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Objective: Growth hormone insensitivity (GHI) encompasses growth restriction, normal/elevated growth hormone (GH), and low insulin-like growth factor I (IGF1). "Nonclassical" GHI is poorly characterized and is rarely caused by heterozygous dominant-negative (DN) variants located in the intracellular or transmembrane domains of the GH receptor (GHR). We sought to determine the molecular mechanisms underpinning the growth restriction in 2 GHI cases. Methods and Design: A custom-made genetic investigative pipeline was exploited to identify the genetic cause of growth restriction in patients with GHI. Nanoluc binary technology (NanoBiT), in vitro splicing assays, western blotting, and flow cytometry, characterized the novel GHR variants. Results: Novel heterozygous GHR variants were identified in 2 unrelated patients with GHI. In vitro splicing assays indicated both variants activated the same alternative splice acceptor site resulting in aberrant splicing and exclusion of 26 base pairs of GHR exon 9. The GHR variants produced truncated receptors and impaired GH-induced GHR signaling. NanoBiT complementation and flow cytometry showed increased cell surface expression of variant GHR homo/heterodimers compared to wild-type (WT) homodimers and increased recombinant human GH binding to variant GHR homo/heterodimers and GH binding protein (GHBP) cleaved from the variant GHRs. The findings demonstrated increased variant GHR dimers and GHBP with resultant GH sequestration. Conclusion: We identified and characterized 2 novel, naturally occurring truncated GHR gene variants. Intriguingly, these DN GHR variants act via the same cryptic splice acceptor site, highlighting impairing GH binding to excess GHBP as a potential therapeutic approach. [ABSTRACT FROM AUTHOR]

Lung injury from smoke inhalation manifests as airway and parenchymal damage, at times leading to the acute respiratory distress syndrome. From the beginning of this millennium, the approach to mechanical ventilation in the patient with ARDS was based on reduction of tidal volume to 6 milliliters/kilogram of ideal body weight, maintaining a ceiling of plateau pressure, and titration of driving pressure (plateau pressure minus PEEP). Beyond these broad constraints, there is little specification for the mechanics of ventilator settings, consideration of the metabolic impact of the disease process on the patient, or interaction of patient disease and ventilator settings. Various studies suggest that inhomogeneity of lung injury, which increases the risk of regional lung trauma from mechanical ventilation, may be found in the patient with smoke inhalation. We now appreciate that energy transfer principles may affect optimal ventilator management and come into play in damaged heterogenous lungs. Mechanical ventilation in the patient with inhalation injury should consider various factors. Self-injurious respiratory demand by the patient can be reduced using analgesia and sedation. Dynamic factors beginning with rate management can reduce the incidence of potentially damaging ventilation. Moreover, preclinical study is underway to examine the flow of gas based on the ventilator mode selected, which may also be a factor triggering regional lung injury. [ABSTRACT FROM AUTHOR]

Context: The causal role of endogenous estradiol in cancers other than breast and endometrial cancer remains unclear. Objective: This Mendelian randomization study assessed the causal associations of endogenous 17β-estradiol (E2), the most potent estrogen, with cancer risk in women. Methods: As primary genetic instrument, we used a genetic variant in the CYP19A1 gene that is strongly associated with serum E2 levels. Summary statistics genetic data for the association of the E2 variant with breast, endometrial, and ovarian cancer were obtained from large-scale consortia. We additionally estimated the associations of the E2 variant with any and 20 site-specific cancers in 198 825 women of European descent in UK Biobank. Odds ratios (OR) of cancer per 0.01 unit increase in log-transformed serum E2 levels in pmol/L were estimated using the Wald ratio. Results: Genetic predisposition to higher serum E2 levels was associated with increased risk of estrogen receptor (ER)-positive breast cancer (OR 1.02; 95% CI, 1.01-1.03; P = 2.5 × 10−3), endometrial cancer overall (OR 1.09; 95% CI, 1.06-1.11; P = 7.3 × 10−13), and endometrial cancer of the endometrioid histology subtype (OR 1.10; 95% CI, 1.07-1.13; P = 2.1 × 10−11). There were suggestive associations with breast cancer overall (OR 1.01; 95% CI, 1.00-1.02; P = 0.02), ovarian cancer of the endometrioid subtype (OR 1.05; 95% CI, 1.01-1.10; P = 0.02), and stomach cancer (OR 1.12; 95% CI, 1.00-1.26; P = 0.05), but no significant association with other cancers. Conclusion: This study supports a role of E2 in the development of ER-positive breast cancer and endometrioid endometrial cancer but found no strong association with other cancers in women. [ABSTRACT FROM AUTHOR]

