Comparison of tumor-infiltrating lymphocytes of breast cancer in core needle biopsies and resected specimens: a retrospective analysis

Abstract

Purpose

Neoadjuvant chemotherapy (NAC) is being increasingly used to treat locally advanced breast cancer and to conserve the breast. In triple-negative breast cancer and HER2-positive breast cancer, a high density of tumor-infiltrating lymphocytes (TILs) is an important predictor of NAC response. Thus far, it remains unclear whether the TIL scores in core needle biopsies (CNBs) are closely representative of those in the whole tumor section in resected specimens. This study aimed to evaluate the concordance between the TIL scores of CNBs and resected specimens of breast cancer.

Methods

A total of 220 matched pairs of CNBs and resected specimens of breast cancer were included. Stromal TILs were scored on slides stained with hematoxylin and eosin. Clinicopathologic parameters and the agreement of the TIL scores between CNBs and resected specimens were statistically analyzed.

Results

The average TIL score was approximately 4.4% higher for the resected specimens than for the CNBs. When the tumors were divided into two groups according to a 60% TIL score cut-off (low and intermediate TIL vs. high TIL), 8.2% showed discordance between the CNB and resected specimen. The overall intraclass correlation coefficient (ICC) value of the TIL score was 0.895 (95% confidence interval, 0.864–0.920, P < 0.001), and all molecular subtypes showed ICC values over 0.8 (P < 0.001). The ICC values were > 0.9 when ≥ 5 cores were included in the CNBs. Tumors with discordant TILs were characterized by histologic grade III, ER negativity, high proliferative index, and HER2 and triple-negative subtypes. A high proliferative index was an independent risk factor for TIL discordance.

Conclusions

The TIL score in CNB specimens is a reliable value that reflects the TIL status of the entire tumor in resected specimens of breast cancer. More than five CNB cores may accurately predict the TIL score of the entire tumor.

https://ift.tt/2kQiLqB

Spotlight on… Gabriella Campadelli-Fiume

Biographical Summary

My first education was in biochemical pathogenesis of disease at the University of Bologna, Italy, University College, London and Max Planck institute, Heidelberg. I entered Virology in 1972 in the University of Bologna, where I still work. I am the head of the molecular virology laboratory in the Department of Experimental Medicine, University of Bologna. The focus of my research is on the molecular mechanisms of herpes simplex virus (HSV) entry into the cell, and on how to modify the HSV tropism in order to generate highly cancer-specific, highly safe, yet fully virulent oncolytic herpesviruses. Academically, I fostered the integration of the Italian Virology in the European Virology.

https://ift.tt/2sv6fRG

Long-term outcomes of total body irradiation plus cyclophosphamide versus busulfan plus cyclophosphamide as conditioning regimen for acute lymphoblastic leukemia: a comparative study

Abstract

The role of total body irradiation (TBI) in allogeneic hematopoietic stem cell transplantation (HCT) for adult acute lymphoblastic leukemia (ALL) remains controversial. Therefore, we investigated long-term treatment outcomes of transplanted ALL patients aiming to identify prognostic factors and the impact of conditioning. We enrolled consecutive ALL patients transplanted from 1990 to 2016, following TBI- or busulfan (Bu)-based conditioning regimen. We studied 151 ALL patients transplanted in first complete remission (CR) (60), other CR (33), or relapsed/refractory disease (58) from sibling (87), and HLA-matched (42) or mismatched (17) unrelated and alternative donors (5). High-dose fractionated TBI-based conditioning was administered in 84. No differences were observed in baseline characteristics, except for disease stage at transplant, donor type, and graft source. With a follow-up of 19.0 (0.5–170.5) in TBI and 14.5 (1.2–319.1) months in non-TBI patients, there was no difference in acute (grades II–IV) or chronic GVHD, thrombotic microangiopathy, and bacterial or fungal infections. Only viral infections were significantly increased in the non-TBI group. There was no significant difference in the cumulative incidence (CI) of treatment-related or relapse mortality and disease-free or overall survival (OS). In the multivariate analysis, unfavorable pre-transplant predictors of OS were age (p = 0.024), advanced disease stage (p = 0.007), and female-to-male donor (p = 0.006). Interestingly, TBI patients younger than 40 years had significantly higher OS (55.1%, p = 0.023) and DFS (48.6%, p = 0.020). In conclusion, high-dose TBI is feasible in younger patients providing better survival. The choice between TBI- or Bu-conditioning regimens remains challenging.

https://ift.tt/2Lo4YT8

Extent of regional lymph node surgery and impact on outcomes in patients with early-stage breast cancer and limited axillary disease undergoing mastectomy

Abstract

Purpose

Management of the axilla in patients with early-stage breast cancer (ESBC) has evolved. Recent trials support less extensive axillary surgery in patients undergoing mastectomy. We examine factors affecting regional lymph node (RLN) surgery and outcomes in patients with ESBC undergoing mastectomy.

Methods

Women with clinical T1/2 N0 M0 invasive BC who underwent mastectomy with 1–2 positive nodes were selected from the National Cancer Database (2004–2015). Axillary surgery was defined by number of RLNs examined: 1–5 sentinel LN dissection (SLND), and ≥ 10 axillary LND (ALND). Binary logistic regression and survival analyses were performed to assess the association between axillary surgery and clinical characteristics, and overall survival (OS), respectively.

Results

34,243 patients were included: 13,821 SLND (40%) and 20,422 ALND (60%). SLND significantly increased from 21% (2004) to 45% (2015) (p < .001). Independent factors associated with SLND were treatment year, non-Academic centers, geographic region, tumor histology, and postmastectomy radiotherapy (PMRT). Multivariable survival analysis showed that ALND was associated with better OS (HR 0.78, 95% CI 0.72–0.83, p < .001) relative to SLND; however, there was no difference in patients with LN micrometastases treated without RT (HR 0.87, 95% CI 0.73–1.05, p = .153) or patients receiving PMRT (HR 0.92, 95% CI 0.76–1.13, p = .433).

Conclusions

SLND has significantly increased in patients undergoing mastectomy with limited axillary disease and is influenced by patient, tumor, and treatment factors. Survival outcomes did not differ by axillary treatment for patients with LN micrometastases treated without RT or patients who received PMRT. SLND may be considered in select patients with ESBC and limited axillary disease undergoing mastectomy.

https://ift.tt/2Hk7aJg

Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC

The standard of care for patients with metastatic non–small-cell lung cancer (NSCLC) who have not previously received treatment includes platinum-doublet chemotherapy with or without bevacizumab for those with nonsquamous cancer, targeted therapies for those with oncogenic alterations,…

https://ift.tt/2kNhVL3

Therapeutic Symptomatic Strategies in the Parasomnias

Abstract

Purpose of review

The purpose of this review was to discuss the currently available pharmacologic and non-pharmacologic treatment options for parasomnias.

Recent findings

Recent pathophysiological findings about sleep structure in parasomnias helped understanding several drug mechanisms of action. Serotoninergic theory accounts for the effect of serotoninergic drugs. Study about spectral analysis of sleep showed the effect of clonazepam on spectral bands. Cannabinoids proved to be effective in some of parasomnias, as in many other neurological disorders.

Summary

A series of therapeutic strategies were analyzed and compared. Benzodiazepines, antidepressant drugs, and l-5-hydroxytryptophan may be beneficial in DOA. SSRI and topiramate are effective in SRED. RBD responds to clonazepam, melatonin, and to a lesser extent to dopaminergic and anticholinergic agents. Prazosin and cannabinoids are effective in nightmare disorder. Sleep paralysis may respond to antidepressant agents. Tricyclic antidepressant may be effective in sleep-related hallucinations and exploding head syndrome. Sleep enuresis may be successfully treated with desmopressin, anticholinergic drugs, and imipramine.

https://ift.tt/2JsBBSx

Microbiota and Type 2 immune responses

Kathy D McCoy | Aline Ignacio | Markus B Geuking

https://ift.tt/2JjRyap

All along the watchtower: group 2 innate lymphoid cells in allergic responses

Madelene W Dahlgren | Ari B Molofsky

https://ift.tt/2Jgccbf

Why do proteases mess up with antigen presentation by re-shuffling antigen sequences?

Juliane Liepe | Huib Ovaa | Michele Mishto

https://ift.tt/2Hmvvhl

Identification of clonal hematopoiesis mutations in solid tumor patients undergoing unpaired next-generation sequencing assays

Purpose: In this era of precision-based medicine, for optimal patient care, results reported from commercial next-generation sequencing assays should adequately reflect the burden of somatic mutations in the tumor being sequenced. Here, we sought to determine the prevalence of clonal hematopoiesis leading to possible misattribution of tumor mutation calls on unpaired FoundationMedicine® next-generation sequencing assays. Experimental Design: This was a retrospective cohort study of individuals undergoing next-generation sequencing of solid tumors from two large cancer centers. We identified and quantified mutations in genes known to be frequently altered in clonal hematopoiesis (DNMT3A, TET2, ASXL1, TP53, ATM, CHEK2, SF3B1, CBL, JAK2) that were returned to physicians on clinical FoundationMedicine® reports. For a subset of patients, we explored the frequency of true clonal hematopoiesis by comparing mutations on FoundationMedicine® reports with matched blood sequencing. Results: Mutations in genes that are frequently altered in clonal hematopoiesis were identified in 65% (1139/1757) of patients undergoing next-generation sequencing. When excluding TP53, which is often mutated in solid tumors, these events were still seen in 35% (619/1757) of patients. Utilizing paired blood specimens, we were able to confirm that 8% (18/226) of mutations reported in these genes were true clonal hematopoiesis events. The majority of DNMT3A mutations (64%, 7/11) and minority of TP53 mutations (4%, 2/50) were clonal hematopoiesis. Conclusion: Clonal hematopoiesis mutations are commonly reported on unpaired next-generation sequencing testing. It is important to recognize clonal hematopoiesis as a possible cause of misattribution of mutation origin when applying next-generation sequencing findings to a patient's care.

https://ift.tt/2HlIT5f

BRCA1/2 testing: therapeutic implications for breast cancer management

BRCA1/2 testing: therapeutic implications for breast cancer management

<i>BRCA</i>1/2 testing: therapeutic implications for breast cancer management, Published online: 05 June 2018; doi:10.1038/s41416-018-0127-5

BRCA1/2 testing: therapeutic implications for breast cancer management

https://ift.tt/2kPM8cG

RIPK4 promotes bladder urothelial carcinoma cell aggressiveness by upregulating VEGF-A through the NF-κB pathway

RIPK4 promotes bladder urothelial carcinoma cell aggressiveness by upregulating VEGF-A through the NF-κB pathway

RIPK4 promotes bladder urothelial carcinoma cell aggressiveness by upregulating VEGF-A through the NF-κB pathway, Published online: 05 June 2018; doi:10.1038/s41416-018-0116-8

RIPK4 promotes bladder urothelial carcinoma cell aggressiveness by upregulating VEGF-A through the NF-κB pathway

https://ift.tt/2HkIFeP

Safety, pharmacokinetics, and preliminary efficacy of E6201 in patients with advanced solid tumours, including melanoma: results of a phase 1 study

Safety, pharmacokinetics, and preliminary efficacy of E6201 in patients with advanced solid tumours, including melanoma: results of a phase 1 study

Safety, pharmacokinetics, and preliminary efficacy of E6201 in patients with advanced solid tumours, including melanoma: results of a phase 1 study, Published online: 05 June 2018; doi:10.1038/s41416-018-0099-5

Safety, pharmacokinetics, and preliminary efficacy of E6201 in patients with advanced solid tumours, including melanoma: results of a phase 1 study

https://ift.tt/2kPoexW

In vivo Efficacy of Relebactam (MK-7655) in Combination with Imipenem/Cilastatin in Murine Infection Models [PublishAheadOfPrint]

