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Δευτέρα 29 Ιανουαρίου 2018
Sex Difference of Angiotensin IV–, LVV-Hemorphin 7–, and Oxytocin-Induced Antiallodynia at the Spinal Level in Mice With Neuropathic Pain
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The Evolving Dilemma of Factor XI in Pregnancy: Suggestions for Management
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A Systematic Review of Outcomes Associated With Withholding or Continuing Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers Before Noncardiac Surgery
BACKGROUND: The global rate of major noncardiac surgical procedures is increasing annually, and of those patients presenting for surgery, increasing numbers are taking either an angiotensin-converting enzyme inhibitor (ACE-I) or an angiotensin receptor blocker (ARB). The current recommendations of whether to continue or withhold ACE-I and ARB in the perioperative period are conflicting. Previous meta-analyses have linked preoperative ACE-I/ARB therapy to the increased incidence of postinduction hypotension; however, they have failed to correlate this with adverse patient outcomes. The aim of this meta-analysis was to determine whether continuation or withholding ACE-I or ARB therapy in the perioperative period is associated with mortality and major morbidity. METHODS: This meta-analysis was prospectively registered on PROSPERO (CRD42017055291). A comprehensive search of MEDLINE (PubMed), CINAHL (EBSCO host), ProQuest, Cochrane database, Scopus, and Web of Science was conducted on December 6, 2016. We included adult patients >18 years of age on chronic ACE-I or ARB therapy who underwent noncardiac surgery in which ACE-I or ARB was either withheld or continued on the morning of surgery. Primary outcomes included all-cause mortality and major cardiac events (MACE). Secondary outcomes included the risk of congestive heart failure, acute kidney injury, stroke, intraoperative/postoperative hypotension, and the length of hospital stay. RESULTS: After abstract review, the full text of 25 studies was retrieved, of which 9 fulfilled the inclusion criteria: 5 were randomized control trials, and 4 were cohort studies. These studies included a total of 6022 patients on chronic ACE-I/ARB therapy before noncardiac surgery. A total of 1816 patients withheld treatment the morning of surgery and 4206 continued their ACE-I/ARB. Preoperative demographics were similar between the 2 groups. Withholding ACE-I/ARB therapy was not associated with a difference in mortality (odds ratio [OR], 0.97; 95% confidence interval [CI], 0.62–1.52; I2 = 0%) or MACE (OR, 1.12; 95% CI, 0.82–1.52; I2 = 0%). However, withholding therapy was associated with significantly less intraoperative hypotension (OR, 0.63; 95% CI, 0.47–0.85; I2 = 71%). No effect estimate could be pooled concerning length of hospital stay and congestive heart failure. CONCLUSIONS: This meta-analysis did not demonstrate an association between perioperative administration of ACE-I/ARB and mortality or MACE. It did, however, confirm the current observation that perioperative continuation of ACE-I/ARBs is associated with an increased incidence of intraoperative hypotension. A large randomized control trial is necessary to determine the appropriate perioperative management of ACE-I and ARBs. Accepted for publication December 19, 2017. Funding: No outside funding was utilized in the search and retrieval of all articles. All funding was from departmental resources. Conflicts of Interest: See Disclosures at the end of the article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://ift.tt/KegmMq). PROSPERO registry: CRD42017055291. Reprints will not be available from the authors. Address correspondence to Caryl Hollmann, MBChB, DA (SA), Department of Anaesthesia and Perioperative Medicine, D23, Groote Schuur Hospital, University of Cape Town, Observatory, Cape Town 7925, South Africa. Address e-mail to carylhollmann@gmail.com. © 2018 International Anesthesia Research Society
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Activation of Melatonin Receptors by Ramelteon Induces Cardioprotection by Postconditioning in the Rat Heart
Activation of melatonin receptors protects the heart against ischemia-reperfusion injury. Ramelteon, a clinically used drug for insomnia, acts via activation of melatonin receptors. We investigated whether ramelteon induces acute infarct size reduction by postconditioning. Male Wistar rats were randomized to 6 groups. Hearts were treated with melatonin and ramelteon at the beginning of reperfusion. The melatonin receptor inhibitor luzindole was administered with and without melatonin and ramelteon, respectively. Ramelteon reduced infarct size to the same extent as melatonin. Both effects were completely abolished by luzindole. The results show for the first time that ramelteon induces cardioprotection by postconditioning. Accepted for publication September 27, 2017. Funding: This work was supported by departmental funding only. The authors declare no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://ift.tt/KegmMq). Reprints will not be available from the authors. Address correspondence to Ragnar Huhn, MD, PhD, Department of Anesthesiology, University Hospital Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany. Address e-mail to Ragnar.Huhn@med.uni-duesseldorf.de. © 2018 International Anesthesia Research Society
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Summative Objective Structured Clinical Examination Assessment at the End of Anesthesia Residency for Perioperative Ultrasound
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Intermediate-dose cytarabine plus mitoxantrone versus standard-dose cytarabine plus daunorubicine for acute myeloid leukemia in elderly patients
Abstract
Background
The combination of intermediate-dose cytarabine plus mitoxantrone (IMA) can induce high complete remission rates with acceptable toxicity in elderly patients with acute myeloid leukemia (AML). We present the final results of a randomized-controlled trial comparing IMA with the standard 7 + 3 induction regimen consisting of continuous infusion daunorubicin plus cytarabine (DA). Patients and methods
Patients with newly diagnosed AML >60 years were randomized to receive either intermediate-dose cytarabine (1000 mg/m2 BID days 1,3,5,7) plus mitoxantrone (10 mg/m2 days 1-3) (IMA) or standard induction therapy with cytarabine (100 mg/m2 continuously days 1-7) plus daunorubicin (45 mg/m2 days 3-5) (DA). Patients in complete remission after DA received intermediate-dose cytarabine plus amsacrine as consolidation treatment, whereas patients after IMA were consolidated with standard-dose cytarabine plus mitoxantrone. Results
Between February 2005 and October 2009, 485 patients were randomized; 241 for treatment arm DA and 244 for IMA; 76% of patients were >65 years. The CR rate after DA was 39% (95%-CI; 33-45) versus 55% (95%-CI; 49-61) after IMA (OR 1.89, p=0.001). The six-week early-death rate was 14% in both arms. Relapse-free survival (RFS) curves were superimposable in the first year, but separated afterwards, resulting in 3-year RFS rates of 29% versus 14% in the DA versus IMA arms, respectively (p=0.042). The median OS was 10 months in both arms (p=0.513). Conclusion
The dose escalation of cytarabine in induction therapy lead to improved remission rates in the elderly AML patients. This did not translate into a survival advantage, most likely due to differences in consolidation treatment. Thus, effective consolidation strategies need to be further explored. In combination with an effective consolidation strategy, the use of intermediate dose cytarabine in induction may improve curative treatment for elderly AML patients.http://ift.tt/2DMbt2V
Immunohistochemical assessment of the diagnostic utility of PD-L1: a preliminary analysis of anti-PD-L1 antibody (SP142) for lymphoproliferative diseases with tumour and nonmalignant Hodgkin/Reed-Sternberg (HRS)-like cells
Abstract
Aims
The programmed death 1 (PD1)/PD1 ligand (PD-L1) axis plays an important role in tumour cells escape from immune control. PD-L1 immunohistochemistry is a useful predictor of immunotherapy response, but is still not widely used in the diagnostic setting. Here we describe results using PD-L1 immunohistochemistry during routine diagnostics in lymphoma.
Methods and results
Ninety-one lymphoproliferative disease cases sharing tumour and nonmalignant Hodgkin/Reed-Sternberg (HRS)-like cells with and without Epstein-Barr virus (EBV) association were investigated by immunohistochemistry for PD-L1 (clone SP142). PD-L1 expression was present in more than 5% of tumour or nonmalignant HRS-like cells in 100% of EBV+ classical (C) Hodgkin lymphoma (HL) (n=10) and EBV-negative nodular sclerosis CHL (n=8); 40% of EBV+ diffuse large B-cell lymphoma, not otherwise specified (DLBCL-NOS) (n= 20); and 4% of nodal peripheral T-cell lymphoma of follicular helper T-cell type (PTCL-TFH) (n=22). In contrast, nodular lymphocyte predominant HL (n=4), lymphocyte-rich CHL (n=6), EBV+ hyperplasia (n=8), plasmablastic lymphoma (n= 3), and anaplastic lymphoma kinase-negative anaplastic large cell lymphoma (n=5) seldom exhibited PD-L1 in their large cells. Assessing PD-L1 positivity in tumour and nonmalignant large cells was helpful in differentiating between CHL vs nodal PTCL-TFH (P<0.0001) or EBV+ DLBCL-NOS (P=0.0052) and between EBV+ DLBCL-NOS vs nodal PTCL-TFH (P=0.0052), with PD-L1 expression indicating the first diagnosis in each of those sets.
Conclusion
Immunohistochemical evaluation of PD-L1 expression in tumour and nonmalignant HRS-like large cells may be useful for assessing either immune escape or immunodeficiency in their pathogenesis.
This article is protected by copyright. All rights reserved.
