Simple models of the chemical field around swimming plankton

Background. Cervical cancer is the fourth most common cancer in women, and we recently reported human leukocyte antigen (HLA) alleles showing strong associations with cervical neoplasia risk and protection. HLA ligands are recognized by killer immunoglobulin-like receptors (KIRs) expressed on a range of immune cell subsets, governing their proinflammatory activity. We hypothesized that the inheritance of particular HLA-KIR combinations would increase cervical neoplasia risk. Methods. Here, we used HLA and KIR dosages imputed from single-nucleotide polymorphism genotype data from 2143 cervical neoplasia cases and 13 858 healthy controls of European decent. Results. The following 4 novel HLA alleles were identified in association with cervical neoplasia, owing to their linkage disequilibrium with known cervical neoplasia-associated HLA-DRB1 alleles: HLA-DRB3*9901 (odds ratio [OR], 1.24; P = 2.49 × 10−9), HLA-DRB5*0101 (OR, 1.29; P = 2.26 × 10−8), HLA-DRB5*9901 (OR, 0.77; P = 1.90 × 10−9), and HLA-DRB3*0301 (OR, 0.63; P = 4.06 × 10−5). We also found that homozygosity of HLA-C1 group alleles is a protective factor for human papillomavirus type 16 (HPV16)-related cervical neoplasia (C1/C1; OR, 0.79; P = .005). This protective association was restricted to carriers of either KIR2DL2 (OR, 0.67; P = .00045) or KIR2DS2 (OR, 0.69; P = .0006). Conclusions. Our findings suggest that HLA-C1 group alleles play a role in protecting against HPV16-related cervical neoplasia, mainly through a KIR-mediated mechanism

Frequency and patterns of early recanalization after vasectomy

BACKGROUND: Our understanding of early post-vasectomy recanalization is limited to histopathological studies. The objective of this study was to estimate the frequency and to describe semen analysis patterns of early recanalization after vasectomy. METHODS: Charts displaying serial post-vasectomy semen analyses were created using the semen analysis results from 826 and 389 men participating in a randomized trial of fascial interposition (FI) and an observational study of cautery, respectively. In the FI trial, participants were randomly allocated to vas occlusion by ligation and excision with or without FI. In the cautery study, sites used their usual cautery occlusion technique, two with and two without FI. Presumed early recanalization was based on the assessment of individual semen analysis charts by three independent reviewers. Discrepancies were resolved by consensus. RESULTS: Presumed early recanalization was characterized by a very low sperm concentration within two weeks after vasectomy followed by return to large numbers of sperm over the next few weeks. The overall proportion of men with presumed early recanalization was 13% (95% CI 12%–15%). The risk was highest with ligation and excision without FI (25%) and lowest for thermal cautery with FI (0%). The highest proportion of presumed early recanalization was observed among men classified as vasectomy failures. CONCLUSION: Early recanalization, occurring within the first weeks after vasectomy, is more common than generally recognized. Its frequency depends on the occlusion technique performed

Label-free integrative pharmacology on-target of drugs at the β2-adrenergic receptor

We describe a label-free integrative pharmacology on-target (iPOT) method to assess the pharmacology of drugs at the β2-adrenergic receptor. This method combines dynamic mass redistribution (DMR) assays using an array of probe molecule-hijacked cells with similarity analysis. The whole cell DMR assays track cell system-based, ligand-directed, and kinetics-dependent biased activities of the drugs, and translates their on-target pharmacology into numerical descriptors which are subject to similarity analysis. We demonstrate that the approach establishes an effective link between the label-free pharmacology and in vivo therapeutic indications of drugs

Doppler ultrasound in the measurement of pulse wave velocity: agreement with the Complior method

Aortic stiffness is an independent predictor factor for cardiovascular risk. Different methods for determining pulse wave velocity (PWV) are used, among which the most common are mechanical methods such as SphygmoCor or Complior, which require specific devices and are limited by technical difficulty in obtaining measurements. Doppler guided by 2D ultrasound is a good alternative to these methods. We studied 40 patients (29 male, aged 21 to 82 years) comparing the Complior method with Doppler. Agreement of both devices was high (R = 0.91, 0.84-0.95, 95% CI). The reproducibility analysis revealed no intra-nor interobserver differences. Based on these results, we conclude that Doppler ultrasound is a reliable and reproducible alternative to other established methods for the measurement of aortic PWV

Do electronic health records affect the patient-psychiatrist relationship? A before & after study of psychiatric outpatients

