PCA-induced respiratory depression simulating stroke following endoluminal repair of abdominal aortic aneurysm: a case report

<p>Abstract</p> <p>Aim</p> <p>To report a case of severe respiratory depression with PCA fentanyl use simulating stroke in a patient who underwent routine elective endoluminal graft repair for abdominal aortic aneurysm (AAA)</p> <p>Case presentation</p> <p>A 78-year-old obese lady underwent routine endoluminal graft repair for AAA that was progressively increasing in size. Following an uneventful operation postoperative analgesia was managed with a patient-controlled analgesia (PCA) device with fentanyl. On the morning following operation the patient was found to be unusually drowsy and unresponsive to stimuli. Her GCS level was 11 with plantars upgoing bilaterally. A provisional diagnosis of stroke was made. Urgent transfer to a high-dependency unit (HDU) was arranged and she was given ventilatory support with a BiPap device. CT was performed and found to be normal. Arterial blood gas (ABG) analysis showed respiratory acidosis with PaCO₂81 mmHg, PaO₂140 mmHg, pH 7.17 and base excess -2 mmol/l. A total dose of 600 mcg of fentanyl was self-administered in the 16 hours following emergence from general anaesthesia. Naloxone was given with good effect. There was an increase in the creatinine level from 90 μmol/L preoperatively to 167 μmol/L on the first postoperative day. The patient remained on BiPap for two days that resulted in marked improvement in gas exchange. Recovery was complete.</p

The geography of recent genetic ancestry across Europe

The recent genealogical history of human populations is a complex mosaic formed by individual migration, large-scale population movements, and other demographic events. Population genomics datasets can provide a window into this recent history, as rare traces of recent shared genetic ancestry are detectable due to long segments of shared genomic material. We make use of genomic data for 2,257 Europeans (the POPRES dataset) to conduct one of the first surveys of recent genealogical ancestry over the past three thousand years at a continental scale. We detected 1.9 million shared genomic segments, and used the lengths of these to infer the distribution of shared ancestors across time and geography. We find that a pair of modern Europeans living in neighboring populations share around 10-50 genetic common ancestors from the last 1500 years, and upwards of 500 genetic ancestors from the previous 1000 years. These numbers drop off exponentially with geographic distance, but since genetic ancestry is rare, individuals from opposite ends of Europe are still expected to share millions of common genealogical ancestors over the last 1000 years. There is substantial regional variation in the number of shared genetic ancestors: especially high numbers of common ancestors between many eastern populations likely date to the Slavic and/or Hunnic expansions, while much lower levels of common ancestry in the Italian and Iberian peninsulas may indicate weaker demographic effects of Germanic expansions into these areas and/or more stably structured populations. Recent shared ancestry in modern Europeans is ubiquitous, and clearly shows the impact of both small-scale migration and large historical events. Population genomic datasets have considerable power to uncover recent demographic history, and will allow a much fuller picture of the close genealogical kinship of individuals across the world.Comment: Full size figures available from http://www.eve.ucdavis.edu/~plralph/research.html; or html version at http://ralphlab.usc.edu/ibd/ibd-paper/ibd-writeup.xhtm

Efficacy of PermaNet® 2.0 and PermaNet® 3.0 against insecticide-resistant Anopheles gambiae in experimental huts in Côte d'Ivoire