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Gender, Race and Disease Etiology Predict De Novo Malignancy Risk following Liver Transplantation: Insights for Future Individualized Cancer Screening Guidance
AbstractBackgroundMalignancy after liver transplant (LT) is a leading cause of mortality, but data is limited. The aim of this study was to identify patients at higher risk for de novo malignancies after LT in a large multicenter database.MethodsThe Scientific Registry of Transplant Recipients database comprising all 108,412 liver transplant recipients across the U.S. between 1987 and March 2015 was analyzed with a median follow-up of 6.95 years. Potential risk factors for malignancies after LT were assessed using Cox regression analysis for the outcome of time to first malignancy.ResultsMean age 51.9 ± 10.8 years, 64.6% male, 74.5% Caucasian, and 15.8% with previous malignancy. Malignancies during follow-up were 4,483 (41.3%) skin, 1,519 (14.0%) hematologic, and 4,842 (44.7%) solid organ. The 10-year probability of de novo malignancy was 11.5% (11.3-11.8%). On multivariable analysis, age by decade (HR 1.52; p
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http://ift.tt/2DMKRuy
Incidence of Cytomegalovirus DNAemia in Pediatric Kidney Transplant Recipients after Cessation of Antiviral Prophylaxis
AbstractBackgroundLate cytomegalovirus (CMV) infection can occur after cessation of viral prophylaxis in kidney transplant recipients, yet, timing of infection is unclear and longer duration of prophylaxis may be warranted.MethodsWe conducted a retrospective cohort study of 86 children (35 CMV donor seropositive, recipient seronegative [D+R-] and 51 CMV recipient seropositive [R+])
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Successful sequential liver and haematopoietic stem cell transplantation in a child with CD40 ligand deficiency and Cryptosporidium-induced liver cirrhosis
ABSTRACTBACKGROUNDHematopoietic stem cell transplantation (HSCT) is curative in patients with primary immunodeficiencies. However, pre-HSCT conditioning entails unacceptably high risks if the liver is compromised. The presence of a recurrent opportunistic infection affecting the biliary tree and determining liver cirrhosis with portal hypertension posed particular decisional difficulties in a seven-year-old child with X-linked CD40-ligand deficiency. We aim at adding to the scanty experience available on such rare cases, as successful management with sequential liver transplantation (LT) and HSCT has been reported in detail only in one young adult to date.METHODSa closely sequential strategy, with a surgical complication-free LT, followed by reduced-intensity conditioning, allowed HSCT to be performed only one month after LT, preventing Cryptosporidium parvum recolonization of the liver graft.RESULTScombined sequential LT and HSCT resolved the cirrhotic evolution and corrected the immunodeficiency so that the infection responsible for the progressive sclerosing cholangitis did not recur.CONCLUSIONShopefully this report of the successful resolution of a potentially fatal combination of immunodeficiency and chronic opportunistic infection with end-stage organ damage in a child, will encourage others to adopt a sequential transplant approach to this highly complex pathology. However, caution is to be exercised to carefully balance the risks intrinsic to transplant surgery and immunosuppression in primary immunodeficiencies. BACKGROUND Hematopoietic stem cell transplantation (HSCT) is curative in patients with primary immunodeficiencies. However, pre-HSCT conditioning entails unacceptably high risks if the liver is compromised. The presence of a recurrent opportunistic infection affecting the biliary tree and determining liver cirrhosis with portal hypertension posed particular decisional difficulties in a seven-year-old child with X-linked CD40-ligand deficiency. We aim at adding to the scanty experience available on such rare cases, as successful management with sequential liver transplantation (LT) and HSCT has been reported in detail only in one young adult to date. METHODS a closely sequential strategy, with a surgical complication-free LT, followed by reduced-intensity conditioning, allowed HSCT to be performed only one month after LT, preventing Cryptosporidium parvum recolonization of the liver graft. RESULTS combined sequential LT and HSCT resolved the cirrhotic evolution and corrected the immunodeficiency so that the infection responsible for the progressive sclerosing cholangitis did not recur. CONCLUSIONS hopefully this report of the successful resolution of a potentially fatal combination of immunodeficiency and chronic opportunistic infection with end-stage organ damage in a child, will encourage others to adopt a sequential transplant approach to this highly complex pathology. However, caution is to be exercised to carefully balance the risks intrinsic to transplant surgery and immunosuppression in primary immunodeficiencies. Corresponding Author: Pier Luigi Calvo, MD, Paediatrician, Gastroenterologist & Hepatologist, Regina Margherita Children's Hospital, AOU Città della Salute e della Scienza, Piazza Polonia, 94, 10126 Turin, ITALY. pcalvo@cittadellasalute.to.it AUTHORSHIP PAGE QP, DOD and CPL had the patient under their care and conceived, designed and wrote the article. TF, RR, SM planned and performed liver transplant and critically reviewed the paper. DE performed liver histological analysis. CF, VE, FF performed haematopoietic stem cell transplantation and critically reviewed the paper. PM followed the patient after liver transplant and critically reviewed the paper. All authors listed contributed to writing the manuscript and are responsible for the content of the paper. The authors declare no conflicts of interest. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
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http://ift.tt/2DMKRe2
Women Beat Expectations When Playing Chess Against Men
Data from 160,000 ranked chess players and more than 5 million chess matches suggest that women playing against men perform better than expected based on their official chess ratings, according to findings published in Psychological Science. The study results indicate that women players are not affected by negative stereotypes about women's chess abilities during competition games, in contrast with previous research on the phenomenon of "stereotype threat" which has suggested that awareness of negative stereotypes can hamper women's performance.
"These findings show that even famous psychological phenomena may not be present all the time. Factors other than stereotype threat appear to be more important in determining men and women's tournament chess performance," says psychological scientist and study author Tom Stafford of The University of Sheffield.
"Looking at such a large real-world sample allows us a lot of confidence that our numbers are reliable," Stafford adds.
Being aware of a negative stereotype is thought to make individuals more anxious, more self-conscious, and less able to suppress negative thoughts – outcomes that ultimately hamper their ability to perform the task at hand.
Because women are noticeably underrepresented in the world of competitive chess, stereotype threat may be especially salient to women chess players. Previous experiments have provided some evidence for stereotype threat in chess, suggesting that women were less likely to win a match when they believed they were playing a male opponent.
To investigate this phenomenon in the real world, Stafford analyzed data from standard tournament chess games played between rated players from January 2008 through August 2015. The FIDE rating system continuously incorporates game outcomes to update players' ratings. These ratings can be used to predict who will win in a match between any two players. In total, the analyses included data from 150,977 men and 16,158 women playing in 5,558,110 games.
Overall, men had a slightly higher average FIDE rating than women. But the game outcomes indicated that women won matches against men more often than would have been predicted given each player's rating. This pattern held across the whole range of rating differences.
In other words, women outperformed expectations when playing a man compared with when they played against other women, a finding that runs contrary to the negative effect that one would expect as a result of stereotype threat.
The findings surprised Stafford and he notes that any conclusions are limited to the context of tournament chess and rated players.
"The news is good for female chess players, of whom there are exploding numbers. Although discrimination is real and pervasive, women playing tournament chess do not seem to be at a disadvantage when paired with men," Stafford says.
"This study of one social attitude in one domain—gender stereotypes in chess—does nothing to disprove the reality of discrimination generally, but it does suggest that this one mechanism, stereotype threat, may be more limited in its applicability than one might conclude from reading the experimental literature alone," Stafford concludes in his research article.
This research was supported in part by a Leverhulme Trust project grant on bias and blame (RPG-2013-326).
All materials have been made publicly available via the Open Science Framework. The complete Open Practices Disclosure for this article is available online. This article has received the badge for Open Materials.
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Content analysis of consumer information about knee arthroscopy in Australia
Background
Despite the availability of consistent guidelines recommending against arthroscopic treatment for people with symptomatic knee osteoarthritis, Australian data indicate continued use of this treatment modality. A paucity of easy to understand and reliable consumer information about knee arthroscopy may be one explanatory factor. The aim of this study was to determine whether consumer information about knee arthroscopy available in Australia is adequate to inform evidence-based decision-making for people with symptomatic osteoarthritis.
Methods
We performed a content analysis of consumer information about knee arthroscopy for symptomatic osteoarthritis. Information sources were identified from the Australian Commission on Quality and Safety in Health Care and Internet searches conducted 20–28 May 2015. Search terms were 'knee arthroscopy', 'knee pain', 'osteoarthritis knee' and 'meniscal tear', and 'orthopaedic surgeon' linked to each Australian capital city. Two independent reviewers selected documents for inclusion and extracted data. Main outcomes were specific advice regarding use of arthroscopic treatment for people with knee osteoarthritis, mention of guidelines, and/or supporting evidence.
Results
Ninety-three documents were analyzed (44 were a paragraph or less). Only eight made a clear recommendation against use of arthroscopy for all/most people with knee osteoarthritis. None included an explicit statement attributed to a guideline, while only six provided any research evidence to support their advice. Wikipedia provided the most valid information but it may be incomprehensible to the average reader.
Conclusion
Currently available consumer information about knee arthroscopy in Australia may be inadequate to help people with symptomatic knee osteoarthritis make informed decisions about this treatment.
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Poly herbal formulation with anti-elastase and anti-oxidant properties for skin anti-aging
Skin forms an important part of human innate immune system. Wrinkles, thinning and roughening of skin are some of the symptoms that affect the skin as it ages. Reactive oxygen species induced oxidative stress ...
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Sheng-ji Hua-yu formula promotes diabetic wound healing of re-epithelization via Activin/Follistatin regulation
Sheng-ji Hua-yu(SJHY) formula is one of the most useful Traditional Chinese medicine (TCM) in the treatment of the delayed diabetic wound. However, elucidating the related molecular biological mechanism of how...
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Stimulatory effect of icariin on the proliferation of neural stem cells from rat hippocampus
Icariin (ICA), a major ingredient of Epimediumbrevicornum, has various pharmacological activities including central nervous system protective functions such as the improvement of learning and memory function in m...
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Comparison of the efficacy of nafcillin and glycopeptides as definitive therapy for patients with methicillin-susceptible Staphylococcus aureus bacteremia: a retrospective cohort study
Studies have shown that the prognosis of the treatment of methicillin-susceptible S. aureus (MSSA) with glycopeptides is inferior compared to treatment with β-lactam. However, there are only few studies comparing...
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Late presentation for HIV care in Southwest Ethiopia in 2003–2015: prevalence, trend, outcomes and risk factors
Early presentation for HIV care is vital as an initial tread in the UNAIDS 90–90–90 targets. However, late presentation for HIV care (LP) challenges achieving the targets. This study assessed the prevalence, t...
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A topical treatment containing heat-treated Lactobacillus johnsonii NCC 533 reduces Staphylococcus aureus adhesion and induces antimicrobial peptide expression in an in vitro reconstructed human epidermis model
Abstract
Staphylococcus aureus colonization is thought to contribute to the pathophysiology of atopic dermatitis (AD). AD patients exhibit reduced levels of cutaneous antimicrobial peptides (AMPs), which may explain their increased susceptibility to infections. Using an in vitro reconstructed human epidermis (RHE) model, we sought to determine whether topical application of a non-replicating probiotic, heat-treated Lactobacillus johnsonii NCC 533 (HT La1), could inhibit S. aureus adhesion to skin and boost cutaneous innate immunity. We found that application of HT La1 suspension to RHE samples reduced the binding of radiolabeled S. aureus by up to 74%. To investigate a potential effect of HT La1 on innate immunity, we analyzed the expression of nine AMP genes, including those encoding beta defensins and S100 proteins, following topical application of HT La1 in suspension or in a daily moisturizer lotion. Analyzed genes were induced by up to four-fold in a dose-dependent manner by HT La1 in suspension, and by up to 2.4-fold by HT La1 in the moisturizer lotion. Finally, using ELISA and immunohistochemical detection, we evaluated the expression and secretion of the AMPs hBD-2 and psoriasin, and determined that both proteins were induced by topical HT La1, particularly in the stratum corneum of the RHE. These findings demonstrate that a topically applied, non-replicating probiotic can modulate endogenous AMP expression and inhibit binding of S. aureus to an RHE model in vitro. Moreover, they suggest that a topical formulation containing HT La1 could benefit atopic skin by enhancing cutaneous innate immunity and reducing S. aureus colonization.