The World Health Organization has identified antimicrobial resistance as a global public health threat as the prevalence and spread of antibiotic resistance among bacterial pathogens worldwide are staggering. Carbapenems, such as imipenem and meropenem have been used to treat multidrug-resistant bacteria; however, since the development of resistance to carbapenems, β-lactam antibiotics in combination with β-lactamase inhibitors (BLI) has been one of the most successful strategies to enhance the activity of β-lactam antibiotics. Relebactam (REL) is a new BLI which has been found to inhibit Class A and Class C β-lactamases in vitro. REL has been reported to restore imipenem's activity against both imipenem-resistant Pseudomonas aeruginosa and Klebsiella pneumoniae. Reported here are the in vivo efficacy studies of the imipenem-cilastatin (IMI)/REL combination in mouse models of disseminated and pulmonary infection caused by imipenem-resistant clinical isolates of P. aeruginosa and K. pneumoniae. The combination was also evaluated in a P. aeruginosa delayed pulmonary model of infection. IMI/REL was found to be effective in the disseminated model of infection with log reduction in P. aeruginosa CFUs of 3.73, 3.13, and 1.72 at REL doses of 40, 20, and 10 mg/kg, respectively. For K. pneumoniae, log reductions in CFU of 2.36, 3.06, and 2.29 were reported at REL doses of 80, 40, and 20 mg/kg, respectively. The combination was less effective in the delayed pulmonary model than in the immediate pulmonary model; however, overall REL was found to be effective against these imipenem-resistant strains.

https://ift.tt/2JbG9NN

Pentamidine for Prophylaxis against Pneumocystis jirovecii Pneumonia in Pediatric Oncology Patients Receiving Immunosuppressive Chemotherapy [PublishAheadOfPrint]

Background: Pneumocystis jirovecii pneumonia is a life-threatening opportunistic infection in children receiving immunosuppressive chemotherapy. Without prophylaxis, up to 25% of pediatric oncology patients receiving chemotherapy will develop Pneumocystis jirovecii pneumonia. Trimethoprim-sulfamethoxazole is the preferred agent for prophylaxis against Pneumocystis jirovecii pneumonia. Pentamidine may be an acceptable alternative for pediatric patients unable to tolerate trimethoprim-sulfamethoxazole.

Methods: A retrospective review was conducted of pediatric oncology patients who received ≥ 1 dose of pentamidine for Pneumocystis jirovecii pneumonia prophylaxis between January 2007 and August 2014. Electronic medical records were reviewed to determine incidence of breakthrough Pneumocystis jirovecii pneumonia or discontinuation of pentamidine associated with adverse events.

Results: A total of 754 patients received pentamidine prophylaxis during the period. There were no cases of probable or proven Pneumocystis pneumonia, and 4 cases (0.5%) of possible Pneumocystis pneumonia. The incidence of possible breakthrough Pneumocystis pneumonia was not significantly different between subgroups based on age (< 12 months [1.7%] vs. ≥ 12 months [0.4%], p=0.3), route of administration (aerosolized [0%] vs. intravenous [1.0%], p=0.2), or hematopoietic stem cell transplant status (transplant [0.4%] vs. no transplant [0.8%], p=0.6). Pentamidine was discontinued due to an adverse drug event in 23 children (3.1%); more frequently for aerosolized than intravenous administration (7.6% vs. 2.2%, P=0.004).

Conclusions: Intravenous or inhaled pentamidine may be a safe and effective second-line alternative for prophylaxis against Pneumocystis jirovecii pneumonia in children with cancer receiving immunosuppressive chemotherapy or hematopoietic stem cell transplantation.

https://ift.tt/2HkAtv4

Non-proteinogenic Amino Acid Containing Nucleotide Prodrug to Improve Oral Delivery of a Hepatitis C Virus Treatment [PublishAheadOfPrint]

Delivery of pharmacologically active nucleoside triphosphate analogs to sites of viral infection is challenging. In prior work we identified a 2'-C-methyl-1'-cyano-7-deaza-adenosine C-nucleotide analog with desirable selectivity and potency for the treatment of HCV infection. However, the prodrug selected for clinical development, GS-6620, required a high dose for meaningful efficacy and had unacceptable variability due to poor oral absorption as a result of suboptimal solubility, intestinal metabolism and efflux transport. While obtaining clinical proof of concept for the nucleotide analog, a more effective prodrug strategy would be necessary for clinical utility. Here we report an alternate prodrug of the same nucleoside analog identified to address liabilities of GS-6620. A phosphoramidate prodrug containing the non-proteinogenic amino acid methylalanine, an isopropyl ester and phenol in the (S) conformation at phosphorous, GS2, was found to have improved solubility, intestinal stability and hepatic activation. GS2 is a more selective substrate for hepatically expressed carboxyl esterase (CES) 1 and is resistant to hydrolysis by more widely expressed hydrolases including cathepsin A (CatA) and CES2. Unlike GS-6620, GS2 was not cleaved by intestinally expressed CES2 and as a result, was stable in intestinal extracts. Levels of liver triphosphate following oral administration of GS2 in animals were higher than GS-6620 even when administered under optimal conditions for GS-6620 absorption. Combined these properties suggest that GS2 will have better oral absorption in the clinic when administered in a solid dosage form and the potential to extend the clinical proof of concept obtained with GS-6620.

https://ift.tt/2Hle6FT

Artemisone and artemiside - potent pan-reactive antimalarial agents that also synergize redox imbalance in P. falciparum transmissible gametocyte stages [PublishAheadOfPrint]

The emergence of resistance towards artemisinin combination therapies (ACTs) by the malaria parasite Plasmodium falciparum has the potential to severely compromise malaria control. Therefore, development of new artemisinins in combination with new drugs that impart activities towards both intraerythrocytic proliferative asexual and transmissible gametocyte stages, in particular those of resistant parasites, are urgently required. We define artemisinins as oxidant drugs through their ability to oxidize reduced flavin cofactors of flavin disulfide reductases critical for maintaining redox-homeostasis in the malaria parasite. Here we compare the activities of 10-amino artemisinin derivatives towards the asexual and gametocyte stages of P. falciparum parasites. Of these, artemisone and artemiside inhibited asexual and gametocyte stages, particularly stage V gametocytes in the low nM range. Further, treatment of both early and late gametocyte stages with artemisone or artemiside combined with the pro-oxidant redox partner methylene blue displays notable synergism. These data suggest that modulation of redox-homeostasis likely is an important druggable process, particularly in gametocytes, and thereby enhances the prospect of using combinations of oxidant and redox drugs for malaria control.

https://ift.tt/2JadQiW

In Vivo Efficacy of Plazomicin Alone or in Combination with Meropenem or Tigecycline against Enterobacteriaceae Isolates Exhibiting Various Resistance Mechanisms in an Immunocompetent Murine Septicemia Model [PublishAheadOfPrint]

Background: Plazomicin is a next-generation aminoglycoside with potent in vitro activity against multidrug- and carbapenem-resistant Enterobacteriaceae. The objective of this study was to assess the efficacy of plazomicin exposure, alone and in combination with meropenem or tigecycline, against Enterobacteriaceae in the immunocompetent murine septicemia model.

Methods: ICR mice were inoculated intraperitoneally with bacterial suspensions. Eight Enterobacteriaceae isolates with wide ranges of plazomicin, meropenem and tigecycline MICs were utilized. Treatment mice were administered plazomicin, meropenem or tigecycline human-equivalent doses alone or in combinations of plazomicin/meropenem and plazomicin/tigecycline. Treatments were initiated 1h post-infection and continued for 24h. Efficacy was assessed by survival through 96h.

Results: Compared with controls, plazomicin monotherapy produced significant improvement in survival for all isolates (P<0.05) and resulted in overall survival of 86% (n=50) and 53.3% (n=30) for isolates with plazomicin MIC ≤4 and ≥8 mg/L, respectively (P<0.05). Survival of meropenem and tigecycline groups correlated well with their respective susceptibilities, with incremental increase in survival observed at lower MIC values. For isolate KP 561 (plazomicin, meropenem and tigecycline MICs of 8, >32 and 2 mg/L, respectively), combination therapies showed significant reduction in mortality compared with any monotherapy (P<0.05).

Conclusion: Plazomicin monotherapy resulted in improved survival in the immunocompetent murine septicemia model, notably for isolates with plazomicin MIC ≤4 mg/L. As evidenced by our current data, co-administration of meropenem or tigecycline could potentially lead to further improvement in survival. These data support a role for plazomicin in the management of septicemia due to Enterobacteriaceae with plazomicin MIC ≤4 mg/L, including carbapenem-resistant isolates.

https://ift.tt/2JbeQmS

In vitro and intracellular activity of imipenem combined to rifabutin and avibactam against Mycobacterium abscessus [PublishAheadOfPrint]

Repurposing drugs may be useful as an add-on in the treatment of Mycobacterium abscessus pulmonary infections, which are particularly difficult to cure. M. abscessus naturally produces a β-lactamase, Bla_Mab, which is inhibited by avibactam. The recommended regimens include imipenem, which is hydrolyzed by Bla_Mab and used without any β-lactamase inhibitor. Here, we determine whether the addition of rifabutin improves the activity of imipenem alone or in combination with avibactam against M. abscessus CIP104536. Rifabutin at 16 μg/ml was only bacteriostatic (MIC = 4 μg/ml) and was moderately synergistic in combination with imipenem (FIC index of 0.38). Addition of rifabutin (16 μg/ml) moderately increased killing by a low (8 μg/ml) but not by a high (32 μg/ml) concentration of imipenem. Addition of avibactam (4 μg/ml) did not further increase killing by the former combination. In infected macrophages, rifabutin (16 μg/ml) increased the activity of imipenem at 8 and 32 μg/ml achieving 3- and 100-fold reductions in the number of intracellular bacteria, respectively. Avibactam (16 μg/ml) improved killing by imipenem at 8 μg/ml. A 5-fold killing was obtained for a triple combination comprising avibactam (16 μg/ml) and therapeutically-achievable doses of imipenem (8 μg/ml) and rifabutin (1 μg/ml). These results indicate that the imipenem-rifabutin combination should be further considered for the treatment of M. abscessus pulmonary infections in cystic fibrosis patients and that addition of a β-lactamase inhibitor might improve its efficacy. Mechanistically, the impact of Bla_Mab inhibition by avibactam on antibiotic activity was assessed by comparing CIP104536 and a β-lactamase-deficient derivative.

https://ift.tt/2sH4Gz1

Effect of Linezolid plus Bedaquiline against Mycobacterium tuberculosis in Log-Phase, Acid-Phase and Non-Replicating-Persister (NRP)-Phase in an In vitro Assay [PublishAheadOfPrint]

Tuberculosis is the ninth-leading cause of death worldwide. Treatment success is approximately 80% for susceptible strains and decreases to 30% for extensively resistant strains. Shortening therapy duration for Mycobacterium tuberculosis (Mtb) is a major goal, which can be attained with the use of combination therapy. However, the identification of the most promising combination is a challenge given the quantity of older and newer agents available. Our objective was to identify promising 2-drug combinations using an in vitro strategy to ultimately be tested in an in vitro Hollow Fiber Infection Model (HFIM) and in animal models. We studied the effect of the combination of linezolid (LZD) and bedaquiline (BDQ) on Mtb strain H37Rv in Log- and Acid-Phase growth and Mtb strain 18b in Log- and Non-Replicating-Persister-Phase growth in a plate system containing a 9 x 8 matrix of concentrations of both drugs alone and in combinations. Characterization of the interaction as antagonistic, additive, or synergistic was performed using the Greco Universal Response Surface Approach (URSA) model. Our results indicate that the interaction between LZD and BDQ is additive for bacterial killing in both strains for both of the metabolic states tested. This prescreen strategy was suitable to identify LZD and BDQ as a promising combination to be further tested in the HFIM. The presence of non-overlapping mechanisms of drug action suggests each drug in the combination will likely be effective in suppressing emergence of resistance by Mtb to the companion drug, which holds promise in improving treatment outcomes for tuberculosis.