<p>Abstract</p> <p>Background</p> <p>Pyrethroid resistance in vectors could limit the efficacy of long-lasting insecticidal nets (LLINs) because all LLINs are currently treated with pyrethroids. The goal of this study was to evaluate the efficacy and wash resistance of PermaNet^®3.0 compared to PermaNet^®2.0 in an area of high pyrethroid in Côte d'Ivoire. PermaNet^®3.0 is impregnated with deltamethrin at 85 mg/m²on the sides of the net and with deltamethrin and piperonyl butoxide on the roof. PermaNet^®2.0 is impregnated with deltamethrin at 55 mg/m²across the entire net.</p> <p>Methods</p> <p>The study was conducted in the station of Yaokoffikro, in central Côte d'Ivoire. The efficacy of intact unwashed and washed LLINs was compared over a 12-week period with a conventionally-treated net (CTN) washed to just before exhaustion. WHO cone bioassays were performed on sub-sections of the nets, using wild-resistant <it>An. gambiae </it>and Kisumu strains. Mosquitoes were collected five days per week and were identified to genus and species level and classified as dead or alive, then unfed or blood-fed.</p> <p>Results</p> <p>Mortality rates of over 80% from cone bioassays with wild-caught pyrethroid-resistant <it>An. gambiae </it>s.s were recorded only with unwashed PermaNet^®3.0. Over 12 weeks, a total of 7,291 mosquitoes were collected. There were significantly more <it>An. gambiae </it>s.s. and <it>Culex </it>spp. caught in control huts than with other treatments (P < 0.001). The proportion of mosquitoes exiting the huts was significantly lower with the control than for the treatment arms (P < 0.001). Mortality rates with resistant <it>An. gambiae </it>s.s and <it>Culex </it>spp, were lower for the control than for other treatments (P < 0.001), which did not differ (P > 0.05) except for unwashed PermaNet^®3.0 (P < 0.001), which gave significantly higher mortality (P < 0.001).</p> <p>Conclusions</p> <p>This study showed that unwashed PermaNet^®3.0 caused significantly higher mortality against pyrethroid resistant <it>An. gambiae s.s </it>and <it>Culex </it>spp than PermaNet^®2.0 and the CTN. The increased efficacy with unwashed PermaNet^®3.0 over PermaNet^®2.0 and the CTN was also demonstrated by higher KD and mortality rates (KD > 95% and mortality rate > 80%) in cone bioassays performed with wild pyrethroid-resistant <it>An. gambiae s.s </it>from Yaokoffikro.</p

Unique V3 Loop Sequence Derived from the R2 Strain of HIV-Type 1 Elicits Broad Neutralizing Antibodies

DNA vaccines expressing the envelope (Env) of the human immunodeficiency virus type 1 (HIV-1) have been relatively ineffective at generating high-titer, long-lasting, neutralizing antibodies. In this study, DNA vaccines were constructed to express the gp120 subunit of Env from the isolate HIV-1R2 using both wild-type and codon- ptimized gene sequences. Three copies of the murine C3d were added to the carboxyl terminus to enhance the immunogenicity of the expressed fusion protein. Mice (BALB/c) vaccinated with DNA plasmid expressing the gp120R2 using codon-optimized Env sequences elicited high-titer anti-Env antibodies regardless of conjugation to C3d. In contrast, only mice vaccinated with DNA using wild-type gp120R2 sequences fused to mC3d3, had detectable anti- Env antibodies. Interestingly, mice vaccinated with DNA expressing gp120R2 from codon-optimized sequences elicited antibodies that neutralized both homologous and heterologous HIV-1 isolates. To determine if the unique sequence found in the crown of the V3 loop of the EnvR2 was responsible for the elicitation of the cross-clade neutralizing antibodies, the codons encoding for the Pro-Met (amino acids 313–314) were introduced into the sequences encoding the gp120ADA (R5) or gp12089.6 (R5X4). Mice vaccinated with gp120ADA–mC3d3–DNA with the Pro–Met mutation had antibodies that neutralized HIV-1 infection, but not the gp12089.6–mC3d3–DNA. Therefore, the use of the unique sequences in the EnvR2 introduced into an R5 tropic envelope, in conjunction with C3d fusion, was effective at broadening the number of viruses that could be neutralized. However, the introduction of this same sequence into an R5X4-tropic envelope was ineffective in eliciting improved cross-clade neutralizing antibodies. Originally published AIDS Research and Human Retroviruses, Vol. 20, No. 11, Nov 200

Semen molecular and cellular features: these parameters can reliably predict subsequent ART outcome in a goat model

