Towards understanding the mechanisms of actions of CEACAM6 in cancer progression

Abstract

Human carcinoembryonic antigen (CEA) is the prototypic member of highly related cell surface glycoproteins that includes Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) and others. CEACAM6 (formerly NCA) that belongs to the immunoglobulin superfamily, is a cell adhesion proteins of the CEA family. It is normally expressed on the epithelial surfaces and the surface of myeloid (CD66c). CEACAM6 is a multi-functional glycoprotein that mediates homotypic binding with other CEA family members and heterotypic binding with integrin receptors. It functions by organizing tissue architecture and regulating different signal transduction, while aberrant expression leads to the development of human malignancies. It was firstly discovered in proliferating cells of adenomas and hyperplastic polyps in comparison to benign colonic tissue when over-expressed on the surface of various cell types in model systems. CEACAM6, functions as a pan-inhibitor of cell differentiation and cell polarization, and it also cause distortion of tissue architecture. Moreover, over-expression of CEACAM6 modulates cancer progression through aberrant cell differentiation, anti-apoptosis, cell growth and resistance to therapeutic agents. In addition, CEACAM6 over-expression in multiple malignancies promoting cell invasion and metastasis thereby representing an acquired advantage of tumor cells directly responsible for an invasive phenotype. This review will focus on the findings supporting the mechanism of actions linking the oncogenic potential of CEACAM6 to the onset of cancer progression and pathogenesis specially in breast cancer, and to validate CEACAM6 as a target to pave the way towards the design of efficient therapeutic strategies against BC.

This article is protected by copyright. All rights reserved.

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Co-existence of freshwater and marine T4-like myoviruses in a typical subtropical estuary

Abstract

Viruses are the most abundant biological entities on Earth and play an important role in microbial community dynamics and biogeochemical cycling, yet their ecological characteristics in estuarine ecosystems are unclear. Here, virioplankton communities in a typical subtropical estuary, the Jiulong River estuary (JRE) in China, were investigated. The abundance of virioplankton ranged from 1.01 ± 0.05 × 10⁷ to 1.62 ± 0.09 × 10⁷ particles mL⁻¹ in JRE, and the population size of viruses was correlated with temperature and nutrient levels. Three tailed viral morphotypes (myovirus, siphovirus and podovirus) were observed. Phylogenetic analysis showed that most of the g23 sequences in the JRE fell into three previously established groups (Marine, Paddy and Lake Groups) and two potential Estuary Groups. This demonstrates the co-existence of typical freshwater and marine T4-like myoviruses in the estuarine ecosystem, suggesting the movement of viruses and their hosts among biomes. Additionally, the spatial variation of g23 sequences suggests a geographic distribution pattern of T4-like myoviruses in the JRE, which might be shaped by the environmental gradient and/or their host distribution. These results provide valuable insights into the abundance, diversity and distribution patterns of virioplankton, as well as the factors influencing them, in subtropical estuarine ecosystems.

http://ift.tt/2z51bYN

A dysbiosis index to assess microbial changes in fecal samples of dogs with chronic inflammatory enteropathy

Abstract

Recent studies have identified various bacterial groups that are altered in dogs with chronic inflammatory enteropathies (CE) compared to healthy dogs. The study aim was to use quantitative PCR (qPCR) assays to confirm these findings in a larger number of dogs, and to build a mathematical algorithm to report these microbiota changes as a dysbiosis index (DI). Fecal DNA from 95 healthy dogs and 106 dogs with histologically confirmed CE was analyzed. Samples were grouped into a training set and a validation set. Various mathematical models and combination of qPCR assays were evaluated to find a model with highest discriminatory power. The final qPCR panel consisted of eight bacterial groups: total bacteria, Faecalibacterium, Turicibacter, Escherichia coli, Streptococcus, Blautia, Fusobacterium and Clostridium hiranonis. The qPCR-based DI was built based on the nearest centroid classifier, and reports the degree of dysbiosis in a single numerical value that measures the closeness in the l₂ – norm of the test sample to the mean prototype of each class. A negative DI indicates normobiosis, whereas a positive DI indicates dysbiosis. For a threshold of 0, the DI based on the combined dataset achieved 74% sensitivity and 95% specificity to separate healthy and CE dogs.

http://ift.tt/2j8dnS9

High-throughput sequencing revealed novel Dehalococcoidia in dechlorinating microbial enrichments from PCB-contaminated marine sediments

Abstract

In this study, six PCE-to-ethene dechlorinating cultures, fed with a fermentable substrate (lactate) or hydrogen as electron donor, were obtained from PCB and PCE dechlorinating microcosms constructed with PCB-contaminated marine sediments. A novel Chloroflexi member (OTU-DIS1) affiliated to Dehalococcoidales Incertae Sedis, only distantly related to known dechlorinating bacteria, dominated the enrichment cultures (up to 86% of total OTUs). Sulfate-, thiosulfate- and sulfur-reducing bacteria affiliated to genera Desulfobacter, Dethiosulfatibacter and Desulfuromusa were also found to lesser extent. Remarkably, tceA, vcrA and the bifunctional PCE/PCB dehalogenase genes pcbA1, pcbA4 and pcbA5 were found in all dechlorinating microbial enrichments indicating the coexistence of different Dehalococcoides mccartyi strains. The reductive dechlorination rate in each culture remained unvaried over long-term operation (≈ 30 months) and ranged between 0.85 and 0.97 mmol Cl⁻¹ released L⁻¹ d⁻¹ in the lactate-fed microbial enrichments and between 0.66 and 0.85 mmol Cl⁻¹ released L⁻¹ d⁻¹ in the H₂-fed microbial enrichments. Overall, this study highlights the presence of yet unexplored biodiversity in PCBs contaminated marine sediments and indicates these environments as promising sources of novel organohalide-respiring bacteria.

http://ift.tt/2AoXAlS

Tissue damage induced midgut stem cell proliferation and microbial dysbiosis in Spodoptera litura

Abstract

In the past decade, gut microbiota has come to the fore in search for the cause of disregulation in intestinal homeostasis. Here, we report a possible link between gut microbial dynamics and stress-inducing factors using the leaf worm moth Spodoptera litura as a model organism. Investigation reveals that S. litura exhibits dysbiosis i.e. alteration in the gut microbiota composition that might induce or suppress inflammation upon exposure to dextran sulfate sodium salt, a tissue damaging agent (DSS, 40 kD). It primarily corresponds to an expansion of the bacterial phylotypes Enterobacter sp., Pseudomonas sp., Escherichia sp. and Acinetobacter sp. belonging to subclass Gammaproteobacteria. To assess the role played by gut residents in midgut inflammation, we re-colonized the axenic insects with Pseudomonas, Enterobacter and Acinetobacter individually. We observed that Pseudomonas and Enterobacter monoassociated insects exhibit inflammatory effects like damage to gut epithelium and hyperproliferation of stem cells under stress conditions. Conversely, Acinetobacter promotes fitness in larvae and reduces inflammatory effects of DSS. However, we failed to detect phenotypic inflammatory changes like midgut epithelium damage and stem cell proliferation in axenic insects reared on DSS-supplemented diet. Our results highlight that gut commensals that apparently remain low in abundance and benign under typical conditions can exert modulatory (positive or negative) effects on host fitness in the presence of stimulator.

http://ift.tt/2j4IlKG

Comparison of Thaumarchaeotal populations from four deep sea basins

Abstract

The nitrogen cycle in the marine environment is strongly affected by ammonia-oxidizing Thaumarchaeota. In some marine settings, Thaumarchaeotes can comprise a large percentage of the prokaryotic population. To better understand the biogeographic patterns of Thaumarchaeotes, we sought to investigate differences in their abundance and phylogenetic diversity between geographically distinct basins. Samples were collected from four marine basins (The Caspian Sea, the Great Australian Bight, and the Central and Eastern Mediterranean). The concentration of bacterial and archaeal 16S rRNA genes and archaeal amoA genes were assessed using qPCR. Minimum entropy decomposition was used to elucidate the fine-scale diversity of Thaumarchaeotes. We demonstrated that there were significant differences in the abundance and diversity of Thaumarchaeotes between these four basins. The diversity of Thaumarchaeotal oligotypes differed between basins with many oligotypes only present in one of the four basins, which suggests that their distribution showed biogeographic patterning. There were also significant differences in Thaumarchaeotal community structure between these basins. This would suggest that geographically distant, yet geochemically similar basins may house distinct Thaumarchaeaotal populations. These findings suggest that Thaumarchaeota are very diverse and that biogeography in part contributes in determining the diversity and distribution of Thaumarchaeotes.

http://ift.tt/2AoONR9

Community structure of rare methanogenic archaea: insight from a single functional group

Abstract

The rare biosphere, the low abundant microbial populations, is suggested to be a conserved way of microbial life. Here we conducted a molecular survey of rare methanogenic archaea in the environment targeting the mcrA gene in order to test if general concepts associated with the structure of the rare bacterial biosphere also apply to single functional groups. Similar to what is known about rare bacterial communities, the contribution of rare methanogens to the alpha diversity is much larger than to Bray-Curtis measures. Moreover, a similar core group of methanogens harbored by the abundant and rare communities suggests similar sources and environmental controls of both groups. Among the communities of different levels of rarity, the conditionally rare methanogenic taxa largely account for the overall community dynamics of the rare biosphere and likely enter the dominant community under favorable environmental conditions. In addition, we observed a positive correlation between the alpha diversity and the production of methane when the rare taxa were taken into account. This supports the concept that increasing microbial biodiversity enhances ecological function. The composition and environmental associations of the rare methanogenic biosphere allow us to conclude that rarity is a conserved way also for single functional groups.

http://ift.tt/2j6EuNt

Broad-range survey of vector-borne pathogens and tick host identification of Ixodes ricinus from Southern Czech Republic

Abstract

Ixodes ricinus ticks are vectors of numerous human and animal pathogens. They are host generalists able to feed on more than 300 vertebrate species. The prevalence of tick-borne pathogens is influenced by host–vector–pathogen interactions that results in spatial distribution of infection risk. Broad-range polymerase chain reaction electrospray ionization mass spectrometry (PCR/ESI-MS) was used to analyze 435 I. ricinus nymphs from four localities in the south of the Czech Republic for the species identification of tick-borne pathogens. Borrelia burgdorferi sensu lato spirochetes were the most common pathogen detected in the ticks; 21% of ticks were positive for a single genospecies and 2% were co-infected with two genospecies. Other tick-borne pathogens detected included Rickettsia helvetica (3.9%), R. monacensis (0.2%), Anaplasma phagocytophilum (2.8%), Babesia venatorum (0.9%), and Ba. microti (0.5%). The vertebrate host of the ticks was determined using PCR followed by reverse line blot hybridization from the tick's blood-meal remnants. The host was identified for 61% of ticks. DNA of two hosts was detected in 16% of samples with successful host identification. The majority of ticks had fed on artiodactyls (50.7%) followed by rodents (28.6%) and birds (7.8%). Other host species were wild boar, deer, squirrels, field mice and voles.

http://ift.tt/2AoXue0

Effects of host traits and land-use changes on the gut microbiota of the Namibian black-backed jackal ( Canis mesomelas )

