Amelioration of bleomycin-induced pulmonary fibrosis by chlorogenic acid through endoplasmic reticulum stress inhibition

Abstract

To investigate the inhibitory effects of chlorogenic acid on pulmonary fibrosis and the internal mechanisms in vivo and in vitro. 30 male BALB/C mice were randomized into 5 groups: control group, pulmonary fibrosis model group, low, middle and high dose of chlorogenic acid groups. Mice in pulmonary fibrosis model group were administered 5.0 mg/kg bleomycin with intracheal instillation and mice in 3 chlorogenic acid groups were treated with chlorogenic acid every day for 28 days after bleomycin administration. Lung tissue histology was observed using HE staining. Primary pulmonary fibroblasts were isolated and cultured. The expressions of fibrosis related factors (α-SMA and collagen I), as well as ER stress markers (CHOP and GRP78) were determined by both real-time PCR assay and Western blotting, while the expressions of other ER stress signaling pathway factors PERK, IRE-1, ATF-6 and protein levels of caspase-12, caspase-9, caspase-3, PARP were determined by Western blotting. RLE-6TN cell line induced by TGF-β1 was also used to verify the amelioration effects in vitro study. In both in vivo and in vitro studies, TUNEL staining was used to evaluate cell apoptosis. Expressions of collagen I, α-SMA, GRP78, and CHOP were significantly inhibited by chlorogenic acid in dose-dependent manner. Similarly, decreasing levels of cleaved caspase-12, caspase-9, caspase-3 and increasing level of uncleaved PARP were observed in chlorogenic acid groups compared with those in the fibrosis group both in vivo and in vitro. Chlorogenic acid could also significantly down-regulate the level of phosphorylation of PERK and cleaved ATF-6 in vivo study. Moreover, MTT assay demonstrated chlorogenic acid could enhance proliferation of RLE-6TN cells induced by TGFβ1 in vitro. And the apoptosis assays indicated that chlorogenic acid could significantly inhibit cell apoptosis both in vivo and in vitro studies. Chlorogenic acid could inhibit the pulmonary fibrosis through endoplasmic reticulum stress inhibition in vivo and in vitro.

http://ift.tt/2ujT6Kd

Activation of serotonergic neurons in the medullary caudal raphe shortens the laryngeal chemoreflex in anaesthetized neonatal rats

New Findings

• What is the central question of this study?

  Does activation of serotonergic neurons in the caudal medullary raphe, some of which project to the nucleus of the solitary tract, shorten the laryngeal chemoreflex?

• What is the main finding and its importance?

  We found that serotonin originating from neurons in the caudal raphe acts through a 5-HT₃ receptor located in the nucleus of the solitary tract to terminate reflex apnoea. Failure or deficiency of this arousal-related process is likely to be relevant to the pathogenesis of sudden infant death syndrome.

Failure to terminate apnoea and arouse is likely to contribute to sudden infant death syndrome (SIDS). Serotonin is deficient in the brainstems of babies who have died of SIDS. We tested the hypothesis that activation of serotoninergic neurons in the caudal medullary raphe, some of which project to the nucleus of the solitary tract (NTS), would shorten the laryngeal chemoreflex (LCR). We studied anaesthetized neonatal rat pups between postnatal days 9 and 17. We injected 5–40 μl of water into the larynx to elicit the LCR and measured the duration of respiratory disruption. Microinjection of 50 nl of 100 μm AMPA into the caudal medullary raphe shortened the apnoeas (P < 0.001) and respiratory inhibition (P < 0.005) associated with the LCR. When 50 nl of 30 mm ondansetron, a 5-HT₃ antagonist, was microinjected bilaterally into the NTS, AMPA microinjected into the caudal raphe no longer shortened the LCR. After bilateral microinjection of vehicle into the NTS, AMPA microinjection into the caudal raphe significantly shortened the LCR. AMPA, a glutamate receptor agonist, may activate many neurons within the caudal raphe, but blocking the 5-HT₃ receptor-dependent responses in the NTS prevented the shortening of the LCR associated with AMPA microinjections into the caudal raphe. Thus, serotonin originating from neurons in the caudal raphe acts through a 5-HT₃ receptor located in the NTS to terminate or shorten the LCR. Serotonin is deficient in the brainstems of babies who have died of SIDS, and deficient serotonergic termination of apnoea is likely to be relevant to the pathogenesis of SIDS.

http://ift.tt/2sHyA4a

Genetic study of the PAH locus in the Iranian population: familial gene mutations and minihaplotypes

Abstract

Phenylketonuria (PKU), one of the most common inborn errors of amino acid metabolism, is caused by mutations in the phenylalanine hydroxylase (PAH) gene (PAH). PKU has wide allelic heterogeneity, and over 600 different disease-causing mutations in PAH have been detected to date. Up to now, there have been no reports on the minihaplotype (VNTR/STR) analysis of PAH locus in the Iranian population. The aims of the present study were to determine PAH mutations and minihaplotypes in Iranian families with PAH deficiency and to investigate the correlation between them. A total of 81 Iranian families with PAH deficiency were examined using PCR-sequencing of all 13 PAH exons and their flanking intron regions to identify sequence variations. Fragment analysis of the PAH minihaplotypes was performed by capillary electrophoresis for 59 families. In our study, 33 different mutations were found accounting for 95% of the total mutant alleles. The majority of these mutations (72%) were distributed across exons 7, 11, 2 and their flanking intronic regions. Mutation c.1066-11G > A was the most common with a frequency of 20.37%. The less frequent mutations, p.Arg261Gln (8%), p.Arg243Ter (7.4%), p.Leu48Ser (7.4%), p.Lys363Asnfs*37 (6.79%), c.969 + 5G > A (6.17%), p.Pro281Leu (5.56), c.168 + 5G > C (5.56), and p.Arg261Ter (4.94) together comprised about 52% of all mutant alleles. In this study, a total of seventeen PAH gene minihaplotypes were detected, six of which associated exclusively with particular mutations. Our findings indicate a broad PAH mutation spectrum in the Iranian population, which is consistent with previous studies reporting a wide range of PAH mutations, most likely due to ethnic heterogeneity. High prevalence of c.1066-11G > A mutation linked to minihaplotype 7/250 among both Iranian and Mediterranean populations is indicative of historical and geographical links between them. Also, strong association between particular mutations and minihaplotypes could be useful for prenatal diagnosis (PND) and preimplantation genetic diagnosis (PGD) in affected families.

http://ift.tt/2tL80Mx

The mTOR inhibition in concurrence with ERK1/2 activation is involved in excessive autophagy induced by glycyrrhizin in hepatocellular carcinoma

Abstract

Autophagy is a life phenomenon in which autophagosomes remove damaged or aging organelles and long-lived circulating proteins to maintain the cell's stability. However, disorders of excessive autophagy are a response of cancer cells to a variety of anticancer treatments which lead to cancer cell death. The Akt/mammalian target of rapamycin (mTOR) and the extracellular signal-regulated kinase 1/2 (ERK1/2) pathways are both involved in nutrient-induced autophagic phenomenon and exhibit vital relevance to oncogenesis in various cancer cell types, including hepatocellular carcinoma (HCC). However, the influence of autophagy for cancer cell death remains controversial and few scientists have investigated the variation of these two signaling pathways in cancer cell autophagic phenomenon induced by anticancer treatment simultaneously. Here, we explored the anticancer efficacy and mechanisms of glycyrrhizin (GL), a bioactive compound of licorice with little toxicity in normal cells. It is interesting that inhibition of Akt/mTOR signaling in concurrence with enhanced ERK1/2 activity exists in GL-induced autophagy and cytotoxicity in HepG2 and MHCC97-H hepatocellular carcinoma cells. These results imply that the GL-related anticancer ability might correlate with the induction of autophagy. The influence of induced autophagic phenomenon on cell viability might depend on the severity of autophagy and be pathway specific. In the subsequent subcutaneous xenograft experiment in vivo with MHCC97-H cells, GL obviously exhibited its inhibitory efficacy in tumor growth via inducing excess autophagy in MHCC97-H cells (P < 0.05). Our data prompt that GL possesses a property of excess autophagic phenomenon induction in HCC and exerts high anticancer efficacy in vitro and in vivo. This warrants further investigation toward possible clinical applications in patients with HCC.

Glycyrrhizin can induce excessive autophagic phenomenon in hepatocellular carcinoma cell lines. Autophagy-mediated cell death is also a credible route of tumor suppression pathway.

http://ift.tt/2skZLCO

Meta-analysis of first-line therapies with maintenance regimens for advanced non-small-cell lung cancer (NSCLC) in molecularly and clinically selected populations

Abstract

Evidence has suggested survival benefits of maintenance for advanced NSCLC patients not progressing after first-line chemotherapy. Additionally, particular first-line targeted therapies have shown survival improvements in selected populations. Optimal first-line and maintenance therapies remain unclear. Here, currently available evidence was synthesized to elucidate optimal first-line and maintenance therapy within patient groups. Literature was searched for randomized trials evaluating first-line and maintenance regimens in advanced NSCLC patients. Bayesian network meta-analysis was performed within molecularly and clinically selected groups. The primary outcome was combined clinically meaningful OS and PFS benefits. A total of 87 records on 56 trials evaluating first-line treatments with maintenance were included. Results showed combined clinically meaningful OS and PFS benefits with particular first-line with maintenance treatments, (1) first-line intercalated chemotherapy+erlotinib, maintenance erlotinib in patients with EGFR mutations, (2) first-line afatinib, maintenance afatinib in patients with EGFR deletion 19, (3) first-line chemotherapy + bevacizumab, maintenance bevacizumab in EGFR wild-type patients, (4) chemotherapy+conatumumab, maintenance conatumumab in patients with squamous histology, (5) chemotherapy+cetuximab, maintenance cetuximab or chemotherapy + necitumumab, maintenance necitumumab in EGFR FISH-positive patients with squamous histology, and (6) first-line chemotherapy+bevacizumab, maintenance bevacizumab or first-line sequential chemotherapy+gefitinib, maintenance gefitinib in patients clinically enriched for EGFR mutations with nonsquamous histology. No treatment showed combined clinically meaningful OS and PFS benefits in patients with EGFR L858R or nonsquamous histology. Particular first-line with maintenance treatments show meaningful OS and PFS benefits in patients selected by EGFR mutation or histology. Further research is needed to achieve effective therapy for patients with EGFR mutation L858R or nonsquamous histology.

First-line with maintenance therapies have shown benefits in selected advanced NSCLC populations. Here, first-line with maintenance treatments are compared within patient groups and clinically meaningful benefits are shown for particular first-line with maintenance therapies in selected patients.

http://ift.tt/2tEac8k

Priority reviews: innovation and safety [Letters]

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Drug pricing reforms promising but problematic [News]

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Impact of the North American Free Trade Agreement on high-fructose corn syrup supply in Canada: a natural experiment using synthetic control methods [Research]

BACKGROUND:

Critics of free trade agreements have argued that they threaten public health, as they eliminate barriers to trade in potentially harmful products, such as sugar. Here we analyze the North American Free Trade Agreement (NAFTA), testing the hypothesis that lowering tariffs on food and beverage syrups that contain high-fructose corn syrup (HFCS) increased its use in foods consumed in Canada.

METHODS:

We used supply data from the Food and Agriculture Organization of the United Nations to assess changes in supply of caloric sweeteners including HFCS after NAFTA. We estimate the impact of NAFTA on supply of HFCS in Canada using an innovative, quasi-experimental methodology — synthetic control methods — that creates a control group with which to compare Canada's outcomes. Additional robustness tests were performed for sample, control groups and model specification.

RESULTS:

Tariff reductions in NAFTA coincided with a 41.6 (95% confidence interval 25.1 to 58.2) kilocalorie per capita daily increase in the supply of caloric sweeteners including HFCS. This change was not observed in the control groups, including Australia and the United Kingdom, as well as a composite control of 16 countries. Results were robust to placebo tests and additional sensitivity analyses.