Currently, the assessment of sperm function in a raw or processed semen sample is not able to reliably predict sperm ability to withstand freezing and thawing procedures and in vivo fertility and/or assisted reproductive biotechnologies (ART) outcome. The aim of the present study was to investigate which parameters among a battery of analyses could predict subsequent spermatozoa in vitro fertilization ability and hence blastocyst output in a goat model. Ejaculates were obtained by artificial vagina from 3 adult goats (Capra hircus) aged 2 years (A, B and C). In order to assess the predictive value of viability, computer assisted sperm analyzer (CASA) motility parameters and ATP intracellular concentration before and after thawing and of DNA integrity after thawing on subsequent embryo output after an in vitro fertility test, a logistic regression analysis was used. Individual differences in semen parameters were evident for semen viability after thawing and DNA integrity. Results of IVF test showed that spermatozoa collected from A and B lead to higher cleavage rates (0 < 0.01) and blastocysts output (p < 0.05) compared with C. Logistic regression analysis model explained a deviance of 72% (p < 0.0001), directly related with the mean percentage of rapid spermatozoa in fresh semen (p < 0.01), semen viability after thawing (p < 0.01), and with two of the three comet parameters considered, i.e tail DNA percentage and comet length (p < 0.0001). DNA integrity alone had a high predictive value on IVF outcome with frozen/thawed semen (deviance explained: 57%). The model proposed here represents one of the many possible ways to explain differences found in embryo output following IVF with different semen donors and may represent a useful tool to select the most suitable donors for semen cryopreservation

High-intensity exercise to promote accelerated improvements in cardiorespiratory fitness (HI-PACE): study protocol for a randomized controlled trial

Background: African Americans have a disproportionate prevalence and incidence of type 2 diabetes compared with Caucasians. Recent evidence indicates that low cardiorespiratory fitness (CRF) level, an independent risk factor for type 2 diabetes, is also more prevalent in African Americans than Caucasians. Numerous studies in Caucasian populations suggest that vigorous exercise intensity may promote greater improvements in CRF and other type 2 diabetes risk factors (e.g., reduction of glucose/insulin levels, pulse wave velocity, and body fat) than moderate intensity. However, current evidence comparing health benefits of different aerobic exercise intensities on type 2 diabetes risk factors in African Americans is negligible. This is clinically important as African Americans have a greater risk for type 2 diabetes and are less likely to meet public health recommendations for physical activity than Caucasians. The purpose of the HI-PACE (High-Intensity exercise to Promote Accelerated improvements in CardiorEspiratory fitness) study is to evaluate whether high-intensity aerobic exercise elicits greater improvements in CRF, insulin action, and arterial stiffness than moderate-intensity exercise in African Americans. Methods/Design: A randomized controlled trial will be performed on overweight and obese (body mass index of 25–45 kg/m2) African Americans (35–65 years) (n = 60). Participants will be randomly assigned to moderate-intensity (MOD-INT) or high-intensity (HIGH-INT) aerobic exercise training or a non-exercise control group (CON) for 24 weeks. Supervised exercise will be performed at a heart rate associated with 45–55% and 70–80% of VO2 max in the MOD-INT and HIGH-INT groups, respectively, for an exercise dose of 600 metabolic equivalents of task (MET)-minutes per week (consistent with public health recommendations). The primary outcome is change in CRF. Secondary outcomes include change in insulin sensitivity (measured via an intravenous glucose tolerance test), skeletal muscle mitochondrial oxidative capacity (via near-infrared spectroscopy), skeletal muscle measurements (i.e., citrate synthase, COX IV, GLUT-4, CPT-1, and PGC1-α), arterial stiffness (via carotid-femoral pulse wave velocity), body fat, C-reactive protein, and psychological outcomes (quality of life/exercise enjoyment). Discussion: The anticipated results of the HI-PACE study will provide vital information on the health effects of high-intensity exercise in African Americans. This study will advance health disparity research and has the potential to influence future public health guidelines for physical activity

Stock markets and effective exchange rates in European countries: threshold cointegration findings