Context: Adult height is highly heritable, yet no genetic predictor has demonstrated clinical utility compared to mid-parental height.Objective: To develop a polygenic risk score for adult height and evaluate its clinical utility.Design: A polygenic risk score was constructed based on meta-analysis of genomewide association studies and evaluated on the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort.Subjects: Participants included 442 599 genotyped White British individuals in the UK Biobank and 941 genotyped child-parent trios of European ancestry in the ALSPAC cohort.Interventions: None.Main Outcome Measures: Standing height was measured using stadiometer; Standing height 2 SDs below the sex-specific population average was considered as short stature.Results: Combined with sex, a polygenic risk score captured 71.1% of the total variance in adult height in the UK Biobank. In the ALSPAC cohort, the polygenic risk score was able to identify children who developed adulthood short stature with an area under the receiver operating characteristic curve (AUROC) of 0.84, which is close to that of mid-parental height. Combining this polygenic risk score with mid-parental height or only one of the child's parent's height could improve the AUROC to at most 0.90. The polygenic risk score could also substitute mid-parental height in age-specific Khamis-Roche height predictors and achieve an equally strong discriminative power in identifying children with a short stature in adulthood.Conclusions: A polygenic risk score could be considered as an alternative or adjunct to mid-parental height to improve screening for children at risk of developing short stature in adulthood in European ancestry populations. [ABSTRACT FROM AUTHOR]

Objectives: Pseudomonas aeruginosa is an important pathogen in chronic suppurative respiratory diseases, with adverse effects on severity, healthcare utilization and quality of life. Aerosolized combined biofilm disruption and iron chelators offer novel proof-of-concept for improving airway antimicrobial efficacy. Our aim was to assess the activity of desferrioxamine, Dornase alfa (DNase) and antibiotics on biofilm formation and against mature preformed biofilms of P. aeruginosa.Methods: Fifty-six isolates of P. aeruginosa were screened for biofilm production and seven isolates with varying capacity to form biofilms were referred for further study. Three antibiotics (colistin, tobramycin and ciprofloxacin) as well as desferrioxamine and DNase were assessed for their ability to prevent biofilm formation using the crystal violet assay. The same method was used to assess their impact on mature biofilms. Each agent, as well as combinations of these agents, was also assessed for its effect on the metabolic activity and viability of preformed P. aeruginosa biofilm by the resazurin reduction assay and by performing viable counts.Results: Antibiotics alone prevented the development of biofilms and partly reduced the viability of mature biofilms. Desferrioxamine and DNase did not reduce biofilm formation. For most isolates, desferrioxamine and DNase did not offer any clear advantage over the use of antibiotics alone with respect to reducing the viability of Pseudomonas biofilms.Conclusions: Colistin, tobramycin and ciprofloxacin prevented biofilm formation by P. aeruginosa and reduced the viability of mature biofilms. For most isolates, there was no clear advantage of combining these antimicrobials with desferrioxamine or DNase. [ABSTRACT FROM AUTHOR]

It is hoped that sharing these experiences will be of value to clinicians, microbiologists, public health professionals and policymakers involved in similar activities in other parts of the world. As part of this programme, countries were encouraged to develop National Action Plans to tackle AMR that are aligned with the GAP but adapted to national priorities and country-specific contexts. In response to the global threat to public health posed by antimicrobial resistance (AMR), the World Health Assembly formulated a Global Action Plan (GAP) in 2015. [Extracted from the article]

Background: Insulinemia and type 2 diabetes (T2D) have been associated with endometrial cancer risk in numerous observational studies. However, the causality of these associations is uncertain. Here we use a Mendelian randomization (MR) approach to assess whether insulinemia and T2D are causally associated with endometrial cancer.Methods: We used single nucleotide polymorphisms (SNPs) associated with T2D (49 variants), fasting glucose (36 variants), fasting insulin (18 variants), early insulin secretion (17 variants), and body mass index (BMI) (32 variants) as instrumental variables in MR analyses. We calculated MR estimates for each risk factor with endometrial cancer using an inverse-variance weighted method with SNP-endometrial cancer associations from 1287 case patients and 8273 control participants.Results: Genetically predicted higher fasting insulin levels were associated with greater risk of endometrial cancer (odds ratio [OR] per standard deviation = 2.34, 95% confidence internal [CI] = 1.06 to 5.14, P = .03). Consistently, genetically predicted higher 30-minute postchallenge insulin levels were also associated with endometrial cancer risk (OR = 1.40, 95% CI = 1.12 to 1.76, P = .003). We observed no associations between genetic risk of type 2 diabetes (OR = 0.91, 95% CI = 0.79 to 1.04, P = .16) or higher fasting glucose (OR = 1.00, 95% CI = 0.67 to 1.50, P = .99) and endometrial cancer. In contrast, endometrial cancer risk was higher in individuals with genetically predicted higher BMI (OR = 3.86, 95% CI = 2.24 to 6.64, P = 1.2x10(-6)).Conclusion: This study provides evidence to support a causal association of higher insulin levels, independently of BMI, with endometrial cancer risk. [ABSTRACT FROM AUTHOR]

