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Παρασκευή 5 Ιανουαρίου 2018

Children with autism spectrum disorder have unstable neural responses to sound

Abstract

Autism spectrum disorder (ASD) is diverse, manifesting in a wide array of phenotypes. However, a consistent theme is reduced communicative and social abilities. Auditory processing deficits have been shown in individuals with ASD—these deficits may play a role in the communication difficulties ASD individuals experience. Specifically, children with ASD have delayed neural timing and poorer tracking of a changing pitch relative to their typically developing peers. Given that accurate processing of sound requires highly coordinated and consistent neural activity, we hypothesized that these auditory processing deficits stem from a failure to respond to sound in a consistent manner. Therefore, we predicted that individuals with ASD have reduced neural stability in response to sound. We recorded the frequency-following response (FFR), an evoked response that mirrors the acoustic features of its stimulus, of high-functioning children with ASD age 7–13 years. Evident across multiple speech stimuli, children with ASD have less stable FFRs to speech sounds relative to their typically developing peers. This reduced auditory stability could contribute to the language and communication profiles observed in individuals with ASD.



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The Influences of Chromium Supplementation on Glycemic Control, Markers of Cardio-Metabolic Risk, and Oxidative Stress in Infertile Polycystic ovary Syndrome Women Candidate for In vitro Fertilization: a Randomized, Double-Blind, Placebo-Controlled Trial

Abstract

This study was carried out to investigate the effects of chromium intake on glycemic control, markers of cardio-metabolic risk, and oxidative stress in infertile polycystic ovary syndrome (PCOS) women candidate for in vitro fertilization (IVF). This randomized double-blind, placebo-controlled trial was done among 40 subjects with infertile PCOS candidate for IVF, aged 18–40 years old. Individuals were randomly allocated into two groups to take either 200 μg/day of chromium (n = 20) or placebo (n = 20) for 8 weeks. Biochemical parameters were assessed at baseline and at end-of-trial. Compared with the placebo, taking chromium supplements led to significant reductions in fasting plasma glucose (− 2.3 ± 5.7 vs. + 0.9 ± 3.1 mg/dL, P = 0.03), insulin levels (− 1.4 ± 2.1 vs. + 0.4 ± 1.7 μIU/mL, P = 0.004), homeostatic model of assessment for insulin resistance (− 0.3 ± 0.5 vs. + 0.1 ± 0.4, P = 0.005), and a significant increase in quantitative insulin sensitivity check index (+ 0.004 ± 0.008 vs. − 0.001 ± 0.008, P = 0.03). In addition, chromium supplementation significantly decreased serum triglycerides (− 19.2 ± 33.8 vs. + 8.3 ± 21.7 mg/dL, P = 0.004), VLDL- (− 3.8 ± 6.8 vs. + 1.7 ± 4.3 mg/dL, P = 0.004) and total cholesterol concentrations (− 15.3 ± 26.2 vs. − 0.6 ± 15.9 mg/dL, P = 0.03) compared with the placebo. Additionally, taking chromium supplements was associated with a significant increase in plasma total antioxidant capacity (+ 153.9 ± 46.1 vs. − 7.8 ± 43.9 mmol/L, P < 0.001) and a significant reduction in malondialdehyde values (−0.3 ± 0.3 vs. + 0.1 ± 0.2 μmol/L, P = 0.001) compared with the placebo. Overall, our study supported that chromium administration for 8 weeks to infertile PCOS women candidate for IVF had beneficial impacts on glycemic control, few variables of cardio-metabolic risk, and oxidative stress.



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Glaucoma related retinal oximetry: a technology update

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Physiologic anisocoria under various lighting conditions

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Strong coupling between slow oscillations and wide fast ripples in children with epileptic spasms: Investigation of modulation index and occurrence rate

Summary

Objective

Epileptic spasms (ES) often become drug-resistant. To reveal the electrophysiological difference between children with ES (ES+) and without ES (ES−), we compared the occurrence rate (OR) of high-frequency oscillations (HFOs) and the modulation index (MI) of coupling between slow and fast oscillations.

In ES+, we hypothesized that (1) pathological HFOs are more widely distributed and (2) slow oscillations show stronger coupling with pathological HFOs than in ES−.

Methods

We retrospectively reviewed 24 children with drug-resistant multilobar onset epilepsy, who underwent intracranial video electroencephalography prior to multilobar resections. We measured the OR of HFOs and determined the electrodes with a high rate of HFOs by cluster analysis. We calculated MI, which reflects the degree of coupling between HFO (ripple/fast ripple [FR]) amplitude and 5 different frequency bands of delta and theta activities (0.5-1 Hz, 1-2 Hz, 2-3 Hz, 3-4 Hz, 4-8 Hz).

Results

In ES+ (n = 10), the OR(FRs), the number of electrodes with high-rate FRs, and the MI(FRs & 3-4 Hz) in all electrodes were significantly higher than in ES− (n = 14). In both the ES+ and ES− groups, MI(ripples/FRs & 3-4 Hz) was the highest among the 5 frequency bands. Within the good seizure outcome group, the OR(FRs) and the MI(FRs & 3-4 Hz) in the resected area in ES+ were significantly higher than in ES− (OR[FRs], P = .04; MI[FRs & 3-4 Hz], P = .04).

Significance

In ES+, the larger number of high-rate FR electrodes indicates more widespread epileptogenicity than in ES−. High values of OR(FRs) and MI(FRs & 3-4 Hz) in ES+ compared to ES− are a signature of the severity of epileptogenicity. We proved that ES+ children who achieved seizure freedom following multilobar resections exhibited strong coupling between slow oscillations and FRs.



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Neonatal phenobarbital exposure disrupts GABAergic synaptic maturation in rat CA1 neurons

Summary

Objective

Phenobarbital is the most commonly utilized drug for the treatment of neonatal seizures. The use of phenobarbital continues despite growing evidence that it exerts suboptimal seizure control and is associated with long-term alterations in brain structure, function, and behavior. Alterations following neonatal phenobarbital exposure include acute induction of neuronal apoptosis, disruption of synaptic development in the striatum, and a host of behavioral deficits. These behavioral deficits include those in learning and memory mediated by the hippocampus. However, the synaptic changes caused by acute exposure to phenobarbital that lead to lasting effects on brain function and behavior remain understudied.

Methods

Postnatal day (P)7 rat pups were treated with phenobarbital (75 mg/kg) or saline. On P13-14 or P29-37, acute slices were prepared and whole-cell patch-clamp recordings were made from CA1 pyramidal neurons.

Results

At P14 we found an increase in miniature inhibitory postsynaptic current (mIPSC) frequency in the phenobarbital-exposed as compared to the saline-exposed group. In addition to this change in mIPSC frequency, the phenobarbital group displayed larger bicuculline-sensitive tonic currents, decreased capacitance and membrane time constant, and a surprising persistence of giant depolarizing potentials. At P29+, the frequency of mIPSCs in the saline-exposed group had increased significantly from the frequency at P14, typical of normal synaptic development; at this age the phenobarbital-exposed group displayed a lower mIPSC frequency than did the control group. Spontaneous inhibitory postsynaptic current (sIPSC) frequency was unaffected at either P14 or P29+.

Significance

These neurophysiological alterations following phenobarbital exposure provide a potential mechanism by which acute phenobarbital exposure can have a long-lasting impact on brain development and behavior.



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Tanshinone IIA induces cell death via Beclin-1-dependent autophagy in oral squamous cell carcinoma SCC-9 cell line

Abstract

Tanshinone IIA (TAN) is one of the major functional compounds of Salvia miltiorrhiza Bunge and possesses the ability to suppress the growth of multiple cancer cell types via its apoptosis- and autophagy-inducing functions. In this study, the effect of TAN therapy on the survival of oral squamous cell carcinoma (OSCC) was evaluated, and the underlying mechanism involved in the treatment was investigated. Human oral squamous cell carcinoma cell SCC-9 was used for in vitro assays and induction in an OSCC xenograft mouse model. The tumor cells were subjected to TAN administration at different concentrations. Then the apoptosis and autophagy processes in SCC-9 cells were evaluated and the activities of Beclin-1/Atg7/Atg12-Atg5 and PI3K/Akt/mTOR pathways were determined. In addition, by knocking down the expression of Beclin-1 in SCC-9 cells, the study also assessed the role of the indicator in the anti-OSCC effect of TAN. Results of in vitro assays were further validated with an OSCC xenograft mouse model. Administration of TAN-induced cell apoptosis and upregulated the expression of cleaved-caspase-3. Simultaneously, the autophagy process in SCC-9 cells was initiated by TAN, which was signaled by the formation of autophagosomes and increase in the ratio of LC3 II/LC3I. The above processes were associated with the activation of Beclin-1/Atg7/Atg12-Atg5 signaling and inhibition of PI3K/Akt/mTOR signaling. Our results also inferred a partially Beclin-1-dependent mechanism of action of TAN in OSCC cells: knockdown of the Beclin-1 blocked the effect of TAN on SCC-9 cells both in vivo and in vitro. Our study provided a preliminary explanation of the mechanism involved in TAN effect: the agent exerted its autophagy-inducing effect against OSCC in a multipronged manner, by both inducing the Beclin-1/Atg7/Atg12-Atg5 pathway and suppressing the PI3K/Akt/mTOR pathway.

Thumbnail image of graphical abstract

Suppressing effect of Tanshinone IIA (TAN) on the survival of oral squamous cell carcinoma (OSCC), which was dependent on the Beclin-1-induced autophagic process.



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Beliefs about Sexual Assault in India and Britain are Explained by Attitudes Toward Women and Hostile Sexism

Abstract

As many as one in five women worldwide will be sexually assaulted over the course of her lifetime (United Nations 2008), yet myths that downplay the prevalence and severity of sexual assault are still widely accepted. Are myths about sexual assault (rape myths) more likely to be accepted in cultures that endorse more traditional gender roles and attitudes toward women? To explore the relationships among rape myth acceptance, attitudes toward women, and hostile and benevolent sexism, data were collected from 112 Indian and 117 British adults, samples from two cultures differing widely in their gender role traditionalism. Analyses confirmed a cultural difference in rape myth acceptance, with the more traditional culture, India, accepting myths to a greater extent than the more egalitarian culture, Britain. Indian participants' greater rape myth acceptance was explained by their more traditional gender role attitudes and hostile sexism. We discuss ways in which promoting gender egalitarianism may help to break down negative beliefs and reduce the stigma surrounding sexual assault, especially in India, for example through interventions which increase exposure to women in less traditional roles (e.g., those in positions of power).



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“Stroppy Bitches Who Just Need to Learn How to Settle”? Young Single Women and Norms of Femininity and Heterosexuality

Abstract

The (older) single woman has evoked numerous negative sociocultural stereotypes in recent (Western) history, with "being single" a fraught position for (heterosexual) women. Have shifts toward gendered equality changed this stereotype? We interviewed 21 young heterosexual women in Aotearoa (New Zealand) about their experiences of being single. We focused on young adulthood (ages 25–35), a time when having children might be a particularly salient concern. Women's experiences of being single were inextricable from their wider experiences of heterosexuality and pressures to enact a "desirable" femininity. A thematic analysis identified four patterned sets of pressures, which we conceptualised as rules that govern hetero-relating: (a) pressures and expectations surrounding beauty standards, (b) (allowing for) aspects of male control and superiority, (c) acceptable/unacceptable gendered standards of sexuality, and (d) eventual and mandatory (heterosexual) coupling (by a "certain" age). Participants remained largely subject to traditional ideas around heterosexual gender roles, with identifiable punishments for "unfeminine" behaviour. Many women did articulate resistance and critique, even as most also expressed complicity. In this context, singledom was constructed as a "defective' state," even if desired, suggesting it remains a complex and precarious position to occupy.



