and indication for surgery. RESULTS: Between 1 January 2016 and 31 December 2018, 982 patients underwent hysterectomy for benign non-obstetric indication and adequate pre-operative ultrasound was available for 260. The MCR demonstrated limited diagnostic ability for adenomyosis (area under the receiver operating characteristic curve (AUROC) 0.58, 95% CI 0.51-0.65). However, when applied to cases with no uterine fibroid included in the MCR calculation (n = 133) there was a strong association between MCR and diagnosis of adenomyosis (odds ratio: 5.79, 95% CI: 2.15, 15.62, P = 0.001) with AUROC for this model 0.68 (95% CI: 0.59, 0.77). At an MCR cut-point of 1.74, sensitivity is 67.16% and specificity is 66.15%, with 66.67% of samples correctly classified. CONCLUSIONS: While diagnostic accuracy was suboptimal, the MCR outperforms traditional ultrasound diagnostic features of adenomyosis. The MCR may offer a simple imaging measurement for adenomyosis.

Trends in US Outpatient Antibiotic Prescriptions During the Coronavirus Disease 2019 Pandemic.

BACKGROUND: The objective of our study was to describe trends in US outpatient antibiotic prescriptions from January through May 2020 and compare with trends in previous years (2017-2019). METHODS: We used data from the IQVIA Total Patient Tracker to estimate the monthly number of patients dispensed antibiotic prescriptions from retail pharmacies from January 2017 through May 2020. We averaged estimates from 2017 through 2019 and defined expected seasonal change as the average percent change from January to May 2017-2019. We calculated percentage point and volume changes in the number of patients dispensed antibiotics from January to May 2020 exceeding expected seasonal changes. We also calculated average percent change in number of patients dispensed antibiotics per month in 2017-2019 versus 2020. Data were analyzed overall and by agent, class, patient age, state, and prescriber specialty. RESULTS: From January to May 2020, the number of patients dispensed antibiotic prescriptions decreased from 20.3 to 9.9 million, exceeding seasonally expected decreases by 33 percentage points and 6.6 million patients. The largest changes in 2017-2019 versus 2020 were observed in April (-39%) and May (-42%). The number of patients dispensed azithromycin increased from February to March 2020 then decreased. Overall, beyond-expected decreases were greatest among children (≤19 years) and agents used for respiratory infections, dentistry, and surgical prophylaxis. CONCLUSIONS: From January 2020 to May 2020, the number of outpatients with antibiotic prescriptions decreased substantially more than would be expected because of seasonal trends alone, possibly related to the coronavirus disease 2019 pandemic and associated mitigation measures.

Changes in US Outpatient Antibiotic Prescriptions From 2011-2016.

BACKGROUND: While antibiotics are life-saving drugs, their use is not without risk, including adverse events and antibiotic resistance. The majority of US antibiotic prescriptions are prescribed in outpatient settings, making outpatient antibiotic prescribing an important antibiotic stewardship target. The primary objective of this study was to describe trends in US outpatient oral antibiotic prescriptions from 2011-2016. METHODS: We estimated annual oral antibiotic prescription rates using national prescription dispensing count data from IQVIA Xponent, divided by census estimates for 2011-2016. We calculated the ratio of broad- to narrow-spectrum prescriptions by dividing broad-spectrum prescription rates by narrow-spectrum prescription rates. We used Poisson models to estimate prevalence rate ratios, comparing 2011 and 2016 antibiotic prescription rates, and linear models to evaluate temporal trends throughout the study period. RESULTS: Oral antibiotic prescription rates decreased 5%, from 877 prescriptions per 1000 persons in 2011 to 836 per 1000 persons in 2016. During this period, rates of prescriptions dispensed to children decreased 13%, while adult rates increased 2%. The ratio of broad- to narrow-spectrum antibiotics decreased from 1.62 in 2011 to 1.49 in 2016, driven by decreases in macrolides and fluoroquinolones. The proportion of prescriptions written by nurse practitioners and physician assistants increased during the study period; in 2016, these providers prescribed over one-quarter of all antibiotic prescriptions. CONCLUSIONS: Outpatient antibiotic prescription rates, especially of broad-spectrum agents, have decreased in recent years. Clinicians who prescribe to adults, including nurse practitioners and physician assistants, are important targets for antibiotic stewardship.