Abstract

Host traits and environmental factors drive the natural variation in gut microbiota, and disruption in homeostasis can cause infections and chronic diseases. African wildlife is increasingly facing human-induced agricultural habitats, which also amplifies the contact probability with livestock with unknown consequences for wildlife gut microbiotas and the risk of transmission of potentially pathogenic bacteria. We applied high-throughput sequencing of bacterial 16S rRNA genes and microsatellite genotyping to investigate the impact of host traits and habitat use on the gut microbiotas of black-backed jackals (Canis mesomelas). This abundant carnivore inhabits livestock and game farms in central Namibia and is often persecuted as pathogen reservoir and vector. We further compared the gut microbiotas of black-backed jackals to other wild and domestic carnivores, herbivores and an omnivore, to disentangle the effects of environment, host species and dietary preference. In black-backed jackals, intrinsic host traits had a stronger impact in shaping the host–bacteria relationship than environmental factors. Nevertheless, the abundance of bacterial operational taxonomic units (OTUs) differed in individuals from livestock and game farms for specific bacterial genera such as Lactobacillus and Clostridium. We found, however, no evidence that black-backed jackals harbour abnormal levels of OTUs related to potential bacterial pathogens or that livestock farming has a negative impact on their health. We present here the first study investigating simultaneously the impact of host traits and environmental factors on gut microbiotas of a wildlife carnivore that occurs in a human-modified habitat.

http://ift.tt/2j96csD

Ammonia oxidisers in a non-nitrifying Brazilian savanna soil

Abstract

Low nitrification rates in Brazilian savanna (Cerrado) soils have puzzled researchers for decades. Potential mechanisms include biological inhibitors, low pH, low microbial abundance and low soil moisture content, which hinders microbial activity, including ammonia oxidation. Two approaches were used to evaluate these potential mechanisms: (i) manipulation of soil moisture and pH in microcosms containing Cerrado soil and (ii) assessment of nitrification inhibition in slurries containing mixtures of Cerrado soil and an actively nitrifying agricultural soil. Despite high ammonium concentration in Cerrado soil microcosms, little NO₃⁻ accumulation was observed with increasing moisture or pH, but in some Cerrado soil slurries, ammonia-oxidising archaea (AOA) amoA transcripts were detected after 14 days. In mixed soil slurries, the final NO₃⁻ concentration reflected the initial proportions of agricultural and Cerrado soils in the mixture, providing no evidence of nitrification inhibitors in Cerrado soil. AOA community denaturing gradient gel electrophoresis profiles were similar in the mixed and nitrifying soils. These results suggest that nitrification in Cerrado soils is not constrained by water availability, ammonium availability, low pH or biological inhibitors, and alternative potential explanations for low nitrification levels are discussed.

http://ift.tt/2AoOFkD

Free amino nitrogen concentration correlates to total yeast assimilable nitrogen concentration in apple juice

Abstract

Yeast assimilable nitrogen (YAN) is essential for yeast growth and metabolism during apple (Malus x domestica Borkh.) cider fermentation. YAN concentration and composition can impact cider fermentation kinetics and the formation of volatile aroma compounds by yeast. The YAN concentration and composition of apples grown in Virginia, USA over the course of two seasons was determined through analysis of both free amino nitrogen (FAN) and ammonium ion concentration. FAN was the largest fraction of YAN, with a mean value of 51 mg N L⁻¹ FAN compared to 9 mg N L⁻¹ ammonium. Observed YAN values ranged from nine to 249 mg N L⁻¹, with a mean value of 59 mg N L⁻¹. Ninety-four percent of all samples analyzed in this study contained <140 mg N L⁻¹ YAN, a concentration generally considered the minimum level needed in grape-based wines for yeast to fully utilize all of the fermentable sugars. FAN concentration was correlated with total YAN concentration, but ammonium concentration was not. Likewise, there was no correlation between FAN and ammonium concentration.

Yeast assimilable nitrogen (YAN), an important parameter in cider fermentation, was measured in two growing seasons in a range of apple cultivars grown in Virginia, USA and used in cider production. The concentration of free amino nitrogen was correlated with the total yeast assimilable nitrogen concentration, a finding that could streamline the process of total YAN determination for cider makers. The YAN concentration was not consistent from year to year, and on average, was below the minimum recommended value for successful fermentation.

http://ift.tt/2hlOX6Z

Zika virus (ZIKV) Replication is Substantially Inhibited by Novel Favipiravir and Interferon-alpha Combination Regimens [PublishAheadOfPrint]

Zika virus (ZIKV) is a major public health concern due to its overwhelming spread into the Americas. Currently there are neither licensed vaccines nor antiviral therapies available for the treatment of ZIKV. We aimed to identify and rationally optimize effective therapeutic regimens for ZIKV by evaluating the antiviral potential of approved broad-spectrum antiviral agents favipiravir (FAV), interferon-alpha (IFN), and ribavirin (RBV) as single agent and combinations. For these studies, Vero cells were infected with ZIKV in the presence of increasing concentrations of FAV, IFN, or/and RBV for four days. Supernatants were harvested daily and viral burden was quantified by plaque assay on Vero cells. The time-course of viral burden during treatment in vitro was characterized by a novel translational, mechanism-based model which was subsequently used to rationally optimize combination dosage regimens. The combination regimen of FAV plus IFN provided the greatest extent of viral inhibition without cytotoxicity, reducing viral burden by 4.4-log₁₀ plaque forming units/ml at concentrations of 250 μM FAV with 100 IU/ml IFN. Importantly, these concentrations are achievable in man. The translational, mechanism-based model yielded unbiased and reasonably precise curve fits. Simulations with the model predicted that clinically relevant regimens of FAV plus IFN would markedly reduce viral burden in man, resulting in at least a 10,000-fold reduction in virus during the first four days of treatment. These findings highlight the substantial promise of rationally optimized FAV plus IFN combination dosage regimens which should be further investigated to combat ZIKV.

http://ift.tt/2yCMzAk

Validation of putative apicoplast targeting drugs using a chemical supplementation assay in cultured human malaria parasites [PublishAheadOfPrint]

Malaria parasites contain a relict plastid, the apicoplast, which is considered an excellent drug target due to its bacterial-like ancestry. Numerous parasiticidals have been proposed to target the apicoplast, but few have had their actual targets substantiated. Isopentenyl pyrophosphate (IPP) production is the sole required function of the apicoplast in the blood stage of the parasite life cycle, and IPP supplementation rescues parasites from apicoplast perturbing drugs. Hence, any drug that kills parasites when IPP is supplied in culture must have a non-apicoplast target. Here we use IPP supplementation to discriminate whether 23 purported apicoplast targeting drugs are on or off-target. We demonstrate that a prokaryotic DNA replication inhibitor (ciprofloxacin), several prokaryotic translation inhibitors (chloramphenicol, doxycycline, tetracycline, clindamycin, azithromycin, erythromycin, clarithromycin), a tRNA synthase inhibitor (mupirocine), and two IPP synthesis pathway inhibitors (fosmidomycin or FR900098) have apicoplast targets. Intriguingly, the latter two drugs leave the apicoplast intact, whereas the others eventually result in apicoplast loss. Actinonin, an inhibitor of bacterial post-translation modification does not produce a typical delayed-death response but is rescued with IPP, thereby confirming its apicoplast target. Parasites treated with putative apicoplast fatty acid pathway inhibitors could not be rescued, demonstrating that these drugs have their primary targets outside the apicoplast, which agrees with dispensability of the apicoplast fatty acid synthesis pathways in the blood stage of malaria parasites. IPP supplementation provides a simple test of whether a compound has a target in the apicoplast and can be used to screen novel compounds for mode of action.

http://ift.tt/2m0kZXS

Acinetobacter pittii from companion animals co-harbouring blaOXA-58, the tet39 region and other resistance genes on a single plasmid [PublishAheadOfPrint]

Besides Acinetobacter baumannii, A. pittii is an important nosocomial pathogen (1, 2)....

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Cloning and Expression of Novel Aminoglycoside Phosphotransferase Genes from Campylobacter and Their Role in the Resistance to Six Aminoglycosides [PublishAheadOfPrint]

Nine aph genes, including aph(2'')-Ib, Ic, Ig, If, If1, If3, Ih, aac(6')-Ie/aph(2'')-Ia, and aac(6')-Ie/aph(2'')-If2 were previously identified in Campylobacter. To measure the contribution of these alleles to aminoglycoside resistance, we cloned nine genes into the pBluescript and expressed them in E. coli DH5α. The nine aph expressed in E.coli showed varying levels of resistance to gentamicin, kanamycin and tobramycin. Three genes, aac(6'')-Ie/aph(2'')-Ia, aph2''-If1 and aph2''-Ig showed increased MICs to amikacin and five aph genes were transferrable.

http://ift.tt/2lWpVgl

Environmental triazole induces cross-resistance to clinical drugs and affects morphophysiology and virulence of Cryptococcus gattii and C. neoformans [PublishAheadOfPrint]

Cryptococcus gattii and Cryptococcus neoformans are environmental fungi that cause cryptococcosis, which is usually treated with amphotericin B and fluconazole. However, therapeutic failure is increasing because of the emergence of resistant strains. Because these species are constantly isolated from vegetal materials and the usage of agrochemicals is growing, we postulate pesticides could be responsible for the altered susceptibility of these fungi to clinical drugs. Therefore, we evaluated the influence of the pesticide tebuconazole on the susceptibility to clinical drugs, morphophysiology, and virulence of C. gattii and C. neoformans strains. The results showed that tebuconazole exposure caused in vitro cross-resistance (CR) between the agrochemical and clinical azoles (fluconazole, itraconazole, ravuconazole), but not with amphotericin B. In some strains, CR was observed even after the exposure ceased. Further, tebuconazole exposure changed the morphology, including pseudohyphae formation in C. neoformans H99, and surface charge of the cells. Although the virulence of both species previously exposed to tebuconazole was decreased in mice, the tebuconazole-exposed colonies recovered from the lungs were more resistant to azole drugs than non-exposed cells. This in vivo CR was confirmed when fluconazole was not able to reduce the fungal burden in the lungs of mice. The tolerance to azoles could be due the increased of expression of the ERG11 in both species, and efflux pumps (AFR1 and MDR1) in C. neoformans. Our study supports the idea that agrochemical usage can significantly affect human pathogens present in the environment by affecting their resistance to clinical drugs.

http://ift.tt/2yBUttT

RISK FACTORS AND OUTCOMES FOR INEFFECTIVE EMPIRIC TREATMENT IN GRAM-NEGATIVE SEPSIS: STRATIFICATION BY ONSET OF INFECTION [PublishAheadOfPrint]

Sepsis and septic shock remain serious infections with reported mortality rates in excess of forty percent. Timely antibiotic therapy in sepsis and septic shock is recognized as an important determinant of outcome. However, the administration of ineffective empiric treatment (IET) (an initial antibiotic regimen that is not active against the identified pathogen(s) based on in vitro susceptibility testing) is associated with excess mortality compared to effective empiric treatment (EET). We examined all hospitalized patients between January 2010 and October 2015 at Barnes-Jewish Hospital with the presence of a sterile site (blood, or pleural, abdominal, cerebrospinal, synovial, and pericardial fluid) culture positive for Gram-negative (GN) bacteria combined with primary or secondary ICD-9-CM codes for severe sepsis (995.92) or septic shock (785.52). Variables significantly associated with early-onset (< 48 hours of hospitalization) IET of GN sterile site sepsis and septic shock included age, recent hospitalization and prior intravenous antibiotics. Late-onset IET was associated with increasing hospitalization days before infection onset and prior intravenous antibiotic administration. For patients with early-onset infection we found no difference in survival between patients receiving IET and EET. However, patients receiving IET in the late-onset infection group had a statistically lower survival compared to those receiving EET. These data suggest that risk factors and outcomes for IET can vary based on the onset of infection. Our results also highlight the importance of prior intravenous antibiotic exposure as a risk factor for IET in GN bacterial infections regardless of the onset on infection.