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Preoperative to postoperative change in neutrophil-to-lymphocyte ratio predict survival in colorectal cancer patients

Future Oncology, Ahead of Print.


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Is there a pathological relationship between microalbuminuria and Helicobacter pylori vacA and cagA genes in type 2 diabetic patients?

Abstract

Diabetes is one of the most common metabolic disorders worldwide. Microalbuminuria, one of the complications following elevated glucose levels, is used as a simple and effective method of kidney function analysis in diabetic patients. Early stage diagnosis of microalbuminuria is useful in monitoring and prevention of the progression of diabetic nephropathy. Due to a lower immunity, diabetic patients are more susceptible. Reports have shown that cytotoxin-associated gene A (cagA)-positive Helicobacter pylori is one of the effective factors responsible in microalbuminuria pathology. However, a lack of information on the relationship between microalbuminuria in type II diabetes and vacuolating cytotoxin A (vacA) is evident. The present study aimed at the relationship between microalbuminuria in type II diabetes and vacA and cagA genes from H. pylori. A total of 88 type II diabetic patients referred to the Isfahan Endocrine and Metabolism Research Center participated in this study. Nested PCR was performed to exclude host genes, and consequently, H. pylori genotyping was performed based on vacA and cagA. Out of the 88 patients, 68.2 % (60/88) of them have microalbuminuria. A total of 18.2 % of the patients were infected with H. pylori in which 75 % of them showed microalbuminuria and 18.8 % of this group had simultaneously microalbuminuria and expression of cagA. The association between microalbuminuria and H. pylori infection was not statistically significant (p = 0.52). Considering the population size and criteria of choice, statistical analysis did not show any significant relationship between the virulence genes vacA and cagA of H. pylori and microalbuminuria in type II diabetic patients.



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Correction to: Effects of dust particles on body weight and some haematological parameters in rats in Maiduguri metropolis, Nigeria

Abstract

The original version of this paper unfortunately captured the name of Dr. Yahi incorrectly. It should be Dauda Yahi instead of Y. Dauda in the original paper.



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The evaluation of the serum level of IL-10 in OLP patients

Abstract

Lichen planus (LP) is an autoimmune chronic inflammatory disease. Interleukin 10 (IL-10) can inhibit the synthesis of pre-inflammatory cytokines. Regarding the role of inflammatory cytokines in lichen planus patients, evaluating the serums level of IL-10 in such patients can declare the potential role of this cytokine. In this study, 44 serum samples from patients with lichen planus and 44 serum samples from healthy participants were collected during 2015–2016. The patients with clinical or histopathological confirmation for oral lichen planus (OLP) were included in the case group, and the healthy patients were recruited in the control group. The serum level of IL-10 was measured by ELISA kits. In this cross-sectional study between 2015 and 2016, the serum level of IL-10 was measured in 53 females (60.22%) and 35 males (39.77%). In the lichen planus group, 44 subjects and in the control group, 44 healthy participants were enrolled. The mean serum level of IL-10 in oral lichen planus patients was reported as 3.68 ± 3.44 pg/ml and this was 0 ± 0 pg/ml in the healthy control group. The mean serum level of IL-10 in oral lichen planus patients was significantly more than the mean serum level of IL-10 in the control participants (P = 0.042).There was no relation between serum level of IL-10 in OLP patients and age (P = 0.771) and sex (P = 0.547) of participants. The findings indicated significant difference between the serum level of IL-10 and types of oral lichen planus lesions (P < 0.001). This study indicated that significant elevation of IL-10 in OLP patients might be important in immunomodulating of this disease, although the exact mechanism is not clear.



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Interleukin-6-572 promoter gene polymorphism and its association with chronic hepatitis C-induced hepatocellular carcinoma: an Egyptian study

Abstract

Hepatocellular carcinoma (HCC) is the most common type of liver cancer, where the risk of its development is always multifactorial. Human interleukin-6 (IL-6) is a pro-inflammatory cytokine that plays a crucial role in the regulation of immune response and defense against viral infection; it was hypothesized that this cytokine may participate in the process of liver damage. The aim of our study was to investigate IL-6-572 C/G gene polymorphism in patients with HCC as compared with healthy controls in an Egyptian population, in order to see if there is a significant association between IL-6 gene polymorphism and susceptibility to HCC development. A total of 165 subjects divided into 55 HCV, 60 HCC, and 50 healthy subjects were enrolled in the study for evaluation. Genomic DNA was extracted from the peripheral blood, and genotyping was performed using RT-multiplex PCR (real-time multiplex polymerase chain reaction) methodology. G/C, G/G, and C/C frequencies in HCV patients were 16.4, 78.2, and 5.5%, respectively; furthermore, the frequencies were 18.3, 75.0, and 6.7% in HCC patients, and 28.0, 62.0, and 10.0% in the control group, respectively. The frequencies of G and C alleles in HCV patients were 86.4 and 13.6% and in HCC patients were 84.2 and 15.8% while in the control group, the frequencies were 76.0 and 24.0%, respectively. There was no significant difference between the studied groups regarding G/C, G/G, and C/C frequencies or G and C allele's frequencies. IL-6-572 promoter gene polymorphism is neither associated with HCV infection nor with development of HCC. Further studies including bigger sample size are suggested.



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The effect of melatonin on expression of p53 and ovarian preantral follicle development isolated from vitrified ovary

Abstract

Ovarian vitrification is a strategy for conservation of fertility of young female patients, suffering from infertility, due to iatrogenic loss of ovarian function, resulting from chemotherapy and/or radiation therapy. The purpose of this study was to determine the influence of melatonin on expression of p53 and the developmental rate of preantral follicles isolated from vitrified and non-vitrified ovaries. This experimental study was carried out on 40, 14-day-old female mice (NMRI). One ovary from each mouse was used randomly for the vitrification procedure. Preantral follicles with a diameter of 120–140 μm derived from vitrified-warmed and non-vitrified ovarian tissues were cultured individually in α-MEM medium supplemented with or without melatonin. The expression of p53, diameter of follicle, survival rate, and number of antral follicles were compared using post hoc LSD, t test, and chi-square test, respectively in four groups: non-vitrified and non-melatonin (NVNM), non-vitrified and melatonin (NVM), vitrified and non-melatonin (VNM), vitrified and melatonin (VM). p53 gene was expressed in four groups and was strongly expressed in the antral follicles of VNM (p = 0.011). The addition of melatonin increased survival rate and the mean diameter of follicles in vitrified group (p = 0.001). There were no significant differences in antral formation of follicles between different groups. Adding melatonin to culture medium reduced expression of p53 apoptotic gene in vitrified group and improves in vitro maturation and survival rate in isolated follicles from vitrified ovaries.



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Addition of yucca extract and glutamine in the diet of chicks had a protective effect against coccidiosis

Abstract

Some challenge has been faced by farmers and among them are the decline of animal performance and mortality rate in the growth phase. One of the main causes of low performance is gastrointestinal problems, most of them caused by parasitic infections. Among the protozoa of major importance that affect the poultry in the first weeks of life, stands out the genus Eimeria, a parasite that causes intestinal malabsorption. The current study used 40 chicks, 1-day old, separated into four groups that received the same diet with different levels of yucca extract and glutamine supplementation. The animals were weighed at 10 and 15 days of age, where five chicks per group were used to evaluate the presence of oocysts, intestinal lesions, and biochemical variables. The addition of glutamine and yucca extract caused positive effect controlling coccidiosis, decreasing the presence of oocysts in both periods (Friedman = 37; p = 0.001); in addition, both served to protect the gut against the injury caused by the infection. Increased total protein values on day 15 (Friedman = 12; p < 0.001) in the control group due to increased levels of globulin (Friedman = 31; p = 0.02), exacerbating an inflammatory response against infection. At the same time, triglyceride levels (Friedman = 28.64; p < 0.001) and uric acid (Friedman = 28.64; p < 0.001) were lower in the control group compared to treated groups, which might be a consequence of malabsorption syndrome seen in cases of coccidiosis. In relation to the antioxidant enzymes, it was observed a reduction on SOD levels (Friedman = 13.51, p = 0.03) and CAT (Friedman = 13.65; p = 0.05) in the supplemented groups in relation to the control group at 15 days, due to lower parasitism and intestinal lesions. Based on the preliminary results, we conclude that the supplementation of glutamine and yucca extract had positive effects on the health and growth of broilers, with coccidiostatic action.



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Retrospective study on the etiology and clinical signs of canine otitis

Abstract

The survey comprised 5870 dogs with surgical diagnoses for the period 1 January 2010 to 31 December 2014, out of which 269 (4.58%) were diagnosed with otitis. The total number of isolates was 53: 17 coagulase-positive staphylococci, 2 beta-hemolytic staphylococci, 16 Pseudomonas aeruginosa, 7 Proteus mirabilis, 9 Malassezia pachydermatis, and 2 Candida spp. Bacterial and fungal infections were most frequently encountered in the summer (26; 49.06%) then in the autumn (13 isolates, 24.54%), and winter and spring (7 isolates, 13.21%). The highest number of isolates (21.4%) was resistant to chloramphenicol, followed by those resistant to gentamicin (16.6%), enrofloxacin (14.3%), and amoxicillin/clavulanic acid (9.5%). Head shaking was the commonest clinical sign (59.48%), followed by ear scratching (88 dogs), pain (81 dogs), and ear discharge (71 dogs). Acute otitis cases were 53.53%, followed by chronic (29.37%) and recurrent cases (17.10%).



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Lysiloma acapulcensis leaves contain anthelmintic metabolites that reduce the gastrointestinal nematode egg population in sheep faeces

Abstract

One metabolite against lamb gastrointestinal nematodes (GIN) was identified from extracts of Lysiloma acapulcensis leaves. Firstly, an aqueous extract of L. acapulcensis leaves and two fractions, organic and aqueous, were evaluated at different concentrations against Haemonchus contortus eggs and histotrophic larvae. In other experiment, 35 Pelibuey GIN-infected lambs were randomly divided into five groups, as follows: (1) ivermectin (0.2 mg/kg BW); (2) control (untreated); (3) rutin (10 mg/kg BW, as a flavonoid comparison control); (4) L. acapulcensis leaves ethyl acetate fraction (EtAc-F, 25 mg/kg BW); and (5) L. acapulcensis leaves (dried and grinded, 5 g/kg BW). The EtAc-F fraction caused 94.8% egg-hatching inhibition (P < 0.05, 6.25 mg/ml). Likewise, at 50 mg/ml, this fraction resulted in 100% larval mortality. In the second experiment, the highest eggs per gram (EPG) of faeces reduction caused by ivermectin was 80.2% (ȳ = 61.8%); meanwhile, rutin showed a highest EPG reduction = 66.2% (ȳ = 37.5%). Similarly, EtAc-F fraction showed 62.9% EPG highest reduction (ȳ = 32.5%). On the other hand, lambs fed with L. acapulcensis leaves showed a maximum EPG reduction = 50.1% (ȳ = 29.4%). Chromatography analysis (HPLC; NRM) of EtAc-F fraction revealed the presence of myricitrin as a major compound. Lysiloma acapulcensis leaves EtAc-F exhibited the highest in vitro activity against H. contortus eggs and larvae. The low efficacy of ivermectin suggests the presence of anthelmintic resistance. Lysiloma acapulcensis leaves and fractions can be considered in future experiments searching for a sustainable alternative of GIN control.