Assessment of intimate partner violence abuse ratings by recently abused and never abused women.

BACKGROUND: There are a paucity of directly reported intimate partner violence survivors' experiences, especially in women of color. This study measures recently/currently abused women's ratings of varied abuse events compared to ratings from never abused women. METHODS: Women in a single, urban, public hospital emergency department (ED) were screened for intimate partner violence using the Abuse Assessment Screen (AAS). Two groups were identified - women abused within 1 year by an intimate partner or family member and those who screened negative for abuse. Using a two-group longitudinal survey and interview format, women completed visual analog scale ratings (0-100) for each of 20 abuse events/types. For analysis, each abuse type was placed on the 0-100 scale according to its designated rating. RESULTS: Average age of participants in the abuse group (n = 30) was 33. Never abused women averaged age 50 (n = 32). The majority of participants were African-American: abused 67% and never abused 94%. Abused women rated name-calling (p < 0.02) and put-downs (p < 0.01) as more severe than never abused women. Other non-physical and physical forms of abuse such as threats, control, burns or forced sex were perceived more similarly between groups. CONCLUSIONS: Abused women perceive verbal abuse events differently compared to never abused women.

Specular highlights improve color constancy when other cues are weakened.

Previous studies suggest that to achieve color constancy, the human visual system makes use of multiple cues, including a priori assumptions about the illumination ("daylight priors"). Specular highlights have been proposed to aid constancy, but the evidence for their usefulness is mixed. Here, we used a novel cue-combination approach to test whether the presence of specular highlights or the validity of a daylight prior improves illumination chromaticity estimates, inferred from achromatic settings, to determine whether and under which conditions either cue contributes to color constancy. Observers made achromatic settings within three-dimensional rendered scenes containing matte or glossy shapes, illuminated by either daylight or nondaylight illuminations. We assessed both the variability of these settings and their accuracy, in terms of the standard color constancy index (CCI). When a spectrally uniform background was present, neither CCIs nor variability improved with specular highlights or daylight illuminants (Experiment 1). When a Mondrian background was introduced, CCIs decreased overall but were higher for scenes containing glossy, as opposed to matte, shapes (Experiments 2 and 3). There was no overall reduction in variability of settings and no benefit for scenes illuminated by daylights. Taken together, these results suggest that the human visual system indeed uses specular highlights to improve color constancy but only when other cues, such as from the local surround, are weakened.

Antibiotic Prescriptions Associated With Dental-Related Emergency Department Visits.

STUDY OBJECTIVE: The frequency of antibiotic prescribing and types of antibiotics prescribed for dental conditions presenting to the emergency department (ED) is not well known. The objective of this study is to quantify how often and which dental diagnoses made in the ED resulted in an antibiotic prescription. METHODS: From 2011 to 2015, there were an estimated 2.2 million (95% confidence interval [CI] 1.9 to 2.5 million) ED visits per year for dental-related conditions, which accounted for 1.6% (95% CI 1.5% to 1.7%) of ED visits. This is based on an unweighted 2,125 observations from the National Hospital Ambulatory Medical Care Survey in which a dental-related diagnosis was made. RESULTS: An antibiotic, most often a narrow-spectrum penicillin or clindamycin, was prescribed in 65% (95% CI 61% to 68%) of ED visits with any dental diagnosis. The most common dental diagnoses for all ages were unspecified disorder of the teeth and supporting structures (44%; 95% CI 41% to 48%; International Classification of Diseases, Ninth Revision, Clinical Modification[ICD-9-CM] code 525.9), periapical abscess without sinus (21%; 95% CI 18% to 25%; ICD-9-CM code 522.5), and dental caries (18%; 95% CI 15% to 22%; ICD-9-CM code 521.0). Recommended treatments for these conditions are usually dental procedures rather than antibiotics. CONCLUSION: The common use of antibiotics for dental conditions in the ED may indicate the need for greater access to both preventive and urgent care from dentists and other related specialists as well as the need for clearer clinical guidance and provider education related to oral infections.