INTERPRETATION:

NAFTA was strongly associated with a marked rise in HFCS supply and likely consumption in Canada. Our study provides evidence that even a seemingly modest change to product tariffs in free trade agreements can substantially alter population-wide dietary behaviour and exposure to risk factors.

http://ift.tt/2sGVKrw

The "new" medical model, fragmented clinical care and philosophy of medicine [Letters]

http://ift.tt/2tbxuBd

Type 2 diabetes in a four-year-old child [Practice]

http://ift.tt/2tbg5Zy

Trade and public health [Commentary]

http://ift.tt/2tbGUwV

Testing for heritable thrombophilia in acute venous thromboembolism [Practice]

http://ift.tt/2sGY69O

The new medical model: why medicine needs philosophy [Letters]

http://ift.tt/2sGY8yI

Complications after long-term inferior vena cava filter placement [Practice]

http://ift.tt/2tbHV84

Fewer Canadian MDs heading to the US [News]

http://ift.tt/2sGXelL

Johns Hopkins: A Canadian medical school? [Humanities]

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Ukrainians battle escalating HIV epidemic [News]

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Improving psychoeducation for women fearful of childbirth: Evaluation of a research translation project

Publication date: Available online 3 July 2017
Source:Women and Birth
Author(s): Jennifer Fenwick, Jocelyn Toohill, Valerie Slavin, Debra K. Creedy, Jenny Gamble
BackgroundPsychoeducation counselling delivered by midwives has been demonstrated to reduce maternal fear and improve women's confidence for birth. Translating the evidence in practice presents challenges. A systematic approach to the implementation of evidence and evaluation of this process can improve knowledge translation.AimTo implement and evaluate the translation of psychoeducation counselling on (1) midwives' knowledge, skills and confidence to provide the counselling; (2) perceived barriers and enablers to embedding the psychoeducation counselling in practice; and (3) pregnant women's levels of fear.MethodsUsing a mixed methods approach, data were collected using a pre (n=22) and post (n=21) training survey, recorded interviews (n=17), diaries (n=6), and retrospective audit of fear of birth scores. Data were analysed using descriptive statistics, independent sample t-tests, and chi-square tests. Latent content analysis was used to analyse the qualitative data.ResultsTraining in the counselling framework significantly improved midwives' knowledge, skills and confidence to counsel women on psychosocial issues and reduce fear scores for women reporting high childbirth fear. The main barriers to midwives introducing counselling into routine care related to the fragmentation of care delivery during pregnancy. Conversely continuity of care by a known midwife was considered an enabler.ConclusionPsychoeducation provided by midwives is of benefit to women experiencing high levels of birth fear. While psychoeducation training was successful in enhancing midwives' knowledge, skills and confidence; embedding the counselling framework in everyday practice was challenging. Counselling is more easily implemented within midwifery caseload models which enable midwives to build relationships with women across their pregnancy.



http://ift.tt/2tDPjdm

Issue Cover (July 2017)

Cover image by Dr. Natalie Doig (MRC Brain Network Dynamics Unit, Department of Pharmacology, Oxford). The cover image is of a frontal section of mouse brain showing many regions of the basal ganglia. The section was triple-immunostained to reveal tyrosine hydroxylase (TH; cyan), parvalbumin (PV; green) and choline acetyltransferase (magenta).

http://ift.tt/2slcNjm

Transcriptional Profiling of Biofilm Regulators Identified by an Overexpression Screen in Saccharomyces cerevisiae

Biofilm formation by microorganisms is a major cause of recurring infections and removal of biofilms has proven to be extremely difficult given their inherent drug resistance. Understanding the biological processes that underlie biofilm formation is thus extremely important and could lead to the development of more effective drug therapies, resulting in better infection outcomes. Using the yeast S. cerevisiae as a biofilm model, overexpression screens identified DIG1, SFL1, HEK2, TOS8, SAN1 and ROF1/YHR177W as regulators of biofilm formation. Subsequent RNA-seq analysis of biofilm and non-biofilm forming strains revealed that all of the overexpression strains, other than DIG1 and TOS8, were adopting a single differential expression profile, although induced to varying degrees. TOS8 adopted a separate profile, while the expression profile of DIG1 reflected the common pattern seen in most of the strains, plus substantial DIG1-specific expression changes. We interpret the existence of the common transcriptional pattern seen across multiple, unrelated overexpression strains as reflecting a transcriptional state, that the yeast cell can access through regulatory signaling mechanisms, allowing an adaptive morphological change between biofilm-forming and non-biofilm states.

http://ift.tt/2ujO9RP

In Vivo Emergence of Resistance to Novel Cephalosporin-{beta}-lactamase Inhibitor Combinations Through the Duplication of the Amino Acid D149 from OXA-2 {beta}-lactamase (OXA-539) in ST235 Pseudomonas aeruginosa [PublishAheadOfPrint]

Resistance development to novel cephalosporin-β-lactamase inhibitor combinations during ceftazidime treatment of a surgical infection by Pseudomonas aeruginosa was investigated. Both, initial (97C2) and final (98G1) isolates, belonged to the high-risk clone ST235 and were resistant to carbapenems (oprD-), fluoroquinolones (GyrA-T83I, ParC-S87L) and aminoglycosides (aacA7/aacA8/aadA6). 98G1 additionally showed resistance to ceftazidime, ceftazidime-avibactam and ceftolozane-tazobactam. Sequencing identified bla_OXA-2 in 97C2, but 98G1 contained a 3-bp insertion leading to the duplication of the key residue D149 (designated OXA-539). Evaluation of PAO1 transformants producing cloned OXA-2 or OXA-539 confirmed that D149 duplication was the cause of resistance. Active surveillance of the emergence of resistance to these new valuable agents is warranted.

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Assessment of clinical pharmacokinetic drug-drug interaction of antimalarial drugs {alpha}/{beta}-arteether and sulfadoxine-pyrimethamine [PublishAheadOfPrint]

The antimalarial drugs combination therapy is now being widely used for treatment of uncomplicated malaria. The objective of the present study was to investigate the effects of co-administration of intramuscular α/β-arteether (AE) and oral sulfadoxine-pyrimethamine (SP) on the pharmacokinetic properties of each drug as a drug–drug interaction study to support developing the fixed-dose combination therapy. Single-dose, open-label, crossover clinical trial was conducted in healthy adult Indian male volunteers (18–45 years, n=13), received single dose of AE, SP and combination dose of AE and SP. Blood samples were collected upto 21 days post administration and concentrations of α-arteether, β-arteether, sulfadoxine and pyrimethamine were determined by using validated liquid chromatography–tandem mass spectrometry method. Pharmacokinetic parameters were calculated and statistically analyzed to calculate geometric mean ratio and confidence interval. Following single dose co-administration of intramuscular AE and oral SP, the pharmacokinetic properties of α/β-arteether were not significantly affected, and α/β-arteether had no significant effect on the pharmacokinetic properties of SP in these selected groups of healthy volunteers. However, more investigations would be needed to explore this further.

http://ift.tt/2uEpQxa

A novel 6-benzyl ether benzoxaborole is active against Mycobacterium tuberculosis in vitro [PublishAheadOfPrint]

We identified a novel 6-benzyl ether benzoxaborole with potent activity against Mycobacterium tuberculosis. The compound had a minimum inhibitory concentration of 2 μM in liquid medium. The compound was also able to prevent growth on solid medium at 0.8 μM and was active against intracellular bacteria (IC₅₀ = 3.6 μM) without cytotoxicity against eukaryotic cells (IC₅₀ >100 μM). We isolated resistant mutants (MIC ≥100 μM), which had mutations in Rv1683, Rv3068c and Rv0047c.

http://ift.tt/2tGAK8p

Population Pharmacokinetics and Dose Optimization of Teicoplanin during Venoarterial Extracorporeal Membrane Oxygenation [PublishAheadOfPrint]

Pharmacokinetics (PK) of drugs are known to be significantly altered in patients receiving extracorporeal membrane oxygenation (ECMO). However, clinical PK studies of drugs administered during ECMO are scarce and proper dosing adjustment is yet to be established. We developed a population PK model for teicoplanin, investigated covariates influencing teicoplanin exposure, and suggested an optimal dosing regimen for ECMO patients. PK samples were collected from ten adult patients, and a population PK analysis as well as simulations were performed to identify an optimal teicoplanin dose needed to provide a >50% probability of target attainment at 72 hours using a trough concentration target of >10 μg/mL for mild to moderate infections and of >15 μg/mL for severe infections. Teicoplanin was well described by a two-compartment PK model with first-order elimination. Presence of ECMO was associated with a lower central volume of distribution, and continuous renal replacement therapy (CRRT) with a higher peripheral volume of distribution. For mild to moderate infections, an optimal dose was a loading dose (LD) 600 mg and a maintenance dose (MD) 400 mg for ECMO patients not receiving CRRT; and a LD 800 mg and a MD 600 mg for those receiving CRRT. For severe infections, an optimal dose was a LD 1000 mg and a MD 800 mg for ECMO patients not receiving CRRT; and a LD 1200 mg and a MD 1000 mg for those receiving CRRT. In conclusion, higher than the standard doses are needed to achieve fast and appropriate teicoplanin exposure during ECMO.

http://ift.tt/2uEh0zy

OXA-244-producing Escherichia coli isolates: a challenge for clinical microbiology laboratories [PublishAheadOfPrint]

OXA-244 is a single point mutant derivative of OXA-48 displaying reduced carbapenemase activity. Here, we report microbiological features of 7 OXA-244-producing E. coli isolates. Only one isolate grew on the ChromID® CARBA SMART medium (bioMérieux), but 6/7 grew on ChromID® ESBL medium (bioMérieux), as they co-produced either an extended spectrum β-lactamase and or a plasmid-encoded cephalosporinase. The production of a carbapenemase was detected in 57.1%, 71.4%, 71.4%, and 100% of the E. coli isolates using the Carba NP test, the RAPIDEC® CARBA NP (bioMérieux), a MALDI-TOF MS hydrolysis assay (Bruker), and OXA-48 K-SeT® (Coris bioconcept), respectively. Our results indicate that OXA-244-producing E. coli isolates are difficult to detect, which may lead to their silent spread.

http://ift.tt/2tG4YIC

In vitro susceptibility of the relapsing fever spirochete Borrelia miyamotoi to antimicrobial agents. [PublishAheadOfPrint]

Hard tick-borne relapsing fever (HTBRF) is an emerging infectious disease throughout the temperate zone caused by the relapsing fever spirochete Borrelia miyamotoi. Antibiotic treatment of HTBRF is empirically based on the treatment of Lyme borreliosis, however antibiotic susceptibility of B. miyamotoi has not been studied to date. Thus, we set out to determine the in vitro antimicrobial susceptibility of B. miyamotoi.

A microdilution method with 96-well microtiter plates was used to determine antibiotic susceptibility of two B. miyamotoi strains isolated on two different continents (Asia and North America), two Borrelia burgdorferi sensu lato (s.l.) strains and one Borrelia hermsii isolate for comparison. The MIC and MBC were determined by both microscopy and colorimetric assays.

We were able to show that both B. miyamotoi strains and B. hermsii demonstrated greater susceptibility to doxycycline and azithromycin, equal susceptibility to ceftriaxone and proved to be resistant to amoxicillin in vitro as compared to the B. burgdorferi s.l. isolates. The MIC and MBC of amoxicillin for B. miyamotoi evaluated by microscopy were 16-32 mg/L and 32-128 mg/L, respectively. Since B. miyamotoi is susceptible to doxycycline, azithromycin and ceftriaxone in vitro, our data suggests that these antibiotics can be used for treatment of HTBRF. Oral amoxicillin is currently used as an alternative for the treatment of HTBRF, however since we found antimicrobial resistance of the tested B. miyamotoi strains to amoxicillin in vitro, this warrants further study.

http://ift.tt/2uEwUKa

Mitochondrial toxicity of linezolid in blood cells and skin nerve fibers: influence of mitochondrial genetics [PublishAheadOfPrint]

Background: The antibiotic linezolid is a ribosomal inhibitor with excellent efficacy. Despite reduction in the administration period to 28 days, side effects usually of hematologic or neuropathic origin are still reported due to secondary inhibition of mitochondrial protein synthesis. Susceptibility to linezolid toxicity remains unknown.

Objective: To understand clinical heterogenicity in response to identical linezolid exposition through the exhaustive examination of the molecular basis of tissue-dependent mitotoxicity, derived cell dysfunction and mitochondrial genetic association to adverse effects of linezolid under the recommended period of administration.