http://ift.tt/2m3iJPJ

Evaluation of Oritavancin Dosing Strategies against Vancomycin-Resistant Enterococcus faecium Isolates with or without Reduced Susceptibility to Daptomycin in an in vitro Pharmacokinetic/Pharmacodynamic Model. [PublishAheadOfPrint]

Clinical development of nonsusceptibility to the lipopeptide antibiotic daptomycin remains a serious concern during therapy for infections caused by vancomycin-resistant Enterococcus faecium (VREfm). The long-acting lipoglycopeptide oritavancin exhibits potent in vitro activity against VREfm although its safety and efficacy in treating clinical VREfm infections have not been established. In this study, novel dosing regimens of daptomycin and oritavancin were assessed against both VREfm and daptomycin-nonsusceptible VREfm isolates in an in vitro pharmacokinetic/pharmacodynamic model.

http://ift.tt/2yDciZa

Overtreatment of Asymptomatic Candiduria among Hospitalized Patients: A Multi-institutional Study [PublishAheadOfPrint]

Candiduria is common in hospitalized patients and asymptomatic candiduria contributes to antifungal overuse. Guidelines for asymptomatic candiduria do not recommend antifungal use, rather the elimination of predisposing factors. It is unknown whether these recommendations are being followed. The primary objective of this study was to characterize candiduria management among hospitalized patients. This was a retrospective cohort study of a random sample of 305 hospitalized patients with candiduria at four U.S. medical centers from January 2010 to December 2013. Patients were classified as asymptomatic or symptomatic based on established criteria and data were collected by chart review. IDSA treatment guideline adherence and its association with clinical outcomes including candiduria recurrence (short- and long-term) and 30-day readmission were assessed. Eighty percent of patients were classified asymptomatic candiduria. Overall, 143 (47%) patients were not managed according to guidelines including 105/243 (43%) in the asymptomatic candiduria group and 38/62 (61%) in the symptomatic group (p=0.01). Discordance among asymptomatic patients was driven by overtreatment with an antifungal (98/105, 93%). Thirty-three percent of patients with asymptomatic candiduria not managed according to guidelines were treated for over 7 days, and 5% received over 14 days of therapy. Fluconazole was the most commonly used empiric antifungal among asymptomatic candiduria patients (96%) followed by micafungin (4%). Asymptomatic candiduria patients not managed according to guidelines had a trend toward higher 30-day readmission (35% vs. 26%, p=0.27). Inappropriate management of candiduria among hospitalized patients was high, leading to over-treatment with antifungal therapy.

http://ift.tt/2lXJWmO

Combating multi-drug resistant pathogens with host-directed non-antibiotic therapeutics [PublishAheadOfPrint]

Earlier, we reported that 3 Food and Drug Administration-approved drugs, trifluoperazine (TFP, anti-psychotic), amoxapine (AXPN, anti-depressant), and doxapram (DXP, breathing stimulant), identified from an in vitro murine macrophage cytotoxicity screen, provided 40-60% protection to mice against pneumonic plague when administered at the time of infection for 1-3 days. In this study, the therapeutic potential of these drugs was further evaluated in mice when administered up to 48 h post-infection against pneumonic plague. While efficacy of TFP was somewhat diminished as treatment was delayed to 24 h, protection of mice with AXPN and DXP increased as treatment was progressively delayed to 24 h. At 48 h post infection, these drugs, when administered in combination with levofloxacin, provided significant, up to 100%, protection to animals against pneumonic or bubonic challenge. Likewise, when used in combination with vancomycin, all three drugs provided 80-100% protection from fatal oral Clostridium difficile infection in mice when administered 24 h post infection. Furthermore, AXPN provided 40-60% protection against respiratory infection with Klebsiella pneumoniae when administered at the time of infection or 24 h post infection. Using the same in vitro cytotoxicity assay, we identified additional 76/780 non-antibiotic drugs effective against K. pneumoniae. For Acinetobacter baumannii, 121 non-antibiotic drugs were identified to inhibit bacterial-induced cytotoxicity in murine macrophages. Of these 121 drugs, 13 inhibited macrophage cytotoxicity with two additional multiple-antibiotic resistant strains. Six of these drugs decreased intracellular survival of all three A. baumannii strains in macrophages. These results provided further evidence of the broad applicability and utilization of drug repurposing screening to identify new therapeutics to combat multi-drug resistant pathogens of public health concern.

http://ift.tt/2yBUpdD

Comparative Assessment of Tedizolid Pharmacokinetics and Tissue Penetration Between Diabetic Patients with Wound Infections and Healthy Volunteers via In Vivo Microdialysis [PublishAheadOfPrint]

Herein, we present pharmacokinetic and tissue penetration data for oral tedizolid in hospitalized patients with diabetic foot infections (DFI) compared with healthy volunteers. Participants received oral tedizolid phosphate 200mg every 24 hours for 3 doses to achieve steady-state. A microdialysis catheter was inserted into the subcutaneous tissue near the margin of the wound for patients or into thigh tissue of volunteers. Following the 3^rd dose, 12 blood and 14 dialysate fluid samples were collected over 24 hours to characterize tedizolid concentrations in plasma and interstitial extracellular fluid of soft tissue. Mean ± SD tedizolid pharmacokinetic parameters in plasma for patients compared with volunteers, respectively, were: maximum concentration (C_max) = 1.5 ± 0.5 versus 2.7 ± 1.1 mg/L (p=0.005), time to C_max (T_max) [median (range)] = 5.9 (1.2-8.0) versus 2.5 (2.0-3.0 hours (p=0.003), half-life (t_1/2) = 9.1 ± 3.6 versus 8.9 ± 2.2 hours (p=0.932), and plasma area under the curve for the dosing interval (AUC_p) = 18.5 ± 9.7 versus 28.7 ± 9.6 mg_·h/L (p=0.004). The tissue AUC for the dosing interval was 3.4 ± 1.5 versus 5.2 ± 1.6 mg_·h/L (p=0.075). Tissue penetration, median (range) was 1.1 (0.3 - 1.6) versus 0.8 (0.7-1.0) (p=0.351). Despite lower plasma C_max and delayed T_max values for patients with DFI relative to healthy volunteers, the penetration and exposure into tissue were similar. Based on available pharmacodynamic thresholds for tedizolid, the plasma and tissue exposures using the oral 200mg once-daily regimen are suitable for further study in treatment of DFI.

http://ift.tt/2lYzgV2

Activity of Meropenem-Vaborbactam in Mouse Models of Infection due to KPC-producing Carbapenem-Resistant Enterobacteriaceae (CRE) [PublishAheadOfPrint]

Meropenem-vaborbactam (Vabomere™) is highly active against Gram-negative pathogens, especially KPC-producing, carbapenem-resistant Enterobacteriaceae. The objective of these studies was to evaluate the efficacy of meropenem alone and in combination with vaborbactam in mouse thigh and lung infection models. Thighs or lungs of neutropenic mice were infected with KPC-producing carbapenem-resistant Enterobacteriaceae with meropenem MICs ranging from ≤ 0.06 – 8 mg/L in the presence of vaborbactam 8 mg/L. Mice were treated with meropenem alone or meropenem in combination with vaborbactam every 2 hours for 24 hours to provide exposures comparable to 2 g doses of each component in humans. Meropenem administered in combination with vaborbactam produced bacterial killing in all strains tested while treatment with meropenem alone either produced less than 0.5 log CFU/tissue of bacterial killing or none at all. In the thigh model, eleven strains were treated with the combination of meropenem plus vaborbactam (300 + 50 mg/kg). This combination produced between 0.8 to 2.89 logs of bacterial killing compared to untreated controls at the start of treatment. In the lung infection model, two strains were treated with the same dosage regimen of meropenem and vaborbactam. The combination produced more than 1.83 logs of bacterial killing against both strains tested compared to untreated controls at the start of treatment. Overall, these data suggest that meropenem-vaborbactam may have utility in the treatment of infections due to KPC-producing, carbapenem-resistant Enterobacteriaceae.

http://ift.tt/2yDceso

Metabolic Mitigation of Staphylococcus aureus Vancomycin Intermediate-Level Susceptibility [PublishAheadOfPrint]

Staphylococcus aureus is a major human pathogen whose infections are increasingly difficult to treat due to increased antibiotic resistance, including resistance to vancomycin. Vancomycin intermediate-level susceptibility S. aureus (VISA) strains develop resistance to vancomycin through adaptive changes that are incompletely understood. Central to this adaptation are metabolic changes that permit growth in the presence of vancomycin. To define the metabolic changes associated with adaptive resistance to vancomycin in S. aureus, the metabolomes of a vancomycin sensitive and VISA strain pair isolated from the same patient shortly after vancomycin therapy began and following vancomycin treatment failure were analyzed. The metabolic adaptations included increased acetogenesis, carbon flow through the pentose phosphate pathway, wall teichoic acid and peptidoglycan precursor biosynthesis, and purine biosynthesis and decreased tricarboxylic acid (TCA) cycle activity. The significance of these metabolic pathways for vancomycin intermediate susceptibility was determined by assessing the synergist potential of human-use approved inhibitors of these pathways in combination with vancomycin against VISA strains. Importantly, inhibitors of amino sugar and purine biosynthesis acted synergistically with vancomycin to kill a diverse set of VISA strains, suggesting that combinatorial therapy could augment the efficacy of vancomycin even in patients infected with VISA strains.

http://ift.tt/2m1zKtA

Improving Genomic Prediction in Cassava Field Experiments Using Spatial Analysis

Cassava (Manihot esculenta Crantz) is an important staple food in sub-Saharan Africa. Breeding experiments were conducted at the International Institute of Tropical Agriculture in cassava to select elite parents. Taking into account the heterogeneity in the field while evaluating these trials can increase the accuracy in estimation of breeding values. We used an exploratory approach using the parametric spatial kernels Power, Spherical, and Gaussian to determine the best kernel for a given scenario. The spatial kernel was fit simultaneously with a genomic kernel in a genomic selection model. Predictability of these models was tested through a 10-fold cross-validation method repeated five times. The best model was chosen as the one with the lowest prediction root mean squared error compared to that of the base model having no spatial kernel. Results from our real and simulated data studies indicated that predictability can be increased by accounting for spatial variation irrespective of the heritability of the trait. In real data scenarios we observed that the accuracy can be increased by a median value of 3.4%. Through simulations we showed that a 21% increase in accuracy can be achieved. We also found that Range (row) directional spatial kernels, mostly Gaussian, explained the spatial variance in 71% of the scenarios when spatial correlation was significant.

http://ift.tt/2zCIr3l

Characterization of a beta-glucosidase from Bacillus licheniformis and its effect on bioflocculant degradation

Bacillus licheniformis CGMCC 2876, an aerobic spore-forming bacterium, produces a polysaccharide bioflocculant that is biodegradable and harmless. The present study determined that β-gluc...