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Study protocol for a randomised, controlled platform trial estimating the effect of autobiographical Memory Flexibility training (MemFlex) on relapse of recurrent major depressive disorder
Introduction
Major depressive disorder (MDD) is a chronic condition. Although current treatment approaches are effective in reducing acute depressive symptoms, rates of relapse are high. Chronic and inflexible retrieval of autobiographical memories, and in particular a bias towards negative and overgeneral memories, is a reliable predictor of relapse. This randomised controlled single-blind trial will determine whether a therapist-guided self-help intervention to ameliorate autobiographical memory biases using Memory Flexibility training (MemFlex) will increase the experience of depression-free days, relative to a psychoeducation control condition, in the 12 months following intervention.
Methods and analysisIndividuals (aged 18 and above) with a diagnosis of recurrent MDD will be recruited when remitted from a major depressive episode. Participants will be randomly allocated to complete 4 weeks of a workbook providing either MemFlex training, or psychoeducation on factors that increase risk of relapse. Assessment of diagnostic status, self-report depressive symptoms, depression-free days and cognitive risk factors for depression will be completed post-intervention, and at 6 and 12 months follow-up. The cognitive target of MemFlex will be change in memory flexibility on the Autobiographical Memory Test- Alternating Instructions. The primary clinical endpoints will be the number of depression-free days in the 12 months following workbook completion, and time to depressive relapse.
Ethics and disseminationEthics approval has been granted by the NHS National Research Ethics Committee (East of England, 11/H0305/1). Results from this study will provide a point-estimate of the effect of MemFlex on depressive relapse, which will be used to inform a fully powered trial evaluating the potential of MemFlex as an effective, low-cost and low-intensity option for reducing relapse of MDD.
Trial registration numberhttp://ift.tt/2DMZdLp
Evaluating the role of prereduction hip traction in the management of infants and children with developmental dysplasia of the hip (DDH): protocol for a systematic review and planned meta-analysis
Introduction
Developmental dysplasia of the hip (DDH) affects 4–6 per 1000 live births in developed countries. Effective treatment to realign the hip is necessary to avoid long-term morbidities and maximise functional outcome. Treatment options depend on patient age but typically involve hip bracing and/or reduction under general anaesthetic. Some centres also employ prereduction hip traction. Historical papers suggest traction reduces risk of avascular necrosis (AVN) femoral head and reduces requirement for open reduction. However, several studies including a large retrospective cohort study, dispute this. We propose to perform the first systematic review and meta-analysis to clarify the value of prereduction hip traction in the management of DDH in children under the age of 3 years by identifying whether it impacts on the rate of successful closed reduction (CR) and risk of AVN.
Methods and analysisWe will search MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials to identify potentially relevant studies. Studies reporting on incidence of successful CR, AVN femoral head and complications associated with prereduction hip traction in children of less than 3 years with DDH will be eligible for inclusion. Only randomised controlled trials, prospective and retrospective case–control and comparative cohort studies will be included in quantitative review. There will be no study design restrictions for inclusion in qualitative review. Following study selection, full-text paper retrieval, data extraction and synthesis, studies will be assessed for risk of bias and heterogeneity. If the included studies are sufficiently homogeneous, then we will perform meta-analysis. A narrative synthesis of the systematic review's results will also be presented.
Ethics and disseminationFormal ethical approval is not required as primary patient data will not be collected. The systematic review's results will be disseminated through a peer-reviewed publication.
Trial registration numberCRD42017064254; Pre-results.
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Time in therapeutic range and stability over time for warfarin users in clinical practice: a retrospective cohort study using linked routinely collected health data in Alberta, Canada
Objectives
Whether warfarin-treated patients with non-valvular atrial fibrillation (NVAF) who exhibit good control will experience deterioration in control over time is uncertain. We designed this study to examine the time in therapeutic range (TTR) in a population-based cohort of patients with NVAF recently initiated on warfarin.
DesignRetrospective cohort study using routinely collected health data from 2008 to 2015.
SettingThe Canadian province of Alberta.
ParticipantsAll adults with NVAF who were taking warfarin for >1 month.
Main outcome measuresFrequency of international normalised ratio (INR) monitoring and the Rosendaal TTR with time zero set at 31 days after the first warfarin dispensation.
ResultsOf 57 669 patients with NVAF dispensed warfarin for >1 month, 17 099 (29.7%) had <3 INRs measured in months 1–6. Of the 40 570 who went for regular INR monitoring in months 1–6 (median number of INRs 11, IQR 7–16), 16 639 (41.0%) met the definition of good control (TTR > 65%); good control continued to be exhibited by 8177 (57.1% of those who remained on warfarin) during months 7–12 and 6804 (56.8% of continuing warfarin users) in months 13–18. Good control in the first 6 months predicted good control over the subsequent year: adjusted OR (aOR) 4.0(95%CI 3.8 to 4.2), c index 0.685(95%CI 0.679 to 0.691) for months 7–12 and aOR 3.2(95%CI 3.1 to 3.3), c index 0.665(95%CI 0.659 to 0.671) for months 13–18.
ConclusionsNearly one-third of warfarin-treated patients had insufficient INR monitoring—this could influence the initial choice of anticoagulant and identifies a target for future quality improvement efforts. Of those warfarin-treated patients who went for regular INR monitoring, 41% exhibited levels of control similar to that in randomised trials and this deteriorated by half over time. However, in patients who have already exhibited adherence with regular monitoring and good TTR, warfarin may still be a reliable anticoagulation option.
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Chronic postsurgical pain following breast reconstruction: a commentary and critique
Abstract
In line with other major surgeries including breast cancer surgery (BCS), recent studies suggest a striking rate of chronic postsurgical pain (CPSP) following breast reconstruction. This commentary will critically examine evidence for the degree to which the prevalence of CPSP following breast reconstruction is directly attributable to reconstructive surgery. The discussion will trace similarities and distinctions between breast reconstruction and BCS in considering the risk for CPSP, and describe recent advances in the definition of CPSP, highlighting methodological limitations in the general investigation of CPSP, which also characterize the study of CPSP more specifically for breast reconstruction outcome. A convenience sample of relevant studies examining CPSP following breast reconstruction reveals inadequate evidence to support a serious concern for reconstruction-induced CPSP and further that these studies fail to adhere to recommended methodological standards to effectively isolate surgery as the etiology of persistent pain reported by women following reconstructive surgery. Suggestions for future exploration of problematic chronic pain after breast reconstruction are considered.
http://ift.tt/2nmIb0N
Two Paths Diverged in the Brain, Ray Guillery Chose the One Less Studied
Abstract
Ray Guillery profoundly affected my work as a theorist studying the neocortex. What I treasured about Ray was that he didn't just report his experimental findings, he promoted bold new interpretations of them. He challenged conventional wisdom, and, therefore, challenged all neuroscientists to think differently. In this essay, I describe one of Ray's bold ideas, the critical role of the thalamus in how information flows from region to region in the neocortex.
This article is protected by copyright. All rights reserved.
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Early Blindness is Associated with Increased Volume of the Uncinate Fasciculus
Abstract
Growing evidence demonstrates dramatic structural and functional neuroplastic changes in individuals born with early onset blindness. For example, crossmodal sensory processing at the level of the occipital cortex appears to be associated with adaptive behaviors in the blind. However, detailed studies examining the structural properties of key white matter pathways in other regions of the brain remain limited. Given that blind individuals rely heavily on their sense of hearing, we examined the structural properties of two important pathways involved with auditory processing namely, the uncinate and arcuate fasciculi. High angular resolution diffusion imaging (HARDI) tractography was used to examine structural parameters (i.e. tract volume and quantitative anisotropy, or QA) of these two fasciculi in a sample of 13 early blind individuals and 14 normally sighted controls. Compared to controls, early blind individuals showed a significant increase in the volume of the left uncinate fasciculus. A small area of increased QA was also observed half way along the right arcuate fasciculus in the blind group. These findings contribute to our knowledge regarding the broad neuroplastic changes associated with profound early blindness.
This article is protected by copyright. All rights reserved.
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When neuroscience met clinical pathology: partitioning experimental variation to aid data interpretation in neuroscience
Abstract
In animal experiments, neuroscientists typically assess the effectiveness of interventions by comparing the average response of groups of treated and untreated animals. While providing useful insights, focusing only on group effects risks overemphasis of small, statistically significant but physiologically unimportant differences. Such differences can be created by analytical variability or physiological within-individual variation, especially if the number of animals in each group is small enough that one or two outlier values can have considerable impact on the summary measures for the group.
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Homeobox transcription factor DLX4 is not necessary for skin development and homeostasis
Abstract
Dlx4 is a member of a family of homeobox genes with homology to Drosophila distal-less (dll) gene. We show that Dlx4 expression pattern partially overlaps with its cis-linked gene Dlx3 during mouse development as well as in neonatal and adult skin. In mice, Dlx4 is expressed in the branchial arches, embryonic limbs, digits, nose, hair follicle and in the basal and suprabasal layers of mouse interfollicular epidermis in neonatal and adult skin. We show that inactivation of Dlx4 in mice did not result in any overtly gross pathology. Skin development, homeostasis and response to TPA treatment was similar in mice with loss of Dlx4 compared to wild type counterparts.
This article is protected by copyright. All rights reserved.