Methods: Peripheral blood mononuclear cells (PBMC) and skin nerve fibers from 19 and 6 patients, respectively, were evaluated before and after 28-day linezolid treatment to assess mitochondrial and cell toxic consequences. Mitochondrial DNA haplotypes and SNPs in ribosomal sequences where linezolid binds to mitochondrial ribosome were additionally analyzed to investigate genetic contribution.

Results: Linezolid reduced mitochondrial protein levels, complex IV activity and mitochondrial mass in PBMC and trended to increase apoptosis. In skin tissue, mitochondrial amount increased within nerve fiber accompanied by subclinical axonal swelling. Mitochondrial U haplogroup, mutations in 12SrRNA and polymorphisms m.2706A>G, m.3197T>C and m.3010G>A in 16SrRNA trended to be associated to increased mitochondrial and clinical adverse effects.

Conclusions: Even with a shorter administration, adverse effects of linezolid are reported by 63% of patients. Linezolid exerts correlated tissue-dependent mitotoxicity responsible for downstream cellular consequences (blood cell death and nerve fiber swelling) leading to adverse hematologic and peripheral nervous side effects. Multicentric studies should confirm genetic susceptibility in bigger cohorts.

http://ift.tt/2tGtYPX

First report of Klebsiella oxytoca strain simultaneously producing NDM-1, IMP-4 and KPC-2 carbapenemases [PublishAheadOfPrint]

The nucleotide sequences of 5 plasmids from one Klebsiella oxytoca isolate were determined using the PacBio RS II system. Plasmid analysis revealed that bla_NDM-1 was carried on an IncX3 plasmid. The bla_IMP-4 and bla_KPC-2 were located on an IncN and an IncP-6 plasmid, respectively. Comparative sequence analysis highlighted the successful spread of carbapenemase-harbouring plasmids among different enterobacterial species. It reports for the first time coproducing NDM-1, KPC-2 and IMP-4 carbapenemases on a K. oxytoca isolate.

http://ift.tt/2uEi3zm

Plasmids of diverse Inc groups disseminate the fosfomycin resistance gene fosA3 among Escherichia coli from pigs, chickens and dairy cows in Northeast China [PublishAheadOfPrint]

Thirty-nine fosfomycin-resistant E. coli isolates carrying fosA3 were obtained from pigs, chickens, dairy cows and staff in four Northeastern provinces of China during 06/2015-04/2016. The fosA3 was co-located with bla_CTX-M genes on conjugative plasmids of the incompatibility groups IncN (n=12), IncN-F33:A-:B- (n=2), IncF33:A-:B- (n=14), IncF14:A-:B- (n=2), and IncI1/ST136 (n=9). Four different genetic contexts of fosA3 were detected among the 39 E. coli isolates. Three potential epidemic plasmids circulated among E. coli strains from this region.

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Digital PCR for detection and quantification of fluoroquinolone resistance in Legionella pneumophila. [PublishAheadOfPrint]

The emergence of fluoroquinolone (FQ)-resistant mutants of Legionella pneumophila in infected humans has been previously reported using a next-generation DNA sequencing (NGS) approach. This finding could explain part of the therapeutic failures observed in legionellosis patients treated with these antibiotics. The aim of this study was to develop digital PCR (dPCR) assays allowing rapid and accurate detection and quantification of these resistant mutants in respiratory samples, especially when the proportion of mutants in a wild-type background is low. We designed three dPCRgyrA assays to detect and differentiate the wild-type and one of the three gyrA mutations previously described as associated with FQ resistance in L. pneumophila: 248C>T (T83I), 259G>A (D87N), and 259G>C (D87H). To assess the performance of these assays, mixtures of FQ-resistant and -susceptible strains of L. pneumophila were analyzed, and the results were compared with those obtained with Sanger DNA sequencing and real-time quantitative PCR (qPCR) technologies. The dPCRgyrA assays were able to detect mutated gyrA sequences in the presence of wild-type sequences up to 1:1000 resistant:susceptible allele ratios. In comparison, Sanger DNA sequencing and qPCR were less sensitive, allowing detection of gyrA mutants up to 1:1 and 1:10 ratios, respectively. When testing 38 respiratory samples from 23 legionellosis patients (69.6% treated with a FQ), dPCRgyrA detected small amounts of gyrA mutants in four (10.5%) samples from three (13.0%) patients. These results demonstrate that dPCR is a highly sensitive alternative to quantify FQ resistance in L. pneumophila, and it could be used in clinical practice to detect patients that could be at higher risk of therapeutic failure.

http://ift.tt/2uErtex

Characterization of a large antibiotic resistance plasmid found in enteropathogenic Escherichia coli strain B171 and its relatedness to plasmids of diverse E. coli and Shigella [PublishAheadOfPrint]

Enteropathogenic Escherichia coli (EPEC) are a leading cause of severe infantile diarrhea in developing countries. Previous research has focused on the diversity of the EPEC virulence plasmid, whereas less is known regarding the genetic content and distribution of antibiotic resistance plasmids carried by EPEC. A previous study demonstrated that in addition to the virulence plasmid, reference EPEC strain B171 harbors a second, larger plasmid that confers antibiotic resistance. To further understand the genetic diversity and dissemination of antibiotic resistance plasmids among EPEC, we describe the complete sequence of an antibiotic resistance plasmid from EPEC strain B171. The resistance plasmid, pB171_90, has a completed sequence length of 90,229 bp, a GC content of 54.55%, and carries protein-encoding genes involved in conjugative transfer, resistance to tetracycline (tetA), sulfonamides (sulI), and mercury, as well as several virulence-associated genes including the transcriptional regulator hha, and the putative calcium sequestration inhibitor (csi). In silico detection of the pB171_90 genes among 4,798 publicly-available E. coli genome assemblies indicates the unique genes of pB171_90 (csi and traI) are primarily restricted to genomes identified as EPEC and enterotoxigenic E. coli. However, conserved regions of the pB171_90 plasmid containing genes involved in replication, stability, and antibiotic resistance were identified among diverse E. coli pathotypes. Interestingly, pB171_90 also exhibited significant similarity with a sequenced plasmid from S. dysenteriae type I. Our findings demonstrate the mosaic nature of EPEC antibiotic resistance plasmids, and highlight the need for additional sequence-based characterization of antibiotic resistance plasmids harbored by pathogenic E. coli.

http://ift.tt/2tGxbzi

Identification and mode of action of a plant natural product targeting human fungal pathogens [PublishAheadOfPrint]

Candida albicans is a major cause of fungal diseases in humans and its resistance to available drugs is of concern. In an attempt to identify novel antifungal agents, we initiated a small scale screening of a 199 natural plant compounds (NPs) library. In vitro susceptibility profiling experiments identified 33 NPs with activity against C. albicans (MIC₅₀ ≤ 32 μg/ml). Among the selected NPs, the sterol alkaloid tomatidine was further investigated. Tomatidine originates from Solanum lycopersicum (tomato) and exhibited high fungistatic activity against Candida species (MIC₅₀ ≤ 1 μg/ml) but no cytotoxicity against mammalian cells. Genome-wide transcriptional analysis of C. albicans tomatidine-treated cells revealed a major alteration (upregulation) of ergosterol genes suggesting that the ergosterol pathway was targeted by this NP. Consistent with this transcriptional response, sterol content analysis of tomatidine-treated cells showed not only inhibition of Erg6 (C-24 sterol methyltransferase) but also of Erg4 (C-24 sterol reductase) activity. A forward genetic approach in Saccharomyces cerevisiae coupled with whole genome sequencing identified 2 non-synonymous mutations in ERG6 (amino acids: D249G and G132D) responsible for tomatidine resistance. Our results therefore identified unambiguously Erg6, a sterol C-24 methyltransferase absent in mammals, as the main direct target of tomatidine. We tested the in vivo efficacy of tomatidine in a mouse model of C. albicans systemic infection. Treatment with a nano-crystal pharmacological formulation successfully decreased the fungal burden in infected kidneys as compared to placebo and thus confirmed the potential of tomatidine as a therapeutic agent.

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Effects of Isavuconazole on the Plasma Concentrations of Tacrolimus among Solid Organ Transplant Patients [PublishAheadOfPrint]

We evaluated the interaction between isavuconazole and tacrolimus among 55 organ transplant recipients. After isavuconazole discontinuation, tacrolimus concentration/dose normalized by weight (C/D) was reduced by 16%. Liver transplant recipients experienced the largest C/D reduction. A 1.3-fold decrease in tacrolimus daily dose was required to maintain desired tacrolimus levels. There was considerable inter-patient variability in the magnitude of the drug interaction. Tacrolimus doses should not be adjusted uniformly, but rather guided by therapeutic drug monitoring.

http://ift.tt/2tGx9aE

Subinhibitory concentrations of trimethoprim and sulfamethoxazole prevent biofilm formation by Acinetobacter baumannii through inhibition of Csu pili expression [PublishAheadOfPrint]

Acinetobacter baumannii is emerging as a multi-drug resistant nosocomial pathogen of increasing threat to human health worldwide. Pili are important bacterial virulence factors, playing a role in attachment to host cells and biofilm formation. The Csu pilus, assembled via the chaperone-usher secretion system, has been studied in A. baumannii ATCC 19606. Here we show that, in opposition to previous reports, the common lab strain ATCC 17978 produces Csu pili. We found that, although ATCC 17978 is resistant to sulfamethoxazole (Smx) and trimethoprim (Tmp), subinhibitory concentrations of these antibiotics abolish the expression of Csu and consequently a dramatic reduction in biofilm formation in ATCC 17978. Smx and Tmp act synergistically inhibiting the enzymatic systems involved in the bacterial synthesis of tetrahydrofolate (THF), which is required for the synthesis of nucleotides. The effect of these antibiotics was partially relieved by exogenous addition of THF, indicating that Smx and Tmp turn off Csu assembly by inducing folate stress. We propose that, for Acinetobacter, nanomolar concentrations of Smx and Tmp represent a "danger signal". In response to this signal, Csu expression is repressed, allowing biofilm dispersal and escape from potentially inhibitory concentrations of antibiotics. The roles of antibiotics as signalling molecules start to be increasingly acknowledged, which have clear implications for both, the treatment of bacterial diseases, and the understanding of the complex microbial interactions in the environment.

http://ift.tt/2uEzG1Y

Clinical Features of Breakthrough Acinetobacter Bacteremia during Carbapenem Therapy: A Multicenter Study [PublishAheadOfPrint]

Breakthrough Acinetobacter bacteremia during carbapenem therapy is not uncommon and creates therapeutic dilemmas for clinicians. This study was conducted to evaluate the clinical and microbiological characteristics of breakthrough Acinetobacter bacteremia during carbapenem therapy and to assess the efficacy of various antimicrobial therapies. We analyzed 100 adults who developed breakthrough Acinetobacter bacteremia during carbapenem therapy at 4 medical centers over a 6-year period. Their 30-day mortality rate was 57.0% and the carbapenem resistance rate of their isolates was 87.0%. Among patients with carbapenem-resistant Acinetobacter bacteremia, breakthrough bacteremia during carbapenem therapy was associated with a significant higher 14-day mortality (51.7% versus 37.4%, P = 0.025 by bivariate analysis) and a higher 30-day mortality (P = 0.037 by log-rank test of survival analysis) than in the non-breakthrough group. For treatment of breakthrough Acinetobacter bacteremia during carbapenem therapy, tigecycline-based therapy was associated with a significantly higher 30-day mortality (80.0%) than continued carbapenem therapy (52.5%) and colistin-based therapy (57.9%) by survival analysis (P = 0.047 and 0.045 by log-rank test, respectively). Cox regression controlling for confounders, including severity of illness indices, demonstrated that patients treated with tigecycline-based therapy for breakthrough Acinetobacter bacteremia was an independent predictor of 30-day mortality (hazard ratio, 3.659; 95% confidence interval, 1.794-7.465; P < 0.001). Patients with breakthrough Acinetobacter bacteremia during carbapenem therapy posed a poor outcome. Tigecycline should be used cautiously for treatment of breakthrough Acinetobacter bacteremia that develops during carbapenem therapy.

http://ift.tt/2tGp9qa

Repurposing thiram and disulfiram as antibacterial agents for multi-drug resistant Staphylococcus aureus infections [PublishAheadOfPrint]