https://ift.tt/2kMhYqs

Efficacy of Meglumine Antimoniate under Low Polymerization State Orally Administrated in Murine Model of Visceral Leishmaniasis [PublishAheadOfPrint]

Progress towards the improvement of meglumine antimoniate (MA) commercially known as Glucantime®, a highly effective but also toxic antileishmanial drug, has been hindered by the lack of knowledge and control on its chemical composition. Here, MA was manipulated chemically with the aim of achieving an orally effective drug. MA compounds were synthesized from either antimony pentachloride (MA-SbCl₅) or potassium hexahydroxyantimonate (MA-KSb(OH)₆) and prepared under low polymerization state. Those were compared to Glucantime® regarding chemical composition, permeation properties across cellulose membrane and Caco-2 cell monolayer and uptake by peritoneal macrophages. MA-SbCl₅ and MA-KSb(OH)₆ were characterized as less polymerized and more permeable 2:2 Sb-meglumine complexes, when compared to Glucantime® that consisted in a mixture of 2:3 and 3:3 Sb-meglumine complexes. The antileishmanial activity and hepatic uptake of all compounds were evaluated after oral administration in BALB/c mice infected with Leishmania infantum chagasi, as model of visceral leishmaniasis (VL). The synthetic MA compounds given at 300 mg Sb/kg/12h for 30 days reduced significantly spleen and liver parasite burdens, in contrast to Glucantime® at the same dose. The greater activity of synthetic compounds could be attributed to their higher intestinal absorption and accumulation efficiency in the liver. MA-SbCl₅ given orally was as efficacious as Glucantime® by parenteral route (80 mg Sb/kg/24h IP). This data taken altogether suggests that treatment with less polymerized form of MA by oral route may be effective for the treatment of VL.

https://ift.tt/2sE7i0T

Diversity of carbapenemase-producing Escherichia coli isolates, France 2012-2013 [PublishAheadOfPrint]

With the dissemination of carbapenemase-producing Enterobacteriaceae (CPE) worldwide, carbapenem-hydrolyzing enzymes are increasingly reported among Escherichia coli, the first hospital and community-acquired opportunistic pathogen. Here, we have performed an epidemiological survey of carbapenemase-producing E. coli (CP-Ec) isolates received at the French National Reference Centre (F-NRC) in 2012 and 2013. Antimicrobial susceptibilities for last resort antibiotics and antimicrobial compounds commonly used to treat urinary tract infections were determined by broth microdilution. Clonal relationship was assessed using rep-PCR and MLST typing. From this collection of 140 carbapenemase-producing E. coli, (74%) produced an OXA-48-like carbapenemase followed by NDM (21%). A link with a foreign country was suspected for 37% of infected/colonized patients. Most of the isolates were from screening (56%) and from urine samples (26%). Colistin, fosfomycin and nitrofurantoin possessed the most consistent activity with 100%, 95% and 96% of susceptibility, respectively. A wide diversity of carbapenemase-producing E. coli isolates has been found (50 different STs). The most prevalent clones were (i) E. coli ST38 producing-OXA-48 (n=21), a clone related to Turkey and North African countries, (ii) E. coli ST-90 producing OXA-204 (n=9), which was responsible of an outbreak related to a contaminated duodenoscope, and (iii) E. coli ST-410 producing OXA-181 (n=5) recovered from patients of different geographical origin. These specific clones might be considered high-risk clones for the dissemination of carbapenemases in E. coli. The wide diversity of STs combined with the increasing number of CP-Ec isolates received by the F-NRC suggests a likely dissemination of CP-Ec isolates in the community.

https://ift.tt/2Ja5APL

Evaluation of the Bactericidal Activity of Plazomicin and Comparators against Multidrug-resistant Enterobacteriaceae [PublishAheadOfPrint]

The next-generation aminoglycoside plazomicin, in development for infections due to multi-drug resistant (MDR) Enterobacteriaceae, was evaluated alongside comparators for bactericidal activity in minimum bactericidal concentration (MBC) and time-kill (TK) assays against MDR Enterobacteriaceae isolates with characterized aminoglycoside and β-lactam resistance mechanisms. Overall, plazomicin and colistin were the most potent, with plazomicin demonstrating an MBC_50/90 of 0.5/4 μg/mL and sustained 3-log₁₀ kill against MDR Escherichia coli, Klebsiella pneumoniae and Enterobacter spp.

https://ift.tt/2Hjj1qQ

Few conserved amino acids in the small multidrug resistance transporter EmrE influence drug polyselectivity. [PublishAheadOfPrint]

EmrE is the archetypical member of the small multidrug resistance transporter family and confers resistance to a wide range of disinfectants and dyes known as quaternary cation compounds (QCCs). The aim of this study was to examine which conserved amino acids play an important role in substrate selectivity. Based on previous analysis of EmrE homologs, a total of 33 conserved residues were targeted for cysteine or alanine replacements within E. coli EmrE. The antimicrobial resistance of each EmrE variant expressed in E. coli strain JW0451 (lacking dominant pump acrB) was tested against a collection of 16 different QCCs using agar spot dilution plating to determine MIC values. The results determined that few conserved residues were drug polyselective: the active site residue E14 (E14D and E14A) and 4 additional conserved residues (A10C, F44C, L47C, W63A) based on ≥4 fold decreases in MIC values. EmrE variants (I11C, V15C, P32C, I62C, L93C, S105C) enhanced resistance to polyaromatic QCCs, while the remaining EmrE variants reduced resistance to one or more QCCs with shared chemical features: acylation, tri-and tetra-phenylation, aromaticity, and dicationic charge. Mapping EmrE variants onto transmembrane helical wheel projections using the highest resolved EmrE structure suggests that polyselective EmrE variants were located closest to helical faces surrounding the predicted drug binding pocket, while EmrE variants with greater drug specificity mapped onto distal helical faces. This study reveals that few conserved residues are essential for drug polyselectivity and indicates that aromatic QCC selection involves a greater portion of conserved residues compared to other QCCs.

Importance EmrE is an archetypical member of the small multidrug resistance efflux pump family and its members are frequently identified from mobile genetic elements and multidrug resistant plasmids. This study examines conserved residues in EmrE and their MIC to various quaternary ammonium compounds which may shed light on the importance of conserved residues in other EmrE orthologues. In this study, few conserved EmrE residue replacements are required for drug polyselectivity but indicate that many conserved residues that may be important for polyaromatic QCC selection which may be useful for future efflux pump inhibition and inactivation studies.

https://ift.tt/2kRCplP

In Vitro Activity of Plazomicin against Gram-Negative and Gram-Positive Isolates Collected from United States Hospitals and Comparative Activity of Aminoglycosides against Carbapenem-Resistant Enterobacteriaceae and Isolates Carrying Carbapenemase Genes [PublishAheadOfPrint]

Plazomicin and comparators agents were tested using the CLSI reference broth microdilution method against 4,825 clinical isolates collected during 2014 and 2015 in 70 United States hospitals as part of the ALERT (Antimicrobial Longitudinal Evaluation and Resistance Trends) program. Plazomicin (MIC_50/90, 0.5/2 μg/ml) inhibited 99.2% of 4,362 Enterobacteriaceae at ≤4 μg/ml. Amikacin, gentamicin, and tobramycin inhibited 98.9%, 90.3%, and 90.3% of these isolates, respectively, applying CLSI breakpoints. The activity of plazomicin was similar among Enterobacteriaceae species with MIC₅₀ values ranging from 0.25 to 1 μg/ml, with exception of Proteus mirabilis and indole-positive Proteaee that displayed MIC₅₀ values of 2 μg/ml. Against 97 carbapenem-resistant Enterobacteriaceae (CRE) that included 87 isolates carrying bla_KPC, plazomicin inhibited all but 1 isolate at ≤2 μg/ml (99.0% and 98.9%, respectively). Amikacin and gentamicin inhibited 64.9% and 56.7% of the CRE isolates at the respective CLSI breakpoints. Plazomicin inhibited 96.5/95.5% of the gentamicin-resistant, 96.9/96.5% of the tobramycin-resistant and 64.3/90.0% of the amikacin-resistant isolates using CLSI/EUCAST breakpoints. The activity of plazomicin against Pseudomonas aeruginosa (MIC_50/90, 4/16 μg/ml) and Acinetobacter spp. (MIC_50/90, 2/16 μg/ml) isolates was similar. Plazomicin was active against coagulase-negative staphylococci (MIC_50/90, 0.12/0.5 μg/ml) and Staphylococcus aureus (MIC_50/90, 0.5/0.5 μg/ml), but had limited activity against Enterococcus spp. (MIC_50/90, 16/64 μg/ml) and Streptococcus pneumoniae (MIC_50/90, 32/64 μg/ml). Plazomicin activity against the Enterobacteriaceae tested, including CRE and isolates carrying bla_KPC from U.S. hospitals, support the development plan for plazomicin to treat serious infections caused by resistant Enterobacteriaceae in patients with limited treatment options.

https://ift.tt/2sGchy6

PET-PCR for Detection of Plasmodium falciparum Plasmepsin 2 Gene copy number [PublishAheadOfPrint]

Piperaquine is an important partner drug used in artemisinin-based combination therapies (ACTs). An increase in the plasmepsin 2 and 3 gene copy number has been associated with decreased susceptibility of Plasmodium falciparum to piperaquine in Cambodia. Here, we developed a photo- induced electron transfer real-time PCR (PET-PCR) assay to quantify the copy number of plasmepsin 2 (PfPM2) that can be used in endemic countries to enhance molecular surveillance.

https://ift.tt/2sB4gKG

Primary fungal prophylaxis in hematological malignancy: A network meta-analysis of randomized controlled trials [PublishAheadOfPrint]

Several new anti-fungal agents have become available for primary fungal prophylaxis of neutropenia fever in haematological malignancy patients. Our aim was to synthesize all evidence on efficacy and enable an integrated comparison of all current treatments.

We performed a systematic literature review to identify all publicly available evidence from randomized controlled trials (RCT). We searched Embase, PubMed, the Cochrane Central Register of Controlled Clinical Trials, and the website www.ClinicalTrials.gov. In total, 54 RCTs were identified, including 13 treatment options. The evidence was synthesised using a network meta-analysis. Relative risk (RR) was adopted.

Posaconazole was ranked highest effectiveness for primary prophylaxis, being the most favorable in terms of (1) the RR for reduction of invasive fungal infection (0.19; 95% confidence interval (CI): 0.11–0.36) and (2) the probability of being the best (94% of the cumulative ranking). Posaconazole also demonstrated its efficacy in preventing invasive aspergillosis and proven fungal infections, with RR of 0.13 (CI: 0.03–0.65) and 0.14 (CI: 0.05–0.38), respectively. However, there was no significant difference among all the anti-fungal agents in all-cause mortality and overall adverse events.