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The differences on efficacy of oxaliplatin in locally advanced colon cancer between mucinous and nonmucinous adenocarcinoma
Abstract
Until now, it remains unclear how to best use the histological subtype in clinical practice. This study aimed to compare differences in the efficacy of postoperative chemotherapy among different histological subtypes of colon adenocarcinomas. Using the Surveillance, Epidemiology, and End Results-Medicare database, 51,200 patients with stage II or III primary colon carcinomas who underwent resection for curative intent between 1992 and 2008 were included. The survival benefit was evaluated using a Cox proportional hazards model, interaction analyses, and propensity score-matched techniques. There was no significant difference in survival for low-risk stage II mucinous adenocarcinoma (MA) or nonmucinous adenocarcinoma (NMA) between 5-FU and oxaliplatin-treated groups (P = 0.387 for MA, P = 0.629 for NMA). Patients with high-risk stage II NMA who received the oxaliplatin chemotherapy regimen had significantly improved cancer-specific survival (CSS) compared with the 5-FU group (P = 0.004), while those with MA saw no improvement (P = 0.690). For stage III tumors, patients with NMA who received the oxaliplatin chemotherapy regimen had significantly improved CSS compared with the 5-FU group (P < 0.001), while those with MA saw no improvement (P = 0.300). There were significant interactions between chemotherapy regimen and histological subtype. For patients with resected colon cancer who received 5-FU-based postoperative chemotherapy, oxaliplatin chemotherapy prolongs CSS for stage III and high-risk stage II NMA. Conversely, there was no similar improvement with addition of oxaliplatin for patients with stage III or stage II MA.
Until now, it remains unclear how to best use the histological subtype in clinical practice. For patients with resected colon cancer who received 5-FU-based postoperative chemotherapy, adding oxaliplatin can improve CSS for patients with stage III or high-risk stage II NMA. Conversely, there was no similar improvement for patients with stage III or high-risk stage II MA.
http://ift.tt/2GtzfON
Distinct predictive impact of FISH abnormality in proteasome inhibitors and immunomodulatory agents response: redefining high-risk multiple myeloma in Asian patients
Abstract
For risk-adaptive therapeutic approaches in multiple myeloma (MM) treatment, we analyzed treatment outcome according to in situ hybridization (FISH) profiles to investigate the prognostic and predictive values of structural variations in a large series of Asian population. A total of 565 newly diagnosed patients with multiple myeloma between January 2005 and June 2015 were evaluated. FISH results showed del(17p13) in 8.8% (29/331), del(13q14) in 35.5% (184/519), t(14;16) in 2.5% (8/326), t(4;14) in 27.9% (109/390), IgH rearrangement in 47.7% (248/520), and +1q21 in 40.8% (211/517). The presence of del(17p13), IgH rearrangement, and t(14;16) was associated with worse overall survival. Interestingly, however, the presence of t(4;14) conferred little prognostic impact. Treatment-specific analysis revealed the presence of del(17p13), t(14;16), IgH rearrangement, and trisomy 1q21 was predictive of unsatisfactory response to bortezomib. On the other hand, patients with del(13q14) and del(9p21) were less likely to benefit from lenalidomide. Autologous stem cell transplantation (autoSCT) was less effective in patients with del(17p13), t(14;16), and trisomy 1q21. Predictive values of del(17p13) and t(14;16) to bortezomib and autoSCT are seemingly universal, but predictive marker del(13q14) and del(9p21) for lenalidomide response appears ethnicity-specific. Thus, FISH profiles in MM treatment should be interpreted with regards to patient's ethnicity.
Treatment-specific analysis revealed the presence of del(17p13), t(14;16), IgH rearrangement, and trisomy 1q21 was predictive of unsatisfactory response to bortezomib. On the other hand, patients with del(13q14) and del(9p21) were less likely to benefit from lenalidomide. Autologous stem cell transplantation was less effective in patients with del(17p13), t(14;16), and trisomy 1q21.
http://ift.tt/2rOO4sh
Identification of a small-molecule ligand of β-arrestin1 as an inhibitor of stromal fibroblast cell migration accelerated by cancer cells
Abstract
Stromal fibroblasts, which occupy a major portion of the tumor microenvironment, play an important role in cancer metastasis. Thus, targeting of these fibroblasts activated by cancer cells (carcinoma-associated fibroblasts; CAFs) might aid in the improved treatment of cancer metastasis. NIH3T3 fibroblasts cocultured with MCF7 cells displayed enhanced migration compared to NIH3T3 fibroblasts cultured alone. We used this system to identify the small-molecule inhibitors responsible for their enhanced migration, a characteristic of CAFs. We selected β-arrestin1, which showed high expression in cocultured cells, as a molecular target for such inhibitors. Cofilin, a protein downstream of β-arrestin1, is activated/dephosphorylated in this condition. The small-molecule ligands of β-arrestin1 obtained by chemical array were then examined using a wound healing coculture assay. RKN5755 was identified as a selective inhibitor of activated fibroblasts. RKN5755 inhibited the enhanced migration of fibroblasts cocultured with cancer cells by binding to β-arrestin1 and interfering with β-arrestin1-mediated cofilin signaling pathways. Therefore, these results demonstrate the role of β-arrestin1 in the activation of fibroblasts and inhibiting this protein by small molecule inhibitor might be a potential therapeutic target for the stromal fibroblast activation (cancer–stroma interaction).
NIH3T3 fibroblasts cocultured with MCF7 cells displayed enhanced migration compared to NIH3T3 fibroblasts cultured alone. Using this system, we identified RKN5755, a selective inhibitor of activated fibroblasts. This small molecule binds to β-arrestin1 and interferes with β-arrestin1-mediated cofilin signaling pathways.
http://ift.tt/2Gwo4VF
Assessment of the American Joint Commission on Cancer 8th Edition Staging System for Patients with Pancreatic Neuroendocrine Tumors: A Surveillance, Epidemiology, and End Results analysis
Abstract
Although several staging systems have been proposed for pancreatic neuroendocrine tumors (pNETs), the optimal staging system remains unclear. Here, we aimed to assess the application of the newly revised 8th edition American Joint Committee on Cancer (AJCC) staging system for exocrine pancreatic carcinoma (EPC) to pNETs, in comparison with that of other staging systems. We identified pNETs patients from the Surveillance, Epidemiology, and End Results (SEER) database (2004–2014). Overall survival was analyzed using Kaplan–Meier curves with the log-rank test. The predictive accuracy of each staging system was assessed by the concordance index (c-index). Cox proportional hazards regression was conducted to calculate the impact of different stages. In total, 2424 patients with pNETs, including 2350 who underwent resection, were identified using SEER data. Patients with different stages were evenly stratified based on the 8th edition AJCC staging system for EPC. Kaplan–Meier curves were well separated in all patients and patients with resection using the 8th edition AJCC staging system for EPC. Moreover, the hazard ratio increased with worsening disease stage. The c-index of the 8th edition AJCC staging system for EPC was similar to that of the other systems. For pNETs patients, the 8th edition AJCC staging system for EPC exhibits good prognostic discrimination among different stages in both all patients and those with resection.
The purpose of our study was to discuss whether the new N category (N0, N1, N2) or the 8th staging systems for PDAC is suitable for pNETs, and the results showed that the 8th staging systems for PDAC are more suitable for pNETs compared with the 8th staging systems for pNETs/ENETS.
http://ift.tt/2rQTeUw
Global named patient use program of afatinib in advanced non-small-cell lung carcinoma patients who progressed following prior therapies
Future Oncology, Ahead of Print.
http://ift.tt/2DXYP04
A case report and a literature review of primary retroperitoneal mucinous cystadenoma: the importance of imaging in diagnosis and management
Future Oncology, Ahead of Print.
http://ift.tt/2FsR7bB
Hypothalamic and liver transcriptome from two critical life-history stages in a migratory songbird
Abstract
Very little is understood about genetic mechanisms underlying the onset of spring migration in latitudinal avian migrants. To gain insight into genetic architecture of the hypothalamus and liver tissues of a long-distance migrant, we examined and compared the transcriptome profile of captive night-migratory blackheaded buntings (Emberiza melanocephala) between photoperiodically-induced winter non-migratory (WnM) and spring migratory (SM) life-history states (LHSs) under short and long days, respectively. High-throughput 454 pyrosequenced transcripts were mapped initially with reference to the genome of two phylogenetically close species, Taeniopygia guttata and Ficedula albicollis. The F. albicollis genome gave higher annotation results, and was used for further analysis. A total of 216 (78 in hypothalamus; 138 in liver) genes were found to be differentially expressed between the WnM and SM LHSs. These genes were enriched for physiological pathways, which may be involved in regulating seasonal migrations in birds. For example, genes that enriched for ATP binding pathway in the hypothalamus were expressed at a significantly higher level in SM than in the WnM LHS. Similarly, upregulated genes associated with myelin sheath and focal adhesion were enriched in the hypothalamus, and those with cell-to-cell junction, intracellular protein transport, calcium ion transport and small GTPase-mediated signal transduction were enriched in the liver. Many of these genes are a part of physiological pathways potentially involved in regulating seasonal migration in birds. These results show molecular changes at the regulatory and metabolic levels associated with seasonal transitions in a long-distance migrant, and provide bases for future studies aimed at unravelling the genetic control of migration in birds.