Antibiotic Expenditures by Medication, Class, and Healthcare Setting in the United States, 2010-2015.

Background: Improving antibiotic use has the potential to decrease healthcare costs by reducing the incidence of antibiotic-resistant infections, antibiotic-associated adverse events, and expenditures due to unnecessary prescriptions. Antibiotic expenditures in 2009 totaled $10.7 billion in the United States. Since then, national and local antibiotic stewardship initiatives have grown. The purpose of this study was to assess trends in antibiotic expenditures by healthcare setting in the United States between 2010 and 2015. Methods: Systemic (nontopical) antibiotic expenditures from January 2010 to December 2015 were extracted from the QuintilesIMS National Sales Perspectives database. These data represent a statistically valid projection of US medication purchases. Regression analyses evaluated trends in expenditures over the study period. Results: Antibiotic expenditures totaled $56.0 billion over the 6-year period; the majority (59.1%) of expenditures were associated with the outpatient setting. Overall antibiotic expenditures in 2015 ($8.8 billion) were 16.6% lower than in 2010 ($10.6 billion). Antibiotic expenditures similarly decreased in the community by 25.5% (P = .05), but outpatient clinics and mail service pharmacy expenditures experienced significant growth (148% and 67% increase, respectively; P < .01 for both). In 2015, 16.5% of antibiotic expenditures in the community were for parenteral formulations, an increase of 25%. Conclusions: From 2010 to 2015, antibiotic expenditures decreased. The majority of antibiotic expenditures were in the outpatient setting, specifically community pharmacies. Expenditures for intravenous agents in the community are increasing and may represent increased use. These results reinforce the importance of antibiotic stewardship efforts across the spectrum of healthcare.

Association between ABCG2 rs2231142 and poor response to allopurinol: replication and meta-analysis.

Objective: ABCG2 rs2231142 (Q141K) has been reported to be associated with poor response to allopurinol, while there are conflicting data on the association between the genetically independent ABCG2 rs10011796 variant and allopurinol response. The aim of this study was to replicate the association of ABCG2 rs2231142 and rs10011796 with allopurinol response and perform a meta-analysis. Methods: Participants in the Long-term Allopurinol Safety Study Evaluating Outcomes in Gout Patients (LASSO) (n = 299) were studied. In patients with evidence of adherence to allopurinol therapy (plasma oxypurinol >20 µmol/l), good response was defined as serum urate <6 mg/dl on allopurinol ⩽300 mg/day and poor response as serum urate ⩾ 6 mg/dl despite allopurinol >300 mg/day. Association of rs2231142 and rs10011796 with poor response was tested in logistic regression models that included age, sex, BMI, ethnicity and estimated glomerular filtration rate. Results from the LASSO study and a subset of participants in the Genetics of Gout in Aotearoa New Zealand study (n = 296, including 264 from a previously published report) were combined by meta-analysis. Results: There was evidence for association of rs2231142 with allopurinol response [odds ratio (OR) = 2.35, P = 7.3 × 10-4] but not for rs10011796 (OR = 1.21, P = 0.33) in the LASSO cohort using an adjusted logistic regression model. Meta-analysis provided evidence of a significant association of rs2231142 with allopurinol response (OR = 2.43, P = 6.2 × 10-7), but not rs10011796 (OR = 1.06, P = 0.69). Conclusion: This study has confirmed the significant association of ABCG2 rs2231142 with poor response to allopurinol.

Chemical Ecology of Chemosensation in Asteroidea: Insights Towards Management Strategies of Pest Species.