Thiram and disulfiram were evaluated as antibacterial agents against multidrug resistant Staphylococcus aureus. Against a 30 member panel comprised of vancomycin-susceptible (VSSA), vancomycin-intermediate (VISA) and vancomycin-resistant (VRSA) strains, the MIC₉₀ values of the respective test agents were 4 and 16 μg/mL. Additional analyses revealed that thiram and disulfiram are rapid-acting bacteriostatic agents with narrow, Gram-positive bacteria spectrum activity. Synergy studies further determined that disulfiram increases the vancomycin susceptibility of three clinical VRSA strains in vitro, thus establishing a potential use in combination therapy.

http://ift.tt/2uExxU9

In Vitro Antibiotic Susceptibilities of Francisella tularensis by Broth Micro-Dilution Following CLSI Methods. [PublishAheadOfPrint]

In vitro susceptibilities for 47 antibiotics were determined in 30 genetic diverse strains of Francisella tularensis by the broth micro-dilution method following Clinical Laboratory Standards Institute (CLSI) methods. The F. tularensis strains demonstrated susceptibility to aminoglycosides, fluoroquinolones and tetracyclines. There was a distinct difference in macrolide susceptibility between "A" and "B" type strains as has been noted previously. Establishing and comparing antibiotic susceptibilities of a diverse but specific set of F. tularensis strains by standardized methods and establishment of population ranges and MIC_50/90 values provides reference information for assessing new antibiotic agents, and provides a baseline to monitor any future emergence of resistance, natural or intentional.

http://ift.tt/2tGtVnf

In Vitro Activity of Ceftolozane-Tazobactam and Other Antimicrobial Agents Against Burkholderia cepacia Complex and Burkholderia gladioli [PublishAheadOfPrint]

We tested the activity of ceftolozane-tazobactam and 13 other antimicrobial agents against 221 strains of Burkholderia cepacia complex and Burkholderia gladioli. Most strains (82%) were cultured from persons with cystic fibrosis, and most (85%) were recovered since 2011. The ceftolozane-tazobactam MIC was ≤ 8 μg/ml for 77% of the strains. However, the MIC range was broad (≤0.5 to >64 μg/ml; MIC_50/90, 2/32 μg/ml). Significant differences in susceptibility to some antimicrobial agents were observed between species.

http://ift.tt/2uEq6MU

Screening the MMV Pathogen Box across multiple pathogens reclassifies starting points for open source drug discovery. [PublishAheadOfPrint]

Open access drug discovery provides a substantial resource for diseases primarily affecting the poor and disadvantaged. The open access Pathogen Box is comprised of a collection of compounds with demonstrated biological activity against specific pathogenic organisms. The supply of this resource by the Medicines for Malaria Venture has the potential to provide new chemical starting points for a number of tropical and neglected diseases, through repurposing of these compounds for use in drug discovery campaigns for these additional pathogens. Here we have tested the Pathogen Box against kinetoplastid parasites and malaria life cycle stages in vitro. Consequently, chemical starting points for malaria, human African trypanosomiasis, Chagas disease and leishmaniasis drug discovery efforts have been identified. Inclusive of this in vitro biological evaluation, outcomes from extensive literature reviews and database searches are provided. This information encompasses commercial availability, literature reference citations, other aliases and ChEMBL number with associated biological activity, where available. The release of this new data for the Pathogen Box collection into the public domain will aid the open source model of drug discovery. Importantly, this will provide novel chemical starting points for drug discovery and target identification in tropical disease research.

http://ift.tt/2tGcSBQ

Activities of LCB01-0371, a novel oxazolidinone, against Mycobacterium abscessus [PublishAheadOfPrint]

Mycobacterium abscessus is a highly pathogenic, drug-resistant, rapidly growing mycobacterium. In this study, we evaluated the in vitro, intracellular, and in vivo activities of LCB01-0371, a novel and safe oxazolidinone derivative, for the treatment of M. abscessus infection and compared its resistance to that of other oxazolidinone drugs. LCB01-0371 was effective against several M. abscessus strains in vitro and in a macrophage model of infection. In the murine model, a similar efficacy to linezolid was achieved, especially in the lungs. We induced laboratory-generated resistance to LCB01-0371; sequencing analysis revealed mutations of rplC T424C and G419A and nucleotide insertion at the 503 position. Furthermore, LCB01-0371 inhibited the growth of amikacin-, cefoxitin-, and clarithromycin-resistant strains. Collectively, our data indicated that LCB01-0371 might represent a promising new class of oxazolidinones with improved safety, which may replace linezolid for the treatment of M. abscessus.

http://ift.tt/2uEaN6Q

Hyperbaric oxygen treatment of spinal cord injury in rat model

The purpose of this study was to investigate the therapeutic effects and mechanisms of hyperbaric oxygen (HBO) treatment on rats following spinal cord injury (SCI).

http://ift.tt/2sAwlEY

Nuclear CD24 drives tumor growth and is predictive of poor patient prognosis

Elevated tumor expression of the cell surface GPI-linked CD24 protein signals poor patient prognosis in many tumor types. However, some cancer cells selected to be negative for surface CD24 (surCD24-) still retain aggressive phenotypes in vitro and in vivo. Here we resolve this apparent paradox with the discovery of biologically active, nuclear CD24 (nucCD24) and finding that its levels are unchanged in surCD24- cells. Using the complementary techniques of biochemical cellular fractionation and immunofluorescence, we demonstrate a signal for CD24 in the nucleus in cells from various histological types of cancer. Nuclear-specific expression of CD24 (NLS-CD24) increased anchorage independent growth in vitro and tumor formation in vivo. Immunohistochemistry of patient tumor samples revealed the presence of nucCD24, whose signal intensity correlated positively with the presence of metastatic disease. Analysis of gene expression between cells expressing CD24 and NLS-CD24 revealed a unique nucCD24 transcriptional signature. The median score derived from this signature was able to stratify overall survival in 4 patient datasets from bladder cancer and 5 patient datasets from colorectal cancer. Patients with high scores (more nucCD24-like) had reduced survival. These findings define a novel and functionally important intracellular location of CD24, they explain why surCD24- cells can remain aggressive, and they highlight the need to consider nucCD24 in both fundamental research and therapeutic development.

http://ift.tt/2uEcJMy

TP53INP1 down-regulation activates a p73-dependent DUSP10/ERK signaling pathway to promote metastasis of hepatocellular carcinoma

Identifying critical factors involved in the metastatic progression of hepatocellular carcinoma (HCC) may offer important therapeutic opportunities. Here we report that the pro-apoptotic stress response factor TP53INP1 is often selectively down-regulated in advanced stage IV and metastatic human HCC tumors. Mechanistic investigations revealed that TP53INP1 down-regulation in early stage HCC cells promoted metastasis via DUSP10 phosphatase-mediated activation of the ERK pathway. The DUSP10 promoter included putative binding sites for p73 directly implicated in modulation by TP53INP1. Overall, our findings showed how TP53INP1 plays a critical in limiting progression of early stage HCC, with implications for developing new therapeutic strategies to attack metastatic HCC.

http://ift.tt/2tGcovD

Characterization of gliomas: from morphology to molecules

Abstract

This article reviews the histologic and molecular characterization of gliomas, including the new "integrated diagnoses" of the World Health Organization Classification, 2016 edition. The entities reviewed within include diffuse gliomas (astrocytoma, oligodendroglioma, glioblastoma), as well as circumscribed and low-grade gliomas (angiocentric glioma, pilocytic astrocytoma, subependymal giant cell astrocytoma, pleomorphic xanthoastrocytoma, pilomyxoid astrocytoma, ependymoma, myxopapillary ependymoma, and subependymoma). Diagnostic, prognostic, and predictive biomarkers are discussed for each entity. We review how molecular testing for IDH1 and ATRX and detection of chromosome 1p/19q codeletion can be used to categorize glioblastomas as IDH-wildtype or IDH-mutant, and lower grade diffuse gliomas into three molecular groups that correlate better with patient outcomes than histologic subtyping. Pediatric diffuse gliomas are highlighted, including diffuse midline glioma, H3 K27M-mutant, and inherited germline mutations that predispose to pediatric gliomas. The utility of genomic profiling of certain gliomas is discussed, including identifying candidates for experimental therapies. This review is meant to be a concise summary of glioma characterization for the practicing pathologist.

http://ift.tt/2tKDq5X

Are There Modifiable Risk Factors to Improve AKI?

Acute kidney injury (AKI) is a common critical syndrome, with high morbidity and mortality. Patients with AKI typically have an adverse prognosis, from incident chronic kidney disease (CKD), progression to end-stage renal disease (ESRD), subsequent cardiovascular disease, and ultimately death. However, there is currently no effective therapy for AKI. Early detection of risk factors for AKI may offer a good approach to prevention or early intervention. Traditional risk factors include extreme age, many common comorbid diseases, such as preexisting CKD, some specific exposures, such as sepsis, and exposure to some nephrotoxic agents. Recently, several novel risk factors for AKI, such as hyperuricemia, hypoalbuminemia, obesity, anemia, and hyperglycemia, have been identified. The underlying mechanisms between these nontraditional risk factors and AKI and whether their correction can reduce AKI occurrence remain to be clarified. This review describes the current epidemiology of AKI, summarizes its outcome, outlines the traditional risk profile, and finally highlights some recently identified novel risk factors.

http://ift.tt/2tKog0C

Prevalence and Genetic Characterization of Cryptosporidium Infection in Java Sparrows (Lonchura oryzivora) in Northern China

Cryptosporidiosis is a cosmopolitan parasitosis that affects a wide range of hosts including birds. As information concerning Cryptosporidium in birds is limited, the present study examined the prevalence and genotypes of Cryptosporidium in Java sparrows in Beijing and Shangqiu, northern China. Three hundred and fifty fecal samples were collected from Java sparrows (Lonchura oryzivora, 225 white Java sparrows and 125 gray Java sparrows) in Beijing and Shangqiu in October 2015, and the samples were examined by PCR amplification of the small subunit ribosomal RNA (SSU rRNA) gene. The overall Cryptosporidium prevalence is 13.42% (47/350), with 16.44% (37/225) in white Java sparrows and 8.00% (10/125) in gray Java sparrows. Cryptosporidium prevalence was 9.82% (16/163) in Java sparrows from Beijing and 16.58% (31/187) in Java sparrows from Shangqiu. The prevalence of Cryptosporidium in females and males was 40.63% (26/64) and 7.34% (21/286), respectively. The Cryptosporidium prevalence in Java sparrows of different ages varied from 10.47% to 16.33%. Sequence analysis of the SSU rRNA gene revealed that all the samples represented C. baileyi. This is the first report of Cryptosporidium in gray Java sparrows in China, which extend the host range for C. baileyi. These results provide baseline information for further studies of molecular epidemiology and control of Cryptosporidium infection in poultry in China.

http://ift.tt/2tKoRiv

Association of Ozone with 5-Fluorouracil and Cisplatin in Regulation of Human Colon Cancer Cell Viability: In Vitro Anti-Inflammatory Properties of Ozone in Colon Cancer Cells Exposed to Lipopolysaccharides

Introduction. Ozone therapy is an effective medical treatment for different diseases like mucositis, psoriasis, acute pain, neurovascular diseases, and cancer. The aim of this study is based on the association of different ozone concentration with 5-fluorouracil and cisplatin in human colon cancer cell (HT29 cell line) in order to investigate possible anticancer synergistic effects. Methods. HT29 cells were incubated with ozone at different concentration ranging from 10 up to 50 μg/ml at different incubation time alone or in combination with cisplatin and 5-fluorouracil. Cell viability was performed by using a modified MTT method. Anti-inflammatory studies were conducted incubating HT29 with or without 20, 30, or 50 μg/ml of ozone before exposure to lipopolysaccharides. Results. Ozone alone has a time and concentration dependent cytotoxicity against HT29 cells (IC50 at 24 h: 30 μg/ml). Association of ozone with drugs increases cytotoxicity by 15–20%. Preincubation of ozone at 50 μg/ml decreases IL-8, IL-6, and IL-1β production by 50, 56, and 70%, respectively, compared to untreated cells. Conclusion. These results indicated that ozone could be useful in colon cancer management in combination with 5-fluorouracil and cisplatin with significant inhibition of cytokines having a central role in colon cancer cell survival and chemoresistance.