This article is protected by copyright. All rights reserved
http://ift.tt/2E0CFub
It is time to move forward into the era of Theranostics
Abstract
Radionuclide therapy, which until 15 years ago included only a few approved therapies, is gaining importance in the treatment of various malignancies. The future of oncology will not be limited to surgery, chemo-, antibody therapies or external radiation; it will include targeted therapy with radionuclides, which will become the standard of care for a variety of malignant diseases in combination or as an alternative to other therapies. Therefore there is a need to train Nuclear Oncologists, who are able to approach oncological diseases, promote development of radiopharmacy, understand the biology of radionuclide treatment, apply radionuclide treatments and be able to use molecular imaging such as PET/CT and SPECT/CT for treatment planning and dosimetry.
http://ift.tt/2DYIlog
Increasing Prevalence of Rifampicin-Resistant Mycobacterium tuberculosis is Associated with the Transmission of Strains Harboring Compensatory Mutations in China: A 10-year Comparative Analysis [PublishAheadOfPrint]
In this report, we conducted bacterial population profile studies to assess trends of rifampicin (RIF) resistance from 2005 to 2015 of Mycobacterium tuberculosis (MTB) isolates collected across China. A total of randomly selected 273 and 269 MTB isolates from 2005 and 2015, respectively, were analyzed. The rates of RIF resistance (36.4%), isoniazid resistance (39.0%), and levofloxacin resistance (25.7%) in 2015 were significantly higher than in 2005 (28.2%, 30.0%, and 15.4%, respectively; P < 0.05). Genotypic data revealed 256 (95.2%) Beijing-type isolates in 2015, a rate significantly higher than that of 2005 (86.4%) (P < 0.01). A higher proportion of mutations were identified within the rifampin resistance determining region (RRDR) of rpoB in isolates from 2015 (99.0%) than in 2005 isolates (85.7%, P < 0.01). In addition, a significantly higher proportion of RIF-resistant isolates carrying compensatory mutations were observed in 2015 (31.6%) than in 2005 (7.8%). Notably, the great majority of these compensatory mutations (91.9%) were observed in isolates that harbored a mutation of codon 531 of the rpoB gene. In conclusion, our data demonstrate that resistance to RIF, isoniazid, and levofloxacin has become significantly more prevalent during the past decade. In addition, the prevalence of the Beijing genotype significantly increased from 2005 to 2015. Notably, a significantly increased frequency of strains with mutations in rpoC or rpoA is observed in those that have codon 531 mutations suggests that they may be compensatory, and may play a role in facilitating transmission.
http://ift.tt/2EqhRKx
Norepinephrine in Combination with Antimicrobial Therapy Increases both the Bacterial Replication Rate and Bactericidal Activity [PublishAheadOfPrint]
We previously demonstrated that the rate and extent of an antimicrobial agent's bactericidal effects was coupled to bacterial replication rate, the latter of which was modulated with sodium chloride concentration. Herein, we describe the results from a 24-h one-compartment in vitro infection model study that was designed to demonstrate that an antimicrobial agent's bactericidal effects could be amplified when administered with a pharmaceutical agent that increases bacterial replication rate. The antimicrobial and growth-promoting agents selected were levofloxacin and norepinephrine, respectively. The challenge isolate was Escherichia coli JMI 21711R (levofloxacin MIC, 8 mg/liter). Within the in vitro infection model, human levofloxacin concentration-time profile (half-life, 7 h) was simulated and the challenge isolate was subjected to an ineffective monotherapy exposure (free-drug area under the concentration-time curve over 24 h divided by the MIC [AUC/MIC ratio] of 6) with and without norepinephrine as a continuous infusion (275 mg/L). Samples were collected from the model during the course of the study for bacterial density determinations and drug concentration assay using liquid chromatography-tandem mass spectrometry (LC-MS/MS). As expected, the norepinephrine and no-treatment control arms failed immediately, followed by levofloxacin monotherapy arm, which failed slowly over time. The levofloxacin-epinephrine regimen resulted in a 2-log10 CFU reduction in bacterial density over the first 6-8 hours of the study, which was followed by regrowth of a highly levofloxacin-resistant subpopulation (MIC, 64 mg/L). These data demonstrate that increasing the rate of bacterial replication with a pharmaceutical product in combination with antimicrobial therapy represents an opportunity to increase the rate and magnitude of bactericidal effect.
http://ift.tt/2DKmo9m
Enhanced ex vivo Plasmodium vivax intraerythrocytic enrichment and maturation for rapid and sensitive parasite growth assays [PublishAheadOfPrint]
Plasmodium vivax chloroquine resistance has been documented in nearly every region endemic for this malaria-causing parasite. Unfortunately, P. vivax resistance surveillance and drug discovery is challenging due to low parasitemias of patient isolates, and poor parasite survival through ex vivo maturation, that reduce the sensitivity and scalability of current P. vivax antimalarial assays. Using cryopreserved patient isolates from Brazil and fresh patient isolates from India, we established a robust enrichment method for P. vivax parasites. We next performed a media screen for formulations that enhance ex vivo survival. Finally, we optimized an isotopic metabolic labelling assay for measuring P. vivax maturation and sensitivity to antimalarials. A KCl Percoll density gradient enrichment method increased parasitemias from small-volume ex vivo isolates by an average of >40-fold. Using Iscove's Modified Dulbecco's Medium for P. vivax ex vivo culture approximately doubled parasite survival through maturation. Coupling these with 3H-hypoxanthine metabolic labeling permitted sensitive and robust measurement of parasite maturation, which was used to measure the sensitivities of Brazilian P. vivax isolates to chloroquine and several novel antimalarials. These techniques can be applied to rapidly and robustly assess the P. vivax isolate sensitivities to antimalarials for resistance surveillance and drug discovery.
http://ift.tt/2EllOji
Identification of the In Vivo Pharmacokinetics and Pharmacodynamic Drivers of Iclaprim [PublishAheadOfPrint]
The neutropenic, murine thigh infection model was used to define the PK/PD index linked to efficacy of iclaprim against S. aureus ATCC 29213 and S. pneumoniae ATCC 10813. The 24h AUC/MIC index was most closely linked to efficacy for S. aureus (R2=0.65), while both the 24h AUC/MIC and the %T>MIC were both strongly associated with effect (R2=0.86 for both parameters) for S. pneumoniae.
http://ift.tt/2DLS4v9
Pharmacokinetics of tedizolid in obese patient after bariatric surgery: a case report [PublishAheadOfPrint]
An obese woman was treated orally by tedizolid 200 mg once daily for a pseudoarthrosis, 10 years after a Roux-en-Y bypass surgery.
Total plasma peak concentration was 2.12 mg/L, 3h after intake and AUC0-24h was 28.3 mg/L*h. The AUC0-24h/MIC ratio for unbound concentrations and for sensible Staphylococcus and Streptococcus strains was at least 10.8, higher than a targeted ratio of 3.
These results support the use of tedizolid without adjustment after a bariatric surgery.
http://ift.tt/2EoNqnC
Population pharmacokinetics and dosing optimisation of ceftazidime in infants [PublishAheadOfPrint]
Objective: Ceftazidime, a third-generation cephalosporin, can be used for thetreatment of adults and children with infections due to susceptible bacteria. To date, the pediatric pharmacokinetic data is limited in infants, and therefore we aimed to evaluate the population pharmacokinetics of ceftazidime in infants and define the appropriate dose to optimize ceftazidime treatment.
Methods: Blood samples were collected from children treated with ceftazidime, and concentrations of drug were quantified by HPLC-UV. A population pharmacokinetic analysis was performed using NONMEM software (version 7.2.0).
Results: Fifty-one infants (age range: 0.1-2.0 years) were included. Sparse pharmacokinetic samples (n = 90) were available for analysis. A one-compartment model with first-order elimination showed the best fit with the data. A covariate analysis identified that body weight, and CLCR were significant covariates influencing ceftazidime clearance. Monte Carlo simulation demonstrated that the currently used dosing regimen of 50 mg/kg twice daily was associated with a high risk of underdosing in infants. In order to reach the target 70% the time of free antimicrobial drug concentration above the minimum inhibitory concentration (fT>MIC), 25 mg/kg q8h and 50 mg/kg q8h were required for a MIC 4 mg/liter and for a MIC 8 mg/liter, respectively.
Conclusion: The population pharmacokinetics characteristics of ceftazidime were evaluated in infants. An evidence-based dosing regimen was established based on simulation.
http://ift.tt/2DLfJMd
CTX-M-55, MCR-1 and fosA producing multi-resistant E. coli in a pediatric infection in France [PublishAheadOfPrint]
Horizontally transferable plasmid-mediated mcr-1 gene encoding a phosphoethanolamine transferase conferring resistance to colistin in multiresistant pathogen may lead to therapeutic impasse....
http://ift.tt/2EnCO8y
Evaluation of a System-specific Function to Describe the Pharmacokinetics of Benzylpenicillin in Term Neonates Undergoing Moderate Hypothermia [PublishAheadOfPrint]
The pharmacokinetic (PK) properties of i.v. benzylpenicillin in term neonates undergoing moderate hypothermia after perinatal asphyxia were evaluated, as to date these are unknown. To do so, a system-specific modeling approach was applied, in which our recently developed covariate model describing developmental and temperature induced changes in amoxicillin clearance (CL) in the same patient study population, was incorporated into a population PK model of benzylpenicillin with a priori birthweight (BW) based allometric scaling. Pediatric population covariate models describing the developmental changes in drug elimination may constitute system-specific information and may therefore be incorporated into PK models of drugs cleared through the same pathway. The performance of this system-specific model was compared to a reference-model. Furthermore, Monte-Carlo simulations were performed to evaluate the optimal dose.
The system-specific model performed as well as the reference-model. Significant correlations were found between CL and postnatal age (PNA), gestational age (GA), body temperature (TEMP), urine output (UO; system-specific model) and multi-organ-failure (reference-model). For a typical patient GA 40 weeks, BW3000 g, 2 days PNA (TEMP 33.5°C), and normal UO (2 ml/kg/h)) benzylpenicillin CL was 0.48 L/h (inter-individual variability (IIV) 49%) and volume of distribution of the central compartment was 0.62 L/kg (IIV of 53%) in the system-specific model.
Based on simulations, we advise a benzylpenicillin i.v. dose regimen of 75,000 IU/kg/day q8h, 150,000 IU/kg/day q8h, and 200,000 IU/kg/day q6h for patients with GA36-37 weeks, 38-41 weeks, and ≥42 weeks, respectively. The system-specific model may be used for other drugs cleared through the same pathway accelerating model development.
http://ift.tt/2DKirBs
Efficacy and Safety of Plazomicin Compared with Levofloxacin in the Treatment of Complicated Urinary Tract Infection and Acute Pyelonephritis: A Multicenter, Randomized, Double-Blind, Phase 2 Study [PublishAheadOfPrint]
Increasing antimicrobial resistance among uropathogens limits treatment options for patients with complicated urinary tract infection (cUTI). Plazomicin, a next-generation aminoglycoside, has in vitro activity against multidrug-resistant Enterobacteriaceae, including isolates resistant to currently available aminoglycosides as well as extended-spectrum β-lactamase-producing and carbapenem-resistant Enterobacteriaceae. We evaluated the efficacy and safety of plazomicin in a double-blind, comparator-controlled, phase 2 study in adults with cUTI or acute pyelonephritis. Patients were randomized 1:1:1 to intravenous plazomicin (10 or 15 mg/kg) or intravenous levofloxacin (750 mg) once daily for 5 days. Co-primary efficacy endpoints were microbiological eradication at test-of-cure (TOC; 5-12 days after last dose) in the modified intent-to-treat (MITT) and microbiologically evaluable (ME) populations. Overall, 145 patients were randomized to treatment. In the plazomicin 10 mg/kg, 15 mg/kg, and levofloxacin groups, respectively, microbiological eradication rates (n/N [95% CI]) were 50.0% (6/12 [21.1-78.9]), 60.8% (31/51 [46.1-74.2]), and 58.6% (17/29 [38.9-76.5]) in the MITT population and 85.7% (6/7 [42.1-99.6]), 88.6% (31/35 [73.3-96.8]), and 81.0% (17/21 [58.1-94.6]) in the ME population. In the MITT population, 66.7% (34.9-90.1), 70.6% (56.2-82.5), and 65.5% (45.7-82.1) of patients were assessed as clinically cured by the investigator at TOC. Adverse events were reported in 31.8%, 35.1%, and 47.7% of patients. Serum creatinine values were generally stable over the course of the study. No plazomicin-treated patients with evaluable audiometry data had postbaseline sensorineural, conductive, or mixed hearing loss. In summary, plazomicin demonstrated microbiological and clinical success rates and an overall safety profile supportive of further clinical development. (ClinicalTrials.gov registration: NCT01096849.)