The analysis of volatile organic compounds (VOCs) as a tool for bacterial identification is reported. Headspace solid-phase microextraction (HS-SPME) coupled to gas chromatography–mass spectrometry (GC–MS) was applied to the analysis of bacterial VOCs with the aim of determining the impact of experimental parameters on the generated VOC profiles. The effect of culture medium, SPME fiber type and GC column were fully evaluated with the Gram-negative bacteria Escherichia coli and Klebsiella pneumoniae and the Gram-positive species Staphylococcus aureus. Multivariate analysis, including cluster analysis and principal component analysis, was applied to VOC data to determine whether the parameters under investigation significantly affected bacterial VOC profiles. Culture medium, and to a lesser extent, SPME fiber type, were found to significantly alter detected bacterial VOC profiles. The detected VOCs varied little with the polarity of the GC column. The results indicate that the generated bacterial VOC profiles need careful evaluation if they are to be used for clinical diagnostics. The whole process is limited by the need to grow the bacteria in broth (18 h) before extraction and analysis (63 min). [ABSTRACT FROM AUTHOR]

The BSAC guidelines on treatment of infectious endocarditis (IE) were last published in 2004. The guidelines presented here have been updated and extended to reflect developments in diagnostics, new trial data and the availability of new antibiotics. The aim of these guidelines, which cover both native valve and prosthetic valve endocarditis, is to standardize the initial investigation and treatment of IE. An extensive review of the literature using a number of different search criteria has been carried out and cited publications used to support any changes we have made to the existing guidelines. Publications referring to in vitro or animal models have only been cited if appropriate clinical data are not available. Randomized, controlled trials suitable for the development of evidenced-based guidelines in this area are still lacking and therefore a consensus approach has again been adopted for most recommendations; however, we have attempted to grade the evidence, where possible. The guidelines have also been extended by the inclusion of sections on clinical diagnosis, echocardiography and surgery. [ABSTRACT FROM PUBLISHER]

Objectives To determine the prevalence and antimicrobial susceptibility of carbapenemase-producing Enterobacteriaceae among hospitalized patients and outpatients attending two military hospitals in Rawalpindi, Pakistan, and to compare the performance of two chromogenic culture media for the isolation of these organisms. Methods Stool samples from 200 distinct patients were cultured on MacConkey agar and subsequently on two chromogenic media—Colorex KPC and a prototype chromogenic medium, ID Carba—designed for the isolation of carbapenemase-producing Enterobacteriaceae. All Gram-negative isolates growing on either chromogenic medium were investigated for carbapenemases by phenotypic and molecular methods. Producers were subjected to susceptibility testing with 40 antimicrobials by VITEK 2 or agar dilution. Results In total, 64 NDM-1-positive isolates of Enterobacteriaceae, belonging to seven distinct species, were recovered from 37 (18.5%) of the stool samples. No other carbapenemase types were confirmed. Nineteen positive samples were identified among 70 from inpatients (prevalence 27.1%) and there were 18 positive samples among 130 from outpatients (prevalence 13.8%). Fifty-six isolates (87.5%) harbouring the NDM-1 enzyme were recovered on ID Carba compared with 41 isolates (64.1%) on Colorex KPC (P = 0.012). Multidrug resistance was prevalent, but no pan-resistant isolates were found, with most isolates susceptible in vitro to colistin (97%), mecillinam (95%), fosfomycin (94%), tigecycline (89%) and nitrofurantoin (78%). Conclusions This study shows a high prevalence of multidrug-resistant Enterobacteriaceae with the NDM-1 enzyme in Rawalpindi. The new chromogenic medium, ID Carba, was more sensitive than Colorex KPC and has potential as a screening medium for isolation of Enterobacteriaceae harbouring the NDM-1 enzyme. [ABSTRACT FROM PUBLISHER]