http://ift.tt/2tKpLLZ

Epidemiology of extended-spectrum beta-lactamase-producing Enterobacteriaceae in an intensive care unit with no single rooms

The transmission of extended-spectrum beta-lactamase-producing enterobacteriaceae (ESBL) is prevented by additional contact precautions, mainly relying on isolation in a single room and hand hygiene. Contact isol...

http://ift.tt/2ujynGw

Psychophysical responses in patients receiving a mock laser within context of an acupuncture clinical trial: an interoceptive perspective

The psychophysical responses induced by verum acupuncture are characterized by a constellation of unique subjective sensory responses commonly termed De Qi. Furthermore, a variety of sham interventions have be...

http://ift.tt/2tKnOzs

Toxicity and antitumor potential of Mesosphaerum sidifolium (Lamiaceae) oil and fenchone, its major component

The essential oil from Mesosphaerum sidifolium (L'Hérit.) Harley & J.F.B.Pastore (syn. Hyptis umbrosa), Lamiaceae (EOM), and its major component, have been tested for toxicity and antitumor activity.

http://ift.tt/2ujphK4

Malnutrition in patients admitted to the medical wards of the Douala General Hospital: a cross-sectional study

Malnutrition is common in acutely ill patients occurring in 30–50% of hospitalized patients. Awareness and screening for malnutrition is lacking in most health institutions in sub-Saharan Africa. This study ai...

http://ift.tt/2tKA4zS

Low- and High-LET Ionizing Radiation Induces Delayed Homologous Recombination that Persists for Two Weeks before Resolving

Radiation Research, Volume 188, Issue 1, Page 82-93, July 2017.


http://ift.tt/2tkfXFA

Inhibition of the Continuum of Radiation-Induced Normal Tissue Injury by a Redox-Active Mn Porphyrin

Radiation Research, Volume 188, Issue 1, Page 94-104, July 2017.


http://ift.tt/2sAi0Z0

Analysis of Saliva Gene Expression during Head and Neck Cancer Radiotherapy: A Pilot Study

Radiation Research, Volume 188, Issue 1, Page 75-81, July 2017.


http://ift.tt/2tjStAe

Andrographis paniculata Diterpenoids Protect against Radiation-Induced Transformation in BALB/3T3 Cells

Radiation Research, Volume 188, Issue 1, Page 66-74, July 2017.


http://ift.tt/2sAkVRr

The Focinator v2-0 – Graphical Interface, Four Channels, Colocalization Analysis and Cell Phase Identification

Radiation Research, Volume 188, Issue 1, Page 114-120, July 2017.


http://ift.tt/2tjM3RD

Radiation-Induced Fibrosis: Mechanisms and Opportunities to Mitigate. Report of an NCI Workshop, September 19, 2016.

Radiation Research, Volume 188, Issue 1, Page 1-20, July 2017.


http://ift.tt/2szKPF7

Investigating the Abscopal Effects of Radioablation on Shielded Bone Marrow in Rodent Models Using Multimodality Imaging

Radiation Research, Volume 188, Issue 1, Page 56-65, July 2017.


http://ift.tt/2tk9PgG

Metformin Attenuates Radiation-Induced Pulmonary Fibrosis in a Murine Model

Radiation Research, Volume 188, Issue 1, Page 105-113, July 2017.


http://ift.tt/2tk9sm4

Metabolic Dysregulation after Neutron Exposures Expected from an Improvised Nuclear Device

Radiation Research, Volume 188, Issue 1, Page 21-34, July 2017.


http://ift.tt/2sA31hN

NMR-based Metabolomics Analysis of Liver from C57BL/6 Mouse Exposed to Ionizing Radiation

Radiation Research, Volume 188, Issue 1, Page 44-55, July 2017.


http://ift.tt/2tjO6Fx

The Lactate Dehydrogenase Inhibitor Gossypol Inhibits Radiation-Induced Pulmonary Fibrosis

Radiation Research, Volume 188, Issue 1, Page 35-43, July 2017.


http://ift.tt/2sAptXR

Unusual metallic penile foreign body

Kulothungan Gunasekaran<br />Mar 27, 2017; 2017:bcr2017219377-bcr2017219377<br />case-report

http://ift.tt/2sA23BT

Case of pneumatosis intestinalis and hepatic portal venous gas following a laparoscopic right hemicolectomy

Edit Elisa Castren<br />Mar 21, 2016; 2016:bcr2016214431-bcr2016214431<br />case-report

http://ift.tt/2sAmO0j

Laryngeal lipoma: a rare cause of acute intermittent airway obstruction

Peter George Deutsch<br />Apr 22, 2016; 2016:bcr2016215506-bcr2016215506<br />case-report

http://ift.tt/2tjHxCW

An unusual case of KBG syndrome with unique oral findings

Abdul Hafiz<br />Jul 17, 2015; 2015:bcr2015210352-bcr2015210352<br />case-report

http://ift.tt/2tkbyTf

Access to essential paediatric eye surgery in the developing world: a case of congenital cataracts left untreated

Marilyn L Vinluan<br />Apr 22, 2015; 2015:bcr2014208197-bcr2014208197<br />case-report

http://ift.tt/2sAmKO7

Pulmonary co-infection with Nocardia and Aspergillus in a patient with adult-onset Still's disease receiving steroids and tacrolimus

Durga Prasanna Misra<br />Nov 14, 2014; 2014:bcr2014207335-bcr2014207335<br />case-report

http://ift.tt/2sA44OP

A rare presentation of multiple dens invaginatus in maxillary dentition

Jigar M Purani<br />Aug 1, 2014; 2014:bcr2013200389-bcr2013200389<br />case-report

http://ift.tt/2tk3YYs

Thoracic vertebral osteomyelitis: an unusual complication of Crohn's disease

Olushola Ajayi<br />Jun 10, 2014; 2014:bcr2013202150-bcr2013202150<br />case-report

http://ift.tt/2sAgBSc

Endodontic retreatment of a mandibular first molar with five root canal systems: an important clinical lesson

Muhammad Hasan<br />Mar 20, 2014; 2014:bcr2013201402-bcr2013201402<br />case-report

http://ift.tt/2tjXadz

Cold finger: urban frostbite in the UK

Stephen Mulgrew<br />Aug 29, 2013; 2013:bcr1120115167-bcr1120115167<br />case-report

http://ift.tt/2sA0hkv

Central nervous system infection with Acanthamoeba in a malnourished child

Sumeeta Khurana<br />Oct 24, 2012; 2012:bcr2012007449-bcr2012007449<br />case-report

http://ift.tt/2tk7lPo

Postmalaria Neurologic Syndrome—Autoimmune Encephalitis With Anti–Voltage-Gated Potassium-Channel Antibodies

http://ift.tt/2ra0QQe

Oral Pharmacologic Treatment of Type 2 Diabetes Mellitus

http://ift.tt/2skeU7l

Growth and Rupture Risk of Small Unruptured Intracranial Aneurysms A Systematic Review

Background:

Small unruptured intracranial aneurysms (UIAs) are increasingly diagnosed. Management depends on growth and rupture risks, which may vary by aneurysm size.

Purpose:

To summarize evidence about the growth and rupture risk of UIAs 7 mm and smaller and to explore differences in growth and rupture risks of very small (≤3 mm) and small (≤5 mm) aneurysms.

Data Sources:

MEDLINE, EMBASE, Scopus, and the Cochrane Library from inception to 2017 (with no language restrictions).

Study Selection:

Published case series and observational studies that reported natural history data on UIAs 7 mm and smaller.

Data Extraction:

2 reviewers abstracted study information, evaluated study quality, and graded strength of evidence.

Data Synthesis:

Of 26 studies, 5, 10, and 8 described the growth rate of aneurysms 3 mm and smaller, 5 mm and smaller, and 7 mm and smaller, respectively, whereas rupture rates were reported in 7, 11, and 13 studies for aneurysms 3 mm and smaller, 5 mm and smaller, and 7 mm and smaller, respectively. The annualized growth rate was less than 3% in all but 1 study for all 3 size categories. The annualized rupture rate was 0%, less than 0.5%, and less than 1% for the 3 size categories, respectively. Strength of evidence was very low quality for growth rates and low quality for rupture rates.

Limitation:

Heterogeneous definitions of growth; heterogeneous and selective treatment and follow-up methods, particularly in high-risk patients.

Conclusion:

Poor-quality evidence suggests that small UIAs have low growth and rupture rates and very small UIAs have little or no risk for rupture.

Primary Funding Source:

None.

http://ift.tt/2rujBgG

Methods and Reporting Studies Assessing Fecal Microbiota Transplantation A Systematic Review

Background:

Fecal microbiota transplantation (FMT) could be a novel treatment option for several chronic diseases associated with altered gut microbiota.

Purpose:

To examine the conduct and reporting of studies assessing FMT.

Data Sources:

Cochrane Central Register of Controlled Trials, PubMed, EMBASE, and Web of Science from inception to 31 January 2017.

Study Selection:

Two reviewers independently examined titles and abstracts to identify all English-language reports of human clinical studies assessing the safety or efficacy of FMT.

Data Extraction:

Three reviewers independently assessed study types and characteristics and the reporting of important methodological components of the FMT intervention.

Data Synthesis:

Most (84%) of the 85 published reports found addressed the use of FMTs for Clostridium difficile infection or inflammatory bowel disease, and most (87%) were non–randomized controlled trials. Important methodological components that were not reported in published studies included the following: eligibility criteria for donors (47%), materials used for collecting stools and the period of collection (96%), methods used for conservation of stools (76%), the amount and type of stools used (for example, fresh or frozen), and duration of stool conservation (67%). Many (58%) did not report an analysis of microbiota composition.

Limitations:

Lack of universal consensus regarding the most important methodological components of FMT and inability to assess the actual conduct of studies and whether the publication process affected the completeness of reporting.

Conclusion:

Key components of FMT interventions, which are necessary to replicate and understand study findings about efficacy and safety, are poorly reported.

Primary Funding Source:

No specific funding.

http://ift.tt/2qOEPWB

Presence of Human Hepegivirus-1 in a Cohort of People Who Inject Drugs

Background:

Next-generation metagenomic sequencing (NGMS) has opened new frontiers in microbial discovery but has been clinically characterized in only a few settings.

Objective:

To explore the plasma virome of persons who inject drugs and to characterize the sensitivity and accuracy of NGMS compared with quantitative clinical standards.

Design:

Longitudinal and cross-sectional studies.

Setting:

A clinical trial (ClinicalTrials.gov: NCT01285050) and a well-characterized cohort study of persons who have injected drugs.

Participants:

Persons co-infected with hepatitis C virus (HCV) and HIV.

Measurements:

Viral nucleic acid in plasma by NGMS and quantitative polymerase chain reaction (PCR).

Results:

Next-generation metagenomic sequencing generated a total of 600 million reads, which included the expected HIV and HCV RNA sequences. HIV and HCV reads were consistently identified only when samples contained more than 10 000 copies/mL or IU/mL, respectively, as determined by quantitative PCR. A novel RNA virus, human hepegivirus-1 (HHpgV-1), was also detected by NGMS in 4 samples from 2 persons in the clinical trial. Through use of a quantitative PCR assay for HHpgV-1, infection was also detected in 17 (10.9%) of 156 members of a cohort of persons who injected drugs. In these persons, HHpgV-1 viremia persisted for a median of at least 4538 days and was associated with detection of other bloodborne viruses, such as HCV RNA and SEN virus D.

Limitation:

The medical importance of HHpgV-1 infection is unknown.

Conclusion:

Although NGMS is insensitive for detection of viruses with relatively low plasma nucleic acid concentrations, it may have broad potential for discovery of new viral infections of possible medical importance, such as HHpgV-1.

Primary Funding Source:

National Institutes of Health.

http://ift.tt/2rumMVS

Oral Pharmacologic Treatment of Type 2 Diabetes Mellitus

http://ift.tt/2skxVq2

Use of the Dual-Antiplatelet Therapy Score to Guide Treatment Duration After Percutaneous Coronary Intervention

Background:

The dual-antiplatelet therapy (DAPT) score was developed to identify patients more likely to derive harm (score Objective:

http://ift.tt/2sgVcMv

Do Sugar-Sweetened Beverages Cause Obesity and Diabetes?

http://ift.tt/2sk6wVv

Triple Therapy Versus Biologic Therapy for Active Rheumatoid Arthritis A Cost-Effectiveness Analysis

Background:

The RACAT (Rheumatoid Arthritis Comparison of Active Therapies) trial found triple therapy to be noninferior to etanercept–methotrexate in patients with active rheumatoid arthritis (RA).