http://ift.tt/2ElW7PL
Surveillance of omadacycline activity tested against clinical isolates from the United States and Europe: Report from the SENTRY Antimicrobial Surveillance Program, 2016 [PublishAheadOfPrint]
Omadacycline was tested against 21,000 bacterial isolates collected prospectively from medical centers in Europe and the United States during 2016. Omadacycline was active against Staphylococcus aureus (MIC50/90, 0.12/0.25 mg/L) including MRSA; streptococci (MIC50/90, 0.06/0.12 mg/L) including Streptococcus pneumoniae, viridans group streptococci, and β-hemolytic streptococci; Enterobacteriaceae including Escherichia coli (MIC50/90, 0.5/2 mg/L); Haemophilus influenzae (MIC50/90, 1/1 mg/L); and Moraxella catarrhalis (MIC50/90, 0.25/0.25 mg/L). Omadacycline merits further study in serious infections where resistant pathogens may be encountered.
http://ift.tt/2DNRrAU
Azithromycin resistance in Shigella spp. in Southeast Asia [PublishAheadOfPrint]
Infection by Shigella spp. is a common cause of dysentery in Southeast Asia. Antimicrobials are thought to be beneficial for treatment, however antimicrobial resistance in Shigella spp. is becoming widespread. We aimed to assess the frequency and mechanisms associated with decreased susceptibility to azithromycin in Southeast Asian Shigella isolates and use these data to assess appropriate susceptibility breakpoints. Shigella isolated in Vietnam and Laos were screened for susceptibility against azithromycin (15μg) by disc diffusion and minimum inhibitory concentration (MIC). Phenotypic resistance was confirmed by PCR amplification of macrolide resistance loci. We compared the genetic relationships and plasmid contents of azithromycin resistant S. sonnei using whole genome sequences. From 475 available Shigella spp. isolated in Vietnam and Laos between 1994 and 2012, 6/181 S. flexneri (3.3%, MIC≥16g/L) and 16/294 S. sonnei (5.4%, MIC≥32g/L) were phenotypically resistant to azithromycin. PCR amplification confirmed a resistance mechanism in 22/475 (4.6%) isolates (19 mphA and 3 ermB). Susceptibility data demonstrated the acceptability of S. flexneri (MIC≥16g/L, zone≤15mm) and S. sonnei (MIC≥32g/L, zone≤11mm) breakpoints with <3% discrepancy. Phylogenetic analysis demonstrated that decreased susceptibility has arisen sporadically in Vietnamese S. sonnei on at least seven occasions between 2000 and 2009, but failed to become established. While the proposed susceptibility breakpoints may allow better recognition of resistant isolates, additional studies are required to assess the impact on clinical outcome. The potential emergence of azithromycin resistance highlights the need for alternative management options for Shigella infections in endemic countries.
http://ift.tt/2EqhQ9r
Clofazimine for Treatment of Pulmonary Extensively Drug-Resistant Tuberculosis in China [PublishAheadOfPrint]
We performed a multicenter, prospective and randomized study to investigate the efficacy and safety of clofazimine (CLO) for treatment of extensively drug-resistant tuberculosis (XDR-TB) in China. Forty-nine patients infected with XDR-TB were randomly assigned to either the control group or the CLO group, both of which received 36 months of individually customized treatment. The primary end-point was the time to sputum-culture conversion on solid medium. Clinical outcomes of patients were evaluated at the time of treatment completion. Of the 22 patients in the experimental group, 7 (31.8%) met the treatment criterion of "cure" and 1 (4.5%) "complete treatment," for a total of 8 (36.4%) exhibiting successful treatment outcomes without relapse. In the control group, 6 patients (22.2%) were "cure" and 6 (22.2%) "complete treatment" by the end of the study. Statistical analysis revealed no significant difference in successful outcome rates between CLO and control groups. The average sputum-culture conversion time was 19.7 months for the experimental group, which was statistically no different than that of the control group (20.3 months, P=0.57). Of the 22 patients in the CLO group, 12 (54.5%) had adverse events after starting CLO treatment. The most frequently observed adverse event was liver damage, with 31.8% (7/22) of patients exhibiting this adverse effect in the CLO group versus 11.1% (3/27) for the control group. Our study demonstrates that inclusion of CLO in background treatment regimens for XDR-TB is of limited benefit, especially since hepatic disorders arise as major adverse events with CLO treatment.
http://ift.tt/2DKmldG
Population pharmacokinetics of cefotaxime and dosage recommendations in children with sickle cell disease. [PublishAheadOfPrint]
The pharmacokinetic profile of most drugs is dependent on patient's covariates and may be influenced by the disease. Cefotaxime is frequently prescribed in pediatric patients with sickle-cell disease (SCD), characterized by vaso-occlusive complications, chronic haemolytic anaemia and defective immunological function predisposing to severe infection. Data on the impact of the disease on cefotaxime disposition are missing. In the present study, our aims were to determine cefotaxime pharmacokinetics when prescribed in SCD children for suspected or proven bacterial infection, identify significant covariates and perform Monte-Carlo simulations to optimize drug dosage. Cefotaxime serum concentrations were measured in 78 pediatric SCD patients receiving cefotaxime intravenously at the daily dose of 200 mg/kg in three or four divided doses over 30 min. A total of 107 concentrations were available for pharmacokinetic analysis. A population pharmacokinetic model was developed with NONMEM and used for Monte-Carlo simulations. Cefotaxime concentrations ranged from 0.05 to 103.7 mg/l. Cefotaxime pharmacokinetics was best described by a one compartment model: The median (range) of estimated weight-normalized V and CL were 0.42 (0.2 to 1.1) l/kg and 0.38 (0.1 to 1.2) l/h/kg. Cefotaxime clearance increased by 22% in patients with acute chest syndrome. Dosing optimization, performed using EUCAST Minimum Inhibitory Concentration (MIC) susceptibility breakpoints, showed that the dose of 100 mg/kg/6h should be used, depending on patients' characteristics and clinical presentation, in order to reach a Time/MIC of 80% in 80% of patients when targeting sensitive Gram positive cocci and Gram negative bacilli with MICs of 1 mg/L or below.
http://ift.tt/2DIIx7X
Antibiotic susceptibility and genotyping of Mycobacterium avium strains that cause pulmonary and disseminated infection [PublishAheadOfPrint]
Mycobacterium avium subsp. hominissuis (MAH) causes mainly disseminated infection in immunocompromised hosts, such as individuals with human immunodeficiency virus (HIV) infection, and pulmonary infection in immunocompetent hosts. However, many aspects of the different types of MAH infection remain unclear. We examined antibiotic susceptibility and genotype in MAH isolates from different hosts by performing drug susceptibility testing using eight antibiotics (clarithromycin, rifampicin, ethambutol, streptomycin, kanamycin, amikacin, ethionamide, and levofloxacin) and variable number tandem repeats (VNTR) typing analysis for 46 isolates from the sputa of HIV-negative patients with pulmonary MAH disease without previous antibiotic treatment and 30 isolates from blood of HIV-positive patients with disseminated MAH disease. Interestingly, isolates from pulmonary MAH disease patients were more resistant to seven drugs except for rifampicin compared with isolates from HIV-positive patients. Moreover, VNTR typing analysis showed that the strains examined in this study were roughly classified into three clusters, and the genetic distance from a reference strain 104 in isolates from pulmonary MAH disease patients was statistically different from that in isolates from HIV-positive patients (p = 0.0018), suggesting that MAH strains that cause pulmonary and disseminated disease have genetically distinct features. Significant differences were noted in susceptibility for seven drugs except for ethambutol among the three clusters. Collectively, these results suggest that an association between types of MAH infection, drug susceptibility, and VNTR genotypes and the properties of MAH strains associated with the development of pulmonary disease are involved in higher antibiotic resistance.
http://ift.tt/2EmzJFL
Importance of Site of Infection and Antibiotic Selection in the Treatment of Carbapenem-Resistant Pseudomonas aeruginosa Sepsis [PublishAheadOfPrint]
In a retrospective analysis of 215 patients with carbapenem-resistant Pseudomonas aeruginosa sepsis, we observed significantly higher risk of mortality associated with respiratory tract infection (risk ratio [RR], 1.20; 95% confidence interval [CI], 1.04-1.39 P=0.010) and lower risk with urinary tract infection (RR, 0.80; 95% CI, 0.71-0.90; P=0.004). Aminoglycoside monotherapy was associated with increased mortality, even after adjusting for confounders (adjusted RR [aRR], 1.72; 95% CI, 1.03-2.85; P=0.037), consistent across multiple sites of infection.
http://ift.tt/2DMorto
The emergence and spread of kelch 13 mutations associated with artemisinin resistance in Plasmodium falciparum parasites in twelve Thai provinces from 2007 - 2016 [PublishAheadOfPrint]
Artemisinin-based combination therapy (ACT) is the most effective and widely used treatment for uncomplicated Plasmodium falciparum (Pf) malaria and is a cornerstone for malaria control and prevention globally. Resistance to artemisinin derivatives has been confirmed in the Greater Mekong Subregion (GMS), which manifest as slow parasite clearance in patients and reduced ring-stage susceptibility to artemisinins in survival assays. The Pf kelch 13 gene mutations associated with artemisinin resistant parasites are now wide-spread in the GMS. We genotyped 277 samples collected during an observational study from 2012-2016 from eight provinces in Thailand to identify Pf kelch 13 mutations. The results were combined with previously reported genotyping results from Thailand to construct a map illustrating the evolution of Pf kelch 13 mutations from 2007 – 2016 in the country. Different mutant alleles were found in strains with different geographical origins. The artemisinin resistant Y493H and R539T mutations were detected mainly in eastern Thailand (bordering Cambodia), while P574L was only found in western Thailand and R561H in northwestern Thailand. The C580Y mutation was found across the entire country and was nearing fixation along the Thai-Cambodia border. Overall the prevalence of artemisinin resistant mutations increased over the last ten years across Thailand, especially along the Thai-Cambodia border. Molecular surveillance and therapeutic efficacy monitoring should be intensified in the region to further assess the extent and spread of artemisinin resistance.
http://ift.tt/2EnCIhc
Risk factors and outcomes of endocarditis due to non-HACEK Gram-negative bacilli: data from the prospective multicenter SEI cohort [PublishAheadOfPrint]
Objective: To investigate predisposing factors and outcomes of non-HACEK Gram-negative bacilli (GNB) infective endocarditis (IE) in a multicenter, contemporary cohort.