<p>Abstract</p> <p>Background</p> <p>A growing body of literature shows that patients accept the use of computers in clinical care. Nonetheless, studies have shown that computers unequivocally change both verbal and non-verbal communication style and increase patients' concerns about the privacy of their records. We found no studies which evaluated the use of Electronic Health Records (EHRs) specifically on psychiatric patient satisfaction, nor any that took place exclusively in a psychiatric treatment setting. Due to the special reliance on communication for psychiatric diagnosis and evaluation, and the emphasis on confidentiality of psychiatric records, the results of previous studies may not apply equally to psychiatric patients.</p> <p>Method</p> <p>We examined the association between EHR use and changes to the patient-psychiatrist relationship. A patient satisfaction survey was administered to psychiatric patient volunteers prior to and following implementation of an EHR. All subjects were adult outpatients with chronic mental illness.</p> <p>Results</p> <p>Survey responses were grouped into categories of "Overall," "Technical," "Interpersonal," "Communication & Education,," "Time," "Confidentiality," "Anxiety," and "Computer Use." Multiple, unpaired, two-tailed t-tests comparing pre- and post-implementation groups showed no significant differences (at the 0.05 level) to any questionnaire category for all subjects combined or when subjects were stratified by primary diagnosis category.</p> <p>Conclusions</p> <p>While many barriers to the adoption of electronic health records do exist, concerns about disruption to the patient-psychiatrist relationship need not be a prominent focus. Attention to communication style, interpersonal manner, and computer proficiency may help maintain the quality of the patient-psychiatrist relationship following EHR implementation.</p

Building an immune-mediated coagulopathy consensus: early recognition and evaluation to enhance post-surgical patient safety

Topical hemostats, fibrin sealants, and surgical adhesives are regularly used in a variety of surgical procedures involving multiple disciplines. Generally, these adjuncts to surgical hemostasis are valuable means for improving wound visualization, reducing blood loss or adding tissue adherence; however, some of these agents are responsible for under-recognized adverse reactions and outcomes. Bovine thrombin, for example, is a topical hemostat with a long history of clinical application that is widely used alone or in combination with other hemostatic agents. Hematologists and coagulation experts are aware that these agents can lead to development of an immune-mediated coagulopathy (IMC). A paucity of data on the incidence of IMC contributes to under-recognition and leaves many surgeons unaware that this clinical entity, originating from normal immune responses to foreign antigen exposure, requires enhanced post-operative vigilance and judicious clinical judgment to achieve best outcomes

Structure and Function of the First Full-Length Murein Peptide Ligase (Mpl) Cell Wall Recycling Protein

Bacterial cell walls contain peptidoglycan, an essential polymer made by enzymes in the Mur pathway. These proteins are specific to bacteria, which make them targets for drug discovery. MurC, MurD, MurE and MurF catalyze the synthesis of the peptidoglycan precursor UDP-N-acetylmuramoyl-L-alanyl-γ-D-glutamyl-meso-diaminopimelyl-D-alanyl-D-alanine by the sequential addition of amino acids onto UDP-N-acetylmuramic acid (UDP-MurNAc). MurC-F enzymes have been extensively studied by biochemistry and X-ray crystallography. In Gram-negative bacteria, ∼30–60% of the bacterial cell wall is recycled during each generation. Part of this recycling process involves the murein peptide ligase (Mpl), which attaches the breakdown product, the tripeptide L-alanyl-γ-D-glutamyl-meso-diaminopimelate, to UDP-MurNAc. We present the crystal structure at 1.65 Å resolution of a full-length Mpl from the permafrost bacterium Psychrobacter arcticus 273-4 (PaMpl). Although the Mpl structure has similarities to Mur enzymes, it has unique sequence and structure features that are likely related to its role in cell wall recycling, a function that differentiates it from the MurC-F enzymes. We have analyzed the sequence-structure relationships that are unique to Mpl proteins and compared them to MurC-F ligases. We have also characterized the biochemical properties of this enzyme (optimal temperature, pH and magnesium binding profiles and kinetic parameters). Although the structure does not contain any bound substrates, we have identified ∼30 residues that are likely to be important for recognition of the tripeptide and UDP-MurNAc substrates, as well as features that are unique to Psychrobacter Mpl proteins. These results provide the basis for future mutational studies for more extensive function characterization of the Mpl sequence-structure relationships

Cryptococcal Cell Morphology Affects Host Cell Interactions and Pathogenicity

Cryptococcus neoformans is a common life-threatening human fungal pathogen. The size of cryptococcal cells is typically 5 to 10 µm. Cell enlargement was observed in vivo, producing cells up to 100 µm. These morphological changes in cell size affected pathogenicity via reducing phagocytosis by host mononuclear cells, increasing resistance to oxidative and nitrosative stress, and correlated with reduced penetration of the central nervous system. Cell enlargement was stimulated by coinfection with strains of opposite mating type, and ste3aΔ pheromone receptor mutant strains had reduced cell enlargement. Finally, analysis of DNA content in this novel cell type revealed that these enlarged cells were polyploid, uninucleate, and produced daughter cells in vivo. These results describe a novel mechanism by which C. neoformans evades host phagocytosis to allow survival of a subset of the population at early stages of infection. Thus, morphological changes play unique and specialized roles during infection