Within the Phylum Echinodermata, the class Asteroidea, commonly known as starfish and sea stars, encompasses a large number of benthos inhabiting genera and species with various feeding modalities including herbivores, carnivores, omnivores and detritivores. The Asteroidea rely on chemosensation throughout their life histories including hunting prey, avoiding or deterring predators, in the formation of spawning aggregations, synchronizing gamete release and targeting appropriate locations for larval settlement. The identities of many of the chemical stimuli that mediate these physiological and behavioural processes remain unresolved even though evidence indicates they play pivotal roles in the functionality of benthic communities. Aspects of chemosensation, as well as putative chemically-mediated behaviours and the molecular mechanisms of chemoreception, within the Asteroidea are reviewed here, with particular reference to the coral reef pest the Crown-of-Thorns starfish Acanthaster planci species complex, in the context of mitigation of population outbreaks.

Identification of putative olfactory G-protein coupled receptors in Crown-of-Thorns starfish, Acanthaster planci.

BACKGROUND: In marine organisms, and in particular for benthic invertebrates including echinoderms, olfaction is a dominant sense with chemosensation being a critical signalling process. Until recently natural product chemistry was the primary investigative approach to elucidate the nature of chemical signals but advances in genomics and transcriptomics over the last decade have facilitated breakthroughs in understanding not only the chemistry but also the molecular mechanisms underpinning chemosensation in aquatic environments. Integration of these approaches has the potential to reveal the fundamental elements influencing community structure of benthic ecosystems as chemical signalling modulates intra- and inter-species interactions. Such knowledge also offers avenues for potential development of novel biological control methods for pest species such as the predatory Crown-of-Thorns starfish (COTS), Acanthaster planci which are the primary biological cause of coral cover loss in the Indo-Pacific. RESULTS: In this study, we have analysed the COTS sensory organs through histological and electron microscopy. We then investigated key elements of the COTS molecular olfactory toolkit, the putative olfactory rhodopsin-like G protein-protein receptors (GPCRs) within its genome and olfactory organ transcriptomes. Many of the identified Acanthaster planci olfactory receptors (ApORs) genes were found to cluster within the COTS genome, indicating rapid evolution and replication from an ancestral olfactory GPCR sequence. Tube feet and terminal sensory tentacles contain the highest proportion of ApORs. In situ hybridisation confirmed the presence of four ApORs, ApOR15, 18, 25 and 43 within COTS sensory organs, however expression of these genes was not specific to the adhesive epidermis, but also within the nerve plexus of tube feet stems and within the myomesothelium. G alpha subunit proteins were also identified in the sensory organs, and we report the spatial localisation of Gαi within the tube foot and sensory tentacle. CONCLUSIONS: We have identified putative COTS olfactory receptors that localise to sensory organs. These results provide a basis for future studies that may enable the development of a biological control not only for COTS, but also other native pest or invasive starfish.

Core Elements of Outpatient Antibiotic Stewardship.

The Core Elements of Outpatient Antibiotic Stewardship provides a framework for antibiotic stewardship for outpatient clinicians and facilities that routinely provide antibiotic treatment. This report augments existing guidance for other clinical settings. In 2014 and 2015, respectively, CDC released the Core Elements of Hospital Antibiotic Stewardship Programs and the Core Elements of Antibiotic Stewardship for Nursing Homes. Antibiotic stewardship is the effort to measure and improve how antibiotics are prescribed by clinicians and used by patients. Improving antibiotic prescribing involves implementing effective strategies to modify prescribing practices to align them with evidence-based recommendations for diagnosis and management. The four core elements of outpatient antibiotic stewardship are commitment, action for policy and practice, tracking and reporting, and education and expertise. Outpatient clinicians and facility leaders can commit to improving antibiotic prescribing and take action by implementing at least one policy or practice aimed at improving antibiotic prescribing practices. Clinicians and leaders of outpatient clinics and health care systems can track antibiotic prescribing practices and regularly report these data back to clinicians. Clinicians can provide educational resources to patients and families on appropriate antibiotic use. Finally, leaders of outpatient clinics and health systems can provide clinicians with education aimed at improving antibiotic prescribing and with access to persons with expertise in antibiotic stewardship. Establishing effective antibiotic stewardship interventions can protect patients and improve clinical outcomes in outpatient health care settings.