Our network meta-analysis provided an integrated overview of the relative efficacy of all available treatment options for primary fungal prophylaxis for neutropenic fever in hematological malignancy patients under myelosuppressive chemotherapy or hematopoietic cell transplantation. On the basis of this analysis, Posaconazole seems to be the most effectiveness prophylaxis option until additional data from head-to-head randomized controlled trials become available.

https://ift.tt/2kNxNxa

Model system identifies kinetic driver of Hsp90 inhibitor activity against African trypanosomes and Plasmodium falciparum [PublishAheadOfPrint]

Hsp90 inhibitors, well-studied in the laboratory and clinic for antitumor indications, have promising activity against protozoan pathogens, including Trypanosoma brucei that causes African sleeping sickness, and malaria parasite Plasmodium falciparum. To progress these experimental drugs toward clinical use we adapted an in vitro dynamic hollow-fiber system and deployed artificial pharmacokinetics to discover the driver of their activity: either concentration or time. Compounds from three major classes of Hsp90 inhibitors in development were evaluated against trypanosomes. In all circumstances tested Hsp90 inhibitors were concentration-driven. By optimally deploying the drug to match kinetic driver, efficacy of a given dose was improved up to five-fold, and maximal efficacy was achieved with a significantly lower drug exposure. The superiority of concentration-driven regimens was evident in vitro over several logs of drug exposure, and was predictive of efficacy in a mouse model of African trypanosomiasis. In studies with P. falciparum, antimalarial activity was similarly concentration-driven. This experimental strategy offers an expedient and versatile translational tool to assess the impact of pharmacokinetics on antiprotozoal activity. Knowing kinetic governance early in drug development provides an additional metric for judging lead compounds and allows incisive design of animal efficacy studies.

https://ift.tt/2kNxEtC

ASCO: Endocrine Tx Noninferior for HR+, HER2− Breast Cancer

MONDAY, June 4, 2018 -- For women with hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative, axillary node-negative breast cancer with a midrange 21-gene recurrence score, adjuvant endocrine therapy is noninferior to...

https://ift.tt/2suZ5wC

ASCO: Sunitinib Alone Noninferior in Metastatic Renal Cell Cancer

MONDAY, June 4, 2018 -- For patients with metastatic renal cell carcinoma classified as having intermediate or poor prognostic risk, sunitinib alone is noninferior to nephrectomy and sunitinib, according to a study published online June 3 in the New...

https://ift.tt/2suZ4ZA

Revising Pooled Cohort Equations Improves CVD Risk Prediction

MONDAY, June 4, 2018 -- Revising the 2013 pooled cohort equations (PCEs) can improve accuracy of cardiovascular disease (CVD) risk prediction, according to a study published online June 5 in the Annals of Internal Medicine. In an effort to improve...

https://ift.tt/2xFIzPx

ASCO: mFOLFIRINOX Improves Survival in Pancreatic Cancer

MONDAY, June 4, 2018 -- The oxaliplatin, leucovorin, irinotecan, and 5-fluorouracil (mFOLFIRINOX) regimen is associated with longer median disease-free and overall survival in pancreatic ductal adenocarcinoma; and, receiving chemotherapy before...

https://ift.tt/2suZ2Rs

Cytoreductive Nephrectomy — Patient Selection Is Key

Metastatic renal-cell carcinoma has diverse clinical presentations ranging from incidental detection to a highly symptomatic systemic illness. Patients with metastatic renal-cell carcinoma are assigned a risk category — favorable, intermediate, or poor — on the basis of two published models…

https://ift.tt/2sHpvKK

Sunitinib Alone or after Nephrectomy in Metastatic Renal-Cell Carcinoma

Kidney cancer accounts for 5% of all cancers in men and 3% of all cancers in women, and approximately 15% of these are metastatic at diagnosis. More than 15 years ago, randomized, controlled trials showed prolonged survival with initial nephrectomy, as compared with immunotherapy alone, among…

https://ift.tt/2Jsropd

Durable Remissions with Ivosidenib in IDH1-Mutated Relapsed or Refractory AML

Somatic mutations within the conserved active site of isocitrate dehydrogenase (IDH) 1 and 2 occur in multiple tumors, including glioma, acute myeloid leukemia (AML), cholangiocarcinoma, and chondrosarcoma. IDH1 and IDH2 mutations confer a neomorphic enzymatic activity, resulting in the reduction…

https://ift.tt/2LgYXYB

A novel STK11 missense mutation (c.346G > T) causing Peutz–Jeghers syndrome in a Chinese male with a negative family history

https://ift.tt/2JryHh0

Non-Cirrhotic Portal Hypertension: A possibly benign but complicated disease

https://ift.tt/2LmFplC

Naloxone Hydrochloride Injection, USP, 0.4 mg/mL, 1 mL in 2.5 mL in the Carpuject™ Single-use Cartridge Syringe System by Hospira: Recall - Due to the Potential Presence of Particulate Matter

[Posted 06/04/2018] AUDIENCE: Pain Management, Pharmacy, Anesthesiology, Emergency Medicine, HealthProfessional    ISSUE: Hospira, Inc., a Pfizer company, is voluntarily recalling lots 72680LL and 76510LL of Naloxone Hydrochloride...

https://ift.tt/2LoyRTI

Naloxone Hydrochloride Injection, USP, 0.4 mg/mL, 1 mL in 2.5 mL in the Carpuject™ Single-use Cartridge Syringe System by Hospira: Recall - Due to the Potential Presence of Particulate Matter

[Posted 06/04/2018] AUDIENCE: Pain Management, Pharmacy, Anesthesiology, Emergency Medicine, HealthProfessional    ISSUE: Hospira, Inc., a Pfizer company, is voluntarily recalling lots 72680LL and 76510LL of Naloxone Hydrochloride...

https://ift.tt/2LoyRTI

Fecal Microbiota Transplantation for Primary Clostridium difficile Infection

To the Editor: Clostridium difficile infection is a major health problem. Antibiotic treatment is associated with a considerable rate of recurrence of infection and is related to the emergence of antibiotic-resistant bacteria. Recently, fecal microbiota transplantation has been shown to be…

https://ift.tt/2xHBmy7

Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer

Breast cancer is the most common cancer in women in the United States and worldwide. Hormone-receptor–positive, axillary node–negative disease accounts for approximately half of all cases of breast cancer in the United States. Adjuvant chemotherapy reduces the risk of recurrence, with effects that…

https://ift.tt/2LgH7oC

The phrase NIFTP accentuates, rather than resolves, the current issues with thyroid neoplasia classification—reply

Ricardo V. Lloyd MD, PhD rvlloyd@wisc.edu

https://ift.tt/2LWLkyQ

Aberrant expression of stress-induced phosphoprotein 1 in colorectal cancer and its clinicopathologic significance

Stress-Inducible Phosphoprotein1 (STIP1) is an adaptor protein that bridges HSP70 and HSP90 folding and a secretory protein that regulates malignant tumor progression. The aim of the present study was to demonstrate the clinicopathological significance and prognostic role of STIP1 in colorectal cancer (CRC). We used data from The Cancer Genome Atlas (TCGA) to analyze STIP1 expression in CRC and utilized 8 pairs of fresh-frozen tissue samples to investigate STIP1 expression in CRC tissues and adjacent normal tissues using quantitative real-time polymerase chain reaction (qRT-PCR) and western blot assays.

https://ift.tt/2Jhl94j

The phrase NIFTP accentuates, rather than resolves, the current issues with thyroid neoplasia classification

Cheng Liu, BmedSci, MBBS, FRCPA john.liu@qimrberghofer.edu.au

https://ift.tt/2LX4x3D

MiR-23b-3p induces the proliferation and metastasis of esophageal squamous cell carcinomas cells through the inhibition of EBF3

Abstract

MicroRNAs (miRNAs), some small non-coding RNAs that regulate gene expression at the posttranscriptional level, are always aberrantly expressed in carcinomas. In this study, we found that miR-23b-3p was remarkably up-regulated in human esophageal squamous cell carcinoma cells and tissues. Moreover, miR-23b-3p could induce the proliferation, invasion, and metastasis in vitro. EBF3 was identified as the direct downstream target gene of miR-23b-3p and ectogenic EBF3 could strongly inhibit the proliferation, invasion, and metastasis in vitro. Furthermore, it was found that miR-23b-3p could regulate epithelial-to-mesenchymal transition progress by blocking EBF3. Therefore, it was concluded that miR-23b-3p targeted EBF3 to accelerate the proliferation, invasion, and metastasis in ESCC.

https://ift.tt/2JhqEQz

BRCA1/2 testing: therapeutic implications for breast cancer management

https://ift.tt/2JaMOb2

RIPK4 promotes bladder urothelial carcinoma cell aggressiveness by upregulating VEGF-A through the NF-κB pathway

https://ift.tt/2sGO2Q3

Safety, pharmacokinetics, and preliminary efficacy of E6201 in patients with advanced solid tumours, including melanoma: results of a phase 1 study

https://ift.tt/2kMEU99

Long Term Late Toxicity, Quality Of Life and Emotional Distress In Nasopharyngeal Carcinoma Patients Treated With Intensity-Modulated Radiotherapy

To report long-term (> 4 year) toxicity and quality of life (QOL) in nasopharyngeal carcinoma (NPC) patients treated with intensity-modulated radiotherapy (IMRT) in a non-endemic center.

https://ift.tt/2J9UR82

MR-only brain radiotherapy: Dosimetric evaluation of synthetic CTs generated by a dilated convolutional neural network

Synthetic CTs of 52 patients treated with intracranial radiotherapy were generated from a conventional MR sequence using a convolutional neural network. Recalculation of clinical treatment plans on the synthetic CTs showed that dose calculation was accurate. A wide range of tumor locations was analyzed, validating the synthesized CTs for implementation of MR-only treatment planning for the brain.

https://ift.tt/2Hj21RL

Title: Choosing Wisely at the end of life: use of shorter courses of palliative radiation for bone metastasis

This population based analysis shows increasing utilization of ASTRO guideline concordant fractionation for palliation of bone metastasis at 64% However, nearly 2/3 of patients received more than 1 fraction of RT in the last 30 days of life.

https://ift.tt/2sFgUs5

Progressive multiple sclerosis patients have a higher burden of autonomic dysfunction compared to relapsing remitting phenotype

Multiple sclerosis (MS) is an idiopathic demyelinating disorder of the central nervous system. It most commonly affects young individuals, between 20 and 40 years-of-age and represents the leading cause of non-traumatic neurologic disability in young adults (Edmonds et al., 2010). Although the exact etiology is unknown, there is a complex interaction between several environmental factors and a distinct genetic susceptibility which results in demyelinating lesions, the pathological hallmark of MS (Compston and Coles, 2008).

https://ift.tt/2JqH4JA

Fulfilling the Promise of Unique Device Identifiers

Medical devices are required to have unique identifiers, which have the potential to provide data to improve patient safety. The authors discuss why this potential is not currently being realized and suggest ways to overcome the barriers.

https://ift.tt/2kRP1K5

Clinical Implications of Revised Pooled Cohort Equations for Estimating Atherosclerotic Cardiovascular Disease Risk

Background:

The 2013 pooled cohort equations (PCEs) are central in prevention guidelines for cardiovascular disease (CVD) but can misestimate CVD risk.

Objective:

To improve the clinical accuracy of CVD risk prediction by revising the 2013 PCEs using newer data and statistical methods.

Design:

Derivation and validation of risk equations.

Setting:

Population-based.

Participants:

26 689 adults aged 40 to 79 years without prior CVD from 6 U.S. cohorts.

Measurements:

Nonfatal myocardial infarction, death from coronary heart disease, or fatal or nonfatal stroke.

Results:

The 2013 PCEs overestimated 10-year risk for atherosclerotic CVD by an average of 20% across risk groups. Misestimation of risk was particularly prominent among black adults, of whom 3.9 million (33% of eligible black persons) had extreme risk estimates (<70% or >250% those of white adults with otherwise-identical risk factor values). Updating these equations improved accuracy among all race and sex subgroups. Approximately 11.8 million U.S. adults previously labeled high-risk (10-year risk ≥7.5%) by the 2013 PCEs would be relabeled lower-risk by the updated equations.