http://ift.tt/2iD3LdZ

Effects of Spaceflight on Astronaut Brain Structure as Indicated on MRI

Microgravity during spaceflight occurs when the force of gravity is unbalanced and the net force becomes so weak that virtual weightlessness results. The effects of microgravity on the brain have received attention in relation to a syndrome involving optic-disk edema and elevated intracranial…

http://ift.tt/2hlqMFL

The Dilemma of Two Innovative Therapies for Spinal Muscular Atrophy

If you have made a diagnosis of spinal muscular atrophy (SMA) type 1 (also known as Werdnig–Hoffman disease) in a child, then you have vivid memories of informing desperate parents that there is nothing you can do for their child. Two innovative therapies for SMA may now bring some hope — but what…

http://ift.tt/2zohaP9

Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy

Spinal muscular atrophy (SMA) is a severe childhood monogenic disease resulting from loss or dysfunction of the gene encoding survival motor neuron 1 (SMN1). The incidence of this disease is approximately 1 in 10,000 live births, with a carrier frequency of 1 in 54. SMA is characterized by the…

http://ift.tt/2zkZdAV

Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy

Spinal muscular atrophy is an autosomal recessive neuromuscular disorder that is characterized by progressive muscle atrophy and weakness, with an estimated incidence of 1 in 11,000 live births. Approximately 60% of infants who are born with spinal muscular atrophy have type 1 disease, which is…

http://ift.tt/2ybPcoA

The Success of Sinister Right-Handers in Baseball

To the Editor: Left-handed people possess less hemispheric lateralization than right-handers, meaning that there is generally less differentiation between the functions of the right and left hemispheres of the brain. In a letter published in the Journal in 1982, McLean and Ciurczak claimed that in…

http://ift.tt/2zo2hwq

Officer of the Law

"I blacked out driving the other day," my patient said. "Just for a few seconds, in a parking lot, and I've been fine ever since." Her neurologic deficits had almost resolved, and I had been ready to send her home. It was a busy night in the emergency department (ED). I had many patients to see,…

http://ift.tt/2y8Ygdz

Histopathological Findings in Brain Tissue Obtained during Epilepsy Surgery

In 2015, the World Health Organization (WHO) recognized epilepsy as a serious public health concern. Approximately 50 million people worldwide currently have epilepsy, and more than 30% of patients with epilepsy have inadequate seizure control with drug therapy. Epilepsy surgery is appropriate for…

http://ift.tt/2hgSR17

Surgery for Drug-Resistant Epilepsy in Children

Children and adolescents with drug-resistant epilepsy are at increased risk for poor long-term intellectual and psychosocial outcomes, along with a poor health-related quality of life. In this form of recalcitrant epilepsy, appropriate surgical management is often undertaken with the goal of…

http://ift.tt/2zkV2Ye

Tezacaftor–Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del

Cystic fibrosis is caused by a reduced quantity or function of cystic fibrosis transmembrane conductance regulator (CFTR) protein, owing to mutations in CFTR. A loss of chloride secretion causes impaction of mucus in the airways, gastrointestinal tract, and exocrine organs, with important clinical…

http://ift.tt/2yb9Chr

Tezacaftor–Ivacaftor in Residual-Function Heterozygotes with Cystic Fibrosis

Cystic fibrosis is a progressive, systemic, life-limiting, autosomal recessive disease that is caused by reduced quantity or function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein due to mutations in the CFTR gene. Loss of chloride transport activity due to defects in…

http://ift.tt/2zkZkfP

Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy

Spinal muscular atrophy (SMA) is a severe childhood monogenic disease resulting from loss or dysfunction of the gene encoding survival motor neuron 1 (SMN1). The incidence of this disease is approximately 1 in 10,000 live births, with a carrier frequency of 1 in 54. SMA is characterized by the…

http://ift.tt/2zkZdAV

Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy

Spinal muscular atrophy is an autosomal recessive neuromuscular disorder that is characterized by progressive muscle atrophy and weakness, with an estimated incidence of 1 in 11,000 live births. Approximately 60% of infants who are born with spinal muscular atrophy have type 1 disease, which is…

http://ift.tt/2ybPcoA

Circling Back for the Diagnosis

Foreword. In this Journal feature, information about a real patient is presented in stages (boldface type) to an expert clinician, who responds to the information, sharing his or her reasoning with the reader (regular type). The authors' commentary follows. Stage. A 28-year-old man presented to the…

http://ift.tt/2j5D99A

Fertility Preservation in Women

In recent years, the demand for fertility preservation for oncologic and nononcologic reasons, as well as personal reasons, has increased dramatically, and meeting this demand will prove a major challenge in the coming years. Currently, embryo cryopreservation and mature-oocyte cryopreservation…

http://ift.tt/2hbouFJ

A CRISPR Way to Diagnose Infectious Diseases

During the past 20 years, tremendous advances in methods involving polymerase-chain-reaction (PCR) assays and DNA sequencing have transformed clinical virology and microbiology laboratories. These new methods allow accurate and rapid diagnosis of a wide array of infectious diseases and facilitate…

http://ift.tt/2zltj7j

Mandating Coverage for Fertility Preservation — A Step in the Right Direction

Connecticut and Rhode Island recently became the first U.S. states to pass legislation requiring insurance coverage of fertility-preservation services for patients about to undergo a medical treatment — surgery, radiation, or chemotherapy — that may have deleterious effects on the gonads. Although…

http://ift.tt/2zBC402

Control of innate-like B cell location for compartmentalised IgM production

Lucy H Jackson-Jones | Cécile Bénézech

http://ift.tt/2lVfKZe

Heme and hemolysis in innate immunity: adding insult to injury

Rui Martins | Sylvia Knapp

http://ift.tt/2lYefd6

Pigmented Macule — A Skin Manifestation of Invasive Breast Cancer

Figure 1.

http://ift.tt/2hOlAHH

Mandating Coverage for Fertility Preservation — A Step in the Right Direction

Connecticut and Rhode Island recently became the first U.S. states to pass legislation requiring insurance coverage of fertility-preservation services for patients about to undergo a medical treatment — surgery, radiation, or chemotherapy — that may have deleterious effects on the gonads. Although…

http://ift.tt/2zBC402

Fertility Preservation in Women

In recent years, the demand for fertility preservation for oncologic and nononcologic reasons, as well as personal reasons, has increased dramatically, and meeting this demand will prove a major challenge in the coming years. Currently, embryo cryopreservation and mature-oocyte cryopreservation…

http://ift.tt/2hbouFJ

Liposuction for Swelling in Patients with Lymphedema

To the Editor: Lymphedema is a progressive, noncurable condition that is caused by anomalous development of the lymphatic system or trauma to lymphatic vasculature. The disease most commonly affects the limbs because of injury to or removal of lymph nodes. Fluid accumulates in the interstitial…

http://ift.tt/2h96yew

Nutritional Management of Chronic Kidney Disease

Chronic kidney disease, defined as evidence of structural or functional renal impairment for 3 or more months, is generally progressive and irreversible, affecting multiple metabolic pathways. Altered protein and energy homeostasis, abnormal protein catabolism, acid–base derangements, and hormonal…

http://ift.tt/2AdZJA0

Primary Care Spending Rate — A Lever for Encouraging Investment in Primary Care

Why doesn't the United States invest more in primary care? A large body of evidence suggests that greater investment in primary care is good for patients and health systems. Greater use of primary care has been associated with lower costs, higher patient satisfaction, fewer hospitalizations and…

http://ift.tt/2zmBLWe

Circling Back for the Diagnosis

Foreword. In this Journal feature, information about a real patient is presented in stages (boldface type) to an expert clinician, who responds to the information, sharing his or her reasoning with the reader (regular type). The authors' commentary follows. Stage. A 28-year-old man presented to the…

http://ift.tt/2j5D99A

Case 33-2017: 22-Month-Old Conjoined Twins

Presentation of Case. Dr. Allan M. Goldstein: A pediatric surgeon at this hospital was contacted by a nonprofit organization to evaluate the possibility of surgical separation of conjoined twin girls. The twins were born by spontaneous vaginal delivery in East Africa. Because of the anticipated…

http://ift.tt/2iBnQ4o

Fertility Preservation in Women

In recent years, the demand for fertility preservation for oncologic and nononcologic reasons, as well as personal reasons, has increased dramatically, and meeting this demand will prove a major challenge in the coming years. Currently, embryo cryopreservation and mature-oocyte cryopreservation…

http://ift.tt/2hbouFJ

Button Magnets in the Nasal Cavity

Figure 1.

http://ift.tt/2AozVlH

Congenital Diaphragmatic Hernia

Figure 1.

http://ift.tt/2hb9qb6

Liposuction for Swelling in Patients with Lymphedema

To the Editor: Lymphedema is a progressive, noncurable condition that is caused by anomalous development of the lymphatic system or trauma to lymphatic vasculature. The disease most commonly affects the limbs because of injury to or removal of lymph nodes. Fluid accumulates in the interstitial…

http://ift.tt/2h96yew

Case 33-2017: 22-Month-Old Conjoined Twins

Presentation of Case. Dr. Allan M. Goldstein: A pediatric surgeon at this hospital was contacted by a nonprofit organization to evaluate the possibility of surgical separation of conjoined twin girls. The twins were born by spontaneous vaginal delivery in East Africa. Because of the anticipated…

http://ift.tt/2iBnQ4o

Button Magnets in the Nasal Cavity

Figure 1.

http://ift.tt/2AozVlH

Histopathological Findings in Brain Tissue Obtained during Epilepsy Surgery

In 2015, the World Health Organization (WHO) recognized epilepsy as a serious public health concern. Approximately 50 million people worldwide currently have epilepsy, and more than 30% of patients with epilepsy have inadequate seizure control with drug therapy. Epilepsy surgery is appropriate for…

http://ift.tt/2hgSR17

Congenital Diaphragmatic Hernia

Figure 1.

http://ift.tt/2hb9qb6

Circling Back for the Diagnosis

Foreword. In this Journal feature, information about a real patient is presented in stages (boldface type) to an expert clinician, who responds to the information, sharing his or her reasoning with the reader (regular type). The authors' commentary follows. Stage. A 28-year-old man presented to the…

http://ift.tt/2j5D99A

Back to the Future in Cardiogenic Shock — Initial PCI of the Culprit Lesion Only

Approximately 5 to 10% of cases of acute myocardial infarction are complicated by cardiogenic shock, which is associated with early mortality of 40 to 50%. Nearly two decades ago, the SHOCK (Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock) trial established that…

http://ift.tt/2hhVWhl

PCI Strategies in Patients with Acute Myocardial Infarction and Cardiogenic Shock

The mortality associated with cardiogenic shock in acute myocardial infarction can be reduced with the use of early revascularization, predominantly percutaneous coronary intervention (PCI), to restore blood flow to the culprit coronary artery. Up to 80% of patients who have cardiogenic shock…

http://ift.tt/2zkDF9W

Journal Clubs in Sports Medicine Fellowship Programs: Results From a National Survey and Recommendations for Quality Improvement

Background: Journal club is a pervasive component of graduate medical education, yet there is no gold standard as to format and logistics. Methods: Survey of primary care sports medicine fellowship directors in the United States. Results: Sixty-nine program directors completed the online questionnaire (40% response rate). There were some common aspects to journal club exhibited by a majority of programs, including the general format, required attendance by fellows and expected or required attendance by faculty, the expectation that participants had at least read the article before the meeting, and that meetings occurred during the workday in the work setting without provision of food. There was considerable variation on other aspects, including the objectives of journal club, who had primary responsibility for organizing the session, the criteria for selection of articles, who was invited to attend, and the perceived problems with journal club. Conclusions: This is the first survey investigating the current state of journal club in primary care sports medicine fellowship programs. Several opportunities for educational enhancements exist within journal clubs in primary care sports medicine, including the use of structured tools to guide discussion, providing mechanisms to evaluate the journal club experience as a whole, inviting multidisciplinary team members (eg, statisticians) to discussions, and ensuring that objectives are explicitly stated to participants.