Objective:

To determine the cost-effectiveness of etanercept–methotrexate versus triple therapy as a first-line strategy.

Design:

A within-trial analysis based on the 353 participants in the RACAT trial and a lifetime analysis that extrapolated costs and outcomes by using a decision analytic cohort model.

Data Sources:

The RACAT trial and sources from the literature.

Target Population:

Patients with active RA despite at least 12 weeks of methotrexate therapy.

Time Horizon:

24 weeks and lifetime.

Perspective:

Societal and Medicare.

Intervention:

Etanercept–methotrexate first versus triple therapy first.

Outcome Measures:

Incremental costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs).

Results of Base-Case Analysis:

The within-trial analysis found that etanercept–methotrexate as first-line therapy provided marginally more QALYs but accumulated substantially higher drug costs. Differences in other costs between strategies were negligible. The ICERs for first-line etanercept–methotrexate and triple therapy were $2.7 million per QALY and $0.98 million per QALY over 24 and 48 weeks, respectively. The lifetime analysis suggested that first-line etanercept–methotrexate would result in 0.15 additional lifetime QALY, but this gain would cost an incremental $77 290, leading to an ICER of $521 520 per QALY per patient.

Results of Sensitivity Analysis:

Considering a long-term perspective, an initial strategy of etanercept–methotrexate and biologics with similar cost and efficacy is unlikely to be cost-effective compared with using triple therapy first, even under optimistic assumptions.

Limitation:

Data on the long-term benefit of triple therapy are uncertain.

Conclusion:

Initiating biologic therapy without trying triple therapy first increases costs while providing minimal incremental benefit.

Primary Funding Source:

The Cooperative Studies Program, Department of Veterans Affairs Office of Research and Development, Canadian Institutes for Health Research, and an interagency agreement with the National Institutes of Health–American Recovery and Reinvestment Act.

http://ift.tt/2sftKeC

Annals for Educators - 4 July 2017

http://ift.tt/2skn5jP

CONSORT Statement for Randomized Trials of Nonpharmacologic Treatments: A 2017 Update and a CONSORT Extension for Nonpharmacologic Trial Abstracts

Incomplete and inadequate reporting is an avoidable waste that reduces the usefulness of research. The CONSORT (Consolidated Standards of Reporting Trials) Statement is an evidence-based reporting guideline that aims to improve research transparency and reduce waste. In 2008, the CONSORT Group developed an extension to the original statement that addressed methodological issues specific to trials of nonpharmacologic treatments (NPTs), such as surgery, rehabilitation, or psychotherapy. This article describes an update of that extension and presents an extension for reporting abstracts of NPT trials. To develop these materials, the authors reviewed pertinent literature published up to July 2016; surveyed authors of NPT trials; and conducted a consensus meeting with editors, trialists, and methodologists.Changes to the CONSORT Statement extension for NPT trials include wording modifications to improve readers' understanding and the addition of 3 new items. These items address whether and how adherence of participants to interventions is assessed or enhanced, description of attempts to limit bias if blinding is not possible, and specification of the delay between randomization and initiation of the intervention. The CONSORT extension for abstracts of NPT trials includes 2 new items that were not specified in the original CONSORT Statement for abstracts. The first addresses reporting of eligibility criteria for centers where the intervention is performed and for care providers. The second addresses reporting of important changes to the intervention versus what was planned. Both the updated CONSORT extension for NPT trials and the CONSORT extension for NPT trial abstracts should help authors, editors, and peer reviewers improve the transparency of NPT trial reports.

http://ift.tt/2sMa1aU

Intensive Care

http://ift.tt/2sk8rJl

Toward Patient-Centered Hospital Design: What Can Airports Teach Us?

Hospitals are still behind when it comes to implementing patient-friendly processes to improve the access and layout of hospital services. Could hospitals learn from airports in meeting the needs of patients?

http://ift.tt/2sfgney

Annals Graphic Medicine - July Plunge

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New Department of Veterans Affairs and Department of Defense Guidelines on Pain Management With Opioids: Comment and Concern

The Department of Veterans Affairs/Department of Defense recently revised guidelines on prescribing opioids for the management of chronic noncancer pain. This commentary discusses the guidelines and why they are a welcome and timely update.

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Incidental Findings in Research Studies: One Student's Experience

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Understanding Veteran Wait Times

The newly appointed secretary of the U.S. Department of Veterans Affairs (VA) describes the response to the access crisis and his vision for the VA that is based on how veterans want to receive care.

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Do Sugar-Sweetened Beverages Cause Obesity and Diabetes?

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Improvement at Any Cost? The Art and Science of Choosing Treatment Strategies for Rheumatoid Arthritis

Bansback and colleagues reported a cost-effectiveness analysis of triple therapy with conventional disease-modifying antirheumatic drugs compared with etanercept and methotrexate. The editorialists discuss the findings.

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Do Sugar-Sweetened Beverages Cause Obesity and Diabetes?

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Fool Me Thrice: The Evolving Story of Multiply Recurrent Clostridium difficile Infection

Ma and colleagues report a retrospective cohort study to address gaps in our knowledge about multiply recurrent Clostridium difficile infection (mrCDI). The editorialists discuss the findings, the limitations of the study, and why a better understanding of the epidemiology of mrCDI is a critical first step toward developing a sound strategy to address this growing public health challenge.

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A cross-sectional study to evaluate second line virological failure and elevated bilirubin as a surrogate for adherence to atazanavir/ritonavir in two urban HIV clinics in Lilongwe, Malawi

Malawi's national antiretroviral therapy program provides atazanavir/ritonavir–based second line regimens which cause concentration-dependent rise in indirect bilirubin. We sought to determine if elevated bili...

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Report of an unsual case of anophthalmia and craniofacial cleft in a newborn with Toxoplasma gondii congenital infection

We present one unusual case of anophthalmia and craniofacial cleft, probably due to congenital toxoplasmosis only.

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Risk factors for measles death: Kyegegwa District, western Uganda, February–September, 2015

On 18 August 2015, Kyegegwa District reported eight deaths during a measles outbreak to the Uganda Ministry of Health (MoH). We investigated this death cluster to verify the cause, identify risk factors, and i...

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Efficacy of an enhanced linkage to HIV care intervention at improving linkage to HIV care and achieving viral suppression following home-based HIV testing in rural Uganda: study protocol for the Ekkubo/PATH cluster randomized controlled trial

Though home-based human immunodeficiency virus (HIV) counseling and testing (HBHCT) is implemented in many sub-Saharan African countries as part of their HIV programs, linkage to HIV care remains a challenge. ...

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Cost-effectiveness analysis of N95 respirators and medical masks to protect healthcare workers in China from respiratory infections

There are substantial differences between the costs of medical masks and N95 respirators. Cost-effectiveness analysis is required to assist decision-makers evaluating alternative healthcare worker (HCW) mask/r...

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High Generic Drug Prices and Market Competition A Retrospective Cohort Study

Background:

Prices for some generic drugs have increased in recent years, adversely affecting patients who rely on them.

Objective:

To determine the association between market competition levels and the change in generic drug prices in the United States.

Design:

Retrospective cohort study.

Setting:

Prescription claims from commercial health plans between 2008 and 2013.

Measurements:

The 5.5 years of data were divided into 11 study periods of 6 months each. The Herfindahl–Hirschman Index (HHI)—calculated by summing the squares of individual manufacturers' market shares, with higher values indicating a less competitive market—and average drug prices were estimated for the generic drugs in each period. The HHI value estimated in the baseline period (first half of 2008) was modeled as a fixed covariate. Models estimated price changes over time by level of competition, adjusting for drug shortages, market size, and dosage forms.

Results:

From 1.08 billion prescription claims, a cohort of 1120 generic drugs was identified. After adjustment, drugs with quadropoly (HHI value of 2500, indicating relatively high levels of competition), duopoly (HHI value of 5000), near-monopoly (HHI value of 8000), and monopoly (HHI value of 10 000) levels of baseline competition were associated with price changes of −31.7% (95% CI, −34.4% to −28.9%), −11.8% (CI, −18.6% to −4.4%), 20.1% (CI, 5.5% to 36.6%), and 47.4% (CI, 25.4% to 73.2%), respectively, over the study period.

Limitation:

Study findings may not be generalizable to drugs that became generic after 2008.

Conclusion:

Market competition levels were associated with a change in generic drug prices. Such measurements may be helpful in identifying older prescription drugs at higher risk for price change in the future.

Primary Funding Source:

None.

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Increasing Incidence of Multiply Recurrent Clostridium difficile Infection in the United States A Cohort Study

Background:

Clostridium difficile infection (CDI), the most common health care–associated infection, often recurs. Fecal microbiota transplantation is increasingly used to treat multiply recurrent CDI (mrCDI).

Objective:

To determine whether the incidence of mrCDI is increasing in proportion to CDI and to identify risk factors for mrCDI.

Design:

Retrospective cohort study.

Setting:

United States.

Participants:

38 911 718 commercially insured patients in the OptumInsight Clinformatics Database, of whom 45 341 developed CDI.

Measurements:

Age- and sex-standardized incidence rates for CDI and mrCDI.

Results:

From 2001 to 2012, the annual incidence of CDI and mrCDI per 1000 person-years increased by 42.7% (from 0.4408 to 0.6289 case) and 188.8% (from 0.0107 to 0.0309 case), respectively. The increase in mrCDI incidence was independent of known risk factors for CDI. Those who developed mrCDI were older (median age, 56.0 vs. 49.0 years; adjusted odds ratio [aOR] per 10-year increase in age, 1.25 [95% CI, 1.21 to 1.29]) and were more likely to be female (63.8% vs. 58.7%; aOR, 1.24 [CI, 1.11 to 1.38]) and to have used antibiotics (72.3% vs. 58.8%; aOR, 1.79 [CI, 1.59 to 2.01]), proton-pump inhibitors (24.6% vs. 18.2%; aOR, 1.14 [CI, 1.01 to 1.29]), or corticosteroids (18.3% vs. 13.7%; aOR, 1.15 [CI, 1.00 to 1.32]) within 90 days of CDI diagnosis. Chronic kidney disease (10.4% vs. 5.6%; aOR, 1.49 [CI, 1.24 to 1.80]) and diagnosis in a nursing home (2.1% vs. 0.6%; aOR, 1.99 [CI, 1.34 to 2.93]) were also associated with increased risk for mrCDI.

Limitation:

The primary analyses included only commercially insured patients in the United States.

Conclusion:

Relative to CDI, mrCDI incidence has disproportionately increased, indicating a rising demand for mrCDI therapies.

Primary Funding Source:

National Institute of Diabetes and Digestive and Kidney Diseases and National Institute of Allergy and Infectious Diseases.

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The Association of Firearm Suicide With Mental Illness, Substance Use Conditions, and Previous Suicide Attempts

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Annals for the Ages: Annals of Internal Medicine Turns 90

In July 2017, Annals of Internal Medicine celebrates 90 years of continuous publication. Recognizing the occasion, the editorialist provides reflections on the history and future of medical journals.

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Erosive Rheumatoid Arthritis After Bilateral Hand Transplantation

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Incorporating Whole-Genome Sequencing Into Primary Care: Falling Barriers and Next Steps

Vassy and colleagues report a pilot study of the effect of adding whole-genome sequencing (WGS) to a standardized family history assessment in primary care. The editorialist notes that the findings demonstrate that primary care physicians are capable of managing WGS findings, healthy patients tolerate this information well, and use and costs seem to increase. The unanswered question remains whether WGS will truly improve patient outcomes.

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CONSORT Extension for Chinese Herbal Medicine Formulas 2017: Recommendations, Explanation, and Elaboration (Traditional Chinese Version)

This article is the traditional Chinese version of the CONSORT Extension for Chinese Herbal Medicine Formulas 2017: Recommendations, Explanation, and Elaboration.