Limitations:

Updating the 2013 PCEs with data from modern cohorts reduced the number of persons considered to be at high risk. Clinicians and patients should consider the potential benefits and harms of reducing the number of persons recommended aspirin, blood pressure, or statin therapy. Our findings also indicate that risk equations will generally become outdated over time and require routine updating.

Conclusion:

Revised PCEs can improve the accuracy of CVD risk estimates.

Primary Funding Source:

National Institutes of Health.

https://ift.tt/2Hhr7A9

When Given a Lemon, Make Lemonade: Revising Cardiovascular Risk Prediction Scores

In their article, Yadlowsky and colleagues evaluated 2 approaches for improving the pooled cohort equations to estimate cardiac risk. The editorialists discuss the findings and the need to develop increasingly accurate tools for cardiac risk estimation in specific patient populations.

https://ift.tt/2kPkH2E

Evolution of Intrahepatic Shunts in a Patient With Hereditary Hemorrhagic Telangiectasia

https://ift.tt/2sGKu0b

Impact of Primary Care Intensive Management on High-Risk Veterans' Costs and Utilization A Randomized Quality Improvement Trial

Background:

Primary care models that offer comprehensive, accessible care to all patients may provide insufficient resources to meet the needs of patients with complex conditions who have the greatest risk for hospitalization.

Objective:

To assess whether augmenting usual primary care with team-based intensive management lowers utilization and costs for high-risk patients.

Design:

Randomized quality improvement trial. (ClinicalTrials.gov: NCT03100526)

Setting:

5 U.S. Department of Veterans Affairs (VA) medical centers.

Patients:

Primary care patients at high risk for hospitalization who had a recent acute care episode.

Intervention:

Locally tailored intensive management programs providing care coordination, goals assessment, health coaching, medication reconciliation, and home visits through an interdisciplinary team, including a physician or nurse practitioner, a nurse, and psychosocial experts.

Measurements:

Utilization and costs (including intensive management program expenses) 12 months before and after randomization.

Results:

2210 patients were randomly assigned, 1105 to intensive management and 1105 to usual care. Patients had a mean age of 63 years and an average of 7 chronic conditions; 90% were men. Of the patients assigned to intensive management, 487 (44%) received intensive outpatient care (that is, ≥3 encounters in person or by telephone) and 204 (18%) received limited intervention. From the pre- to postrandomization periods, mean inpatient costs decreased more for the intensive management than the usual care group (−$2164 [95% CI, −$7916 to $3587]). Outpatient costs increased more for the intensive management than the usual care group ($2636 [CI, $524 to $4748]), driven by greater use of primary care, home care, telephone care, and telehealth. Mean total costs were similar in the 2 groups before and after randomization.

Limitations:

Sites took up to several months to contact eligible patients, limiting the time between treatment and outcome assessment. Only VA costs were assessed.

Conclusion:

High-risk patients with access to an intensive management program received more outpatient care with no increase in total costs.

Primary Funding Source:

Veterans Health Administration Primary Care Services.

https://ift.tt/2kPkDjq

Detection of urinary Chlamydia trachomatis, Mycoplasma genitalium and human papilloma virus in the first trimester of pregnancy by PCR method

Miscarriage and preterm delivery are the most important challenges of pregnancy. Different bacterial and viral infection may cause miscarriage and preterm delivery. Among bacterial factors, Mycoplasma genitalium ...

https://ift.tt/2xH9xq1

Automated and Clinical Breast Imaging Reporting and Data System Density Measures Predict Risk for Screen-Detected and Interval Cancers A Case–Control Study

Background:

In 30 states, women who have had screening mammography are informed of their breast density on the basis of Breast Imaging Reporting and Data System (BI-RADS) density categories estimated subjectively by radiologists. Variation in these clinical categories across and within radiologists has led to discussion about whether automated BI-RADS density should be reported instead.

Objective:

To determine whether breast cancer risk and detection are similar for automated and clinical BI-RADS density measures.

Design:

Case–control.

Setting:

San Francisco Mammography Registry and Mayo Clinic.

Participants:

1609 women with screen-detected cancer, 351 women with interval invasive cancer, and 4409 matched control participants.

Measurements:

Automated and clinical BI-RADS density assessed on digital mammography at 2 time points from September 2006 to October 2014, interval and screen-detected breast cancer risk, and mammography sensitivity.

Results:

Of women whose breast density was categorized by automated BI-RADS more than 6 months to 5 years before diagnosis, those with extremely dense breasts had a 5.65-fold higher interval cancer risk (95% CI, 3.33 to 9.60) and a 1.43-fold higher screen-detected risk (CI, 1.14 to 1.79) than those with scattered fibroglandular densities. Associations of interval and screen-detected cancer with clinical BI-RADS density were similar to those with automated BI-RADS density, regardless of whether density was measured more than 6 months to less than 2 years or 2 to 5 years before diagnosis. Automated and clinical BI-RADS density measures had similar discriminatory accuracy, which was higher for interval than screen-detected cancer (c-statistics: 0.70 vs. 0.62 [P < 0.001] and 0.72 vs. 0.62 [P < 0.001], respectively). Mammography sensitivity was similar for automated and clinical BI-RADS categories: fatty, 93% versus 92%; scattered fibroglandular densities, 90% versus 90%; heterogeneously dense, 82% versus 78%; and extremely dense, 63% versus 64%, respectively.

Limitation:

Neither automated nor clinical BI-RADS density was assessed on tomosynthesis, an emerging breast screening method.

Conclusion:

Automated and clinical BI-RADS density similarly predict interval and screen-detected cancer risk, suggesting that either measure may be used to inform women of their breast density.

Primary Funding Source:

National Cancer Institute.

https://ift.tt/2JBbVQ3

Preventability of Early Versus Late Hospital Readmissions in a National Cohort of General Medicine Patients

Background:

Many experts believe that hospitals with more frequent readmissions provide lower-quality care, but little is known about how the preventability of readmissions might change over the postdischarge time frame.

Objective:

To determine whether readmissions within 7 days of discharge differ from those between 8 and 30 days after discharge with respect to preventability.

Design:

Prospective cohort study.

Setting:

10 academic medical centers in the United States.

Patients:

822 adults readmitted to a general medicine service.

Measurements:

For each readmission, 2 site-specific physician adjudicators used a structured survey instrument to determine whether it was preventable and measured other characteristics.

Results:

Overall, 36.2% of early readmissions versus 23.0% of late readmissions were preventable (median risk difference, 13.0 percentage points [interquartile range, 5.5 to 26.4 percentage points]). Hospitals were identified as better locations for preventing early readmissions (47.2% vs. 25.5%; median risk difference, 22.8 percentage points [interquartile range, 17.9 to 31.8 percentage points]), whereas outpatient clinics (15.2% vs. 6.6%; median risk difference, 10.0 percentage points [interquartile range, 4.6 to 12.2 percentage points]) and home (19.4% vs. 14.0%; median risk difference, 5.6 percentage points [interquartile range, −6.1 to 17.1 percentage points]) were better for preventing late readmissions.

Limitation:

Physician adjudicators were not blinded to readmission timing, community hospitals were not included in the study, and readmissions to nonstudy hospitals were not included in the results.

Conclusion:

Early readmissions were more likely to be preventable and amenable to hospital-based interventions. Late readmissions were less likely to be preventable and were more amenable to ambulatory and home-based interventions.

Primary Funding Source:

Association of American Medical Colleges.

https://ift.tt/2rbSqqt

Acute Kidney Injury

https://ift.tt/2kKA6B8

Long-Term Effectiveness of Sigmoidoscopy Screening on Colorectal Cancer Incidence and Mortality in Women and Men A Randomized Trial

Background:

The long-term effects of sigmoidoscopy screening on colorectal cancer (CRC) incidence and mortality in women and men are unclear.

Objective:

To determine the effectiveness of flexible sigmoidoscopy screening after 15 years of follow-up in women and men.

Design:

Randomized controlled trial. (ClinicalTrials.gov: NCT00119912)

Setting:

Oslo and Telemark County, Norway.

Participants:

Adults aged 50 to 64 years at baseline without prior CRC.

Intervention:

Screening (between 1999 and 2001) with flexible sigmoidoscopy with and without additional fecal blood testing versus no screening. Participants with positive screening results were offered colonoscopy.

Measurements:

Age-adjusted CRC incidence and mortality stratified by sex.

Results:

Of 98 678 persons, 20 552 were randomly assigned to screening and 78 126 to no screening. Adherence rates were 64.7% in women and 61.4% in men. Median follow-up was 14.8 years. The absolute risks for CRC in women were 1.86% in the screening group and 2.05% in the control group (risk difference, −0.19 percentage point [95% CI, −0.49 to 0.11 percentage point]; HR, 0.92 [CI, 0.79 to 1.07]). In men, the corresponding risks were 1.72% and 2.50%, respectively (risk difference, −0.78 percentage point [CI, −1.08 to −0.48 percentage points]; hazard ratio [HR], 0.66 [CI, 0.57 to 0.78]) (P for heterogeneity = 0.004). The absolute risks for death from CRC in women were 0.60% in the screening group and 0.59% in the control group (risk difference, 0.01 percentage point [CI, −0.16 to 0.18 percentage point]; HR, 1.01 [CI, 0.77 to 1.33]). The corresponding risks for death from CRC in men were 0.49% and 0.81%, respectively (risk difference, −0.33 percentage point [CI, −0.49 to −0.16 percentage point]; HR, 0.63 [CI, 0.47 to 0.83]) (P for heterogeneity = 0.014).

Limitation:

Follow-up through national registries.

Conclusion:

Offering sigmoidoscopy screening in Norway reduced CRC incidence and mortality in men but had little or no effect in women.

Primary Funding Source:

Norwegian government and Norwegian Cancer Society.

https://ift.tt/2HUwRSq

Ethics and the Legalization of Physician-Assisted Suicide

https://ift.tt/2kNQqRx

Association Between Prescription Drug Monitoring Programs and Nonfatal and Fatal Drug Overdoses A Systematic Review

Background:

Prescription drug monitoring programs (PDMPs) are a key component of the president's Prescription Drug Abuse Prevention Plan to prevent opioid overdoses in the United States.

Purpose:

To examine whether PDMP implementation is associated with changes in nonfatal and fatal overdoses; identify features of programs differentially associated with those outcomes; and investigate any potential unintended consequences of the programs.

Data Sources:

Eligible publications from MEDLINE, Current Contents Connect (Clarivate Analytics), Science Citation Index (Clarivate Analytics), Social Sciences Citation Index (Clarivate Analytics), and ProQuest Dissertations indexed through 27 December 2017 and additional studies from reference lists.

Study Selection:

Observational studies (published in English) from U.S. states that examined an association between PDMP implementation and nonfatal or fatal overdoses.

Data Extraction:

2 investigators independently extracted data from and rated the risk of bias (ROB) of studies by using established criteria. Consensus determinations involving all investigators were used to grade strength of evidence for each intervention.

Data Synthesis:

Of 2661 records, 17 articles met the inclusion criteria. These articles examined PDMP implementation only (n = 8), program features only (n = 2), PDMP implementation and program features (n = 5), PDMP implementation with mandated provider review combined with pain clinic laws (n = 1), and PDMP robustness (n = 1). Evidence from 3 studies was insufficient to draw conclusions regarding an association between PDMP implementation and nonfatal overdoses. Low-strength evidence from 10 studies suggested a reduction in fatal overdoses with PDMP implementation. Program features associated with a decrease in overdose deaths included mandatory provider review, provider authorization to access PDMP data, frequency of reports, and monitoring of nonscheduled drugs. Three of 6 studies found an increase in heroin overdoses after PDMP implementation.