http://ift.tt/2iAw9h1

Treatment of Primary Acute Patellar Dislocation: Systematic Review and Quantitative Synthesis of the Literature

Purpose: The aim of this study was to evaluate clinical outcomes, rate of redislocation, and complications after conservative or surgical procedures used to treat primary acute patellar dislocation. Methods: A comprehensive search of PubMed, Medline, CINAHL, Cochrane, Embase, and Google Scholar databases using various combinations of the keywords "patella," "dislocation," "treatment," "acute," "primary" was performed. The following data were extracted: demographics, chondral defects and soft tissue lesions, outcome measurements, type of management, recurrence of instability, and complications. Results: A total of 2134 knees in 2086 patients were included, with an average age at dislocation of 20.3 years. The average Kujula score was 75.6 for patients treated conservatively and 88.7 for patients undergoing surgical treatment in the short–medium follow-up (less than 5 years); the average Kujula score was 87.5 for patients treated conservatively and 86.6 for patients undergoing surgical treatment in the long-term follow-up (more than 5 years). The rate of recurrence was significantly lower in the surgical group (25%) than in the conservative group (36.4%). The overall complication rate was 6.5% (29 of 441 knees) in the surgical management group. No complications were reported for patients treated conservatively. Conclusions: Surgical treatment of primary acute patellar dislocation leads to significantly lower rate of redislocation and provides better short–medium clinical outcomes, whereas in the long-term follow-up, results of patients treated conservatively were as good as those of surgical patients. Further randomized controlled trials, describing anatomical abnormalities and soft-tissue integrity that may influence the choice of treatment, are needed. Level of Evidence: Systematic review, level IV.

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Neuromuscular Training Availability and Efficacy in Preventing Anterior Cruciate Ligament Injury in High School Sports: A Retrospective Cohort Study

Objective: To document neuromuscular training (NMT) availability and its relationship to anterior cruciate ligament (ACL) injuries in 4 major high school sports by gender, sport, and rural/urban geography, with the hypothesis that increased exposure to NMT would be associated with fewer ACL injuries. Design: A retrospective cohort study. Setting: All Minnesota high schools identified in the Minnesota State High School League (MSHSL) database for fall 2014 boys' football and soccer, and girls' volleyball and soccer. Participants: All high school athletic directors were surveyed to report their school's fall 2014 experience; 53.5% returned the survey reporting experience with one or more of the sports. Intervention: Athletic directors documented each sport's preseason and in-season exposure to NMT (plyometric exercises, proximal/core muscle strengthening, education and feedback regarding proper body mechanics, and aerobics) and licensed athletic trainers. Main Outcomes: Reported ACL injuries by sport, gender and rural/urban. Results: More than two-thirds of teams incorporated facets of NMT into their sport. Among male athletes, soccer players exposed to licensed athletic trainers experienced significantly fewer ACL injuries (P

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Neuroendocrine Dysfunction in a Young Athlete With Concussion: A Case Report

Abstract: An 18-year-old female ringette and basketball player presented to our sport concussion clinic 27 months after concussion with fatigue, headache, exercise intolerance, polyuria, nocturia, and difficulties concentrating. Her history was remarkable for 4 previous concussions. Her neurologic examination was normal. Neuroendocrine screen including thyroid function, morning cortisol, glucose, and insulin-like growth factor-1 (screening test for growth hormone deficiency) were normal. Further testing for growth hormone deficiency with an insulin hypoglycemia test revealed severe growth hormone deficiency. Urine and serum electrolytes were borderline normal, suggesting partial diabetes insipidus. Treatments with growth hormone replacement lead to complete recovery. This case highlights the importance of maintaining a high index of suspicion for neuroendocrine abnormalities in athletes with persistent symptoms after sport concussion. Symptoms can be nonspecific and go undiagnosed for years, but appropriate recognition and treatment can restore function.

http://ift.tt/2iAw7FV

Depression, Anxiety, and Alcohol Use in Elite Rugby League Players Over a Competitive Season

Objective: To assess the prevalence of symptoms of depression, anxiety, and rates of alcohol misuse in elite rugby league players in Australasia. Design: A cross-sectional, epidemiological study with repeated measures. Setting: Surveys were conducted during the 2015 preseason and in-season. Participants: Four hundred four elite rugby league players participated preseason and 278 players in-season. Main Outcome Measures: Symptoms of depression were measured using the Patient Health Questionnaire-9 scale, symptoms of generalized anxiety disorder (GAD) with the GAD-7 scale, and the Alcohol Use Disorders Identification Test Consumption scale was used to assess hazardous alcohol use. Results: The overall prevalence of depression was 12.6% preseason and 10.1% in-season. Generalized anxiety disorder had a prevalence of 14.6% and 10.1% for these 2 periods. Overall, 68.6% of players had hazardous levels of alcohol use preseason, and 62.8% in-season. There was no significant difference for any of the main outcomes between the periods. Players with a history of mental illnesses had 5.62 greater odds (95% confidence interval [CI], 2.62-12.04) of depression than those without during preseason, and 22.08 greater odds (95% CI, 7.77-62.71) in-season. Players reporting ≥3 previous concussions had 2.02 greater odds (95% CI, 1.07-3.82) of depression than those reporting ≤2 in the preseason sample. Conclusions: Rugby league players have a lower prevalence of depression compared with studies of the general population and other athletes, but a higher prevalence of GAD, and high rates of alcohol misuse. Clubs may consider implementing regular screening for these conditions. Further prospective research to determine causality of independent factors is required.

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Rankings of High School Sports Injury Rates Differ Based on Time Loss Assessments

Objective: To examine how injury definition inclusiveness affects the rank order of injury rates in 27 high school (HS) sports. Design: The National Athletic Treatment, Injury and Outcomes Network (NATION) used certified athletic trainers (ATs) to collect injury and athlete-exposure (AE) data in practices and competitions for 27 HS sports during the 2011/2012 to 2013/2014 academic years. Time loss (TL) injuries resulted in ≥24 hours of participation restriction. Nontime loss (NTL) injuries resulted in

http://ift.tt/2iAw64P

Carbon Monoxide Exposure in Youth Ice Hockey

Objective: To examine the effect of ice resurfacer type on carboxyhemoglobin levels in youth hockey players. We hypothesized that players in arenas with electric resurfacers would have normal, stable carboxyhemoglobin levels during games, whereas those in arenas with internal combustion engine (IC) resurfacers would have an increase in carboxyhemoglobin levels. Design: Prospective cohort study. Setting: Enclosed ice arenas in the northeastern United States. Participants: Convenience sample of players aged 8 to 18 years old in 16 games at different arenas. Eight arenas (37 players) used an IC ice resurfacer and 8 arenas (36 players) an electric resurfacer. Interventions: Carboxyhemoglobin levels (SpCO) were measured using a pulse CO-oximeter before and after the game. Arena air was tested for carbon monoxide (CO) using a metered gas detector. Players completed symptom questionnaires. Main Outcome Measures: The change in SpCO from pregame to postgame was compared between players at arenas with electric versus IC resurfacers. Results: Carbon monoxide was present at 6 of 8 arenas using IC resurfacers, levels ranged from 4 to 42 parts per million. Carbon monoxide was not found at arenas with electric resurfacers. Players at arenas with IC resurfacers had higher median pregame SpCO levels compared with those at electric arenas (4.3% vs 1%, P

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Anterior Knee Impingement in a High-Level Football Punter: A Case Report and Description of the Active–Passive Knee Extension Test

Abstract: A 22-year-old football punter complained of anterior knee pain deep to his patellar tendon that occurred every time the knee of his kicking leg reached full extension during a punt. Arthroscopy confirmed anterior impingement between a fibrous tissue eminence directly anterior to his anterior cruciate ligament (ACL) and the intercondylar roof in full extension. With the eminence removed, full extension no longer caused impingement as demonstrated arthroscopically. He resumed punting at maximal effort 6 weeks postoperatively without pain. We report the active–passive knee extension test, a physical examination maneuver designed to identify patients with anterior knee impingement between tissue anterior to the ACL and the intercondylar roof. This test is a helpful part of the clinical examination in detecting these lesions.

http://ift.tt/2iAw5xN

Disparities in Athletic Trainer Staffing in Secondary School Sport: Implications for Concussion Identification

Objective: First, to assess whether teams at schools with an athletic trainer (AT) on staff had a higher number of diagnosed concussions than teams without medical personnel present. Second, to assess whether the variability in employment of a certified AT by Washington state high schools is patterned by socioeconomic and demographic characteristics. Design: Cross-sectional survey. Setting: Washington state public high schools. Participants: Stratified random sample of football and soccer coaches (n = 270 teams, 144 schools). Independent Variables: Presence of an AT and school characteristics (percentage of students qualifying for free or reduced price lunch, rural location, enrollment). Results: Football and boys' soccer teams at schools with an AT had a significantly greater number of athletes with diagnosed concussions compared to teams at schools without an AT (P

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In Response to: Keep the Physical in Physical Education

No abstract available

http://ift.tt/2haC1xi

HIV Infection Manifesting as Proximal White Onychomycosis

Figure 1.

http://ift.tt/2yanR63

Cholera in Yemen — An Old Foe Rearing Its Ugly Head

Yemen, a country with a population of approximately 25 million located at the southern tip of the Arabian Peninsula, is now experiencing one of the largest cholera outbreaks in recent history. The outbreak, which began in late October 2016 and is reportedly due to Vibrio cholerae O1, serotype…

http://ift.tt/2zoN9k7

HIV Drug Resistance — An Emerging Threat to Epidemic Control

There are now an estimated 19.5 million people worldwide living with HIV and receiving antiretroviral therapy (ART). That's approximately half of all people thought to be living with the virus in 2017 — an extraordinary achievement in global health and human solidarity. The United Nations agencies,…

http://ift.tt/2zBtjU1

A CRISPR Way to Diagnose Infectious Diseases

During the past 20 years, tremendous advances in methods involving polymerase-chain-reaction (PCR) assays and DNA sequencing have transformed clinical virology and microbiology laboratories. These new methods allow accurate and rapid diagnosis of a wide array of infectious diseases and facilitate…

http://ift.tt/2zltj7j

A Renewed Focus on Maternal Health in the United States

Recently, the media have devoted increasing attention to maternal mortality in the United States, as in a ProPublica and National Public Radio article describing the devastating death of a nurse shortly after her first child was born. These reports have heightened public awareness of grim realities…

http://ift.tt/2zAS3eZ

Primary Care Spending Rate — A Lever for Encouraging Investment in Primary Care

Why doesn't the United States invest more in primary care? A large body of evidence suggests that greater investment in primary care is good for patients and health systems. Greater use of primary care has been associated with lower costs, higher patient satisfaction, fewer hospitalizations and…

http://ift.tt/2zmBLWe

Understanding the Planned Parenthood Divide — Albert Lasker and Women’s Health

Albert Lasker, considered the "father of modern advertising," transformed product marketing from an endeavor based on the simple presentation of facts to one finely tuned to consumer psychology, particularly as it pertained to women. At a time when discussion of menstruation was taboo, for example,…

http://ift.tt/2zBtsH3

Cholera in Yemen — An Old Foe Rearing Its Ugly Head

Yemen, a country with a population of approximately 25 million located at the southern tip of the Arabian Peninsula, is now experiencing one of the largest cholera outbreaks in recent history. The outbreak, which began in late October 2016 and is reportedly due to Vibrio cholerae O1, serotype…

http://ift.tt/2zoN9k7

Mandating Coverage for Fertility Preservation — A Step in the Right Direction

Connecticut and Rhode Island recently became the first U.S. states to pass legislation requiring insurance coverage of fertility-preservation services for patients about to undergo a medical treatment — surgery, radiation, or chemotherapy — that may have deleterious effects on the gonads. Although…

http://ift.tt/2zBC402

HIV Drug Resistance — An Emerging Threat to Epidemic Control

There are now an estimated 19.5 million people worldwide living with HIV and receiving antiretroviral therapy (ART). That's approximately half of all people thought to be living with the virus in 2017 — an extraordinary achievement in global health and human solidarity. The United Nations agencies,…

http://ift.tt/2zBtjU1

Is There Merit in Merit Aid?