Patients and Methods: Patients with IE due to GNB prospectively observed in 26 Italian centers from 2004 to 2011 were analyzed. Using a case-control design, each case was compared to three controls with IE by other etiologies matched for age and sex. Logistic regression was performed to identify risk factors for GNB IE. Factors associated with early and late mortality were assessed by Cox regression analysis.
Results: The study group comprised 58 patients with GNB IE. Escherichia coli was the most common pathogen followed by Pseudomonas aeruginosa and Klebsiella pneumoniae. Genitourinary tract as source of infection (OR 13.59, 95% CI 4.63-39.93, p<.001), immunosuppression (OR 5.16, 95% CI 1.60-16.24, p=.006) and presence of a cardiac implantable electronic device (CIED) (OR 3.57, 95% CI 1.55-8.20, p=.003) were factors independently associated with GNB IE. The in-hospital mortality was 13.8%, and rose up to 30.6% at 1 year. A multidrug-resistant etiology was associated with in-hospital (HR 21.849, 95% CI 2.672-178.683, p=0.004) and 1-year mortality (HR 4.408, 95% CI 1.581-12.287, p=0.005).
Conclusions: The presence of a genitourinary focus, immunosuppressive therapy and an indwelling CIED are factors associated with GNB IE. MDR etiology is the major determinant of in-hospital and long-term mortality.
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Role of three Cryptococcus neoformans and C. gattii efflux pump coding genes in response to drug treatment [PublishAheadOfPrint]
Cryptococcus neoformans and C. gattii species complexes are the etiologic agents of cryptococcosis. We have deciphered the roles of three ABC transporters, Afr1, Afr2 and Mdr1 in the representative strains of the two species, C. neoformans H99 and C. gattii R265. Deletion of AFR1 in H99 and R265 drastically reduced the resistance levels to three xenobiotics and three triazoles suggesting that Afr1 is the major drug efflux pump in both strains. Fluconazole susceptibility was not affected when AFR2 or MDR1 was deleted in both strains. However, when these genes were deleted in combination with AFR1, a minor additive effect in susceptibility toward several drugs was observed. Deletion of all three genes in both strains displayed further increases in susceptibility toward fluconazole and itraconazole suggesting that Afr2 and Mdr1 augment Afr1 function in pumping these triazoles. Intracellular accumulation of Nile Red significantly increased in afr1 of both strains but Rhodamine 6G accumulation increased only in mdr1 of H99. Thus, the three efflux pumps play different roles in the two strains when exposed to different azoles and xenobiotics. AFR1 and AFR2 expression were upregulated in H99 and R265 when treated with fluconazole. However, MDR1 expression was only upregulated in R265 under the same conditions. We screened a library of transcriptional factor mutants and identified several mutants that manifested either altered fluconazole sensitivity or an increase in the frequency of fluconazole heteroresistance. Gene expression analysis suggests that the three efflux pumps are regulated independently by different transcription factors in response to fluconazole exposure.
http://ift.tt/2EnCxT4
Clinical Outcomes of Patients with Methicillin-Resistant Staphylococcus aureus Bacteremia Treated with Vancomycin at an Institution with Suppressed MIC Reporting: Impact of Vancomycin MIC [PublishAheadOfPrint]
Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of bacteremia and is associated with significant morbidity and mortality. Prior studies evaluating the association of vancomycin MIC and clinical outcomes in patients with MRSA bacteremia have been inconsistent. This study evaluated the association between vancomycin MIC and 30-day in-hospital mortality in patients with MRSA bacteremia. This was a retrospective cohort study of patients with MRSA bacteremia treated with vancomycin for ≥72 hours from January 2013 to August 2016. Vancomycin MICs were determined by broth microdilution via automated susceptibility testing methods. Study groups consisted of patients with MRSA isolates that had vancomycin MIC<2 μg/ml and MIC=2 μg/ml. Covariates included demographics, severity of illness, comorbidities, ICU admission, infectious diseases consultation, infectious sources, and hospital onset of bacteremia. The primary outcome was 30-day in-hospital mortality. Secondary outcomes included duration of bacteremia, persistent bacteremia ≥7 days, recurrence within 30 days, change to alternative antibiotic therapy, and hospital length of stay. Multivariate logistic regression models were analyzed to control for potential confounding variables. There were a total of 166 patients included for analysis, 91patients with vancomycin MIC<2 μg/ml and 75 patients with MIC=2 μg/ml. In the multivariate logistic regression model, a vancomycin MIC=2 μg/ml, compared to MIC<2 μg/ml, was not significantly associated with 30-day in-hospital mortality after adjusting for confounders. Additionally, all secondary outcomes were not statistically significantly different between study groups. In patients with MRSA bacteremia treated with vancomycin, the vancomycin MIC was not associated with differences in clinical outcomes.
http://ift.tt/2DJJgWA
Pathological response in a triple negative breast cancer cohort treated with neoadjuvant carboplatin and docetaxel according to Lehmann's refined classification
Purpose: Triple-negative breast cancer (TNBC) requires the identification of reliable predictors of response to neoadjuvant chemotherapy (NACT). For this purpose, we aimed to evaluate the performance of the TNBCtype-4 classifier in a cohort of TNBC patients treated with neoadjuvant carboplatin and docetaxel (TCb). Methods: TNBC patients were accrued in a non-randomized trial of neoadjuvant carboplatin AUC 6 and docetaxel 75 mg/m2 for 6 cycles. Response was evaluated in terms of pathological complete response (pCR, ypT0/is ypN0) and residual cancer burden by Symmans et al. Lehmann's subtyping was performed using the TNBCtype online tool from RNAseq data, and germline sequencing of a panel of 7 DNA damage repair genes was conducted. Results: 94 out of the 121 patients enrolled in the trial had RNAseq available. The overall pCR rate was 44.7%. Lehmann subtype distribution was: 34.0% BL1, 20.2% BL2, 23.4% M, 14.9% LAR and 7.4% were classified as ER+. Response to NACT with TCb was significantly associated with Lehmann subtype (p=0.027), even in multivariate analysis including tumor size and nodal involvement, with BL1 patients achieving the highest pCR rate (65.6%), followed by BL2 (47.4%), M (36.4%) and LAR (21.4%). BL1 was associated with a significant younger age at diagnosis and higher ki67 values. Among our 10 germline mutation carriers, 30% were BL1, 40% were BL2 and 30% were M. Conclusions: TNBCtype-4 is associated with a significantly different pCR rates for the different subtypes, with BL1 and LAR displaying the best and worse responses to NACT respectively.
http://ift.tt/2DXr2Eh
Anterior Pituitary Transcriptome Suggests Differences in ACTH Release in Tame and Aggressive Foxes
Domesticated species exhibit a suite of behavioral, endocrinological, and morphological changes referred to as "domestication syndrome." These changes may include a reduction in reactivity of the hypothalamic-pituitary-adrenal (HPA) axis, specifically reduced adrenocorticotropic hormone release from the anterior pituitary. To investigate the biological mechanisms targeted during domestication, we investigated gene expression in the pituitaries of experimentally domesticated foxes (Vulpes vulpes). RNA was sequenced from the anterior pituitary of six foxes selectively bred for tameness ("tame foxes") and six foxes selectively bred for aggression ("aggressive foxes"). Expression, splicing, and network differences identified between the two lines indicated the importance of genes related to regulation of exocytosis, specifically mediated by cAMP, organization of pseudopodia, and cell motility. These findings provide new insights into biological mechanisms that may have been targeted when these lines of foxes were selected for behavior, and suggest new directions for research into HPA axis regulation and the biological underpinnings of domestication.
http://ift.tt/2DQoo3K
Genetic Loci Controlling Carotenoid Biosynthesis in Diverse Tropical Maize Lines
The discovery and use of genetic markers associated with carotenoid levels can help to more effectively exploit the genetic potential of maize for provitamin A accumulation. Provitamin A carotenoids are classes of carotenoids that are precursors of vitamin A, an essential micronutrient in humans. Vitamin A deficiency is a global public health problem affecting millions of people, especially in developing countries. Maize is one of the most important staple crops targeted for provitamin A biofortification to help alleviate vitamin A deficiency in developing countries. A genome-wide association study (GWAS) of maize endosperm carotenoids was conducted using a panel of 130 diverse yellow maize tropical inbred lines genotyped with Genotyping by Sequencing (GBS) SNP markers. Numerous significant association signals co-localizing with the known carotenoid biosynthesis genes crtRB1, lcyE and ZEP1 were identified. The GWAS confirmed previously reported large effects of the two major carotenoid biosynthesis genes lcyE and crtRB1. In addition, significant novel associations were detected for several transcription factors (e.g. RING zinc finger domain and HLH DNA-binding domain super family proteins) that may be involved in regulation of carotenoid biosynthesis in maize. When the GWAS was re-conducted by including the major effects of lcyE and crtRB1 genes as covariates, a SNP in a gene coding for an auxin response factor 20 transcription factor was identified which displayed an association with β-carotene and provitamin A levels. Our study provides a foundation for design and implementation of genomics-assisted selection strategies for provitamin A maize breeding in tropical regions. Our results advance efforts towards identification of additional genes (and allelic variants) involved in the regulation of carotenoid biosynthesis in plants.