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Are Antiplatelet Agents Beneficial in Essential Thrombocythemia? Maybe Yes, Probably No

Chu and colleagues report a systematic review to determine the benefits and risks of treating patients with essential thrombocythemia with antiplatelet agents. The editorialist discusses the uncertainty the review uncovers and the need for high-quality trials to definitively address this important clinical question.

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CONSORT Extension for Chinese Herbal Medicine Formulas 2017: Recommendations, Explanation, and Elaboration (Simplified Chinese Version)

This article is the simplified Chinese version of the CONSORT Extension for Chinese Herbal Medicine Formulas 2017: Recommendations, Explanation, and Elaboration.

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The Relationship of Health Insurance and Mortality: Is Lack of Insurance Deadly?

About 28 million Americans are currently uninsured, and millions more could lose coverage under policy reforms proposed in Congress. At the same time, a growing number of policy leaders have called for going beyond the Affordable Care Act to a single-payer national health insurance system that would cover every American. These policy debates lend particular salience to studies evaluating the health effects of insurance coverage. In 2002, an Institute of Medicine review concluded that lack of insurance increases mortality, but several relevant studies have appeared since that time. This article summarizes current evidence concerning the relationship of insurance and mortality. The evidence strengthens confidence in the Institute of Medicine's conclusion that health insurance saves lives: The odds of dying among the insured relative to the uninsured is 0.71 to 0.97.

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Risk factors of liver metastasis from advanced pancreatic adenocarcinoma: a large multicenter cohort study

Abstract

Background

Clinical prognostic parameters of liver metastasis from pancreatic adenocarcinoma have not been specifically identified.This study is to explore the risk factors of liver metastasis in advanced pancreatic adenocarcinoma (PDAC) patients in China.

Methods

A multicenter cohort study was conducted to explore whether liver metastasis in locally advanced and metastatic PDAC could be reflected by some common laboratory indexes. We collected 1787 advanced PDAC patients from three participating hospitals between 2004 and 2014. The associations between some laboratory indexes and risks of liver metastases were analyzed.

Results

Results have shown that 87% of stage IV patients developed synchronous liver metastasis. Primary tumor location (body/tail vs. head/neck, OR 0.55, 95% CI 0.36-0.83), primary tumor diameter (≥20 mm vs. <20 mm, OR 1.77, 95% CI 1.16–2.70), elevated ALT and AST (OR 1.62, 95% CI 0.92–2.83), and elevated CA19-9 (OR 2.72, 95% CI 1.85–3.99) upon diagnosis are significantly associated with risk of synchronous liver metastasis. Among stage III patients, 30.1% developed metachronous liver metastasis. However, no risk factors were identified among these patients.

Conclusions

Primary tumor location, diameter, elevated ALT and AST, and increased CA19-9 are independent risk factors of synchronous liver metastasis in PDAC patients.

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Reporting and Analysis of Trial-Based Cost-Effectiveness Evaluations in Obstetrics and Gynaecology

Abstract

Background and Objectives

The aim was to systematically review whether the reporting and analysis of trial-based cost-effectiveness evaluations in the field of obstetrics and gynaecology comply with guidelines and recommendations, and whether this has improved over time.

Data Sources and Selection Criteria

A literature search was performed in MEDLINE, the NHS Economic Evaluation Database (NHS EED) and the Health Technology Assessment (HTA) database to identify trial-based cost-effectiveness evaluations in obstetrics and gynaecology published between January 1, 2000 and May 16, 2017. Studies performed in middle- and low-income countries and studies related to prevention, midwifery, and reproduction were excluded.

Data Collection and Analysis

Reporting quality was assessed using the Consolidated Health Economic Evaluation Reporting Standard (CHEERS) statement (a modified version with 21 items, as we focused on trial-based cost-effectiveness evaluations) and the statistical quality was assessed using a literature-based list of criteria (8 items). Exploratory regression analyses were performed to assess the association between reporting and statistical quality scores and publication year.

Results

The electronic search resulted in 5482 potentially eligible studies. Forty-five studies fulfilled the inclusion criteria, 22 in obstetrics and 23 in gynaecology. Twenty-seven (60%) studies did not adhere to 50% (n = 10) or more of the reporting quality items and 32 studies (71%) did not meet 50% (n = 4) or more of the statistical quality items. As for the statistical quality, no study used the appropriate method to assess cost differences, no advanced methods were used to deal with missing data, and clustering of data was ignored in all studies. No significant improvements over time were found in reporting or statistical quality in gynaecology, whereas in obstetrics a significant improvement in reporting and statistical quality was found over time.

Limitations

The focus of this review was on trial-based cost-effectiveness evaluations in obstetrics and gynaecology, so further research is needed to explore whether results from this review are generalizable to other medical disciplines.

Conclusions and Implications of Key Findings

The reporting and analysis of trial-based cost-effectiveness evaluations in gynaecology and obstetrics is generally poor. Since this can result in biased results, incorrect conclusions, and inappropriate healthcare decisions, there is an urgent need for improvement in the methods of cost-effectiveness evaluations in this field.

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Erratum for Perfilyev et al. Impact of polyunsaturated and saturated fat overfeeding on the DNA-methylation pattern in human adipose tissue: a randomized controlled trial. Am J Clin Nutr 2017;105:991-1000. [Errata]

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Discrete Event Simulation-Based Resource Modelling in Health Technology Assessment

Abstract

Objective

The objective of this article was to conduct a systematic review of published research on the use of discrete event simulation (DES) for resource modelling (RM) in health technology assessment (HTA). RM is broadly defined as incorporating and measuring effects of constraints on physical resources (e.g. beds, doctors, nurses) in HTA models.

Methods

Systematic literature searches were conducted in academic databases (JSTOR, SAGE, SPRINGER, SCOPUS, IEEE, Science Direct, PubMed, EMBASE) and grey literature (Google Scholar, NHS journal library), enhanced by manual searchers (i.e. reference list checking, citation searching and hand-searching techniques).

Results

The search strategy yielded 4117 potentially relevant citations. Following the screening and manual searches, ten articles were included. Reviewing these articles provided insights into the applications of RM: firstly, different types of economic analyses, model settings, RM and cost-effectiveness analysis (CEA) outcomes were identified. Secondly, variation in the characteristics of the constraints such as types and nature of constraints and sources of data for the constraints were identified. Thirdly, it was found that including the effects of constraints caused the CEA results to change in these articles.

Conclusion

The review found that DES proved to be an effective technique for RM but there were only a small number of studies applied in HTA. However, these studies showed the important consequences of modelling physical constraints and point to the need for a framework to be developed to guide future applications of this approach.

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Fried potato consumption is associated with elevated mortality: an 8-y longitudinal cohort study [Nutritional epidemiology and public health]

Background: Few studies have assessed the association between potato consumption and mortality.

Objective: We investigated whether potato consumption (including fried and unfried potatoes) is associated with increased premature mortality risk in a North American cohort.

Design: A longitudinal analysis included 4440 participants aged 45–79 y at baseline with an 8-y follow-up from the Osteoarthritis Initiative cohort study. Potato consumption (including fried and unfried potatoes) was analyzed by using a Block Brief 2000 food-frequency questionnaire and categorized as ≤1 time/mo, 2–3 times/mo, 1 time/wk, 2 times/wk, or ≥3 times/wk. Mortality was ascertained through validated cases of death. To investigate the association between potato consumption and mortality, Cox regression models were constructed to estimate HRs with 95% CIs, with adjustment for potential confounders.

Results: Of the 4400 participants, 2551 (57.9%) were women with a mean ± SD age of 61.3 ± 9.2 y. During the 8-y follow-up, 236 participants died. After adjustment for 14 potential baseline confounders, and taking those with the lowest consumption of potatoes as the reference group, participants with the highest consumption of potatoes did not show an increased risk of overall mortality (HR: 1.11; 95% CI: 0.65, 1.91). However, subgroup analyses indicated that participants who consumed fried potatoes 2–3 times/wk (HR: 1.95; 95% CI: 1.11, 3.41) and ≥3 times/wk (HR: 2.26; 95% CI: 1.15, 4.47) were at an increased risk of mortality. The consumption of unfried potatoes was not associated with an increased mortality risk.

Conclusions: The frequent consumption of fried potatoes appears to be associated with an increased mortality risk. Additional studies in larger sample sizes should be performed to confirm if overall potato consumption is associated with higher mortality risk. This trial was registered at clinicaltrials.gov as NCT00080171.

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Neonatal vitamin D status from archived dried blood spots and future risk of fractures in childhood: results from the D-tect study, a population-based case-cohort study [Nutritional epidemiology and public health]

Background: Whether antenatal and neonatal vitamin D status have clinical relevance in fracture prevention has not been examined extensively, although observational studies indicate that fetal life may be a sensitive period in relation to bone growth and mineralization during childhood.

Objective: We examined whether 25-hydroxyvitamin D₃ [25(OH)D₃] concentrations in stored neonatal dried blood spot (DBS) samples are associated with pediatric fracture risk. We hypothesized that in particular, low neonatal vitamin D status may be a risk factor for fracture incidence among children.

Design: In a register-based case-cohort study design, the case group was composed of 1039 individuals who were randomly selected from a total of 82,154 individuals who were born during 1989–1999 and admitted to a Danish hospital with a fracture of the forearm, wrist, scaphoid bone, clavicle, or ankle at age 6–13 y. The subcohort was composed of 1600 individuals randomly selected from all Danish children born during 1989–1999. The neonatal 25(OH)D₃ concentrations in DBS samples were assessed by using highly sensitive chromatography-tandem mass spectrometry.

Results: The mean ± SD 25(OH)D₃ concentration for all subjects was 27.7 ± 18.9 nmol/L [median (IQR): 23.5 nmol/L (13.3, 37.3 nmol/L)] and showed significant monthly variation (P < 0.0001) with the highest values in July and August. Individuals in the middle quintile of neonatal 25(OH)D₃ had lower odds of sustaining a fracture than did those in the lowest quintile (adjusted OR: 0.75; 95% CI: 0.58, 0.96), but a global test did not show any significant overall association (adjusted P = 0.13).

Conclusions: This study suggested that neonatal vitamin D status does not influence subsequent fracture risk in childhood. This is in accordance with studies that report no association between antenatal maternal vitamin D status and childhood fractures. Further studies are needed to examine fracture risk in relation to prenatal vitamin D status in a randomized controlled setting.

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Supplement--Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) TOC link [In Memoriam]

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Calendar of Events [From the American Society for Nutrition]

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Reply to DR Thomas [Letters to the Editor]

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Increased vitamin D intake differentiated according to skin color is needed to meet requirements in young Swedish children during winter: a double-blind randomized clinical trial [Growth, development, and pediatrics]

Background: Dark skin and low exposure to sunlight increase the risk of vitamin D insufficiency in children.

Objective: The aim of the study was to evaluate the amount of vitamin D needed to ascertain that most children >4 y of age attain sufficient serum 25-hydroxyvitamin D [S-25(OH)D; i.e., ≥50 nmol/L] during winter regardless of latitude and skin color.

Design: In a longitudinal, double-blind, randomized, food-based intervention study, 5- to 7-y-old children from northern (63°N) and southern (55°N) Sweden with fair (n = 108) and dark (n = 98) skin were included. Children, stratified by skin color by using Fitzpatrick's definition, were randomly assigned to receive milk-based vitamin D₃ supplements that provided 2 (placebo), 10, or 25 μg/d during 3 winter months.

Results: Mean daily vitamin D intake increased from 6 to 17 μg and 26 μg in the intervention groups supplemented with 10 and 25 μg, respectively. In the intention-to-treat analysis, 90.2% (95% CI: 81.1%, 99.3%) of fair-skinned children randomly assigned to supplementation of 10 μg/d attained sufficient concentrations, whereas 25 μg/d was needed in dark-skinned children to reach sufficiency in 95.1% (95% CI: 88.5%, 100%). In children adherent to the study product, 97% (95% CI: 91.3%, 100%) and 87.9% (95% CI: 76.8%, 99%) of fair- and dark-skinned children, respectively, achieved sufficient concentrations if supplemented with 10 μg/d. By using 95% prediction intervals for 30 and 50 nmol S-25(OH)D/L, intakes of 6 and 20 μg/d are required in fair-skinned children, whereas 14 and 28 μg/d are required in children with dark skin.