© 2015, Eurasia Business and Economics Society. The nexus between stock markets and exchange rates is examined in the case of eight European countries. The sample consists of four economies with national currencies and four that have adopted the euro. Thus, if differences between the two groups in the relationship governing the two markets exist, they will be unveiled. To this effect, a threshold cointegration methodology is adopted that allows for more reliable inferences to be drawn for both the short and long run nexus between the two markets. Monthly data is used covering the period 01/2000–12/2014. The findings reported herein offer support in favor of the portfolio approach thesis over the recent economic crisis period, but this finding is not the case for the entire sample. Bidirectional causality is found for Norway and the UK, pointing to a currency effect on stock markets. In view of the findings reported herein, policies aiming at reducing uncertainty in the stock markets can exert beneficial effects on currency markets

Management of obstetric anal sphincter injury: a systematic review & national practice survey

BACKGROUND: We aim to establish the evidence base for the recognition and management of obstetric anal sphincter injury (OASI) and to compare this with current practice amongst UK obstetricians and coloproctologists. METHODS: A systematic review of the literature and a postal questionnaire survey of consultant obstetricians, trainee obstetricians and consultant coloproctologists was carried out. RESULTS: We found a wide variation in experience of repairing acute anal sphincter injury. The group with largest experience were consultant obstetricians (46.5% undertaking ≥ 5 repairs/year), whilst only 10% of responding colorectal surgeons had similar levels of experience (p < 0.001). There was extensive misunderstanding in terms of the definition of obstetric anal sphincter injuries. Overall, trainees had a greater knowledge of the correct classification (p < 0.01). Observational studies suggest that a new 'overlap' repair using PDS sutures with antibiotic cover gives better functional results. However, our literature search found only one randomised controlled trial (RCT) on the technique of repair of OASI, which showed no difference in incidence of anal incontinence at three months. Despite this, there was a wide variation in practice, with 337(50%) consultants, 82 (55%) trainees and 80 (89%) coloproctologists already using the 'overlap' method for repair of a torn EAS (p < 0.001). Although over 50% of colorectal surgeons would undertake long-term follow-up of their patients, this was the practice of less than 10% of obstetricians (p < 0.001). Whilst over 70% of coloproctologists would recommend an elective caesarean section in a subsequent pregnancy, only 22% of obstetric consultants and 14% of trainees (p < 0.001). CONCLUSION: An agreed classification of OASI, development of national guidelines, formalised training, multidisciplinary management and further definitive research is strongly recommended

OptForce: An Optimization Procedure for Identifying All Genetic Manipulations Leading to Targeted Overproductions

Computational procedures for predicting metabolic interventions leading to the overproduction of biochemicals in microbial strains are widely in use. However, these methods rely on surrogate biological objectives (e.g., maximize growth rate or minimize metabolic adjustments) and do not make use of flux measurements often available for the wild-type strain. In this work, we introduce the OptForce procedure that identifies all possible engineering interventions by classifying reactions in the metabolic model depending upon whether their flux values must increase, decrease or become equal to zero to meet a pre-specified overproduction target. We hierarchically apply this classification rule for pairs, triples, quadruples, etc. of reactions. This leads to the identification of a sufficient and non-redundant set of fluxes that must change (i.e., MUST set) to meet a pre-specified overproduction target. Starting with this set we subsequently extract a minimal set of fluxes that must actively be forced through genetic manipulations (i.e., FORCE set) to ensure that all fluxes in the network are consistent with the overproduction objective. We demonstrate our OptForce framework for succinate production in Escherichia coli using the most recent in silico E. coli model, iAF1260. The method not only recapitulates existing engineering strategies but also reveals non-intuitive ones that boost succinate production by performing coordinated changes on pathways distant from the last steps of succinate synthesis

Analysis of protein-coding genetic variation in 60,706 humans

Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. Here we describe the aggregation and analysis of high-quality exome (protein-coding region) DNA sequence data for 60,706 individuals of diverse ancestries generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We have used this catalogue to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; identifying 3,230 genes with near-complete depletion of predicted protein-truncating variants, with 72% of these genes having no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human 'knockout' variants in protein-coding genes