Bisphenol A Does Not Mimic Estrogen in the Promotion of the In Vitro Response of Murine Dendritic Cells to Toll-Like Receptor Ligands.

Sex hormones affect immune responses and might promote autoimmunity. Endocrine disrupting chemicals such as bisphenol A (BPA) may mimic their immune effects. Conventional dendritic cells (cDCs) are pivotal initiators of immune responses upon activation by danger signals coming from pathogens or distressed tissues through triggering of the Toll-like receptors (TLRs). We generated in vitro murine cDCs in the absence of estrogens and measured the effects of exogenously added estrogen or BPA on their differentiation and activation by the TLR ligands LPS and CpG. Estrogen enhanced the differentiation of GM-CSF-dependent cDCs from bone marrow precursors in vitro, and the selective estrogen receptor modulators (SERMs) tamoxifen and fulvestrant blocked these effects. Moreover, estrogen augmented the upregulation of costimulatory molecules and proinflammatory cytokines (IL-12p70 and TNFα) upon stimulation by TLR9 ligand CpG, while the response to LPS was less estrogen-dependent. These effects are partially explained by an estrogen-dependent regulation of TLR9 expression. BPA did not promote cDC differentiation nor activation upon TLR stimulation. Our results suggest that estrogen promotes immune responses by increasing DC activation, with a preferential effect on TLR9 over TLR4 stimulation, and highlight the influence of estrogens in DC cultures, while BPA does not mimic estrogen in the DC functions that we tested.

Exploring the genetic basis of 3MC syndrome: Findings in 12 further families.

The 3MC syndromes are a group of rare autosomal recessive disorders where the main clinical features are cleft lip and palate, hypertelorism, highly arched eyebrows, caudal appendage, postnatal growth deficiency, and genitourinary tract anomalies. Ophthalmological abnormalities, most notably anterior chamber defects may also be seen. We describe the clinical and molecular findings in 13 individuals with suspected 3MC syndrome from 12 previously unreported families. The exclusion of the MASP1 and COLEC11 Loci in two individuals from different consanguineous families and the absence of mutations in four further individuals sequenced for both genes raises the possibility that that there is further genetic heterogeneity of 3MC syndrome.

Influence of Genotype on Warfarin Maintenance Dose Predictions Produced Using a Bayesian Dose Individualization Tool.

BACKGROUND: A previously established Bayesian dosing tool for warfarin was found to produce biased maintenance dose predictions. In this study, we aimed (1) to determine whether the biased warfarin dose predictions previously observed could be replicated in a new cohort of patients from 2 different clinical settings, (2) to explore the influence of CYP2C9 and VKORC1 genotype on predictive performance of the Bayesian dosing tool, and (3) to determine whether the previous population used to develop the kinetic-pharmacodynamic model underpinning the Bayesian dosing tool was sufficiently different from the test (posterior) population to account for the biased dose predictions. METHODS: The warfarin maintenance doses for 140 patients were predicted using the dosing tool and compared with the observed maintenance dose. The impact of genotype was assessed by predicting maintenance doses with prior parameter values known to be altered by genetic variability (eg, EC50 for VKORC1 genotype). The prior population was evaluated by fitting the published kinetic-pharmacodynamic model, which underpins the Bayesian tool, to the observed data using NONMEM and comparing the model parameter estimates with published values. RESULTS: The Bayesian tool produced positively biased dose predictions in the new cohort of patients (mean prediction error [95% confidence interval]; 0.32 mg/d [0.14-0.5]). The bias was only observed in patients requiring ≥7 mg/d. The direction and magnitude of the observed bias was not influenced by genotype. The prior model provided a good fit to our data, which suggests that the bias was not caused by different prior and posterior populations. CONCLUSIONS: Maintenance doses for patients requiring ≥7 mg/d were overpredicted. The bias was not due to the influence of genotype nor was it related to differences between the prior and posterior populations. There is a need for a more mechanistic model that captures warfarin dose-response relationship at higher warfarin doses.