Estimating the burden of selected non-communicable diseases in Africa: a systematic review of the evidence

Background The burden of non-communicable diseases (NCDs) is rapidly increasing globally, and particularly in Africa, where the health focus, until recently, has been on infectious diseases. The response to this growing burden of NCDs in Africa has been affected owing to a poor understanding of the burden of NCDs, and the relative lack of data and low level of research on NCDs in the continent. Recent estimates on the burden of NCDs in Africa have been mostly derived from modelling based on data from other countries imputed into African countries, and not usually based on data originating from Africa itself. In instances where few data were available, estimates have been characterized by extrapolation and over-modelling of the scarce data. It is therefore believed that underestimation of NCDs burden in many parts of Africa cannot be unexpected. With a gradual increase in average life expectancy across Africa, the region now experiencing the fastest rate of urbanization globally, and an increase adoption of unhealthy lifestyles, the burden of NCDs is expected to rise. This thesis will, therefore, be focussing on understanding the prevalence, and/or where there are available data, the incidence, of four major NCDs in Africa, which have contributed highly to the burden of NCDs, not only in Africa, but also globally. Methods I conducted a systematic search of the literature on three main databases (Medline, EMBASE and Global Health) for epidemiological studies on NCDs conducted in Africa. I retained and extracted data from original population-based (cohort or cross sectional), and/or health service records (hospital or registry-based studies) on prevalence and/or incidence rates of four major NCDs in Africa. These include: cardiovascular diseases (hypertension and stroke), diabetes, major cancer types (cervical, breast, prostate, ovary, oesophagus, bladder, Kaposi, liver, stomach, colorectal, lung and non-Hodgkin lymphoma), and chronic respiratory diseases (chronic obstructive pulmonary disease (COPD) and asthma). From extracted crude prevalence and incidence rates, a random effect meta-analysis was conducted and reported for each NCD. An epidemiological model was applied on all extracted data points. The fitted curve explaining the largest proportion of variance (best fit) from the model was further applied. The equation generated from the fitted curve was used to determine the prevalence and cases of the specific NCD in Africa at midpoints of the United Nations (UN) population 5-year age-group population estimates for Africa. Results From the literature search, studies on hypertension had the highest publication output at 7680, 92 of which were selected, spreading across 31 African countries. Cancer had 9762 publications and 39 were selected across 20 countries; diabetes had 3701 publications and 48 were selected across 28 countries; stroke had 1227 publications and 19 were selected across 10 countries; asthma had 790 publications and 45 were selected across 24 countries; and COPD had the lowest output with 243 publications and 13 were selected across 8 countries. From studies reporting prevalence rates, hypertension, with a total sample size of 197734, accounted for 130.2 million cases and a prevalence of 25.9% (23.5, 34.0) in Africa in 2010. This is followed by asthma, with a sample size of 187904, accounting for 58.2 million cases and a prevalence of 6.6% (2.4, 7.9); COPD, with a sample size of 24747, accounting for 26.3 million cases and a prevalence of 13.4% (9.4, 22.1); diabetes, with a sample size of 102517, accounting for 24.5 million cases and a prevalence of 4.0% (2.7, 6.4); and stroke, with a sample size of about 6.3 million, accounting for 1.94 million cases and a prevalence of 317.3 per 100000 population (314.0, 748.2). From studies reporting incidence rates, stroke accounted for 496 thousand new cases in Africa in 2010, with a prevalence of 81.3 per 100000 person years (13.2, 94.9). For the 12 cancer types reviewed, a total of 775 thousand new cases were estimated in Africa in 2010 from registry-based data covering a total population of about 33 million. Among women, cervical cancer and breast cancer had 129 thousand and 81 thousand new cases, with incidence rates of 28.2 (22.1, 34.3) and 17.7 (13.0, 22.4) per 100000 person years, respectively. Among men, prostate cancer and Kaposi sarcoma closely follows with 75 thousand and 74 thousand new cases, with incidence rates of 14.5 (10.9, 18.0) and 14.3 (11.9, 16.7) per 100000 person years, respectively. Conclusion This study suggests the prevalence rates of the four major NCDs reviewed (cardiovascular diseases (hypertension and stroke), diabetes, major cancer types, and chronic respiratory diseases (COPD and asthma) in Africa are high relative to global estimates. Due to the lack of data on many NCDs across the continent, there are still doubts on the true prevalence of these diseases relative to the current African population. There is need for improvement in health information system and overall data management, especially at country level in Africa. Governments of African nations, international organizations, experts and other stakeholders need to invest more on NCDs research, particularly mortality, risk factors, and health determinants to have evidenced-based facts on the drivers of this epidemic in the continent, and prompt better, effective and overall public health response to NCDs in Africa