The implications of Pope John Paul II's 2004 Allocution on vegetative states remain unclear despite dozens of articles and a recent clarifying statement from the Vatican. Yet few have considered its implications for those with end-stage progressive dementia, such as Alzheimer's disease. Although recent studies suggest tube feeding is burdensome and not beneficial for such patients, the Allocution would nonetheless seem to forbid patients from forgoing it. But this seems to be in tension with the Catholic bioethical tradition as a whole and may therefore be a consequence that the pope did not intend. Because the recent Vatican clarification specifically addresses Alzheimer’s, it is especially important to know what duties it intends to impose on those with dementia. Problems with how it would apply to such patients casts doubt on whether it should be applied to patients in vegetative states at all. [ABSTRACT FROM PUBLISHER]

A letter to editor in response to an article in context with detection of potential respiratory pathogens in the mouths of older people admitted in hospitals in Great Britain, is presented.

Examines John Locke's philosophy for religious toleration referencing the document "Letter Concerning Toleration." Background of Locke's arguments regarding toleration; Religious and temporal role of morality; Limitations of Locke's theology.

A letter to the editor is presented in response to an article by F. Jansaker and colleagues on the treatment of patients with Enterobacteriaceae urinary tract infection using pivmecillinam.

Establishment of the Office of War Information is primarily intended as an effort to solve a complicated tangle of administrative problems. Information, propaganda and censorship activities have been hampered by jurisdictional disputes, and lack of adequate coordination has resulted in criticism by Congress and the press. Despite the frequent assertions by minorities in Congress and by some newspapers that the government should not engage in propaganda, there will continue to be plenty of it. There hasn't been much debate on the purposes and methods of utilitarian propaganda, for the objectives are specific and the techniques familiar. There have been so many arguments on "morale" propaganda that it would require chapters to report them all. The transcripts of foreign short-wave broadcasts reveal one common denominator for almost all Nazi and Japanese radio propaganda. Able propagandists know that group discussion is democracy's thinking process, and that their arguments will be won only insofar as they find effective expression, and carry conviction, in the free exchanges of opinion among the hundreds of thousands of formal and informal groups which make up the society.

The article discusses DRIVE-AB (Driving re-investment in Research and Development and responsible antibiotic use) is a project composed of public and private partners funded by the Innovative Medicines Initiative (IMI) and European Pharmaceutical Industry Association (EFPIA).

The article reports on an antimicrobial resistance surveillance study "Survey of Antibiotic Resistance," and includes threats posed by antibiotic resistance; improving public health; and rates of antimicrobial resistance in different European countries.

This article by the Assistant Director of the National Zoological Park. Washington. D.C, reviews the history of zoological research and describes developments at the National Zoo. Until recently, scientific research in zoos lagged. Excellent work in husbandry was not systematically recorded or published. Few scientists were attached to zoos and most zoo curators were too burdened with animal management to conduct major research. Several zoos now ha e substantial research activities. The National Zoo has organized a research division and is building a research facility scheduled for completion in 1968. [ABSTRACT FROM AUTHOR]

Mendelian randomization is the use of genetic variants as instrumental variables to estimate causal effects of risk factors on outcomes. The total causal effect of a risk factor is the change in the outcome resulting from intervening on the risk factor. This total causal effect may potentially encompass multiple mediating mechanisms. For a proposed mediator, the direct effect of the risk factor is the change in the outcome resulting from a change in the risk factor, keeping the mediator constant. A difference between the total effect and the direct effect indicates that the causal pathway from the risk factor to the outcome acts at least in part via the mediator (an indirect effect). Here, we show that Mendelian randomization estimates of total and direct effects can be obtained using summarized data on genetic associations with the risk factor, mediator, and outcome, potentially from different data sources. We perform simulations to test the validity of this approach when there is unmeasured confounding and/or bidirectional effects between the risk factor and mediator. We illustrate this method using the relationship between age at menarche and risk of breast cancer, with body mass index (BMI) as a potential mediator. We show an inverse direct causal effect of age at menarche on risk of breast cancer (independent of BMI), and a positive indirect effect via BMI. In conclusion, multivariable Mendelian randomization using summarized genetic data provides a rapid and accessible analytic strategy that can be undertaken using publicly available data to better understand causal mechanisms. [ABSTRACT FROM AUTHOR]