Limitation:

Few studies, high ROB, and heterogeneous analytic methods and outcome measurement.

Conclusion:

Evidence that PDMP implementation either increases or decreases nonfatal or fatal overdoses is largely insufficient, as is evidence regarding positive associations between specific administrative features and successful programs. Some evidence showed unintended consequences. Research is needed to identify a set of "best practices" and complementary initiatives to address these consequences.

Primary Funding Source:

National Institute on Drug Abuse and Bureau of Justice Assistance.

https://ift.tt/2wpWR6c

Heart Failure

Heart failure affects more than 6 million people in the United States and incurs a heavy toll in morbidity, mortality, and health care costs. It frequently coexists with other important disorders, including hypertension, coronary artery disease, diabetes, and obesity. Decades of clinical trials have shown that several medications and interventions are effective for improving outcomes; however, mortality and hospitalization rates remain high. More recently, additional medications and devices have shown promise in reducing the health burden of heart failure.

https://ift.tt/2kLf1q6

Methods for Evaluating Natural Experiments in Obesity A Systematic Review

Background:

Given the obesity pandemic, rigorous methodological approaches, including natural experiments, are needed.

Purpose:

To identify studies that report effects of programs, policies, or built environment changes on obesity prevention and control and to describe their methods.

Data Sources:

PubMed, CINAHL, PsycINFO, and EconLit (January 2000 to August 2017).

Study Selection:

Natural experiments and experimental studies evaluating a program, policy, or built environment change in U.S. or non-U.S. populations by using measures of obesity or obesity-related health behaviors.

Data Extraction:

2 reviewers serially extracted data on study design, population characteristics, data sources and linkages, measures, and analytic methods and independently evaluated risk of bias.

Data Synthesis:

294 studies (188 U.S., 106 non-U.S.) were identified, including 156 natural experiments (53%), 118 experimental studies (40%), and 20 (7%) with unclear study design. Studies used 106 (71 U.S., 35 non-U.S.) data systems; 37% of the U.S. data systems were linked to another data source. For outcomes, 112 studies reported childhood weight and 32 adult weight; 152 had physical activity and 148 had dietary measures. For analysis, natural experiments most commonly used cross-sectional comparisons of exposed and unexposed groups (n = 55 [35%]). Most natural experiments had a high risk of bias, and 63% had weak handling of withdrawals and dropouts.

Limitation:

Outcomes restricted to obesity measures and health behaviors; inconsistent or unclear descriptions of natural experiment designs; and imperfect methods for assessing risk of bias in natural experiments.

Conclusion:

Many methodologically diverse natural experiments and experimental studies were identified that reported effects of U.S. and non-U.S. programs, policies, or built environment changes on obesity prevention and control. The findings reinforce the need for methodological and analytic advances that would strengthen evaluations of obesity prevention and control initiatives.

Primary Funding Source:

National Institutes of Health, Office of Disease Prevention, and Agency for Healthcare Research and Quality. (PROSPERO: CRD42017055750)

https://ift.tt/2I6jzEX

Ethics and the Legalization of Physician-Assisted Suicide

https://ift.tt/2svjDVK

How Would You Manage This Patient With Osteoporosis? Grand Rounds Discussion From Beth Israel Deaconess Medical Center

Osteoporosis is a skeletal disorder characterized by reduced bone strength that increases the risk for fracture. Approximately 10 million men and women in the United States have osteoporosis, and more than 2 million osteoporosis-related fractures occur annually. In 2016, the American Association of Clinical Endocrinologists issued the "Clinical Practice Guideline for the Diagnosis and Treatment of Postmenopausal Osteoporosis," and in 2017, the American College of Physicians issued the guideline "Treatment of Low Bone Density or Osteoporosis to Prevent Fracture in Men and Women." Both guidelines agree that patients diagnosed with osteoporosis should be treated with an antiresorptive agent, such as alendronate, that has been shown to reduce hip and vertebral fractures. However, there is no consensus on how long patients with osteoporosis should be treated and whether bone density should be monitored during and after the treatment period. In this Beyond the Guidelines, 2 experts discuss management of osteoporosis in general and for a specific patient, the role of bone density monitoring during and after a 5-year course of alendronate, and treatment recommendations for a patient whose bone density decreases during or after a 5-year course of alendronate.

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Acute Kidney Injury

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National Institutes of Health Pathways to Prevention Workshop: Methods for Evaluating Natural Experiments in Obesity

On 5 and 6 December 2017, the National Institutes of Health (NIH) convened the Pathways to Prevention Workshop: Methods for Evaluating Natural Experiments in Obesity to identify the status of methods for assessing natural experiments to reduce obesity, areas in which these methods could be improved, and research needs for advancing the field. This article considers findings from a systematic evidence review on methods for evaluating natural experiments in obesity, workshop presentations by experts and stakeholders, and public comment. Research gaps are identified, and recommendations related to 4 key issues are provided.Recommendations on population-based data sources and data integration include maximizing use and sharing of existing surveillance and research databases and ensuring significant effort to integrate and link databases. Recommendations on measurement include use of standardized and validated measures of obesity-related outcomes and exposures, systematic measurement of co-benefits and unintended consequences, and expanded use of validated technologies for measurement. Study design recommendations include improving guidance, documentation, and communication about methods used; increasing use of designs that minimize bias in natural experiments; and more carefully selecting control groups. Cross-cutting recommendations target activities that the NIH and other funders might undertake to improve the rigor of natural experiments in obesity, including training and collaboration on modeling and causal inference, promoting the importance of community engagement in the conduct of natural experiments, ensuring maintenance of relevant surveillance systems, and supporting extended follow-up assessments for exemplar natural experiments.To combat the significant public health threat posed by obesity, researchers should continue to take advantage of natural experiments. The recommendations in this report aim to strengthen evidence from such studies.

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T1

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Integrated Inpatient Medical and Psychiatric Care: Experiences of 5 Institutions

Some hospitalized patients with comorbid, chronic medical and psychiatric illnesses may benefit from admission to an integrated unit that can provide care for both conditions. This commentary describes integrated medical–psychiatric inpatient care units implemented in 5 U.S. institutions, the facilitators of and barriers to this model, and the benefits in terms of patient outcomes and provider satisfaction.

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Sigmoidoscopy Screening for Colorectal Cancer

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If You Can't Beat It, Join It: Uncertainty and Trust in Medicine

The quest to eliminate uncertainty in clinical decision making has become central to biomedical research over the past 50 years, driving the emergence of evidence-based medicine, precision medicine, and most recently biomedical artificial intelligence. This commentary discusses how, despite being a source of discomfort, the handling of uncertainty can also have an important positive effect on medical care.

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Ethics and the Legalization of Physician-Assisted Suicide

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The Need for Closed-Loop Systems for Management of Abnormal Test Results

The authors observe that their hospital performed approximately equal numbers of screening mammograms and Pap smears each year. Follow-up was appropriate for more than 99% of abnormal mammograms but only 91% of abnormal Pap smears. They examine the reasons for these differences and propose improvements for follow-up of abnormal results from other diagnostic tests.

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Ethics and the Legalization of Physician-Assisted Suicide

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Man Versus Machine: Does Automated Computer Density Measurement Add Value?

Kerlikowske and colleagues have evaluated whether, given the variability of radiologists' subjective assessment of breast density, machine measurements should be introduced. The editorialists discuss the findings and what we need to know before deciding whether machine measurement of breast density provides health care value.

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Liquid-filled Intragastric Balloons by Apollo Endosurgery and ReShape Lifesciences: Letter to Health Care Providers - New Labeling About Potential Risks

[Posted 06/04/2018] AUDIENCE: Gastroenterology, Risk Manager, Health Professional, Patient ISSUE: In collaboration with the manufacturers, the FDA has approved new labeling for the Orbera and ReShape balloon systems with more information about...

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Identification, Management, and Transition of Care for Patients With Opioid Use Disorder in the Emergency Department

Because of a soaring number of opioid-related deaths during the past decade, opioid use disorder has become a prominent issue in both the scientific literature and lay press. Although most of the focus within the emergency medicine community has been on opioid prescribing—specifically, on reducing the incidence of opioid prescribing and examining alternative pain treatment—interest is heightening in identifying and managing patients with opioid use disorder in an effective and evidence-based manner.

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How the Availability of Observation Status Affects Emergency Physician Decisionmaking

This study seeks to understand how emergency physicians decide to use observation services, and how placing a patient under observation influences physicians' subsequent decisionmaking.

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Adverse Effects of Immune Checkpoint Therapy in Cancer Patients Visiting the Emergency Department of a Comprehensive Cancer Center

Cancer immunotherapy is evolving rapidly and is transforming cancer care. During the last decade, immune checkpoint therapies have been developed to enhance the immune response; however, specific adverse effects related to autoimmunity are increasingly apparent. This study aims to fill the knowledge gap related to the spectrum of immune-related adverse effects among cancer patients visiting emergency departments (EDs).

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Liquid-filled Intragastric Balloons by Apollo Endosurgery and ReShape Lifesciences: Letter to Health Care Providers - New Labeling About Potential Risks

[Posted 06/04/2018] AUDIENCE: Gastroenterology, Risk Manager, Health Professional, Patient ISSUE: In collaboration with the manufacturers, the FDA has approved new labeling for the Orbera and ReShape balloon systems with more information about...

https://ift.tt/2Jakwxm

Repeat participation in annual cross-sectional surveys of drug users and its implications for analysis

We sought to establish the extent of repeat participation in a large annual cross-sectional survey of people who inject drugs and assess its implications for analysis.

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An evaluation of the short physical performance battery following pulmonary rehabilitation in patients with chronic obstructive pulmonary disease

There is a need for simple tools to evaluate physical performance in patients with COPD before and after pulmonary rehabilitation. The aims of this study were to evaluate changes in short physical performance ...

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National report on aggressions to physicians in Spain 2010–2015: violence in the workplace—ecological study

Aggressions against health staff is a phenomenon that is not widely studied worldwide. To date, there is no national study analyzing this situation in Spain. Our objective is to describe and analyze aggression...

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High heterotrophic counts in potable water and antimicrobial resistance among indicator organisms in two peri-urban communities of Karachi, Pakistan

Fecal contamination of potable water leads to unsafe water supply. Although many urban areas of large metropolitan cities receive safe water, peri-urban areas are often not monitored by public health authoriti...

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Prucalopride inhibits the glioma cells proliferation and induces autophagy via AKT-mTOR pathway

Glioma is the most fatal primary brain glioma in central nervous system mainly attributed to its high invasion. Prucalopride, a Serotonin-4 (5-HT4) receptor agonist, has been reported to regulate neurodevelopm...

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A case report: a heterozygous deletion (2791_2805 del) in exon 18 of the filamin C gene causing filamin C-related myofibrillar myopathies in a Chinese family

Filamin C-related myofibrillar myopathies (MFM) are progressive skeletal myopathies with an autosomal dominant inheritance pattern. The conditions are caused by mutations of the filamin C gene (FLNC) located in t...

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Benefit of Liposomal Bupivacaine for Pain in TKA Questioned

MONDAY, June 4, 2018 -- Liposomal bupivacaine use in patients undergoing total knee arthroplasty is not associated with clinically meaningful reductions in inpatient opioid use, resource utilization, or opioid-related complications, according to a...

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Case Shows Biotin Can Interfere With Multiple Endocrine Tests

MONDAY, June 4, 2018 -- Biotin, which is included in many hair, skin, and nail growth over-the-counter products, can affect multiple hormone levels, according to a case study published online May 10 in the Journal of the Endocrine Society. Heather...