In 2016, the average cost of attending medical school (including tuition and fees) in the United States was $253,720 for in-state graduates and $313,897 for out-of-state graduates. Nearly three in four graduates had educational debt, and the median educational debt was $190,000. Average debt…

http://ift.tt/2zoMYFt

Which Road to Universal Coverage?

According to a June 2017 poll, Americans agree by a 60-to-39 margin that the federal government bears a responsibility to ensure health care for all Americans; 33% said that they favored a "single-payer" health system, 12% more than in 2014. The prevailing belief that the government should actively…

http://ift.tt/2zCdIU7

How to Think about "Medicare for All"

In April 1946, President Harry Truman introduced a single-payer health plan and met the same reaction that would greet Senator Bernie Sanders (I-VT) and his colleagues when they proposed "Medicare for All" in September 2017. "It is believed by competent Congressional observers to have little chance…

http://ift.tt/2zmL9Jm

The role of colorectal endoscopic submucosal dissection in patients with ulcerative colitis

Patients with ulcerative colitis have an increased risk of colorectal dysplasia. Endoscopic submucosal dissection (ESD) for the neoplastic lesions in ulcerative colitis remains controversial. The aim of this study was to clarify the role of ESD in treatment strategy for ulcerative colitis.

http://ift.tt/2j7R5Qh

Utility of multi-detector CT scans after colorectal endoscopic submucosal dissection: a prospective study

Several reports have described the major adverse events after endoscopic submucosal dissection (ESD), such as perforation or bleeding. However, few studies have discussed the occurrence of post-ESD electrocoagulation syndrome (PEECS) after colorectal ESD. Additionally, the occurrence of fever without abdominal pain in patients requires postoperative management similar to that required for PEECS. Therefore, we have defined post-ESD inflammatory syndrome (PEIS) as composed of both PEECS and fever without abdominal pain.

http://ift.tt/2AqwxXw

Per-oral endoscopic myotomy in patients with or without prior Heller myotomy: comparing long-term outcomes in a large U.S. single-center cohort (with videos)

Heller myotomy (HM) is one of the most effective treatments for esophageal achalasia. However, failures do exist and the success rate tends to decrease with time. The efficacy of rescue treatments for patients with failed Heller is limited. A few small-scale studies have reported outcomes of per-oral endoscopic myotomy (POEM) in these patients. We conducted this study to systematically assess feasibility, safety, and efficacy of POEM on post-Heller patients.

http://ift.tt/2An9TPE

Clinical predictors of histological type of gastric cancer

Gastric cancer is classified into differentiated and undifferentiated types according to the degree of glandular differentiation. Undifferentiated-type early gastric cancer (EGC) carries a higher risk of lymph node metastasis than differentiated type, and the indication criteria for endoscopic resection thus differ. This study aimed to clarify the diagnostic abilities of clinical predictors to distinguish between differentiated-type and undifferentiated-type EGCs.

http://ift.tt/2AocsRz

Effects of EUS-guided intratumoral injection of oligonucleotide STNM01 on tumor growth, histology, and overall survival in patients with unresectable pancreatic cancer

Carbohydrate sulfotransferase 15 (CHST15) promotes tumor growth and invasion and is considered to be an emergent therapeutic target for pancreatic cancer. The aim of this study was to evaluate the safety and efficacy of EUS-guided fine-needle injection (EUS-FNI) of STNM01, the double-stranded RNA oligonucleotide that specifically represses CHST15, for use in patients with pancreatic cancer.

http://ift.tt/2j7wOKR

Upper GI involvement in children with familial adenomatous polyposis syndrome: single-center experience and meta-analysis of the literature

Familial adenomatous polyposis (FAP) is a hereditary syndrome that can affect the entire GI tract. Current screening recommendations include esophagogastroduodenoscopy (EGD) starting at age 25 to 30 years or earlier in symptomatic patients. However, there are few reports describing upper GI tract involvement in children with FAP which support the notion of early screening. The aim of our study is to understand the prevalence and severity of upper GI involvement in children with FAP.

http://ift.tt/2Aoc9pT

Programmed Death-1 Ligands, PD-L1 and PD-L2, Show Distinctive and Restricted Patterns of Expression in Lymphoma Subtypes

The success of immunotherapy using immune checkpoint blockade in solid tumors and in relapsed/refractory classical Hodgkin lymphoma and chronic lymphocytic leukemia holds promise for targeted therapy in hematologic malignancies. Since efficacy of immunomodulatory therapy is correlated with numbers of cells that express programmed death (PD-1) ligands, we evaluated the expression of PD-L1 and PD-L2 proteins using immunohistochemistry in over 702 diagnostic lymphoma biopsies. In classical Hodgkin lymphoma, PD-L1 and PD-L2 were expressed in 82% and 41% of cases respectively, and PD-L1 but not PD-L2 expression correlated with Epstein Barr Virus in tumor cells.

http://ift.tt/2zjIws0

Diagnostic Significance of Intratumoral CD8+ Tumor Infiltrating Lymphocytes in Medullary Carcinoma

Invasive ductal carcinomas of breast with marked stromal lymphocytic infiltration have come to be classified as lymphocyte predominant breast cancer (LPBC) because it obtains high pathological complete response rates with neoadjuvant chemotherapy. Medullary carcinoma (MC), which is independent from LPBC, is a rare histological subtype of invasive breast carcinoma accompanied by abundant lymphoplasmacytic infiltration as LPBC. Although MC shows marked cellular and structural atypia, it usually has a favorable outcome.

http://ift.tt/2zitxib

Burkholderia Aortic Aneurysm: A Case Report and Review of the Literature

Melioidosis is a frequently fatal infection caused by the Gram-negative bacillus Burkholderia pseudomallei endemic to Southeast Asia and Northern Australia. It is a rare imported pathogen in the United States and is a potential bioterror agent. We report the case of an 82-year-old previously healthy man who presented with 2 weeks of fever and epigastric pain after he returned from the Philippines. A diagnosis of nondissecting mycotic aneurysm in the descending thoracic aorta was made with the help of CT angiogram and positive blood cultures. The patient completely recovered with a 6-month antibiotic therapy followed by surgical repair of the aneurysm. Given the slight increase in the number of melioidosis cases reported by CDC since 2008, melioidosis might be considered an emerging infectious disease in the United States. The purpose of this report is to raise awareness of the disease among clinicians as well as travelers.

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Outcome after Radiotherapy for Langerhans Cell Histiocytosis Is Dependent on Site of Involvement

Langerhans cell histiocytosis is a rare histiocytic malignancy associated with a wide range of clinical presentations and outcomes. We explored treatment patterns and outcomes in a cohort of 39 patients with 46 radiation-treated lesions. We found the rate of local failure was significantly higher in patients with non-bone lesions, especially of the skin and brain, compared to excellent local control in bone lesions with relatively low doses of radiation.

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Value of elective radiation oncology rotations: how many is too many?

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Functional Outcomes after De-Escalated Chemoradiation for Human Papillomavirus-Positive Oropharyngeal Cancer: Secondary Analysis of a Phase II Trial

For patients with human papillomavirus (HPV)-associated oropharyngeal carcinoma undergoing chemoradiation with induction chemotherapy followed by de-escalated chemoradiation to 54 or 60 Gy with concurrent paclitaxel, functional outcomes, including nutritional status, gastrostomy tube use, dysphagia, and narcotic use, appear similar or favorable to historical controls treated with definitive chemoradiation to 70 Gy. These findings support ongoing efforts to evaluate de-escalated chemoradiation in patients with HPV-associated oropharyngeal carcinoma.

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PARP inhibition combined with thoracic radiation exacerbates esophageal and skin toxicity in C57BL6 mice

PARP inhibitors have been demonstrated to potentiate the anti-tumor effect of radiation in preclinical studies. However, their effect on normal tissue response to radiation is unclear. Here we show that PARP inhibitors not only enhance radiation-induced tumor growth inhibition, but also enhance the response of the esophagus and skin to radiation. Therefore, caution may be warranted when combining PARP inhibition with radiotherapy that includes proliferating normal tissues.

http://ift.tt/2AnpjU6

Low-dose hypersensitive response for residual pATM and γH2AX foci in normal fibroblasts of cancer patients

We demonstrate, for the first time, low-dose hypersensitive response for both residual pATM and γH2AX foci in normal fibroblasts of 4 HRS-positive patients and its lack in fibroblasts of 8 HRS-negative patients. We also show that in HRS-positive fibroblasts not all DSB are recognized by pATM early after irradiation with low dose. The data provide the evidence for the role of DSB recognition by pATM and repair in the mechanism of HRS.

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Corrigendum to “Start-Up Characteristics of a Granule-Based Anammox UASB Reactor Seeded with Anaerobic Granular Sludge”

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Authors’ answers on comment of Abellona et al on Metabolomic analysis for noninvasive diagnosis of hepatic fibrosis degree in patients with chronic hepatitis C

We are pleased to recognize the interest of Abellona ER et al to our study, despite its negative results. Indeed, negative studies are often neglected by the scientific community, but nevertheless may be especially useful to discuss the methodology and how to move further. More specifically one of the criticism of Abellona ER et al was regarding the originality of the study and the small sample size investigated. Indeed, we are well aware of the studies cited by colleagues with similar sample sizes [1,2].

http://ift.tt/2zofUM9

Abnormal Cortical Neural Synchrony During Working Memory in Schizophrenia

Working memory (WM) encompasses the encoding, maintenance, and retrieval of mental representations that guide behavior (Baddeley, 2012; Miyake and Shah, 1999). Recent experimental studies have demonstrated that people with schizophrenia (PSZ) have WM storage capacity deficits which is not simply explained by instability in WM mental representation (Gold et al., 2010) or attentional deficits (Erickson et al., 2015), suggesting that problems in multiple neural processes might contribute to limited WM capacity in PSZ.

http://ift.tt/2zmJ4NC

RLS patients show better nocturnal performance in the Simon task due to diminished visuo-motor priming

The restless legs syndrome (RLS) is a sensory-motor disorder characterized by uncomfortable sensations, especially in the legs, combined with an urge to move. The symptoms are most pronounced at rest in the evening and at night (Allen et al., 2014b; Allen, 2015). In spite of the circadian variation of those sensory and motor symptoms, diurnal changes of potentially associated cognitive functions as well as the underlying neurophysiological and neuroanatomical processes have not yet been investigated.