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Breast carcinoma with 21-gene recurrence score lower than 18: rate of locoregional recurrence in a large series with clinical follow-up

Abstract

Background

The 21-gene recurrence score (RS) assay determines the benefit of adding chemotherapy to endocrine therapy for patients with early stage, estrogen receptor (ER)-positive, HER2-negative breast cancer. The RS risk groups predict the likelihood of distant recurrence and have recently been associated with an increased risk of locoregional recurrence (LRR). This study analyzed clinicopathologic features of patients with low RS and LRR.

Methods

In our institutional database, we identified 1396 consecutive female patients with lymph node negative, ER+/HER2- invasive breast carcinoma and low RS (<18) results, treated at our center from 2008 to 2013. We collected data on clinicopathologic features, treatment and outcome.

Results

The median patient age was 57 years (range 22–90). The median tumor size was 1.2 cm (range 0.3–5.8). Overall, 66.6% (930/1396) women were treated with breast conserving surgery (BCS) and radiation therapy, 3.4% (48/1396) with BCS alone, 29.7% (414/1396) with total mastectomy, and 0.3% (4/1396) with total mastectomy and radiation therapy. Most patients (84.8%; 1184/1396) received endocrine therapy alone, 12.1% (169/1396) were treated with chemotherapy plus endocrine therapy, and only 3.1% (43/1396) received no systemic therapy. At a median follow-up of 52 months, 0.9% (13/1396) of patients developed LRR. Sites of LRR included the ipsilateral breast (n = 8), chest wall (n = 3), axillary node (n = 1), and internal mammary node (n = 1). All patients with LRR had negative resection margins at the initial surgery. The rate of LRR in patients treated with adjuvant endocrine therapy alone was 0.7% (8/1184). All eight patients received standard local treatment. Three patients had lymphovascular invasion but no other significant risk factors for LRR were identified.

Conclusions

Our study of node negative, ER+/HER2- breast cancer patients with low RS observed extremely low rates of LRR: 0.9% (13/1396) in the whole cohort and 0.7% (8/1184) in patients treated with endocrine therapy alone. As the largest series to date, we report detailed clinicopathologic data and clinical outcomes of this cohort and provide a comprehensive characterization of patients who developed LRR.



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A systematic review of clinic and community intervention to increase fecal testing for colorectal cancer in rural and low-income populations in the United States – How, what and when?

Abstract

Background

Interventions to improve fecal testing for colorectal cancer (CRC) exist, but are not yet routine practice. We conducted this systematic review to determine how implementation strategies and contextual factors influenced the uptake of interventions to increase Fecal Immunochemical Tests (FIT) and Fecal Occult Blood Testing (FOBT) for CRC in rural and low-income populations in the United States.

Methods

We searched Medline and the Cochrane Library from January 1998 through July 2016, and Scopus and clinicaltrials.gov through March 2015, for original articles of interventions to increase fecal testing for CRC. Two reviewers independently screened abstracts, reviewed full-text articles, extracted data and performed quality assessments. A qualitative synthesis described the relationship between changes in fecal testing rates for CRC, intervention components, implementation strategies, and contextual factors. A technical expert panel of primary care professionals, health system leaders, and academicians guided this work.

Results

Of 4218 citations initially identified, 27 unique studies reported in 29 publications met inclusion criteria. Studies were conducted in primary care (n = 20, 74.1%), community (n = 5, 18.5%), or both (n = 2, 7.4%) settings. All studies (n = 27, 100.0%) described multicomponent interventions. In clinic based studies, components that occurred most frequently among the highly effective/effective study arms were provision of kits by direct mail, use of a pre-addressed stamped envelope, client reminders, and provider ordered in-clinic distribution. Interventions were delivered by clinic staff/community members (n = 10, 37.0%), research staff (n = 6, 22.2%), both (n = 10, 37.0%), or it was unclear (n = 1, 3.7%). Over half of the studies lacked information on training or monitoring intervention fidelity (n = 15, 55.6%).

Conclusions

Studies to improve FIT/FOBT in rural and low-income populations utilized multicomponent interventions. The provision of kits through the mail, use of pre-addressed stamped envelopes, client reminders and in-clinic distribution appeared most frequently in the highly effective/effective clinic-based study arms. Few studies described contextual factors or implementation strategies. More robust application of guidelines to support reporting on methods to select, adapt and implement interventions can help end users determine not just which interventions work to improve CRC screening, but which interventions would work best in their setting given specific patient populations, clinical settings, and community characteristics.

Trial registration

In accordance with PRISMA guidelines, our systematic review protocol was registered with PROSPERO, the international prospective register of systematic reviews, on April 16, 2015 (registration number CRD42015019557).



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Doxorubicin resistance in breast cancer cells is mediated by extracellular matrix proteins

Abstract

Background

Cancer cell resistance to therapeutics can result from acquired or de novo-mediated factors. Here, we have utilised advanced breast cancer cell culture models to elucidate de novo doxorubicin resistance mechanisms.

Methods

The response of breast cancer cell lines (MCF-7 and MDA-MB-231) to doxorubicin was examined in an in vitro three-dimensional (3D) cell culture model. Cells were cultured with Matrigel™ enabling cellular arrangements into a 3D architecture in conjunction with cell-to-extracellular matrix (ECM) contact.

Results

Breast cancer cells cultured in a 3D ECM-based model demonstrated altered sensitivity to doxorubicin, when compared to those grown in corresponding two-dimensional (2D) monolayer culture conditions. Investigations into the factors triggering the observed doxorubicin resistance revealed that cell-to-ECM interactions played a pivotal role. This finding correlated with the up-regulation of pro-survival proteins in 3D ECM-containing cell culture conditions following exposure to doxorubicin. Inhibition of integrin signalling in combination with doxorubicin significantly reduced breast cancer cell viability. Furthermore, breast cancer cells grown in a 3D ECM-based model demonstrated a significantly reduced proliferation rate in comparison to cells cultured in 2D conditions.

Conclusion

Collectively, these novel findings reveal resistance mechanisms which may contribute to reduced doxorubicin sensitivity.



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An Adrenergic-Neurotrophin Feedforward Loop Promotes Pancreatic Cancer [Research Watch]

Stress-activated ADRB2 signaling promotes tumor innervation and PDAC development.



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Determination of mTORC1 Complex Structures Reveals Regulatory Mechanisms [Research Watch]

RHEB promotes allosteric activation of mTOR whereas PRAS40 blocks substrate recruitment sites.



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Glutaminolysis Drives Lung Cancer Metastasis via the PLAG1-GDH1 Axis [Research Watch]

PLAG1-mediated GDH1 upregulation promotes LKB1-deficient lung cancer anoikis resistance.



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Myeloproliferative Neoplasms May Be Sensitive to Dual BET/JAK Inhibition [Research Watch]

In myeloproliferative neoplasms (MPN) chromatin changes promote NF-B signaling to drive inflammation.



http://ift.tt/2CLa7Fc

Unintended Side Effects of Transformation Are Very Rare in Cryptococcus neoformans

Received wisdom in the field of fungal biology holds that the process of editing a genome by transformation and homologous recombination is inherently mutagenic. However, that belief is based on circumstantial evidence. We provide the first direct measurement of the effects of transformation on a fungal genome by sequencing the genomes of 29 transformants and 30 untransformed controls to high coverage. Contrary to the received wisdom, our results show that transformation of DNA segments flanked by long targeting sequences, followed by homologous recombination and selection for a drug marker, is extremely safe. If a transformation deletes a gene, that may create selective pressure for a few compensatory mutations, but even when we deleted a gene we found fewer than two point mutations per deletion strain, on average. We also tested these strains for changes in gene expression and found only a few genes that were consistently differentially expressed between wild type and strains modified by genomic insertion of a drug resistance marker. As part of our report, we provide the assembled genome sequence of the commonly used laboratory strain Cryptococcus neoformans var. grubii strain KN99α.



http://ift.tt/2F65zXA

Obtaining Adequate Lamina Propria for Subepithelial Fibrosis Evaluation in Pediatric Eosinophilic Esophagitis

Subepithelial fibrosis in eosinophilic esophagitis (EoE) can be detected only in esophageal biopsies with adequate amounts of lamina propria (LP). We investigated how often pediatric esophageal biopsies contain adequate LP, and whether esophageal eosinophilia influences the acquisition rates.

http://ift.tt/2AyanRQ

Effectiveness of cap-assisted device in the endoscopic removal of food bolus obstruction from the esophagus

The use of a transparent cap has been found to be effective in retrieval of esophageal foreign body. However, data on the use of a cap in food bolus obstruction (FBO) are limited. This study aims to assess the effectiveness of a cap-assisted technique compared with conventional techniques in removal of FBO.

http://ift.tt/2CLVaCL

Endoscopic mucosal resection of laterally spreading lesions around or involving the appendiceal orifice: technique, risk factors for failure, and outcomes of a tertiary referral cohort (with video)

Endoscopic mucosal resection (EMR) of peri-appendiceal sessile laterally spreading lesions (PA-LSLs) is technically demanding due to poor endoscopic access to the appendiceal lumen and the thin colonic wall at the base of the cecum. We aimed to assess the feasibility and safety of EMR for PA-LSLs.

http://ift.tt/2AwSHGd

Comparison of the diagnostic performance between magnifying chromoendoscopy and magnifying narrow-band imaging for superficial colorectal neoplasm: an online survey

Magnifying narrow-band imaging (mag-NBI) and magnifying chromoendoscopy using crystal violet staining for pit pattern analysis (pit pattern) is highly accurate for invasion depth diagnosis for superficial colorectal neoplasm. However, NBI and pit pattern have not been compared.

http://ift.tt/2CM4VAU

Technical feasibility, diagnostic yield, and safety of micro forceps biopsies during EUS evaluation of pancreatic cystic lesions (with video)

Through-the-needle micro forceps are a recent addition to the EUS armamentarium for evaluation of pancreatic cystic lesions (PCLs). The main aim of this study was to assess the technical feasibility, diagnostic yield and safety of EUS-guided micro forceps biopsy for PCLs.

http://ift.tt/2m5j81v

Pancreatic cancer screening in high-risk individuals with germline genetic mutations

Pancreas cancer (PC) is a deadly disease, which is most commonly diagnosed at an incurable stage. Different high-risk genetic variants and cancer syndromes increase the lifetime risk of developing PC. This study aims to assess the yield of initial PC screening in patients with high-risk germline mutations.

http://ift.tt/2AyoDKv

Extrapulmonary small cell carcinoma: an unfortunate case of metastatic disease

A 48- year-old man presented with weight loss and 3 weeks of right sided lower abdominal pain. Liver ultrasound and contrast-enhanced computed tomographic scan of the chest, abdomen, and pelvis revealed a 6.8 x 4.3 cm mass like thickening of ascending colon, with numerous hepatic lesions, enlarged mesenteric lymph nodes, peritoneal nodularity and multiple small (2-4 mm) pulmonary nodules concerning for widely metastatic disease (Figure A). A colonoscopy revealed an ulcerated right colon mass obliterating the lumen (Figure B).