Conclusion: Children with fair and dark skin require vitamin D intakes of 20 and 28 μg/d, respectively, to maintain S-25(OH)D ≥50 nmol/L, whereas intakes of 6 and 14 μg/d, respectively, are required to maintain concentrations ≥30 nmol/L during winter. This trial was registered at clinicaltrials.gov as NCT01741324.

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Dairy fat and cardiovascular disease: adjusting for potential confounders [Letters to the Editor]

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Reply to D Xie and Z Sheng [Letters to the Editor]

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Changes in total energy intake and macronutrient composition after bariatric surgery predict long-term weight outcome: findings from the Swedish Obese Subjects (SOS) study [Nutritional epidemiology and public health]

Background: Approximately 20–30% of obese patients do not achieve successful weight outcomes after bariatric surgery.

Objective: We examined whether short-term changes (≤0.5 y postsurgery) in energy intake and macronutrient composition after bariatric surgery could predict 10-y weight change.

Design: Participants were recruited from the Swedish Obese Subjects (SOS) study, which was a matched (nonrandomized) prospective trial that compared bariatric surgery with usual care for obese patients. A total of 2010 patients who underwent bariatric surgery were included in the study. Physical examinations (e.g., weight) and questionnaires (e.g., dietary questionnaire) were completed before and 0.5, 1, 2, 3, 4, 6, 8, and 10 y after surgery. For the main analytic strategy, a linear mixed model was implemented, which included repeated measures with a random intercept and an unstructured covariance matrix.

Results: Short-term changes in energy intake (P < 0.001) and in relative proportions of energy from carbohydrates (P < 0.001), fat (P < 0.001), and protein (P < 0.05) were associated with 10-y weight change after bariatric surgery. At the 10-y follow-up, men and women with the largest reductions in energy intake had lost 7.3% and 3.9% more weight, respectively, compared with that of subjects with the smallest intake reductions (P < 0.001). Greater weight loss was achieved in men and women who favored protein and carbohydrates over fat and in subjects who favored protein over carbohydrates than in individuals who favored the opposite changes in macronutrient composition (P < 0.05).

Conclusions: The level of energy restriction that is achieved at 0.5 y after bariatric surgery predicts long-term weight loss. Weight loss is also associated with a changing dietary macronutrient composition. This trial was registered at clinicaltrials.gov as NCT01479452.

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Relative contribution of {alpha}-carotene to postprandial vitamin A concentrations in healthy humans after carrot consumption [Vitamins, minerals, and phytochemicals]

Background: Asymmetric α-carotene, a provitamin A carotenoid, is cleaved to produce retinol (vitamin A) and α-retinol (with negligible vitamin A activity). The vitamin A activity of α-carotene–containing foods is likely overestimated because traditional analytic methods do not separate α-retinol derivatives from active retinol.

Objective: This study aimed to accurately characterize intestinal α-carotene cleavage and its relative contribution to postprandial vitamin A in humans after consumption of raw carrots.

Design: Healthy adults (n = 12) consumed a meal containing 300 g raw carrot (providing 27.3 mg β-carotene and 18.7 mg α-carotene). Triglyceride-rich lipoprotein fractions of plasma were isolated and extracted, and α-retinyl palmitate (αRP) and retinyl palmitate were measured over 12 h postprandially via high-performance liquid chromatography–tandem mass spectrometry. The complete profile of all α-retinyl esters and retinyl esters was measured at 6 h, and total absorption of α- and β-carotene was calculated.

Results: αRP was identified and quantified in every subject. No difference in preference for absorption of β- over α-carotene was observed (adjusting for dose, 28% higher, P = 0.103). After absorption, β-carotene trended toward preferential cleavage compared with α-carotene (22% higher, P = 0.084). A large range of provitamin A carotenoid conversion efficiencies was observed, with α-carotene contributing 12–35% of newly converted vitamin A (predicted contribution = 25.5%). In all subjects, a majority of α-retinol was esterified to palmitic acid (as compared with other fatty acids).

Conclusions: α-Retinol is esterified in the enterocyte and transported in the blood analogous to retinol. The percentage of absorption of α-carotene from raw carrots was not significantly different from β-carotene when adjusting for dose, although a trend toward higher cleavage of β-carotene was observed. The results demonstrate large interindividual variability in α-carotene conversion. The contribution of newly absorbed α-carotene to postprandial vitamin A should not be estimated but should be measured directly to accurately assess the vitamin A capacity of α-carotene–containing foods. This trial was registered at clinicaltrials.gov as NCT01432210.

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Sarcopenic obesity, weight loss, and mortality: the English Longitudinal Study of Ageing [Aging]

Background: Age-related sarcopenia describes the loss of muscle strength and often accompanies an increase in adiposity in the elderly.

Objective: We examined the association of sarcopenic obesity and changes in muscle strength and weight with the risk of mortality.

Design: Participants (n = 6864) were community-dwelling men and women (45.6% men; 54.4% women; mean ± SD age: 66.2 ± 9.5 y) from the English Longitudinal Study of Ageing. Handgrip strength and body mass index (BMI; in kg/m²) were measured at baseline and at a 4-y follow-up. Individual participant data were linked with death records from National Health Service registries. Sarcopenic obesity was defined as obese individuals (BMI ≥30) in the lowest tertile of sex-specific grip strength (<35.3 kg for men and <19.6 kg for women).

Results: There were 906 deaths over a mean follow-up of 8 y. Compared with the reference group (normal BMI and highest handgrip tertile), the risk of all-cause mortality increased as grip strength reduced within each BMI category. For participants in the lowest handgrip tertile, there was little difference in the risk between normal BMI (HR: 3.25; 95% CI: 1.86, 5.65), overweight (HR: 2.50; 95% CI: 1.44, 4.35), and obesity (HR: 2.66; 95% CI: 1.86, 3.80) after adjusting for covariates. The risk of all-cause mortality was significantly greater in participants who experienced weight loss over 4 y (HR: 2.21; 95% CI: 1.32, 3.71) and/or reduced hand grip strength (HR: 1.53; 95% CI: 10.07, 2.17) than in those with stable weight and grip strength, with the highest risk in those with both weight loss and reduced strength (HR: 3.77; 95% CI: 2.54, 5.60).

Conclusions: Sarcopenic obesity did not confer any greater risk than sarcopenia alone. Weight loss combined with sarcopenia presented the greatest risk of mortality.

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Learning to like vegetables during breastfeeding: a randomized clinical trial of lactating mothers and infants [Pregnancy and lactation]

Background: What lactating mothers eat flavors breast milk and, in turn, modifies their infants' acceptance of similarly flavored foods.

Objective: We sought to determine the effects of the timing and duration of eating a variety of vegetables during breastfeeding on the liking of vegetables in both members of the dyad.

Design: We conducted a randomized controlled study of 97 mother-infant dyads. Lactating mothers drank vegetable, beet, celery, and carrot juices for 1 mo beginning at 0.5, 1.5, or 2.5 mo postpartum or for 3 mo beginning at 0.5 mo postpartum. The control group drank equal volumes of water and avoided drinking the juices. Mothers rated the tastes of the juices and self-reported dietary intakes at each monthly visit (0.5–4.5 mo). After weaning, when 7.9 mo of age, infants' acceptance of plain, carrot-flavor (exposed flavor), and broccoli-flavor (nonexposed flavor) cereals was assessed on separate days.

Results: The timing of exposure affected the acceptance of the carrot flavor that did not generalize to the novel broccoli flavor. A relatively brief experience (1 mo) with vegetable flavors in mothers' milk, starting at 0.5 mo postpartum, was sufficient to shift the hedonic tone, which resulted in a faster rate of eating carrot-flavored cereal than that in infants who were exposed during subsequent months or not at all. One month of exposure had a greater effect than 3 mo of exposure or no exposure. Regardless of when exposure occurred, infants were less likely to display facial expressions of distaste initially when eating the carrot cereal. Over time, mothers liked the tastes of carrot, beet, and celery juices more, but no changes in dietary intake of vegetables were observed.

Conclusions: Early life may be an optimum time for both infants and their mothers to learn to like the taste of healthy foods. More research is needed to facilitate the liking and eating of these foods by mothers, which will, in turn, increase the likelihood of their feeding these foods to their children. This trial was registered at clinicaltrials.gov as NCT01667549.

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High dietary phosphorus density is a risk factor for incident chronic kidney disease development in diabetic subjects: a community-based prospective cohort study [Renal disease]

Background: High serum phosphorus concentrations are associated with an increased risk of cardiovascular disease and progression of chronic kidney disease (CKD). However, the relation between dietary phosphorus intake and CKD development has not been well evaluated.

Objective: In this study, we investigated the impact of dietary phosphorus density on the development of incident CKD in a cohort of subjects with normal renal function.

Design: Data were retrieved from the Korean Genome and Epidemiology Study, a prospective community-based cohort study. The study cohort consisted of subjects aged 40–69 y, who were followed up biennially from 2001 to 2014. A total of 873 subjects with diabetes mellitus (DM) and 5846 subjects without DM (non-DM) were included in the final analysis. The primary endpoint was incident CKD, defined as a composite of estimated glomerular filtration rate <60 mL · min^–1 · 1.73 m^–2 and/or the development of proteinuria.

Results: In the DM and non-DM groups, the mean ages of the participants were 55.6 ± 8.7 and 51.4 ± 8.6 y, the numbers of male subjects were 454 (52.0%) and 2784 (47.6%), and the mean estimated glomerular filtration rates were 91.6 ± 14.0 and 94.5 ± 14.0 mL · min^–1 · 1.73 m^–2, respectively. The mean values of dietary phosphorus density, defined as the ratio of a single-day dietary phosphorus amount to the total daily calorie intake, were 0.51 ± 0.08 mg/kcal in the DM group and 0.51 ± 0.07 mg/kcal in the non-DM group. During the follow-up, CKD newly developed in 283 (32.4%) and 792 subjects (13.5%) in the DM and non-DM groups, respectively. When the subjects were divided into quartiles according to the dietary phosphorus density in each group, the highest quartile was significantly associated with the development of incident CKD by multiple Cox proportional hazard analysis in the DM group (P = 0.02) but not in the non-DM group (P = 0.72).

Conclusions: High dietary phosphorus density is associated with an increased risk of CKD development in DM patients with normal renal function. The causality in this association needs to be tested in a randomized controlled trial.

http://ift.tt/2szKEJL

Effect of maternal antenatal and newborn supplementation with vitamin A on cognitive development of school-aged children in rural Bangladesh: a follow-up of a placebo-controlled, randomized trial [Growth, development, and pediatrics]

Background: The impact of early vitamin A supplementation on neurodevelopmental function has not been adequately studied. In rural Bangladesh we examined cognitive and motor function and scholastic achievement in a cohort of children who were exposed to vitamin A in utero or at birth.

Objective: The aim of this study was to examine independent and combined effects of antenatal and newborn supplementation with vitamin A on the cognitive function of children at 8 y of age.

Design: A cohort of rural Bangladeshi children from 2 previous double-blind, placebo-controlled cluster-randomized trials were revisited at age 8 y between February 2013 and June 2014. Data on sociodemographic, social, and physical conditions; schooling; child care behavior; anthropometric measures; and cognitive function were collected with the use of various psychometric assessment tools.

Results: Among 11,950 children from the parent trial who were last known to be alive, a subset of 1803 children balanced by treatment group in a selected contiguous study area were re-enrolled and 1613 (89%) provided consent for assessments. Of these, 1577 (87%) children had a complete cognitive evaluation. All groups were highly comparable on baseline variables collected in the previous trials and factors measured at re-enrollment. Overall, there was no impact of either maternal or newborn supplementation with vitamin A on intelligence, memory, and motor function. Compared with placebo, children who received both interventions had significantly better performance in reading, spelling, and math computation, with increased mean (95% CI) scores of 8.0 (2.2, 13.8), 6.8 (1.9, 11.7), and 4.8 (0.6, 9.0), respectively.

Conclusions: General intelligence or memory and motor functions were not affected by antenatal or newborn supplementation with vitamin A. Scholastic performance and aspects of executive function improved when both interventions were provided. These trials were registered at clinicaltrials.gov as NCT00198822 and NCT00128557.

http://ift.tt/2uiBoaj