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Bilateral loss of cortical SEPs predict severe MRI lesions in neonatal hypoxic ischemic encephalopathy treated with hypothermia

Hypoxic-ischemic encephalopathy (HIE) in term neonates is a significant cause of infant mortality and morbidity. As a routine, early assessment of neonatal encephalopathy is based on clinical observation (graded by Sarnat and Sarnat, 1976), MRI and EEG recordings of brain electrical activity while the acquisition of somatosensory evoked potentials (SEPs) in the neonatal period is often hampered by logistic reasons. After moderate whole-body hypothermia (therapeutic hypothermia- TH) proved its efficacy and safety in reducing death and cerebral palsy and improving neurological outcome (Azzopardi et al, 2009), clinicians and researchers needed to test its influence on the most widely used prognostic tools.

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The Sound of Silence

SEE RELATED ARTICLE, P. ■■■.

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Effects of Tai Chi Exercise on Cancer-Related Fatigue in Patients with Nasopharyngeal Carcinoma Undergoing Chemoradiotherapy: A Randomized Controlled Trial

Tai Chi exercise has been shown to improve cancer-related fatigue (CRF) and autonomic nervous system (ANS) balance in some cancer patients or survivors, however, such effects are yet to be verified in nasopharyngeal carcinoma (NPC) patients undergoing chemoradiotherapy.

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The Collusion Classification Grid: a Supervision and Research Tool

We have recently published an article in the Journal of Pain and Symptom Management on collusion (1), in which we clarified its theoretical framework, summarized the scarce palliative and supportive care literature on collusion, and deplored the almost complete lack of research on this clinically prevalent and relevant phenomenon. We also argued that the few studies conducted on collusion in end-of-life care lack methodological robustness. Consequently, we developed a tool, the Collusion Classification Grid (CCG), with the aim of orienting and structuring empirical investigations of collusion.

http://ift.tt/2zjoTjL

Practice patterns of medications for patients with malignant bowel obstruction using a nationwide claims database and the association between treatment outcomes and concomitant use of H2-blockers/proton pump inhibitors and corticosteroids with octreotide

Malignant bowel obstruction (MBO) impairs the quality of life in patients with advanced cancer. Octreotide, acid-suppressing medications such as H₂-receptor antagonists (H₂ blockers) and proton pump inhibitors (PPIs), and corticosteroids are often used in combination for symptom control.

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Unifying interdisciplinary education: designing and implementing an intern simulation educational curriculum to increase confidence in critical care from PGY1 to PGY2

A longitudinal, multidisciplinary critical care simulation curriculum was developed and implemented within a teaching hospital to address the need for consistent, safe, efficient, and unified critical care tra...

http://ift.tt/2zo8c4r

Prevalence of markers of HIV infection among febrile adults and children in Bo, Sierra Leone, 2012–2013

The goal of this study was to examine the prevalence of HIV among febrile patients seeking care in Mercy Hospital, Bo, Sierra Leone, in 2012–2013.

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Effects of freezer storage time on levels of complement biomarkers

There is uncertainty regarding how stable complement analytes are during long-term storage at – 80 °C. As part of our work program we have measured 17 complement biomarkers (C1q, C1 inhibitor, C3, C3a, iC3b, C...

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Development of interstitial pneumonia during treatment with eribulin: a case report

Eribulin is typically used to treat patients with advanced breast cancer, and anti-cancer agents often cause the development of interstitial pneumonia in Japanese patients with advanced cancer. However, few ca...

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Hepatitis C and Human Immunodeficiency Virus Co-Infection in the Era of Direct-Acting Antiviral Agents: No Longer A Difficult to Treat Population

Abstract

Background: The treatment of chronic hepatitis C (HCV) in human immunodeficiency virus 1 (HIV) infected individuals has been historically marked by low sustained virologic response (SVR) rates in comparison to those without HIV infection, resulting in the Food and Drug Administration (FDA) labeling those coinfected as a "special population with an unmet medical need."

Objectives: We systematically reviewed the treatment of chronic HCV infection in those infected with HIV. We propose that with the advent of direct-acting antiviral (DAA) agents, patients co-infected with HCV and HIV have similar SVR rates as HCV mono-infected persons and that DAAs address an unmet medical need in this population.

Methods: A review was performed using Medical Subject Heading (MeSH) terms within the PubMed, EMBASE, and Cochrane Library databases to search for studies dated between January 2004 and July 2017. Keywords used in the study included "hepatitis C," "HIV," "coinfection," and "direct-acting antiviral."

Results: SVR rates for those with HCV and HIV coinfection treated with interferon-based therapies were substantially lower that SVR rates of HCV mono-infected individuals. The advent of DAA agents has resulted in similar SVR rates between mono-infected and co-infected individuals, with SVR greater than 93%. These medications have been demonstrated to have improved safety, efficacy, and tolerability in comparison to interferon-based regimens.

Conclusion: The designation of a "special population" for those with co-infection requires reconsideration. DAA therapies have resulted in similarly high rates of SVR for HCV infection in those with and without HIV infection. Despite these improvements, however, clinicians must be cognizant of negative predictors of SVR and barriers to treatment that may be more common in the coinfected population. This article is protected by copyright. All rights reserved.

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Targeted delivery of miR-199a-3p using self-assembled dipeptide nanoparticles efficiently reduces hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is an aggressive tumor with limited systemic and locoregional modalities of treatment. Although microRNA (miRNA) based therapies have significant potential, their targeted delivery remains a major challenge. miR-199a-3p functions as an important tumor suppressor in HCC, which regulates various cellular processes. Recently, peptide-based nanoparticles (NPs) have been developed to deliver oligonucleotides including miRNA. Here, we describe the synthesis and characterization of arginine α,β-dehydrophenylalanine (RΔF) nanoparticles for the selective delivery of miR-199a-3p to restore dysregulated gene expression in HCC. Targeted delivery was achieved by conjugating lactobionic acid (LA) with RΔF Nps (RΔF-LA NPs), a ligand for the asialoglycoprotein receptor known to be overexpressed in HCC cell lines. RΔF-LA NPs condensed miR-199a-3p had an average size of ∼60nm and a zeta potential of ∼+2.54 mV. RΔF-LA/miR NPs were found to be stable in serum as well as against RNase attack. RΔF-LA/miR NPs showed an enhanced cellular uptake and an efficient delivery of miR-199a-3p leading to a significant increase in miR-199a-3p levels (over 500 fold). The increased miR-199a-3p levels remarkably suppressed cell proliferation and migration as well as induced cellular apoptosis and downregulation of the specific target gene (mTOR) in vitro. RΔF-LA/miR NPs showed high tumor/low organ ratios after intravenous injection in to HCC tumor bearing nude mice. RΔF-LA/miR NPs treated mice demonstrated>50% decline in tumor growth, which also corresponded well with suppression of mTOR protein expression, tumor cell proliferation and increased survival rate (p<0.0.5).

Conclusion: RΔF-LA/miR NPs showed significantly enhanced delivery of the miRNA which underscores their potential for further development as a therapeutic approach for HCC. This article is protected by copyright. All rights reserved.

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Reply to: “Should venous ammonia be used in decision making acute liver failure patients?”

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Optimal threshold of controlled attenuation parameter with MRI-PDFF as the gold standard for the detection of hepatic steatosis

ABSTRACT

The optimal threshold of controlled attenuation parameter (CAP) for the detection of hepatic steatosis using both M and XL probe is unknown in nonalcoholic fatty liver disease (NAFLD). Magnetic resonance imaging proton-density-fat-fraction (MRI-PDFF) is an accurate and precise method to detect presence of hepatic steatosis and is better than CAP. Thus, the aim of this study was to evaluate the diagnostic accuracy and the optimal threshold of CAP for the detection of hepatic steatosis as defined by MRI-PDFF ≥ 5%. This cross-sectional study included 119 adults (59% women), prospectively recruited with and without NAFLD who underwent MRI-PDFF and CAP using either M probe or XL probe when indicated within a six-month period at the NAFLD Research Center, UCSD. Mean (±standard deviation) age and BMI were 52.4 (±15.2) years and 29.9 (±5.5) kg/m², respectively. The prevalence of NAFLD (MRI-PDFF≥5%) and MRI-PDFF≥ 10% was 70.6% and 47.1%, respectively. The area under the ROC (AUROC) of CAP for the detection of MRI-PDFF ≥ 5% was 0.80 (95%CI:0.70-0.90) at the cut-point of 288 dB/m and of MRI-PDFF ≥10% was 0.87 (95%CI:0.80-0.94) at the cut-point of 306 dB/m. When stratified by IQR of CAP, we observed that an IQR below median (30 dB/m) had a robust AUROC compared to IQR above median ([0.92, 95%CI:0.85-1.00] vs. [0.70, 95%CI:0.56-0.85], p-value=0.0117), and these differences were statistically and clinically significant.

Conclusion: The cut-point of CAP for presence of hepatic steatosis (MRI-PDFF ≥ 5%) was 288 dB/m. The diagnostic accuracy of CAP for the detection of hepatic steatosis is more reliable when IQR of CAP is <30 dB/m. These novel data have implications for clinical utility of CAP in the assessment of NAFLD. This article is protected by copyright. All rights reserved.

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Don't forget the general practitioner!

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Incidence and predictors of HBsAg seroclearance after cessation of nucleos(t)ide analogue therapy in HBeAg negative chronic hepatitis B

Abstract

Hepatitis B s antigen (HBsAg) loss is a rare event during nucleos(t)ide analogue (Nuc) therapy. Limited data suggest that stopping Nuc therapy may increase HBsAg loss rate in hepatitis B e antigen (HBeAg) negative patients. A large study was conducted to investigate this issue in more detail. Of the 1075 HBeAg-negative patients treated with Nuc for 156 (61-430) weeks, 6 showed HBsAg seroclearance during treatment at an estimated annual incidence of 0.15%. Of the patients who remained HBsAg seropositive, 691 (52.3 years old, 86% males, 44.6% cirrhosis) had stopped Nuc therapy by Asian-Pacific stopping rule and then were prospectively followed-up. Baseline and on treatment clinical and viral features, treatment duration, consolidation duration, time to undetectable HBV DNA, time to normal ALT, end of treatment (EOT) HBsAg and HBsAg log reduction were compared between patients with and without HBsAg seroclearance after EOT. During a median off-therapy follow-up period of 155 (2-614) weeks, HBsAg seroclearance was confirmed in 42 patients. The 6-year cumulative incidence was 13% with an estimated annual incidence of 1.78%. Cox regression analysis showed that shorter time to undetectable HBV DNA (<12wks), greater HBsAg reduction during therapy (>1 log₁₀), lower EOT HBsAg level (<100 IU/mL), patients with sustained response and relapsers not retreated were factors for off-therapy HBsAg seroclearance. Conclusion: The incidence of HBsAg seroclearance after stopping Nuc was much higher than that during therapy, and was highest in patients without virologic and clinical relapse. Patients with clinical relapse who remain untreated had 7.34 times higher incidence of HBsAg clearance than those received re-treatment, suggesting that transient untreated clinical relapse may drive sufficient immune control to functional cure. This article is protected by copyright. All rights reserved.

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Should venous ammonia be used in decision making acute liver failure patients?

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Discontinuing Inappropriate Medication Use in Nursing Home Residents A Cluster Randomized Controlled Trial

Background:

Inappropriate prescribing is a well-known clinical problem in nursing home residents, but few interventions have focused on reducing inappropriate medication use.

Objective:

To examine successful discontinuation of inappropriate medication use and to improve prescribing in nursing home residents.