http://ift.tt/2CKrm9A

Overall and Comparative Risk of Herpes Zoster With Pharmacotherapy for Inflammatory Bowel Diseases: A Nationwide Cohort Study

Patients with inflammatory bowel disease (IBD) might be at increased risk for herpes zoster infection. We sought to quantify the risk of herpes zoster in patients with IBD and evaluate the effects of IBD and IBD medications on the risk of herpes zoster.

http://ift.tt/2Ay2f3R

Nonpharmacologic Interventions for Improving Sleep Disturbances In Patients with Lung Cancer: A Systematic Review and Meta-Analysis

Lung cancer patients suffer from higher levels of sleep disturbances compared to other cancer patients and this leads to greater distress, poorer function and lower quality of life. Nonpharmacologic interventions have demonstrated improvements in the context of breast cancer but their efficacy in the lung cancer population is unclear.

http://ift.tt/2CYg26A

Decreased Expression of Megalin and Cubilin and Altered Mitochondrial Activity in Tenofovir Nephrotoxicity

Tenofovir disoproxil fumarate (TDF) is a commonly used antiretroviral drug for HIV, rarely causing Fanconi syndrome and acute kidney injury. We retrospectively analyzed the clinico-pathological presentation of 20 cases of tenofovir-induced tubulopathy, and investigated the renal expression of the megalin and cubilin proteins, as well as the mitochondrial respiratory chain activity. Estimated glomerular filtration rate (eGFR) before TDF exposure was 92 ml/min/1,73m2, decreasing to 27.5 ml/min/1,73m2 at the time of biopsy, with 30% of patients requiring renal replacement therapy.

http://ift.tt/2lZho9d

Solitary fibrous tumor with neuroendocrine and squamous dedifferentiation: a potential diagnostic pitfall

Solitary fibrous tumor (SFT) is a ubiquitous mesenchymal neoplasm of deep soft tissue with variable and often unpredictable biological behavior. The lineage is presumed to be fibroblastic and histological features range from benign to overtly malignant with rare tumors showing "dedifferentiation" or transformation to undifferentiated pleomorphic sarcoma. Dedifferentiation in mesenchymal neoplasms is a phenomenon of histologic progression of a well-differentiated neoplasm to a high-grade sarcoma which can differentiate along divergent lines.

http://ift.tt/2CFRMsl

Can the HEART Score Rule Out Acute Coronary Syndromes in the ED?

Nine studies, comprising 11,217 patients, were included for meta-analysis. Major adverse cardiac event prevalence was 15.4% (95% confidence interval [CI] 14.8% to 16.1%) at a mean follow-up of 6 weeks. In the low-risk group (HEART score of 0 to 3), a combined total of 1.6% of patients (95% CI 1.2% to 2.0%) had an incidence of major adverse cardiac event. The pooled sensitivity and specificity of the HEART score for predicting major adverse cardiac events were 96.7% (95% CI 94.0% to 98.2%) and 47.0% (95% CI 41.0% to 53.5%), respectively (Table).

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A novel noninvasive index for the prediction of moderate to severe fibrosis in chronic hepatitis B patients

The evaluation of liver fibrosis stages is essential for the clinical management of chronic hepatitis B (CHB).

http://ift.tt/2CwiX5q

The epigenetically regulated miR-494 associates with stem-cell phenotype and induces sorafenib resistance in hepatocellular carcinoma

The epigenetically regulated miR-494 associates with stem-cell phenotype and induces sorafenib resistance in hepatocellular carcinoma

The epigenetically regulated miR-494 associates with stem-cell phenotype and induces sorafenib resistance in hepatocellular carcinoma, Published online: 05 January 2018; doi:10.1038/s41419-017-0076-6

The epigenetically regulated miR-494 associates with stem-cell phenotype and induces sorafenib resistance in hepatocellular carcinoma

http://ift.tt/2F0jzBX

Anti-Trop2 blockade enhances the therapeutic efficacy of ErbB3 inhibition in head and neck squamous cell carcinoma

Anti-Trop2 blockade enhances the therapeutic efficacy of ErbB3 inhibition in head and neck squamous cell carcinoma

Anti-Trop2 blockade enhances the therapeutic efficacy of ErbB3 inhibition in head and neck squamous cell carcinoma, Published online: 05 January 2018; doi:10.1038/s41419-017-0029-0

Anti-Trop2 blockade enhances the therapeutic efficacy of ErbB3 inhibition in head and neck squamous cell carcinoma

http://ift.tt/2EdAyPU

Short-term retinoic acid treatment sustains pluripotency and suppresses differentiation of human induced pluripotent stem cells

Short-term retinoic acid treatment sustains pluripotency and suppresses differentiation of human induced pluripotent stem cells

Short-term retinoic acid treatment sustains pluripotency and suppresses differentiation of human induced pluripotent stem cells, Published online: 05 January 2018; doi:10.1038/s41419-017-0028-1

Short-term retinoic acid treatment sustains pluripotency and suppresses differentiation of human induced pluripotent stem cells

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Palliative care during and following allogeneic hematopoietic stem cell transplantation

Purpose of review The purpose of this review is to synthesize recent literature regarding the provision of palliative care to patients during and following allogeneic HSCT, highlighting factors, which mediate impairments in health-related quality of life in this patient population, and the intervention approaches and models of care delivery that clinicians can consider to address unmet needs for palliative care and to strengthen patient and family resiliency. Recent findings Provision of palliative care simultaneous with the delivery of treatment directed at the underlying malignancy has emerged as a recommended practice for patients with advanced cancer and high-symptom burden, and a recent randomized trial demonstrates the effectiveness of early palliative care in reducing some of the symptom burden and mood disturbances associated with HSCT. Although more research is needed, there is an expanding body of research-tested interventions to ameliorate the physical and psychological morbidity of HSCT across the transplant trajectory. Summary Palliative care interventions delivered by an interdisciplinary team that includes transplant clinicians and palliative care across the HSCT trajectory can alleviate physical and psychological morbidity, thereby improving the patient and family experience of HSCT. Correspondence to Sandra A. Mitchell, Division of Cancer Control and Population Sciences, Outcomes Research Branch, National Cancer Institute, 9609 Medical Center Drive, 3E-448 Rockville, MD 20850, USA. Tel: +1 240 276 6929; fax: +1 240 276 7906; e-mail: mitchlls@mail.nih.gov Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2F3xUOh

Economic burden of nosocomial infections caused by vancomycin-resistant enterococci

Nosocomial infections due to vancomycin-resistant enterococci (VRE) have become a major problem during the last years. The purpose of this study was to investigate the economic burden of nosocomial VRE infections...

http://ift.tt/2CveOij

Healthcare associated infection and its risk factors among patients admitted to a tertiary hospital in Ethiopia: longitudinal study

Healthcare associated infection (HAI) is alarmingly increasing in low income settings. In Ethiopia, the burden of HAI is still not well described.

http://ift.tt/2CXLUsd

Is weak CD4+ gain in the course of suppressive combination antiretroviral therapy for HIV infection a current clinical challenge? A case report and brief review of the literature

Individuals lacking immune recovery during suppressive cART will still represent a clinical issue in the years to come, given the high proportion of HIV-infected subjects introducing therapy late in the course...

http://ift.tt/2F4vleS

A multi-center study on the risk factors of infection caused by multi-drug resistant Acinetobacter baumannii

Acinetobacter baumannii (AB) is critical for healthcare-associated infections (HAI) with significant regional differences in the resistance rate, but its risk factors and infection trends has not been well studie...

http://ift.tt/2EcDe0u

Medical treatment of an unusual cerebral hydatid disease

Hydatid disease is a worldwide zoonosis produced by the larval stage of cestodes of the Echinococcus genus. Hydatid disease primarily involves the liver and lungs. The brain is involved in less than 2% of cases. ...

http://ift.tt/2F6tdTR

Long-term Lactobacillus rhamnosus BMX 54 application to restore a balanced vaginal ecosystem: a promising solution against HPV-infection

Over recent years, a growing interest has developed in microbiota and in the concept of maintaining a special balance between Lactobacillus and other bacteria species in order to promote women's well-being. The a...

http://ift.tt/2F6t7LZ

Characteristics of wild polio virus outbreak investigation and response in Ethiopia in 2013–2014: implications for prevention of outbreaks due to importations

Ethiopia joined the Global Polio Eradication Initiative (GPEI) in 1996, and by the end of December 2001 circulation of indigenous Wild Polio Virus (WPV) had been interrupted. Nonetheless, the country experienc...

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How Do You Feel? Subjective Perception of Recovery as a Reliable Surrogate of Cognitive and Functional Outcome in Cardiac Arrest Survivors

Objectives: To show that subjective estimate of patient's condition is related to objective cognitive and functional outcome in cardiac arrest survivors. Design: Longitudinal cohort study. Setting: ICU and Neuropsychology Service in two hospitals in Switzerland. Patients: Fifty survivors included from a prospective cohort of 138 patients admitted at the ICU for cardiopulmonary arrest. Interventions: Comprehensive cognitive and functional evaluation at 6 months follow-up. Measurements and Main Results: Subjectively, 70% of survivors reported satisfactory recovery and 29% reported no complaints. Objectively, 76% were classified as good neurologic outcome (Cerebral Performance Category 1), 26% as having no symptoms (modified Rankin Scale 0), and 38% as upper good recovery (Glasgow Outcome Scale Extended 1). Cognitive assessment detected substantial cognitive impairment in 26%, primarily concerning processing speed, language, long-term memory, and executive functions. Subjective complaints severity correlated significantly with objective cognitive impairment (rS = 0.64; p

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Healthcare Utilization and Infection in the Week Prior to Sepsis Hospitalization

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Objectives: To quantify healthcare utilization in the week preceding sepsis hospitalization to identify potential opportunities to improve the recognition and treatment of sepsis prior to admission. Design: Retrospective study. Setting: Two large integrated healthcare delivery systems in the United States. Participants: Hospitalized sepsis patients. Interventions: None. Measurements and Main Results: We quantified clinician-based encounters in each of the 7 days preceding sepsis admission, as well as on the day of admission, and categorized them as: hospitalization, subacute nursing facility, emergency department, urgent care, primary care, and specialty care. We identified the proportion of encounters with diagnoses for acute infection based on 28 single-level Clinical Classification Software categories. We also quantified the use of antibiotics over the same interval and used linear regression to evaluate time trends. We included a total of 14,658 Kaiser Permanente Northern California sepsis hospitalizations and 31,369 Veterans Health Administration sepsis hospitalizations. Over 40% of patients in both cohorts required intensive care. A total of 7,747 Kaiser Permanente Northern California patients (52.9%) and 14,280 Veterans Health Administration patients (45.5%) were seen by a clinician in the week before sepsis. Prior to sepsis, utilization of subacute nursing facilities remained steady, whereas hospital utilization declined. Primary care, specialty care, and emergency department visits increased, particularly at admission day. Among those with a presepsis encounter, 2,648 Kaiser Permanente Northern California patients (34.2%) and 3,858 Veterans Health Administration patients (27.0%) had at least one acute infection diagnosis. An increasing percentage of outpatient encounters also had infectious diagnoses (3.3%/d; 95% CI, 1.5%–5.1%; p