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ASCO: Pembrolizumab Superior for Initial Tx of Advanced NSCLC

MONDAY, June 4, 2018 -- For patients with programmed death ligand 1 (PD-L1)-expressing locally advanced or metastatic non-small-cell lung cancer (NSCLC), pembrolizumab is associated with better overall survival than chemotherapy, regardless of the...

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No New Adverse Events Reported for DTaP Vaccination

MONDAY, June 4, 2018 -- No new or unexpected safety issues have been identified in association with diphtheria-tetanus-acellular pertussis (DTaP) vaccines in the United States, according to a study published online June 4 in Pediatrics. Pedro L....

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Immunotherapy Promising for Slowing Progression of ALS

MONDAY, June 4, 2018 -- A new immunotherapy appears to be well tolerated and possibly of benefit in patients with amyotrophic lateral sclerosis (ALS), according to a phase 1, first-in-human study published online May 18 in Neurology: Neuroimmunology...

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Many Breast Cancer Survivors Do Not Undergo Annual Surveillance

MONDAY, June 4, 2018 -- A considerable proportion of breast cancer survivors do not undergo annual surveillance breast imaging, according to a study published in the May issue of the Journal of the National Comprehensive Cancer Network. Kathryn J....

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ASCO: mCRC Costs Up in Western Washington vs. British Columbia

MONDAY, June 4, 2018 -- Costs of treatment for metastatic colorectal cancer (mCRC) are significantly higher in Western Washington State (WW) than in British Columbia (BC), according to a study presented at the annual meeting of the American Society...

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Research Reveals Unfavorable Beliefs About Frozen Vegetables

MONDAY, June 4, 2018 -- Individuals have a negative bias toward frozen vegetables, according to a study published in the Aug. 1 issue of Appetite. Paul M. Connell, Ph.D., from Stony Brook University in New York, and colleagues examined the negative...

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Few High-Risk Mothers in Boston Took Folic Acid Before Pregnancy

MONDAY, June 4, 2018 -- Among an urban, low-income minority population, few women started folic acid supplementation before pregnancy, according to a study published in the June issue of the American Journal of Public Health. Tina L. Cheng, M.D.,...

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American Indian Reservation Teens at Higher Risk for Drug Use

MONDAY, June 4, 2018 -- American Indian students who live on or near reservations are at high risk for substance use versus U.S. youths in general, according to a study published online May 31 in JAMA Network Open. Randall C. Swaim, Ph.D., and Linda...

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Quantifying Microglia Morphology from Photomicrographs of Immunohistochemistry Prepared Tissue Using ImageJ

Microglia are brain immune cells that survey and react to altered brain physiology through morphologic changes which may be evaluated quantitatively. This protocol outlines an ImageJ based analysis protocol to represent microglia morphology as continuous data according to metrics such as cell ramification, complexity, and shape.

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Endocrine Adjuvant Therapy for Localized Breast Cancer

Investigators now report in the Journal the updated results of two critical trials of endocrine therapy in early-stage breast cancer — SOFT (Suppression of Ovarian Function Trial) and TEXT (Tamoxifen and Exemestane Trial) — with overlapping groups that permitted a combined analysis. As in many…

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Tailoring Adjuvant Endocrine Therapy for Premenopausal Breast Cancer

Adjuvant treatment with tamoxifen for 5 years reduces the recurrence of premenopausal estrogen-receptor–positive breast cancer, with increasing benefits for overall survival during 5 to 15 years of follow-up. Extending the duration of tamoxifen treatment to 10 years further improves outcomes. The…

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Response Prediction of Altered Thyroglobulin Levels After Radioactive Iodine Therapy Aided by Recombinant Human Thyrotropin in Patients with Differentiated Thyroid Cancer

Abstract

Purpose

Thyroglobulin (Tg) may be released from damaged residual thyroid tissues after radioactive iodine (RAI) therapy in patients with differentiated thyroid carcinoma (DTC). We investigated whether altered levels of serum Tg after recombinant human thyrotropin (rhTSH)-aided RAI therapy could be a prognostic marker in patients with DTC.

Methods

We evaluated 68 patients who underwent RAI therapy after total thyroidectomy. Serum Tg levels were measured just before RAI administration (D0Tg) and 7 days after RAI therapy (D7Tg). Patients with a D0Tg level greater than 2.0 ng/mL were excluded to more precisely evaluate the injury effect of RAI in small remnant tissues. The ratioTg was defined as the D7Tg level divided by that on D0Tg. The therapeutic responses were classified as acceptable or non-acceptable. Finally, we investigated which clinicopathologic parameters were associated with therapeutic response.

Results

At the follow-up examination, an acceptable response was observed in 50 patients (73.5%). Univariate analysis revealed significant differences in N stage (P = 0.003) and ratioTg (acceptable vs. non-acceptable responses, 21.9 ± 33.6 vs. 3.8 ± 6.5; P = 0.006). In multivariate analysis, only ratioTg significantly predicted an acceptable response (odds ratio 1.104; 95% confidence interval 1.005–1.213; P = 0.040). A ratioTg above 3.5 predicted an acceptable response with a sensitivity of 66.0%, specificity of 83.3%, and accuracy of 70.6% (area under the curve = 0.718; P = 0.006).

Conclusions

Altered levels of serum Tg after RAI therapy, calculated as the ratioTg (D7Tg/D0Tg), significantly predicted an acceptable response in patients with DTC.

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Probing the Roles of Physical Forces in Early Chick Embryonic Morphogenesis

Here, we present a protocol introducing a set of new ex-ovo experiments and physical modeling approaches for studying the mechanics of morphogenesis during early chick embryonic brain torsion.

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Undiagnosed Cryptococcus gattii meningitis leading to subsequent ventriculoperitoneal shunt infection in a patient with symptoms of normal pressure hydrocephalus: case report and literature review

Cryptococcus gattii is known to be an etiologic agent of human cryptococcosis, particularly in immunocompetent persons. C. gattii infection usually involves the central nervous system, the respiratory tract, or m...

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Polymorphisms in the Th17 cell-related RORC gene are associated with spontaneous clearance of HCV in Chinese women

Female gender and favorable IFNL3 genotypes are the primary independent predictors of spontaneous clearance of HCV infection. However, chronic hepatitis C infection occurs in numerous women carrying favorable IFN...

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Recognizing spatial and temporal clustering patterns of dengue outbreaks in Taiwan

Dengue fever is the most common arboviral infection in humans, with viral transmissions occurring in more than 100 countries in tropical regions. A global strategy for dengue prevention and control was establi...

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Clinical and bacteriological features and prognosis of ascitic fluid infection in Chinese patients with cirrhosis

Spontaneous bacterial peritonitis (SBP) and bacterascites (BA) represent frequent and serious complications in cirrhosis patients with ascites. However, few detailed data are available regarding the clinical a...

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Disseminated Exophiala dermatitidis causing septic arthritis and osteomyelitis

Exophiala dermatitidis is a melanized fungus isolated from many environmental sources. Infections caused by Exophiala species are typically seen in immunocompromised hosts and manifest most commonly as cutaneous ...

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Bispecific light T-cell engagers for gene-based immunotherapy of epidermal growth factor receptor (EGFR)-positive malignancies

Abstract

The recruitment of T-cells by bispecific antibodies secreted from adoptively transferred, gene-modified autologous cells has shown satisfactory results in preclinical cancer models. Even so, the approach's translation into the clinic will require incremental improvements to its efficacy and reduction of its toxicity. Here, we characterized a tandem T-cell recruiting bispecific antibody intended to benefit gene-based immunotherapy approaches, which we call the light T-cell engager (LiTE), consisting of an EGFR-specific single-domain V_HH antibody fused to a CD3-specific scFv. We generated two LiTEs with the anti-EGFR V_HH and the anti-CD3 scFv arranged in both possible orders. Both constructs were well expressed in mammalian cells as highly homogenous monomers in solution with molecular weights of 43 and 41 kDa, respectively. In situ secreted LiTEs bound the cognate antigens of both parental antibodies and triggered the specific cytolysis of EGFR-expressing cancer cells without inducing T-cell activation and cytotoxicity spontaneously or against EGFR-negative cells. Light T-cell engagers are, therefore, suitable for future applications in gene-based immunotherapy approaches.

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Tox and Hound – The Dirty on Dantrolene

by Sarah Shafer Dantrolene is one of the few, true "muscle relaxers". It was discovered in 1967 and approved by the FDA in 1979. Unlike paralytic neuromuscular blockers, dantrolene works post-synaptically, at the sarcoplasmic reticulum in the myocyte. It binds to the ryanodine receptor in skeletal muscle (RYR1), preventing sarcoplasmic calcium-induced calcium release. When RYR1 […]

EMCrit Project by Tox & Hound.

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Detecting Bias in Large-Scale Comparative Analyses: Methods for Expanding the Scope of Hypothesis-Testing with HormoneBase

Synopsis

To address large-scale questions in evolutionary biology, the compilation of data from a variety of sources is often required. This is a major challenge in the development of databases in organismal biology. Here, we describe the procedure we used to reconstruct the phylogeny of the 474 species represented in HormoneBase, including fish, amphibians, mammals, birds, and reptiles. We also provide the methodology used to compile vertebrate environmental, life history, and metabolic rate data for use in conjunction with the HormoneBase database to test hypotheses of the evolution of steroid hormone traits. We then report a series of analyses using these data to determine the extent to which field measures of circulating hormones and associated life history data exhibit taxonomic and geographic bias. By providing a detailed description of the approaches used to compile and evaluate these data and identifying potential biases in the collection of these data, we hope to make the HormoneBase database a more broadly useful resource for the scientific community to address a diversity of comparative questions.

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Cancers, Vol. 10, Pages 182: Cancer Metastases to Bone: Concepts, Mechanisms, and Interactions with Bone Osteoblasts

Cancers, Vol. 10, Pages 182: Cancer Metastases to Bone: Concepts, Mechanisms, and Interactions with Bone Osteoblasts

Cancers doi: 10.3390/cancers10060182

Authors: Alison B. Shupp Alexus D. Kolb Dimpi Mukhopadhyay Karen M. Bussard

The skeleton is a unique structure capable of providing support for the body. Bone resorption and deposition are controlled in a tightly regulated balance between osteoblasts and osteoclasts with no net bone gain or loss. However, under conditions of disease, the balance between bone resorption and deposition is upset. Osteoblasts play an important role in bone homeostasis by depositing new bone osteoid into resorption pits. It is becoming increasingly evident that osteoblasts additionally play key roles in cancer cell dissemination to bone and subsequent metastasis. Our laboratory has evidence that when osteoblasts come into contact with disseminated breast cancer cells, the osteoblasts produce factors that initially reduce breast cancer cell proliferation, yet promote cancer cell survival in bone. Other laboratories have demonstrated that osteoblasts both directly and indirectly contribute to dormant cancer cell reactivation in bone. Moreover, we have demonstrated that osteoblasts undergo an inflammatory stress response in late stages of breast cancer, and produce inflammatory cytokines that are maintenance and survival factors for breast cancer cells and osteoclasts. Advances in understanding interactions between osteoblasts, osteoclasts, and bone metastatic cancer cells will aid in controlling and ultimately preventing cancer cell metastasis to bone.

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Can strain dependent inhibition of cross-bridge binding explain shifts in optimum muscle length?