http://ift.tt/2npErdS
Maize Transposable Elements Ac/Ds as Insertion Mutagenesis Tools in Candida albicans
In non-model systems genetic research is often limited by the lack of techniques for the generation and identification of gene mutations. One approach to overcome this bottleneck is the application of transposons for gene tagging. We have established a two-element transposon tagging system, based on the transposable elements Activator (Ac)/Dissociation (Ds) from maize, for in vivo insertion mutagenesis in the fungal human pathogen Candida albicans. A non-autonomous Ds transposon carrying a selectable marker was constructed into the ADE2 promoter on chromosome 3 and a codon usage-adapted Ac transposase gene was inserted into the neutral NEUT5L locus on chromosome 5. In C. albicans cells expressing the transposase the Ds element efficiently excised and reintegrated elsewhere in the genome, which makes the Ac/Ds transposons promising tools for saturating insertion mutagenesis in clinical strains of C. albicans.
http://ift.tt/2DOLpEB
Whole Genome Sequence Accuracy Is Improved by Replication in a Population of Mutagenized Sorghum
The accurate detection of induced mutations is critical for both forward and reverse genetics studies. Experimental chemical mutagenesis induces relatively few single base changes per individual. In a complex eukaryotic genome, false positive detection of mutations can occur at or above this mutagenesis rate. We demonstrate here, using a population of ethyl methanesulfonate (EMS) treated Sorghum bicolor BTx623 individuals, that using replication to detect false positive induced variants in next-generation sequencing data permits higher throughput variant detection with greater accuracy. We used a lower sequence coverage depth (average of 7X) from 586 independently mutagenized individuals and detected 5,399,493 homozygous SNPs. Of these, 76% originated from only 57,872 genomic positions prone to false positive variant calling. These positions are characterized by high copy number paralogs where the error-prone SNP positions are at copies containing a variant at the SNP position. The ability of short stretches of homology to generate these error prone positions suggests that incompletely assembled or poorly mapped repeated sequences are one driver of these error prone positions. Removal of these false positives left 1,275,872 homozygous and 477,531 heterozygous EMS-induced SNPs which, congruent with the mutagenic mechanism of EMS, were greater than 98% G:C to A:T transitions. Through this analysis we generated a collection of sequence indexed mutants of Sorghum. This collection contains 4,035 high impact homozygous mutations in 3,637 genes and 56,514 homozygous missense mutations in 23,227 genes. Each line contains, on average, 2,177 annotated homozygous SNPs per genome, including seven likely gene knockouts and 96 missense mutations. The number of mutations in a transcript was linearly correlated with the transcript length and also the G+C count, but not with the GC/AT ratio. Analysis of the detected mutagenized positions identified CG-rich patches, and flanking sequences strongly influenced EMS-induced mutation rates. This method for detecting false-positive induced mutations is generally applicable to any organism, is independent of the choice of in silico variant-calling algorithm, and is most valuable when the true mutation rate is likely to be low, such as in laboratory induced mutations or somatic mutation detection in medicine.
http://ift.tt/2nnJCez
Synergistic effect of eugenol with Colistin against clinical isolated Colistin-resistant Escherichia coli strains
Bacterial infections have become more challenging to treat due to the emergence of multidrug-resistant pathogenic bacteria. Combined antibiotics prove to be a relatively effective method to control such resist...
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Celgene Targets Blood Cancers with Major Buys [News in Brief]
Lenalidomide maker diversifies its CAR T portfolio and acquires a near-market JAK inhibitor with Juno, Impact deals.
http://ift.tt/2ElxrH9
Spontaneous Intrahepatic Portal Systemic Venous Shunt: It Can Happen!
A 73-year-old man with a past history of hepatitis C virus infection presented with altered mental status. The patient had multiple previous similar admissions in the past year. It was presumed that the patient had underlying cirrhosis because of a low platelet count. Physical examination did not show any ascites or stigmata of chronic liver disease. A computed tomography scan of the abdomen and pelvis was performed that showed a tortuous venous structure in the left lobe of the liver consistent with a spontaneous intrahepatic portal systemic shunt (Figures A and B).
http://ift.tt/2DLjHnT
Fecal Microbiota Transplantation Is Effective in Relieving Visceral Hypersensitivity in a Postinfectious Model
Aim. To investigate the effect of fecal microbiota transplantation on visceral hypersensitivity compared with Bifidobacterium longum. Methods. Mice visceral hypersensitivity was induced by Trichinella spiralis. After 8 weeks, they were divided into three groups (controls, Bifidobacterium longum, and fecal microbiota transplantation) and were daily treated by gavage with 0.2 ml PBS, Bifidobacterium longum HB55020, or fecal microbiota for 7 days. Visceral hypersensitivity was tested with abdominal withdrawal reflex. Permeability of colon epithelium was assessed with Ussing chamber. Results. After administration of Bifidobacterium longum, compared with mice in postinfectious group, mice had higher pain threshold (). After administration of fecal microbiota, compared with mice in postinfectious group, mice had higher pain threshold (). Fecal microbiota transplantation was as effective as Bifidobacterium in relieving visceral hypersensitivity. Administration of Bifidobacterium longum or fecal microbiota transplantation improved colon epithelium permeability. Expression of occluding-1 was increased. Conclusion. Manipulation of microbiota is effective in relieving visceral hypersensitivity. Fecal microbiota transplantation is as effective as Bifidobacterium longum administration.
http://ift.tt/2DLe49f
Heme Oxygenase-1 Activity as a Correlate to Exercise-Mediated Amelioration of Cognitive Decline and Neuropathological Alterations in an Aging Rat Model of Dementia
Alzheimer's disease (AD) is a neurodegenerative disorder with cognitive impairment. Physical exercise has long been proven to be beneficial in the disorder. The present study was designed to examine the effect of voluntary exercise on spatial memory, imaging, and pathological abnormalities. Particular focus has been given to the role of heme oxygenase-1 (HO-1)—an important cellular cytoprotectant in preserving mental acuity—using an aging rat model of dementia. Male and female Wistar rats were segregated into six groups—namely, (i) aged sedentary (control) females (ASF, ); (ii) aged sedentary (control) males (ASM, ); (iii) aged running females (ARF, ); (iv) aged running males (ARM, ); (v) young control females (YCF, ); and (vi) young control males (YCM, ). Rats in the ARF and ARM groups had free access to a standardized inbuilt running wheel during the 3-month evaluation period. Spatial memory was investigated using the Morris Water Test, imaging and pathological alterations were assessed using positron emission tomography (PET) imaging and histopathological examinations (H&E, Congo red staining), respectively, and HO-1 enzyme activity assays were also conducted. The outcomes suggest that voluntary physical exercise mitigates impaired spatial memory and neuropathological changes exhibited by the aging sedentary group, via elevated HO-1 activity, contributing to the antioxidant capacity in the aging brain.
http://ift.tt/2EnCvuC
Trochanteric fracture-implant motion during healing – A radiostereometry (RSA) study
Publication date: Available online 12 January 2018
Source:Injury
Author(s): Alicja J. Bojan, Anders Jönsson, Hans Granhed, Carl Ekholm, Johan Kärrholm
Cut-out complication remains a major unsolved problem in the treatment of trochanteric hip fractures. A better understanding of the three-dimensional fracture-implant motions is needed to enable further development of clinical strategies and countermeasures. The aim of this clinical study was to characterise and quantify three-dimensional motions between the implant and the bone and between the lag screw and nail of the Gamma nail.Radiostereometry Analysis (RSA) analysis was applied in 20 patients with trochanteric hip fractures treated with an intramedullary nail. The following three-dimensional motions were measured postoperatively, at 1 week, 3, 6 and 12 months: translations of the tip of the lag screw in the femoral head, motions of the lag screw in the nail, femoral head motions relative to the nail and nail movements in the femoral shaft.Cranial migration of the tip of the lag screw dominated over the other two translation components in the femoral head. In all fractures the lag screw slid laterally in the nail and the femoral head moved both laterally and inferiorly towards the nail. All femoral heads translated posteriorly relative to the nail, and rotations occurred in both directions with median values close to zero. The nail tended to retrovert in the femoral shaft.Adverse fracture-implant motions were detected in stable trochanteric hip fractures treated with intramedullary nails with high resolution. Therefore, RSA method can be used to evaluate new implant designs and clinical strategies, which aim to reduce cut-out complications. Future RSA studies should aim at more unstable fractures as these are more likely to fail with cut-out.
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Treatment of acute Achilles tendon rupture with the panda rope bridge technique
Publication date: Available online 16 January 2018
Source:Injury
Author(s): Liangjun Yin, Yahong Wu, Changsong Ren, Yizhong Wang, Ting Fu, Xiangjun Cheng, Ruidong Li, Mao Nie, Yuan Mu
IntroductionAlthough nonsurgical methods and many surgical techniques have been developed for repairing a ruptured Achilles tendon, there is no consensus on its best treatment. In this article, a novel minimally invasive technique called the Panda Rope Bridge Technique (PRBT) is described.MethodsPatient with acute Achilles tendon rupture was operated on in the prone position. The PRBT begin with making the proximal bridge anchor (Krackow sutures in the myotendinous junction), the distal bridge anchor (two suture anchors in the calcaneus bone) and the ropes (threads of the suture anchors) stretched between the anchor sites. Then a small incision was made to debride and reattach the stumps of ruptured tendon. After the surgery, no cast or splint fixation was applied. All patients performed enhanced recovery after surgery (ERAS), which included immediate ankle mobilization from day 1, full weight-bearing walking from day 5 to 7, and gradually take part in athletic exercises from 8 weeks postoperatively.ResultsPBRT was performed in 11patients with acute Achilles tendon rupture between June 2012 and June 2015. No wound infection, fistula, skin necrosis, sural nerve damage, deep venous thrombosis or tendon re-rupture was found. One year after the surgery, all patients reported 100 AOFAS ankle-hindfoot score points and the mean ATRS was 96.6.ConclusionThe PRBT is a simple, effective and minimally invasive technique, with no need for immobilisation of the ankle, making possible immediate and aggressive postoperative rehabilitation.
http://ift.tt/2GrgHPc
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Αλέξανδρος Γ. Σφακιανάκης Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,0030693260717...
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Alimentary Pharmacology &Therapeutics, EarlyView. https://ift.tt/2qECBIJ
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heory of COVID-19 pathogenesis Publication date: November 2020Source: Medical Hypotheses, Volume 144Author(s): Yuichiro J. Suzuki ScienceD...