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Nonejecting Hearts on Femoral Veno-Arterial Extracorporeal Membrane Oxygenation: Aortic Root Blood Stasis and Thrombus Formation—A Case Series and Review of the Literature

Objectives: Cardiogenic shock constitutes the final common pathway of cardiac dysfunction associated with tissue hypoperfusion and organ failure. Besides treatment of the underlying cause, temporary mechanical circulatory support serves as a supportive measure. Extracorporeal membrane oxygenation can effectively prevent hypoxemia and end-organ dysfunction, but knowledge about patient selection, risks, and complications remains sparse. Data Sources: Clinical observation. Study Selection: Case report and review of the literature. Data Extraction: Relevant clinical information. Online databases, including PubMed, Web of Science, Scopus, and OVID, were searched for previous publications. Data Synthesis: We report six cases of patients in refractory cardiogenic shock receiving emergency femoral veno-arterial extracorporeal membrane oxygenation support complicated by echocardiographic evidence of absent blood flow, sedimentation, and thrombus formation in the aortic root. Conclusions: Patients in cardiogenic shock who require femoral veno-arterial extracorporeal membrane oxygenation support are at risk of developing a state of nonejecting heart with thrombus formation in the aortic root. Echocardiography is the cornerstone of diagnosis and documentation of treatment effects. Depending on the likelihood of the presence of clinically relevant thrombotic material in the aortic root, we propose a treatment algorithm for this group of high-risk patients. Drs. Hireche-Chikaoui and Grübler contributed equally. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://ift.tt/29S62lw). The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: martin.gruebler@gmx.net. Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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A Comparative Analysis of Sepsis Identification Methods in an Electronic Database

Objectives: To evaluate the relative validity of criteria for the identification of sepsis in an ICU database. Design: Retrospective cohort study of adult ICU admissions from 2008 to 2012. Setting: Tertiary teaching hospital in Boston, MA. Patients: Initial admission of all adult patients to noncardiac surgical ICUs. Interventions: Comparison of five different algorithms for retrospectively identifying sepsis, including the Sepsis-3 criteria. Measurements and Main Results: 11,791 of 23,620 ICU admissions (49.9%) met criteria for the study. Within this subgroup, 59.9% were suspected of infection on ICU admission, 75.2% of admissions had Sequential Organ Failure Assessment greater than or equal to 2, and 49.1% had both suspicion of infection and Sequential Organ Failure Assessment greater than or equal to 2 thereby meeting the Sepsis-3 criteria. The area under the receiver operator characteristic of Sequential Organ Failure Assessment (0.74) for hospital mortality was consistent with previous studies of the Sepsis-3 criteria. The Centers for Disease Control and Prevention, Angus, Martin, Centers for Medicare & Medicaid Services, and explicit coding methods for identifying sepsis revealed respective sepsis incidences of 31.9%, 28.6%, 14.7%, 11.0%, and 9.0%. In-hospital mortality increased with decreasing cohort size, ranging from 30.1% (explicit codes) to 14.5% (Sepsis-3 criteria). Agreement among the criteria was acceptable (Cronbach's alpha, 0.40–0.62). Conclusions: The new organ dysfunction-based Sepsis-3 criteria have been proposed as a clinical method for identifying sepsis. These criteria identified a larger, less severely ill cohort than that identified by previously used administrative definitions. The Sepsis-3 criteria have several advantages over prior methods, including less susceptibility to coding practices changes, provision of temporal context, and possession of high construct validity. However, the Sepsis-3 criteria also present new challenges, especially when calculated retrospectively. Future studies on sepsis should recognize the differences in outcome incidence among identification methods and contextualize their findings according to the different cohorts identified. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://ift.tt/29S62lw). Supported, in part, by the National Institutes of Health grants R01-EB017205 and R01-GM104987. Drs. Johnson, Raffa, Pollard, and Celi received support for article research from the National Institutes of Health. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: aewj@mit.edu Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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Lack of Early Improvement Predicts Poor Outcome Following Acute Intracerebral Hemorrhage

Objectives: There are limited data as to what degree of early neurologic change best relates to outcome in acute intracerebral hemorrhage. We aimed to derive and validate a threshold for early postintracerebral hemorrhage change that best predicts 90-day outcomes. Design: Derivation: retrospective analysis of collated clinical stroke trial data (Virtual International Stroke Trials Archive). Validation: retrospective analysis of a prospective multicenter cohort study (Prediction of haematoma growth and outcome in patients with intracerebral haemorrhage using the CT-angiography spot sign [PREDICT]). Setting: Neurocritical and ICUs. Patients: Patients with acute intracerebral hemorrhage presenting less than 6 hours. Derivation: 552 patients; validation: 275 patients. Interventions: None. Measurements and Main Results: We generated a receiver operating characteristic curve for the association between 24-hour National Institutes of Health Stroke Scale change and clinical outcome. The primary outcome was a modified Rankin Scale score of 4–6 at 90 days; secondary outcomes were other modified Rankin Scale score ranges (modified Rankin Scale, 2–6, 3–6, 5–6, 6). We employed Youden's J Index to select optimal cut points and calculated sensitivity, specificity, and predictive values. We determined independent predictors via multivariable logistic regression. The derived definitions were validated in the PREDICT cohort. Twenty-four–hour National Institutes of Health Stroke Scale change was strongly associated with 90-day outcome with an area under the receiver operating characteristic curve of 0.75. Youden's method showed an optimum cut point at –0.5, corresponding to National Institutes of Health Stroke Scale change of greater than or equal to 0 (a lack of clinical improvement), which was seen in 46%. Early neurologic change accurately predicted poor outcome when defined as greater than or equal to 0 (sensitivity, 65%; specificity, 73%; positive predictive value, 70%; adjusted odds ratio, 5.05 [CI, 3.25–7.85]) or greater than or equal to 4 (sensitivity, 19%; specificity, 98%; positive predictive value, 91%; adjusted odds ratio, 12.24 [CI, 4.08–36.66]). All definitions reproduced well in the validation cohort. Conclusions: Lack of clinical improvement at 24 hours robustly predicted poor outcome and showed good discrimination for individual patients who would do poorly. These findings are useful for prognostication and may also present as a potential early surrogate outcome for future intracerebral hemorrhage treatment trials. † Deceased. Data collection took place at varying sites. Primary analysis was conducted at the University of Ottawa and Ottawa Hospital Research Institute, Ottawa, ON, Canada. Drs. Yogendrakumar, Smith, and Dowlatshahi were responsible for study concept, design, and statistical analysis. Drs. Yogendrakumar and Dowlatshahi were responsible for drafting the article. All authors participated in acquisition of data (Prediction of haematoma growth and outcome in patients with intracerebral haemorrhage using the CT-angiography spot sign [PREDICT] and Virtual International Stroke Trials Archive) and in critical revisions of the article for intellectual content. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://ift.tt/29S62lw). Dr. Demchuk's institution received funding from Canadian Stroke Consortium and NovoNordisk Canada, and he disclosed off-label product use of recombinant factor VIIa (administered for intracerebral hemorrhage in a limited fashion within the PREDICT study). Dr. Aviv received support for article research from the Canadian Institutes of Health Research. Dr. Lyden's institution received funding from the National Institute of Health (National Institute of Neurological Disorders and Stroke), and he received funding from expert testimony. Dr. Hill disclosed that the PREDICT study was supported by a grant from the Canadian Stroke Consortium. Dr. Dowlatshahi was funded by a uOttawa Department of Medicine Clinician-Scientist Research Chair award and a Heart & Stroke Foundation of Canada New Investigator Award. Dr. Dowlatshahi received funding from Bayer Canada, BMS/Pfizer, and Boerhinger Ingleheim. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: vyogendrakumar@toh.on.ca Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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Decrease in Histidine-Rich Glycoprotein as a Novel Biomarker to Predict Sepsis Among Systemic Inflammatory Response Syndrome

Objectives: Many biomarkers for sepsis are used in clinical practice; however, few have become the standard. We measured plasma histidine-rich glycoprotein levels in patients with systemic inflammatory response syndrome. We compared histidine-rich glycoprotein, procalcitonin, and presepsin levels to assess their significance as biomarkers. Design: Single-center, prospective, observational cohort study. Setting: ICU at an university-affiliated hospital. Patients: Seventy-nine ICU patients (70 with systemic inflammatory response syndrome and 9 without systemic inflammatory response syndrome) and 16 healthy volunteers. Interventions: None. Measurements and Main Results: We collected blood samples from patients within 24 hours of ICU admission. Histidine-rich glycoprotein levels were determined using enzyme-linked immunosorbent assay. The median histidine-rich glycoprotein level in healthy volunteers (n = 16) was 63.00 µg/mL (interquartile range, 51.53–66.21 µg/mL). Histidine-rich glycoprotein levels in systemic inflammatory response syndrome patients (n = 70; 28.72 µg/mL [15.74–41.46 µg/mL]) were lower than those in nonsystemic inflammatory response syndrome patients (n = 9; 38.64 µg/mL [30.26–51.81 µg/mL]; p = 0.049). Of 70 patients with systemic inflammatory response syndrome, 20 had sepsis. Histidine-rich glycoprotein levels were lower in septic patients than in noninfective systemic inflammatory response syndrome patients (8.71 µg/mL [6.72–15.74 µg/mL] vs 33.27 µg/mL [26.57–44.99 µg/mL]; p

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Incidence and Outcomes for Patients With Cirrhosis Admitted to the United Kingdom Critical Care Units

Objective: To assess the epidemiology and outcome of patients with cirrhosis following critical care unit admission. Design: Retrospective cohort study. Setting: Critical care units in England, Wales, and Northern Ireland participating in the U.K. Intensive Care National Audit and Research Centre Case Mix Programme. Patients: Thirty-one thousand three hundred sixty-three patients with cirrhosis identified of 1,168,650 total critical care unit admissions (2.7%) admitted to U.K. critical care units between 1998 and 2012. Interventions: None. Measurements and Main Results: Ten thousand nine hundred thirty-six patients had alcohol-related liver disease (35%). In total, 1.6% of critical care unit admissions in 1998 had cirrhosis rising to 3.1% in 2012. The crude critical care unit mortality of patients with cirrhosis was 41% in 1998 falling to 31% in 2012 (p

http://ift.tt/2CI9mf5

Phase II Study of Bortezomib in Combination with Temozolomide and Regional Radiation Therapy for Upfront Treatment of Patients with Newly-Diagnosed Glioblastoma Multiforme: Safety and Efficacy Assessment

We conducted a phase II study of bortezomib in combination with temozolomide and regional radiotherapy (RT) in 24 newly-diagnosed GBM patients. Addition of bortezomib to current standard care was well-tolerated, and observed toxicities were acceptable. Overall survival rates were improved compared to historical norms, especially in MGMT methylated patients. Further clinical investigation is warranted in larger cohort of patients.

http://ift.tt/2m1uz9N

Local Control following Stereotactic Body Radiation Therapy for Liver Tumors

We have quantitatively evaluated published experiences with hepatic SBRT to determine local control rates for primary and metastatic liver tumors and have examined if outcomes are affected by SBRT dosing regimen. We found that for primary liver tumors SBRT provides high rates of durable local control, with no clear evidence of a dose-response relationship for commonly-utilized schedules. While for liver metastases following SBRT excellent local control rates are seen when utilizing biologically effective doses above 100 Gy10.