Design:

Pragmatic cluster randomized controlled trial, with clustering by elder care physicians and their wards. (ClinicalTrials.gov: NCT01876095)

Setting:

59 Dutch nursing home wards for long-term care.

Patients:

Residents with a life expectancy greater than 4 weeks who consented to treatment with medication.

Intervention:

Multidisciplinary Multistep Medication Review (3MR) consisting of an assessment of the patient perspective, medical history, critical appraisal of medications, a meeting between the treating elder care physician and the pharmacist, and implementation of medication changes.

Measurements:

Successful discontinuation of use of at least 1 inappropriate drug (that is, without relapse or severe withdrawal symptoms) and clinical outcomes (neuropsychiatric symptoms, cognitive function, and quality of life) after 4 months of follow-up.

Results:

Nineteen elder care physicians (33 wards) performed the 3MR, and 16 elder care physicians (26 wards) followed standard procedures. A total of 426 nursing home residents (233 in the intervention group and 193 in the control group) were followed for an average of 144 days (SD, 21). In an analysis of all participants, use of at least 1 inappropriate medication was successfully discontinued for 91 (39.1%) residents in the intervention group versus 57 (29.5%) in the control group (adjusted relative risk, 1.37 [95% CI, 1.02 to 1.75]). Clinical outcomes did not deteriorate between baseline and follow-up.

Limitations:

The 3MR was done only once. Some withdrawal symptoms or relapses may have been missed.

Conclusion:

The 3MR is effective in discontinuing inappropriate medication use in frail nursing home residents without a decline in their well-being.

Primary Funding Source:

Netherlands Organisation for Health Research and Development.

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Annals Story Slam - Dr. Mom Gets Sick

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Do Less Harm: Evaluating HIV Programmatic Alternatives in Response to Cutbacks in Foreign Aid

Background:

Resource-limited nations must consider their response to potential contractions in international support for HIV programs.

Objective:

To evaluate the clinical, epidemiologic, and budgetary consequences of alternative HIV program scale-back strategies in 2 recipient nations, the Republic of South Africa (RSA) and Côte d'Ivoire (CI).

Design:

Model-based comparison between current standard (CD4 count at presentation of 0.260 × 10⁹ cells/L, universal antiretroviral therapy [ART] eligibility, and 5-year retention rate of 84%) and scale-back alternatives, including reduced HIV detection, no ART or delayed initiation (when CD4 count is <0.350 × 10⁹ cells/L), reduced investment in retention, and no viral load monitoring or second-line ART.

Data Sources:

Published RSA- and CI-specific estimates of the HIV care continuum, ART efficacy, and HIV-related costs.

Target Population:

HIV-infected persons, including future incident cases.

Time Horizon:

5 and 10 years.

Perspective:

Modified societal perspective, excluding time and productivity costs.

Outcome Measures:

HIV transmissions and deaths, years of life, and budgetary outlays (2015 U.S. dollars).

Results of Base-Case Analysis:

At 10 years, scale-back strategies increase projected HIV transmissions by 0.5% to 19.4% and deaths by 0.6% to 39.1%. Strategies can produce budgetary savings of up to 30% but no more. Compared with the current standard, nearly every scale-back strategy produces proportionally more HIV deaths (and transmissions, in RSA) than savings. When the least harmful and most efficient alternatives for achieving budget cuts of 10% to 20% are applied, every year of life lost will save roughly $900 in HIV-related outlays in RSA and $600 to $900 in CI.

Results of Sensitivity Analysis:

Scale-back programs, when combined, may result in clinical and budgetary synergies and offsets.

Limitation:

The magnitude and details of budget cuts are not yet known, nor is the degree to which other international partners might step in to restore budget shortfalls.

Conclusion:

Scaling back international aid to HIV programs will have severe adverse clinical consequences; for similar economic savings, certain programmatic scale-back choices result in less harm than others.

Primary Funding Source:

National Institutes of Health and Steve and Deborah Gorlin MGH Research Scholars Award.

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Annals for Educators - 7 November 2017

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The Spectrum of Subclinical Primary Aldosteronism and Incident Hypertension A Cohort Study

Background:

Primary aldosteronism is recognized as a severe form of renin-independent aldosteronism that results in excessive mineralocorticoid receptor (MR) activation.

Objective:

To investigate whether a spectrum of subclinical renin-independent aldosteronism that increases risk for hypertension exists among normotensive persons.

Design:

Cohort study.

Setting:

National community-based study.

Participants:

850 untreated normotensive participants in MESA (Multi-Ethnic Study of Atherosclerosis) with measurements of serum aldosterone and plasma renin activity (PRA).

Measurements:

Longitudinal analyses investigated whether aldosterone concentrations, in the context of physiologic PRA phenotypes (suppressed, ≤0.50 µg/L per hour; indeterminate, 0.51 to 0.99 µg/L per hour; unsuppressed, ≥1.0 µg/L per hour), were associated with incident hypertension (defined as systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, or initiation of antihypertensive medications). Cross-sectional analyses investigated associations between aldosterone and MR activity, assessed via serum potassium and urinary fractional excretion of potassium.

Results:

A suppressed renin phenotype was associated with a higher rate of incident hypertension than other PRA phenotypes (incidence rates per 1000 person-years of follow-up: suppressed renin phenotype, 85.4 events [95% CI, 73.4 to 99.3 events]; indeterminate renin phenotype, 53.3 events [CI, 42.8 to 66.4 events]; unsuppressed renin phenotype, 54.5 events [CI, 41.8 to 71.0 events]). With renin suppression, higher aldosterone concentrations were independently associated with an increased risk for incident hypertension, whereas no association between aldosterone and hypertension was seen when renin was not suppressed. Higher aldosterone concentrations were associated with lower serum potassium and higher urinary excretion of potassium, but only when renin was suppressed.

Limitation:

Sodium and potassium were measured several years before renin and aldosterone.

Conclusion:

Suppression of renin and higher aldosterone concentrations in the context of this renin suppression are associated with an increased risk for hypertension and possibly also with increased MR activity. These findings suggest a clinically relevant spectrum of subclinical primary aldosteronism (renin-independent aldosteronism) in normotension.

Primary Funding Source:

National Institutes of Health.

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Annals Story Slam - Wonder Woman Is a Cartoon Character

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Self-administered Versus Directly Observed Once-Weekly Isoniazid and Rifapentine Treatment of Latent Tuberculosis Infection A Randomized Trial

Background:

Expanding latent tuberculosis treatment is important to decrease active disease globally. Once-weekly isoniazid and rifapentine for 12 doses is effective but limited by requiring direct observation.

Objective:

To compare treatment completion and safety of once-weekly isoniazid and rifapentine by self-administration versus direct observation.

Design:

An open-label, phase 4 randomized clinical trial designed as a noninferiority study with a 15% margin. Seventy-five percent or more of study patients were enrolled from the United States for a prespecified subgroup analysis. (ClinicalTrials.gov: NCT01582711)

Setting:

Outpatient tuberculosis clinics in the United States, Spain, Hong Kong, and South Africa.

Participants:

1002 adults (aged ≥18 years) recommended for treatment of latent tuberculosis infection.

Intervention:

Participants received once-weekly isoniazid and rifapentine by direct observation, self-administration with monthly monitoring, or self-administration with weekly text message reminders and monthly monitoring.

Measurements:

The primary outcome was treatment completion, defined as 11 or more doses within 16 weeks and measured using clinical documentation and pill counts for direct observation, and self-reports, pill counts, and medication event–monitoring devices for self-administration. The main secondary outcome was adverse events.

Results:

Median age was 36 years, 48% of participants were women, and 77% were enrolled at the U.S. sites. Treatment completion was 87.2% (95% CI, 83.1% to 90.5%) in the direct-observation group, 74.0% (CI, 68.9% to 78.6%) in the self-administration group, and 76.4% (CI, 71.3% to 80.8%) in the self-administration–with–reminders group. In the United States, treatment completion was 85.4% (CI, 80.4% to 89.4%), 77.9% (CI, 72.7% to 82.6%), and 76.7% (CI, 70.9% to 81.7%), respectively. Self-administered therapy without reminders was noninferior to direct observation in the United States; no other comparisons met noninferiority criteria. A few drug-related adverse events occurred and were similar across groups.

Limitation:

Persons with latent tuberculosis infection enrolled in South Africa would not routinely be treated programmatically.

Conclusion:

These results support using self-administered, once-weekly isoniazid and rifapentine to treat latent tuberculosis infection in the United States, and such treatment could be considered in similar settings when direct observation is not feasible.

Primary Funding Source:

Centers for Disease Control and Prevention.

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Tailoring Treatment of Latent Tuberculosis to the Needs of Patients and Families

Belknap and colleagues report a multisite randomized clinical trial that showed—in the 9 U.S. sites but not the South African site—similar completion rates for directly observed and self-administered weekly treatment. The editorialists discuss these findings and the importance of tailoring treatment of latent tuberculosis to individual patient circumstances.

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On the Communicability of Chronic Diseases

The World Health Organization now classifies chronic diseases, including cancer, heart disease, and type 2 diabetes, as noncommunicable. The authors present an alternative way to characterize such disorders, arguing that such reframing might improve their prevention and control.

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Epizootic Outbreak of Yellow Fever Virus and Risk for Human Disease in Salvador, Brazil

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Using Retinal Imaging to Study Dementia

The retina shares prominent similarities with the brain and thus represents a unique window to study vasculature and neuronal structure in the brain non-invasively. This protocol describes a method to study dementia using retinal imaging techniques. This method can potentially aid in diagnosis and risk assessment of dementia.

http://ift.tt/2h9pAS5

Modeling Neuronal Death and Degeneration in Mouse Primary Cerebellar Granule Neurons

This protocol describes a simple method for isolating and culturing primary mouse cerebral granule neurons (CGNs) from 6-7 day old pups, efficient transduction of CGNs for loss and gain of function studies, and modelling NMDA-induced neuronal excitotoxicity, low-potassium-induced cell death, DNA-damage, and oxidative stress using the same culture model.

http://ift.tt/2h74fca

Dissection and Immunofluorescent Staining of Mushroom Body and Photoreceptor Neurons in Adult Drosophila melanogaster Brains

This protocol describes the dissection and immunostaining of adult Drosophila melanogaster brain tissues. Specifically, this protocol highlights the use of Drosophila mushroom body and photoreceptor neurons as example neuronal subsets that can be accurately used to uncover general principles underlying many aspects of neuronal development.

http://ift.tt/2h8Ctfp

Antiangiogenic therapy in breast cancer

Summary

Based on a strong rationale for anti-VEGF (vascular endothelial growth factor) treatment in breast cancer and promising preclinical data, great hopes have been placed on the anti-VEGF antibody bevacizumab. Clinical trials, however, reported conflicting results. In metastatic human epidermal growth factor receptor 2(HER2)-negative breast cancer, the addition of bevacizumab to standard chemotherapy improved consistently progression-free survival (PFS), however, without effect on overall survival (OS). In early breast cancer bevacizumab increased the pathologic complete response rate (pCR) after neoadjuvant therapy, but adjuvant trials did not demonstrate an effect on long-term survival. Unfortunately, despite extensive research, there is still no biomarker for bevacizumab efficacy available, making patient selection difficult. This review summarizes all phase III trials investigating efficacy and toxicity of bevacizumab in early, locally advanced and metastatic breast cancer. It recapitulates the main toxicities, gives an overview on biomarker studies and discusses the role and future aspects of antiangiogenic therapy in breast cancer.

http://ift.tt/2j44Hfl