Abstract

Skeletal muscle force is generated by cross-bridge interactions between the overlapping contractile proteins, actin and myosin. The geometry of this overlap gives us the force-length relationship in which maximum isometric force is generated at an intermediate, optimum, length. However, the force-length relationship is not constant; optimum length increases with decreasing muscle activation. This effect is not predicted from actin-myosin overlap. Here we present evidence that this activation-dependent shift in optimum length may be due to series compliance within muscles. As muscles generate force during fixed-end contractions, fibers shorten against series compliance until forces equilibrate and they become isometric. Shortening against series-compliance is proportional to activation, and creates conditions under which shortening-induced force depression may suppress full force development. Greater shortening will result in greater force depression. Hence, optimum length may decrease as activation rises due to greater fiber shortening. We discuss explanations of such history dependence, giving a review of previously proposed processes and suggesting a novel mechanistic explanation for the most likely candidate process based on tropomyosin kinetics. We suggest this mechanism could change the relationship between actin-myosin overlap and cross-bridge binding potential, not only depressing force at any given length, but also altering the relationship between force and length. This would have major consequences for our understanding of in vivo muscle performance.

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Town and country reptiles: A review of reptilian responses to urbanization

Abstract

The majority of the world population is now inhabiting urban areas, and with staggering population growth urbanization is also increasing. While work studying the effects of changing landscapes and specific urban pressures on wildlife is beginning to amass, the majority of this work focuses on avian or mammalian species. However, the effects of urbanization likely vary substantially across taxonomic groups due to differences in habitat requirements and life history. The current paper aims first to broaden the review of urban effects across reptilian species; second, to summarize the responses of reptilian fauna to specific urban features; and third, to assess the directionality of individual and population level responses to urbanization in reptile species. Based on our findings, urban research in reptilian taxa is lacking in the following areas: 1) investigating interactive or additive urban factors 2) measuring multiple morphological, behavioral and physiological endpoints within an animal, 3) linking individual to population-level responses, and 4) testing genetic/genomic differences across an urban environment as evidence for selective pressures.

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Differentiation and induced sensorial alteration of the coronal organ in the asexual life of a tunicate

Abstract

Tunicates, the sister group of vertebrates, possess a mechanoreceptor organ, the coronal organ, which is considered the best candidate to address the controversial issue of vertebrate hair cell evolution. The organ, located at the base of the oral siphon, controls the flow of seawater into the organism and can drive the "squirting" reaction, i.e., the rapid body muscle contraction used to eject dangerous particles during filtration. Coronal sensory cells are secondary mechanoreceptors and share morphological, developmental and molecular traits with vertebrate hair cells. In the colonial tunicate Botryllus schlosseri, we described coronal organ differentiation during asexual development. Moreover, we showed that the ototoxic aminoglycoside gentamicin caused morphological and mechanosensorial impairment in coronal cells. Finally, fenofibrate had a strong protective effect on coronal sensory cells due to gentamicin-induced toxicity, as occurs in vertebrate hair cells. Our results reinforce the hypothesis of homology between vertebrate hair cells and tunicate coronal sensory cells.

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The evolutionary endocrinology of circulating glucocorticoids in free-living vertebrates: recent advances and future directions across scales of study

Synopsis

Circulating glucocorticoid hormone concentrations are dynamic, flexible, and promote adaptive responses following perturbations in an animal's environment. As a result, circulating glucocorticoid levels are thought to shape fitness and have been suggested to be a key trait for predicting how species will cope with novel environmental change. Nevertheless, the factors that shape variation in glucocorticoid-mediated coping mechanisms remain unclear because the evolutionary underpinnings of the function and regulation of these hormones are poorly understood. Here, I summarize recent advances in our understanding of the evolution of circulating glucocorticoids, which have included (i) longitudinal studies exploring microevolutionary processes that shape within- and between-individual variation in glucocorticoids, (ii) interspecific comparative studies highlighting macro-evolutionary patterns of among-species variation in glucocorticoids, and (iii) intraspecific comparative studies which help to disentangle the relative roles of environment, life-history and behaviour in shaping among-population variation in glucocorticoids. Important avenues for future research will include exploring how natural selection may act on different components of the hypothalamus-pituitary-adrenal axis, characterizing patterns of phenotypic plasticity in circulating glucocorticoids across populations and species, as well as exploring how microevolutionary processes differ across taxa or gradients of environmental conditions.

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Designing for Broad Understanding of Science

Abstract

With the acceleration and increasing complexity of macro-scale problems such as climate change, the need for scientists to ensure that their work is understood has become urgent. As citizens and recipients of public funds for research, scientists have an obligation to communicate their findings in ways many people can understand. However, developing translations that are broadly accessible without being "dumbed down" can be challenging. Fortunately, tenets of visual literacy, combined with narrative methods, can help to convey scientific knowledge with fidelity, while sustaining viewers' interest. Here we outline strategies for such translating, with an emphasis on visual approaches. Among the examples is an innovative, NSF-funded professional development initiative in which National Park rangers use scientists' imagery to create compelling explanations for the visiting public. Thoughtful visualizations based on interpretive images, motion pictures, 3D animations and augmented, immersive experiences complement the impact of the natural resource and enhance the role of the park ranger. The visualizations become scaffolds for participatory exchanges in which the ranger transcends the traditional roles of information-holder and presenter, to facilitate provocative conversations that provide members of the public with enjoyable experiences and well-founded bases for reflection and ultimately understanding. The process of generating the supporting visualizations benefits from partnerships with design professionals, who develop opportunities for engaging the public by translating important scientific findings and messages in compelling and memorable ways.

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Biodiversity and Extinction of Hawaiian Land Snails: How Many are Left Now and What Must We Do To Conserve Them – A Reply to Solem (1990)

Abstract

Synopsis: Pacific islands, with their incredible biodiversity, are our finest natural laboratories for evolutionary, ecological and cultural studies. Nowhere, in relation to land area, does land snail diversity reach that of the Pacific islands, with more than 6,000 species, most of which are single island endemics. Unfortunately, land snails are the most imperiled group with the most recorded extinctions since the 1500s, and Pacific island snails make up the majority of those extinctions. In 1990, Dr. Alan Solem, a well renowned malacologist, with expertise in Pacific island land snails, posthumously published a plea to save the remaining Hawaiian land snails before they vanish forever. Now, more than 25 years later, we have finally begun to make inroads into answering the questions "How many Hawaiian land snails remain?" and "What will we need to save them?". Here we provide a belated reply to Solem (1990) and address these questions about Hawaiian land snails. We conclude by building on the actions suggested by Solem and that we feel are still needed to realize his hope of conserving Hawaii's remaining land snails specifically, but also our hope of conserving invertebrates more broadly.

https://ift.tt/2svI6uc

The kingdom of the blind: disentangling fundamental drivers in the evolution of eye loss

Abstract

Light is a fundamentally important biological cue used by almost every animal on earth, to maintain daily rhythms, navigate, forage, find mates or avoid predators. But an enormous number of species live in darkness: in subterranean caves, deep oceans, underground burrows, and within parasitic host bodies, and the loss of eyes appears consistently across these ecosystems. However, the evolutionary mechanisms that lead to the reduction of the visual system remain the subject of great interest and debate more than 150 years after Darwin tackled the issue. Studies of model taxa have discovered significant roles for natural selection, neutral evolution and pleiotropy, but the interplay between them remains unclear. To nail down unifying concepts surrounding the evolution of eye loss, we must embrace the enormous range of affected animals and habitats. The fine developmental details of model systems such as the Mexican cave tetra Astyanax mexicanus have transformed and enriched the field, but these should be complemented by wider studies to identify truly overarching patterns that apply throughout animals. Here, the major evolutionary drivers are placed within a conceptual cost-benefit framework that incorporates the fundamental constraints and forces that influence evolution in the dark. Major physiological, ecological and environmental factors are considered within the context of this framework, which appears faithful to observed patterns in deep-sea and cavernicolous animals. To test evolutionary hypotheses, a comparative phylogenetic approach is recommended, with the goal of studying large groups exhibiting repeated reduction, and then comparing these across habitats, taxa, and lifestyles. Currently, developmental and physiological methods cannot feasibly be used on such large scales, but penetrative imaging techniques could provide detailed morphological data non-invasively and economically for large numbers of species. Comprehensive structural datasets can then be contextualised phylogenetically to examine recurrent trends and associations, and to reconstruct character histories through multiple independent transitions into darkness. By assessing these evolutionary trajectories within an energetic cost-benefit framework, the relationships between fundamental influences can be inferred and compared across different biological and physical parameters. However, substantial numbers of biological and environmental factors affect the evolutionary trajectory of loss, and it is critical that researchers make fair and reasonable comparisons between objectively similar groups.

https://ift.tt/2HlKat8

Body stiffness and damping depend sensitively on the timing of muscle activation in lampreys

Synopsis

Unlike most manmade machines, animals move through their world using flexible bodies and appendages, which bend due to internal muscle and body forces, but also due to forces from the environment. Fishes in particular must cope with fluid dynamic forces that not only resist their overall swimming movements but also may have unsteady flow patterns, vortices, and turbulence, many of which occur more rapidly than what the nervous system can process. Has natural selection led to mechanical properties of fish bodies and their component tissues that can respond very quickly to environmental perturbations? Here, we focus on the mechanical properties of isolated muscle tissue and of the entire intact body in the silver lamprey, Ichthyomyzon unicuspis. We developed two modified work loop protocols to determine the effect of small perturbations on the whole body and on isolated segments of muscle as a function of muscle activation and phase within the swimming cycle. First, we examined how the mechanical properties of the whole lamprey body change depending on the timing of muscle activity. Relative to passive muscle, muscle activation can modulate the effective stiffness by about two-fold and modulate the effective damping by more than 10-fold depending on the activation phase. Next, we performed a standard work loop test on small sections of axial musculature while adding low-amplitude sinusoidal perturbations at specific frequencies. We modeled the data using a new system identification technique based on time-periodic system analysis and harmonic transfer functions and used the resulting models to predict muscle function under novel conditions. We found that the effective stiffness and damping of muscle varies during the swimming cycle, and that the timing of activation can alter both the magnitude and timing of peak stiffness and damping. Moreover, the response of the isolated muscle was highly nonlinear and length dependent, but the body's response was much more linear. We applied the resulting harmonic transfer functions from our experiments to explore the effect of pairs of antagonistic muscles. The results suggest that when muscles work antagonistically, the nonlinearities present in either muscle segment alone are reduced. Together, these results begin to provide an integrative understanding of how activation timing can tune the mechanical response properties of muscles, enabling fish to swim effectively in their complex and unpredictable environment.

https://ift.tt/2kNaOSP

Myofascial loads can occur without fascicle length changes

Abstract

Many studies have shown that connective tissue linkages can transmit force between synergistic muscles and that such force transmission depends on the position of these muscles relative to each other and on properties of their intermuscular connective tissues. Moving neighboring muscles has been reported to cause longitudinal deformations within passive muscles held at a constant muscle-tendon unit (MTU) length (e.g. soleus, SO), but muscle forces were not directly measured. Deformations do not provide a direct measure of the force transmitted between muscles. We combined two different muscle preparations to assess whether myofascial loads exerted by neighboring muscles result in length changes of SO fascicles. We investigated the effects of proximal MTU length changes of two-joint gastrocnemius (GA) and plantaris (PL) muscles on the fascicle length of the one-joint SO muscle within (1) an intact muscle compartment and (2) a disrupted compartment that allowed measurements of fascicle length and distal tendon force of SO simultaneously. SO muscle bellies of Wistar rats (n=5) were implanted with sonomicrometry crystals. In three animals, connectivity between SO and GA+PL was enhanced. Measurements were performed before and during maximal excitation of all plantar flexor muscles. In both setups, MTU length of GA+PL did not affect the length of SO fascicles, neither during passive nor active conditions. However, lengthening the MTU of GA+PL increased distal tendon force of SO by 43.3-97.8% (p < 0.001) and 27.5-182.6% (p < 0.001), respectively. This indicates that substantial myofascial force transmission between SO and synergistic muscle can occur via a connective tissue network running parallel to the series of SO sarcomeres without substantial length changes of SO fascicles.

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