http://ift.tt/2m1rGp8

Patterns of Involved-Field Radiation Therapy (IFRT) Protocol Deviations in Pediatric versus Adolescent and Young Adults with Hodgkin Lymphoma: A Report from the Children’s Oncology Group (COG) AHOD0031

As ******** is the largest phase III study to date on intermediate-risk Hodgkin Lymphoma in pediatric patients, we investigated the patterns of radiation protocol deviation and relapse between the pediatric and adolescent and young adult patient cohorts. We demonstrate that there were no statistically significant differences in deviation patterns between the two cohorts, though of those that received IFRT, there was a significant difference in cumulative incidence rates of relapse between the two groups.

http://ift.tt/2CJRY9K

Radiation as an Effective Salvage Therapy for Secondary CNS Lymphoma

We reviewed the outcomes of patients with secondary central nervous system involvement by diffuse large-B cell lymphoma, who were treated with radiation therapy (RT) at a single institution. RT was associated with high rates of radiographic disease response and local control. Overall survival was superior in patients who achieved a complete or partial response to RT, who underwent autologous stem cell transplantation after RT, and who had brain parenchymal (vs. leptomeningeal) disease.

http://ift.tt/2lZyjZ7

Radiation Dose-Volume Effects for Liver SBRT

Stereotactic Body Radiation Therapy (SBRT) has emerged as an effective, non-invasive treatment option for primary liver cancer and metastatic disease occurring in the liver. While SBRT can be highly effective for establishing local control in hepatic malignancies, there is a tradeoff between tumor control and normal tissue complications. The objective of this work was to review the normal tissue dose-volume effects for SBRT-induced liver and gastrointestinal (GI) toxicities, and derive normal tissue complication probability models.

http://ift.tt/2CJugKU

Exploring the use of educational material about shoulder dysfunction: a Quality Improvement project in people with ALS

Shoulder pain is a common secondary complication of amyotrophic lateral sclerosis (ALS) that can contribute to functional decline and decreased participation in daily activities. The purpose of this study was to assess the effectiveness of an educational brochure aimed at improving knowledge regarding shoulder pain and dysfunction in people with ALS. Participants completed a pre-intervention survey with questions regarding their knowledge of how ALS may affect their shoulders. After completing the pre-survey, they were mailed a brochure that described shoulder health and range of motion and stretching exercises. Four weeks after receiving the brochure, participants were then asked to determine the effectiveness of the educational materials in terms of impact on shoulder-related knowledge and self-efficacy with regards to prevention of shoulder pain and dysfunction. More than 50% of participants reported pain, decreased range of motion, or weakness in at least one shoulder since being diagnosed with ALS. All participants were interested in receiving educational materials and all agreed that the brochure was easy to interpret and understand, with most (87%) reporting it was helpful. Educational brochures are one strategy to improve awareness about shoulder health and to educate ALS patients about exercises that may help reduce shoulder pain and dysfunction. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Funding: Sabrina Paganoni has been funded by the NIH (Career Development Award 2K12HD001097-16). The authors report no conflicts of interest. *Corresponding author: Sabrina Paganoni, MD, PhD, Harvard Medical School, Neurological Clinical Research Institute (NCRI), Massachusetts General Hospital, 165 Cambridge St, Suite 600, Boston, MA 02114, Ph: (617) 643-3452; Fax: (617) 724-7290. Email: spaganoni@partners.org Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2m0LvNh

Abulia due to injury of the prefrontocaudate tract in a stroke patient

No abstract available

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Donor-Specific Antibodies in Kidney Transplant Recipients

Donor-specific antibodies have become an established biomarker predicting antibody-mediated rejection. Antibody-mediated rejection is the leading cause of graft loss after kidney transplant. There are several phenotypes of antibody-mediated rejection along post-transplant course that are determined by the timing and extent of humoral response and the various characteristics of donor-specific antibodies, such as antigen classes, specificity, antibody strength, IgG subclasses, and complement binding capacity. Preformed donor-specific antibodies in sensitized patients can trigger hyperacute rejection, accelerated acute rejection, and early acute antibody-mediated rejection. De novo donor-specific antibodies are associated with late acute antibody-mediated rejection, chronic antibody-mediated rejection, and transplant glomerulopathy. The pathogeneses of antibody-mediated rejection include not only complement-dependent cytotoxicity, but also complement-independent pathways of antibody-mediated cellular cytotoxicity and direct endothelial activation and proliferation. The novel assay for complement binding capacity has improved our ability to predict antibody-mediated rejection phenotypes. C1q binding donor-specific antibodies are closely associated with acute antibody-mediated rejection, more severe graft injuries, and early graft failure, whereas C1q nonbinding donor-specific antibodies correlate with subclinical or chronic antibody-mediated rejection and late graft loss. IgG subclasses have various abilities to activate complement and recruit effector cells through the Fc receptor. Complement binding IgG3 donor-specific antibodies are frequently associated with acute antibody-mediated rejection and severe graft injury, whereas noncomplement binding IgG4 donor-specific antibodies are more correlated with subclinical or chronic antibody-mediated rejection and transplant glomerulopathy. Our in-depth knowledge of complex characteristics of donor-specific antibodies can stratify the patient's immunologic risk, can predict distinct phenotypes of antibody-mediated rejection, and hopefully, will guide our clinical practice to improve the transplant outcomes.



http://ift.tt/2qwbhP9

The Making Dialysis Safer for Patients Coalition: A New Partnership to Prevent Hemodialysis-Related Infections

The Making Dialysis Safer for Patients Coalition is a partnership of organizations and individual stakeholders that share the common goal to prevent bloodstream infections among patients receiving hemodialysis. Led by the Centers for Disease Control and Prevention (CDC), in collaboration with the CDC Foundation, this public-private partnership strives to improve adherence to evidence-based recommendations, share information and experiences, and engage patients in infection prevention efforts.



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Coaching Nephrology Trainees Who Struggle with Clinical Performance



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Maintenance of Certification: Demonstrating Ongoing Competence



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Toward More Meaningful Accountability to the Public: Assessing Lifelong Competence of Physicians



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Transformation of ABIM and What the Changes Mean to Nephrologists



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Maintenance of Certification: Framing the Dialogue



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TESTING Corticosteroids in IgA Nephropathy: A Continuing Challenge



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Hyperkalemia across the Continuum of Kidney Function



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Characteristics and Performance of Unilateral Kidney Transplants from Deceased Donors

Background and objectives

The fraction of kidneys procured for transplant that are discarded is rising in the United States. Identifying donors from whom only one kidney was discarded allows us to control for donor traits and better assess reasons for organ discard.

Design, setting, participants, & measurements

We conducted a retrospective cohort study using United Network for Organ Sharing Standard Transplant Analysis and Research file data to identify deceased donors from whom two kidneys were procured and at least one was transplanted. Unilateral pairs were defined as kidney pairs from a single donor from whom one kidney was discarded ("unilateral discard") but the other was transplanted ("unilateral transplant"). Organ quality was estimated using the Kidney Donor Risk Index and Kidney Donor Profile Index (KDPI). We compared all-cause graft failure rates for unilateral transplants to those for bilateral transplant Kaplan–Meier methods, and life table methodology was used to evaluate 1-, 2-, 3-, and 5-year survival rates of transplants from bilateral and unilateral donors.

Results

Compared with bilateral donors (i.e., both kidneys transplanted) (n=80,584), unilateral donors (i.e., only one kidney transplanted) (n=7625) had higher mean terminal creatinine (1.3±2.1 mg/dl versus 1.1±0.9 mg/dl) and KDPI (67%±25% versus 42%±27%), were older, and were more likely to have hypertension, diabetes, hepatitis C, terminal stroke, or meet Centers for Disease Control and Prevention high-risk donor criteria. Unilateral discards were primarily attributed to factors expected to be similar in both kidneys from a donor: biopsy findings (22%), no interested recipient (13%), and donor history (7%). Anatomic abnormalities (14%), organ damage (11%), and extended ischemia (6%) accounted for about 30% of discards, but were the commonest reasons among low KDPI kidneys. Among kidneys with KDPI≥60%, there was an incremental difference in allograft survival over time (for unilateral versus bilateral transplants, 1-year survival: 83% versus 87%; 3-year survival: 69% versus 73%; 5-year survival: 51% versus 58%).

Conclusions

A large number of discarded kidneys were procured from donors whose contralateral kidneys were transplanted with good post-transplant outcomes.



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The Effect of Extended Release Niacin on Markers of Mineral Metabolism in CKD

Background and objectives

Niacin downregulates intestinal sodium-dependent phosphate transporter 2b expression and reduces intestinal phosphate transport. Short-term studies have suggested that niacin lowers serum phosphate concentrations in patients with CKD and ESRD. However, the long-term effects of niacin on serum phosphate and other mineral markers are unknown.

Design, setting, participants, & measurements

The Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Trial was a randomized, double-blind, placebo-controlled trial testing extended release niacin in persons with prevalent cardiovascular disease. We examined the effect of randomized treatment with niacin (1500 or 2000 mg) or placebo on temporal changes in markers of mineral metabolism in 352 participants with eGFR<60 ml/min per 1.73 m2 over 3 years. Changes in each marker were compared over time between the niacin and placebo arms using linear mixed effects models.

Results

Randomization to niacin led to 0.08 mg/dl lower plasma phosphate concentrations per year of treatment compared with placebo (P<0.01) and 0.25 mg/dl lower mean phosphate 3 years after baseline (3.32 versus 3.57 mg/dl; P=0.03). In contrast, randomization to niacin was not associated with statistically significant changes in plasma intact fibroblast growth factor 23, parathyroid hormone, calcium, or vitamin D metabolites over 3 years.

Conclusions

The use of niacin over 3 years lowered serum phosphorous concentrations but did not affect other markers of mineral metabolism in participants with CKD.



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A Discrete Choice Study of Patient Preferences for Dialysis Modalities

Background and objectives

Improved knowledge about factors that influence patient choices when considering dialysis modality could facilitate health care interventions to increase rates of home dialysis. We aimed to quantify the attributes of dialysis care and the tradeoffs that patients consider when making decisions about dialysis modalities.

Design, setting, participants, & measurements

We conducted a prospective, discrete choice experiment survey with random parameter logit analysis to quantify preferences and tradeoffs for attributes of dialysis treatment in 143 adult patients with CKD expected to require RRT within 12 months (predialysis). The attributes included schedule flexibility, patient out of pocket costs, subsidized transport services, level of nursing support, life expectancy, dialysis training time, wellbeing on dialysis, and dialysis schedule (frequency and duration). We reported outcomes using β-coefficients with corresponding odds ratios and 95% confidence intervals for choosing home-based dialysis (peritoneal dialysis or hemodialysis) compared with facility hemodialysis.

Results

Home-based therapies were significantly preferred with the following attributes: longer survival (odds ratio per year, 1.63; 95% confidence interval, 1.25 to 2.12), increased treatment flexibility (odds ratio, 9.22; 95% confidence interval, 2.71 to 31.3), improved wellbeing (odds ratio, 210; 95% confidence interval, 15 to 2489), and more nursing support (odds ratio, 87.3; 95% confidence interval, 3.8 to 2014). Respondents were willing to accept additional out of pocket costs of approximately New Zealand $400 (United States $271) per month (95% confidence interval, New Zealand $333 to $465) to receive increased nursing support. Patients were willing to accept out of pocket costs of New Zealand $223 (United States $151) per month (95% confidence interval, New Zealand $195 to $251) for more treatment flexibility.

Conclusions

Patients preferred home dialysis over facility-based care when increased nursing support was available and when longer survival, wellbeing, and flexibility were expected. Sociodemographics, such as age, ethnicity, and income, influenced patient choice.



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FGF23 and Left Ventricular Hypertrophy in Children with CKD

Background and Objectives

High plasma concentration of fibroblast growth factor 23 (FGF23) is a risk factor for left ventricular hypertrophy (LVH) in adults with CKD, and induces myocardial hypertrophy in experimental CKD. We hypothesized that high FGF23 levels associate with a higher prevalence of LVH in children with CKD.

Design, setting, participants, & measurements

We performed echocardiograms and measured plasma C-terminal FGF23 concentrations in 587 children with mild-to-moderate CKD enrolled in the Chronic Kidney Disease in Children (CKiD) study. We used linear and logistic regression to analyze the association of plasma FGF23 with left ventricular mass index (LVMI) and LVH (LVMI ≥95th percentile), adjusted for demographics, body mass index, eGFR, and CKD-specific factors. We also examined the relationship between FGF23 and LVH by eGFR level.

Results

Median age was 12 years (interquartile range, 8–15) and eGFR was 50 ml/min per 1.73 m2 (interquartile range, 38–64). Overall prevalence of LVH was 11%. After adjustment for demographics and body mass index, the odds of having LVH was higher by 2.53 (95% confidence interval, 1.28 to 4.97; P<0.01) in participants with FGF23 concentrations ≥170 RU/ml compared with those with FGF23<100 RU/ml, but this association was attenuated after full adjustment. Among participants with eGFR≥45 ml/min per 1.73 m2, the prevalence of LVH was 5.4%, 11.2%, and 15.3% for those with FGF23 <100 RU/ml, 100–169 RU/ml, and ≥170 RU/ml, respectively (Ptrend=0.01). When eGFR was ≥45 ml/min per 1.73 m2, higher FGF23 concentrations were independently associated with LVH (fully adjusted odds ratio, 3.08 in the highest versus lowest FGF23 category; 95% confidence interval, 1.02 to 9.24; P<0.05; fully adjusted odds ratio, 2.02 per doubling of FGF23; 95% confidence interval, 1.29 to 3.17; P<0.01). By contrast, in participants with eGFR<45 ml/min per 1.73 m2, FGF23 did not associate with LVH.

Conclusions

Plasma FGF23 concentration ≥170 RU/ml is an independent predictor of LVH in children with eGFR≥45 ml/min per 1.73 m2.



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Lessons from CKD-Related Genetic Association Studies-Moving Forward

Over the past decade, genetic association studies have uncovered numerous determinants of kidney function in the general, diabetic, hypertensive, CKD, ESRD, and GN-based study populations (e.g., IgA nephropathy, membranous nephropathy, FSGS). These studies have led to numerous novel and unanticipated findings, which are helping improve our understanding of factors and pathways affecting both normal and pathologic kidney function. In this review, we report on major discoveries and advances resulting from this rapidly progressing research domain. We also predict some of the next steps the nephrology community should embrace to accelerate the identification of genetic and molecular processes leading to kidney dysfunction, pathophysiologically based disease subgroups, and specific therapeutic targets, as we attempt to transition toward a more precision-based medicine approach.



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Whole Exome Sequencing of Patients with Steroid-Resistant Nephrotic Syndrome

Background and objectives

Steroid-resistant nephrotic syndrome overwhelmingly progresses to ESRD. More than 30 monogenic genes have been identified to cause steroid-resistant nephrotic syndrome. We previously detected causative mutations using targeted panel sequencing in 30% of patients with steroid-resistant nephrotic syndrome. Panel sequencing has a number of limitations when compared with whole exome sequencing. We employed whole exome sequencing to detect monogenic causes of steroid-resistant nephrotic syndrome in an international cohort of 300 families.

Design, setting, participants, & measurements

Three hundred thirty-five individuals with steroid-resistant nephrotic syndrome from 300 families were recruited from April of 1998 to June of 2016. Age of onset was restricted to <25 years of age. Exome data were evaluated for 33 known monogenic steroid-resistant nephrotic syndrome genes.

Results

In 74 of 300 families (25%), we identified a causative mutation in one of 20 genes known to cause steroid-resistant nephrotic syndrome. In 11 families (3.7%), we detected a mutation in a gene that causes a phenocopy of steroid-resistant nephrotic syndrome. This is consistent with our previously published identification of mutations using a panel approach. We detected a causative mutation in a known steroid-resistant nephrotic syndrome gene in 38% of consanguineous families and in 13% of nonconsanguineous families, and 48% of children with congenital nephrotic syndrome. A total of 68 different mutations were detected in 20 of 33 steroid-resistant nephrotic syndrome genes. Fifteen of these mutations were novel. NPHS1, PLCE1, NPHS2, and SMARCAL1 were the most common genes in which we detected a mutation. In another 28% of families, we detected mutations in one or more candidate genes for steroid-resistant nephrotic syndrome.

Conclusions

Whole exome sequencing is a sensitive approach toward diagnosis of monogenic causes of steroid-resistant nephrotic syndrome. A molecular genetic diagnosis of steroid-resistant nephrotic syndrome may have important consequences for the management of treatment and kidney transplantation in steroid-resistant nephrotic syndrome.



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Randomized, Controlled Trial of TRC101 to Increase Serum Bicarbonate in Patients with CKD

Background and objectives

Metabolic acidosis is common in patients with CKD and has significant adverse effects on kidney, muscle, and bone. We tested the efficacy and safety of TRC101, a novel, sodium-free, nonabsorbed hydrochloric acid binder, to increase serum bicarbonate in patients with CKD and metabolic acidosis.

Design, setting, participants, & measurements

One hundred thirty-five patients were enrolled in this randomized, double-blind, placebo-controlled, multicenter, in-unit study (designated the TRCA-101 Study). Patients had a mean baseline eGFR of 35 ml/min per 1.73 m2, a mean baseline serum bicarbonate of 17.7 mEq/L, and comorbidities, including hypertension (93%), diabetes (70%), and heart failure (21%). Patients ate a controlled diet and were treated for 14 days with placebo or one of four TRC101 dosing regimens (1.5, 3, or 4.5 g twice daily or 6 g once daily). After treatment, patients were discharged and followed for 7–14 days.

Results

All TRC101 treatment groups had a mean within-group increase in serum bicarbonate of ≥1.3 mEq/L (P<0.001) within 72 hours of the first dose and a mean increase in serum bicarbonate of 3.2–3.9 mEq/L (P<0.001) at the end of treatment compared with placebo, in which serum bicarbonate did not change. In the combined TRC101 treatment group, serum bicarbonate was normalized (22–29 mEq/L) at the end of treatment in 35% of patients and increased by ≥4 mEq/L in 39% of patients. After discontinuation of TRC101, serum bicarbonate decreased nearly to baseline levels within 2 weeks. All adverse events were mild or moderate, with gastrointestinal events most common. All patients completed the study.

Conclusions

TRC101 safely and significantly increased the level of serum bicarbonate in patients with metabolic acidosis and CKD.



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Predicting Outcome in Patients with Anti-GBM Glomerulonephritis

Background and objectives

Large studies on long-term kidney outcome in patients with anti-glomerular basement membrane (anti-GBM) GN are lacking. This study aimed to identify clinical and histopathologic parameters that predict kidney outcome in these patients.

Design, setting, participants, & measurements

This retrospective analysis included a total of 123 patients with anti-GBM GN between 1986 and 2015 from six centers worldwide. Their kidney biopsy samples were classified according to the histopathologic classification for ANCA-associated GN. Clinical data such as details of treatment were retrieved from clinical records. The primary outcome parameter was the occurrence of ESRD. Kidney survival was analyzed using the log-rank test and Cox regression analyses.

Results

The 5-year kidney survival rate was 34%, with an improved rate observed among patients diagnosed after 2007 (P=0.01). In patients with anti-GBM GN, histopathologic class and kidney survival were associated (P<0.001). Only one of 15 patients with a focal class biopsy sample (≥50% normal glomeruli) developed ESRD. Patients with a sclerotic class biopsy sample (≥50% globally sclerotic glomeruli) and patients with 100% cellular crescents did not recover from dialysis dependency at presentation. In multivariable analysis, dialysis dependency at presentation (hazard ratio [HR], 3.17; 95% confidence interval [95% CI], 1.59 to 6.32), percentage of normal glomeruli (HR, 0.97; 95% CI, 0.95 to 0.99), and extent of interstitial infiltrate (HR, 2.02; 95% CI, 1.17 to 3.50) were predictors of ESRD during follow-up.

Conclusions

Dialysis dependency, low percentage of normal glomeruli, and large extent of interstitial infiltrate are associated with poor kidney outcome in anti-GBM GN. Kidney outcome has improved during recent years; the success rate doubled after 2007.

Podcast

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Re-Establishing Brain Networks in Patients with ESRD after Successful Kidney Transplantation

Background and objectives

Cognition in ESRD may be improved by kidney transplantation, but mechanisms are unclear. We explored patterns of resting-state networks with resting-state functional magnetic resonance imaging among patients with ESRD before and after kidney transplantation.

Design, setting, participants, & measurements

Thirty-seven patients with ESRD scheduled for kidney transplantation and 22 age-, sex-, and education-matched healthy subjects underwent resting-state functional magnetic resonance imaging. Patients were imaged before and 1 and 6 months after kidney transplantation. Functional connectivity of seven resting-state subnetworks was evaluated: default mode network, dorsal attention network, central executive network, self-referential network, sensorimotor network, visual network, and auditory network. Mixed effects models tested associations of ESRD, kidney transplantation, and neuropsychological measurements with functional connectivity.

Results

Compared with controls, pretransplant patients showed abnormal functional connectivity in six subnetworks. Compared with pretransplant patients, increased functional connectivity was observed in the default mode network, the dorsal attention network, the central executive network, the sensorimotor network, the auditory network, and the visual network 1 and 6 months after kidney transplantation (P=0.01). Six months after kidney transplantation, no significant difference in functional connectivity was observed for the dorsal attention network, the central executive network, the auditory network, or the visual network between patients and controls. Default mode network and sensorimotor network remained significantly different from those in controls when assessed 6 months after kidney transplantation. A relationship between functional connectivity and neuropsychological measurements was found in specific brain regions of some brain networks.

Conclusions

The recovery patterns of resting-state subnetworks vary after kidney transplantation. The dorsal attention network, the central executive network, the auditory network, and the visual network recovered to normal levels, whereas the default mode network and the sensorimotor network did not recover completely 6 months after kidney transplantation. Neural resting-state functional connectivity was lower among patients with ESRD compared with control subjects, but it significantly improved with kidney transplantation. Resting-state subnetworks exhibited variable recovery, in some cases to levels that were no longer significantly different from those of normal controls.



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BP Reduction, Kidney Function Decline, and Cardiovascular Events in Patients without CKD

Background and objectives

In the Systolic Blood Pressure Intervention Trial (SPRINT), intensive systolic BP treatment (target <120 mm Hg) was associated with fewer cardiovascular events and higher incidence of kidney function decline compared with standard treatment (target <140 mm Hg). We evaluated the association between mean arterial pressure reduction, kidney function decline, and cardiovascular events in patients without CKD.

Design, setting, participants, & measurements

We categorized patients in the intensive treatment group of the SPRINT according to mean arterial pressure reduction throughout follow-up: <20, 20 to <40, and ≥40 mm Hg. We defined the primary outcome as kidney function decline (≥30% reduction in eGFR to <60 ml/min per 1.73 m2 on two consecutive determinations at 3-month intervals), and we defined the secondary outcome as cardiovascular events. In a propensity score analysis, patients in each mean arterial pressure reduction category from the intensive treatment group were matched with patients from the standard treatment group to calculate the number needed to treat regarding cardiovascular events and the number needed to harm regarding kidney function decline.

Results

In the intensive treatment group, 1138 (34%) patients attained mean arterial pressure reduction <20 mm Hg, 1857 (56%) attained 20 to <40 mm Hg, and 309 (9%) attained ≥40 mm Hg. Adjusted hazard ratios for kidney function decline were 2.10 (95% confidence interval, 1.22 to 3.59) for mean arterial pressure reduction between 20 and 40 mm Hg and 6.22 (95% confidence interval, 2.75 to 14.08) for mean arterial pressure reduction ≥40 mm Hg. In propensity score analysis, mean arterial pressure reduction <20 mm Hg presented a number needed to treat of 44 and a number needed to harm of 65, reduction between 20 and <40 mm Hg presented a number needed to treat of 42 and a number needed to harm of 35, and reduction ≥40 mm Hg presented a number needed to treat of 95 and a number needed to harm of 16.

Conclusions

In the intensive treatment group of SPRINT, larger declines in mean arterial pressure were associated with higher incidence of kidney function decline. Intensive treatment seemed to be less favorable when a larger reduction in mean arterial pressure was needed to attain the BP target.



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Dysproteinemias and Glomerular Disease

Dysproteinemia is characterized by the overproduction of an Ig by clonal expansion of cells from the B cell lineage. The resultant monoclonal protein can be composed of the entire Ig or its components. Monoclonal proteins are increasingly recognized as a contributor to kidney disease. They can cause injury in all areas of the kidney, including the glomerular, tubular, and vascular compartments. In the glomerulus, the major mechanism of injury is deposition. Examples of this include Ig amyloidosis, monoclonal Ig deposition disease, immunotactoid glomerulopathy, and cryoglobulinemic GN specifically from types 1 and 2 cryoglobulins. Mechanisms that do not involve Ig deposition include the activation of the complement system, which causes complement deposition in C3 glomerulopathy, and cytokines/growth factors as seen in thrombotic microangiopathy and precipitation, which is involved with cryoglobulinemia. It is important to recognize that nephrotoxic monoclonal proteins can be produced by clones from any of the B cell lineages and that a malignant state is not required for the development of kidney disease. The nephrotoxic clones that do not meet requirement for a malignant condition are now called monoclonal gammopathy of renal significance. Whether it is a malignancy or monoclonal gammopathy of renal significance, preservation of renal function requires substantial reduction of the monoclonal protein. With better understanding of the pathogenesis, clone-directed strategies, such as rituximab against CD20 expressing B cell and bortezomib against plasma cell clones, have been used in the treatment of these diseases. These clone-directed therapies been found to be more effective than immunosuppressive regimens used in nonmonoclonal protein–related kidney diseases.



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Paramorphic multicarrier communications for interference mitigation

This paper presents a novel method for enabling communication in cyclostationary interference limited environments by adaptively inserting and exploiting spectral redundancy in an orthogonal frequency division...

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Correction to: Two-way DF relaying assisted D2D communication: ergodic rate and power allocation

Unfortunately, the original version of this article [1] contained an error. The affiliation of Yiyang Ni and Yuxi Wang was incorrect. The correct affiliation is Jiangsu Second Normal University and is presente...

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The Latest Twists in Chromatin Remodeling

In its most restrictive interpretation, the notion of chromatin remodeling refers to the action of chromatin-remodeling enzymes on nucleosomes with the aim of displacing and removing them from the chromatin fiber (the effective polymer formed by a DNA molecule and proteins). This local modification of the fiber structure can have consequences for the initiation and repression of the transcription process, and when the remodeling process spreads along the fiber, it also results in long-range effects essential for fiber condensation.

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Using CRISPR/Cas9 Gene Editing to Investigate the Oncogenic Activity of Mutant Calreticulin in Cytokine Dependent Hematopoietic Cells

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Targeted gene editing using CRISPR/Cas9 has greatly facilitated the understanding of the biological functions of genes. Here, we utilize the CRISPR/Cas9 methodology to model calreticulin mutations in cytokine-dependent hematopoietic cells in order to study their oncogenic activity.

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Emergence of G12 and G9 rotavirus genotypes in the Central African Republic, January 2014 to February 2016

Rotavirus gastroenteritis is a major cause of death among children under 5 years globally. A rotavirus gastroenteritis surveillance program started in October 2011 in the Central African Republic (CAR) with th...

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Utilizing the Modified T-Maze to Assess Functional Memory Outcomes After Cardiac Arrest

This protocol describes the use of a modified T-maze to evaluate functional learning/memory in asphyxia cardiac arrest-induced cerebral ischemia.

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Pa. EMS agency gets equipped with body armor

"You never know what you're getting into on a daily basis," Chief Robert Weidner said. "I'd rather come home to my family at the end of a shift"

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Isocitrate dehydrogenase 1 mutation subtypes at site 132 and their translational potential in glioma

CNS Oncology, Ahead of Print.


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Isolation and Respiratory Measurements of Mitochondria from Arabidopsis thaliana

As mitochondria are only a small percentage of the plant cell, they need to be purified for a range of studies. Mitochondria can be isolated from a variety of plant organs by homogenization, followed by differential and density gradient centrifugation to obtain a highly purified mitochondrial fraction.

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A Prediction Error-driven Retrieval Procedure for Destabilizing and Rewriting Maladaptive Reward Memories in Hazardous Drinkers

This manuscript describes a memory retrieval procedure for destabilizing robust reward memories and rewriting them with counterconditioning prior to their reconsolidation.

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A case of sigmoid volvulus

Clinical presentation

A 53-year-old man was admitted with a 2-week history of bowel obstruction on a background of gradually worsening dyspeptic symptoms associated with vomiting and weight loss. He was under regular gastroenterology review for Barrett's oesophagus and had a recent endoscopic diagnosis of megaduodenum (mainly D1 dilatation) confirmed by barium study (figure 1). He was also known to have bladder emptying problems and an enlarged bladder. His mother died at age 28 due to 'megacolon', and he has a monozygotic twin brother with Barrett's oesophagus.

Figure 1

Barium meal and follow through confirmed dilation of the duodenum with normal small bowel transit.

Abdominal X-ray showed marked large bowel dilatation (figure 2) and urgent CT scan of the abdomen and pelvis confirmed sigmoid volvulus (figure 3).

Figure 2

Urgent abdominal X-ray with prominent large bowel dilatation.

Figure 3

Representative axial image from urgent CT scan  of the abdomen and pelvis indicating sigmoid volvulus.

Despite two attempts at endoscopic decompression, he eventually underwent Hartmann's sigmoidectomy. His postoperative recovery was delayed by prolonged ileus requiring nasogastric drainage and parenteral nutritional support. He was discharged on the 19th day postoperatively.

Question

Aside from the immediate volvulus presentation, should any other diagnosis be considered?



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Case of nasogastric tube dysfunction

Clinical presentation

An elderly female patient was admitted to intensive care for prolonged vasopressor therapy and mechanical ventilation after cardiac arrest and acute percutaneous coronary intervention. Antiplatelet, thyroid hormone replacement and statin therapies were administered through a 14-French nasogastric tube (Nestlé Health Science) and enteral feeding was initiated. Correct position of the nasogastric tube was confirmed radiologically. On the seventh day in the intensive care, our patient was seen to regurgitate soft crumbs into her mouth. The blocked nasogastric tube was removed, but attempts to reinsert another tube failed.

Upper GI endoscopy revealed an obstruction of the oesophagus with a milky-yellowish caseous substance 20 cm from the incisors (figure 1). The proximal part of the mass showed a central hole and ring-shaped layers resembling the cut face of a tree trunk.

Figure 1

Obstruction of the oesophagus with a milky-yellowish caseous substance.

Questions

What caused the obstruction?

How should we manage such a problem?



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Extracellular vesicles as mediators of the progression and chemoresistance of pancreatic cancer and their potential clinical applications

Abstract

Pancreatic cancer is one of the most lethal cancers worldwide due to its insidious symptoms, early metastasis, and chemoresistance. Hence, the underlying mechanisms contributing to pancreatic cancer progression require further exploration. Based on accumulating evidence, extracellular vesicles, including exosomes and microvesicles, play a crucial role in pancreatic cancer progression and chemoresistance. Furthermore, they also possess the potential to be promising biomarkers, therapy targets and tools for treating pancreatic cancer. Therefore, in-depth studies on the role of extracellular vesicles in pancreatic cancer are meaningful. In this review, we focus on the regulatory effects of extracellular vesicles on pancreatic cancer progression, metastasis, cancer-related immunity and chemoresistance, particularly their potential roles as biomarkers and therapeutic targets.



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The draft Trusted Exchange Framework is now open for public comment.



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Response to Treatment of Acute HCV Cost-Effective but at What Price?



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Treatment of Acute HCV Cost-Effective but at What Price?



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Central nervous system gadolinium accumulation in patients undergoing periodical contrast MRI screening for hereditary tumor syndromes

Abstract

Background

Patients with hereditary tumor syndromes undergo periodical magnetic resonance imaging (MRI) screening with Gadolinium contrast. Gadolinium accumulation has recently been described in the central nervous system after repeated administrations. The prevalence and rate of accumulation in different subgroups of patients are unknown. Neither are the mechanism nor clinical impact. This may cause uncertainty about the screening. To explore the prevalence and rate of Gadolinium accumulation in different subgroups, we retrospectively analyzed MRIs of patients with von Hippel-Lindau disease (VHL) and Tuberous Sclerosis Complex (TSC).

Methods

We determined the prevalence and rate of accumulation in the dentate nucleus and globus pallidus on unenhanced T1-weighted MRI from VHL and TSC patients. We compared the signal intensities of these regions to the signal intensity of the pons. We evaluated the impact of number of MRIs, kidney function and liver function on Gadolinium accumulation.

Results

Twenty eight VHL patients and 24 TSC patients were included. The prevalence of accumulation in the dentate nucleus and globus pallidus increased linearly according to number of Gadolinium enhanced MRIs and was higher in the VHL group (100%). A significant linear correlation between number of MRIs and increased signal intensity was observed in the VHL group.

Conclusions

Gadolinium accumulation occurs in almost all patients undergoing contrast MRI screening after >5 MRIs. We advocate a screening protocol for patients with hereditary tumor syndromes that minimizes the Gadolinium dose. This can be accomplished by using a single administration to simultaneously screen for brain, spine and/or abdominal lesions, using an MRI protocol focused on either VHL- or TSC-specific lesions. Higher prevalence and rate of accumulation in VHL patients may be explained by the typical vascular leakage accompanying central nervous system hemangioblastomas.



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