Brachytherapy in Head and Neck Cancers: “Are We Doing It or Are We Done with It”

Abstract

We performed an e-Survey and reviewed the literature on the prevalence of use of brachytherapy in head and neck cancers in order to understand the patterns of care and probable application of this modality. A five-point questionnaire was prepared and sent to 300 oncologists through a web-based survey engine. This was done in preparation for my lecture on "Ongoing Research and Potential Research Avenues" in IBSCON held in Chennai in August 2016. SPSS software was used for the statistical analysis. Of a total of 300 emails that were sent out for the survey, 120 replies were received, which is 40%. Among the results of various questions, (i) 65% of the oncologists felt that there were > 300 ongoing studies in brachytherapy and out of them only 10–20 were on head and neck brachytherapy; (ii) 58% of the responders felt that external beam radiotherapy (EBRT) advances followed by lack of training and experience are the reasons for declining role of brachytherapy; (iii) among the responders, numbers of head and neck brachytherapy performed stand third after gynecological and breast brachytherapy. This survey shows that brachytherapy in head and neck cancers is an essential tool, but seldom practiced. If no path-breaking event happens, we may be dealing with it as a dying art.

http://ift.tt/2oIQMLC

Priorities for Decreasing Morbidity and Mortality in Children With Advanced HIV Disease

Abstract

Early mortality and morbidity remain high in children initiating antiretroviral therapy (ART), especially in sub-Saharan Africa. Many children still present with advanced human immunodeficiency virus (HIV) disease. Tuberculosis, pneumonia, and severe bacterial infections are the main causes of hospital admission in HIV-infected children. In contrast to adults with advanced HIV disease, cryptococcal disease is not common in childhood, although there is a peak in infancy and adolescence. Interventions such as TB screening in symptomatic children, and isoniazid and cotrimoxazole prophylaxis should be implemented. There is evidence suggesting that rapid initiation (within 1 week) of ART in children with severe malnutrition or those with advanced HIV disease admitted to hospital is not beneficial and should be delayed until their condition has been stabilized. Research informing the prevention of severe bacterial infections, the management of pediatric immune reconstitution inflammatory syndrome, and other potential strategies to decrease morbidity and mortality in HIV-infected children are urgently needed.

http://ift.tt/2Fbp0BO

Managing Advanced HIV Disease in a Public Health Approach

Abstract

In 2017, the World Health Organization (WHO) published guidelines for the management of advanced human immunodeficiency virus (HIV) disease within a public health approach. Recent data suggest that more than a third of people starting antiretroviral therapy (ART) do so with advanced HIV disease, and an increasing number of patients re-present to care at an advanced stage of HIV disease following a period of disengagement from care. These guidelines recommend a standardized package of care for adults, adolescents, and children, based on the leading causes of morbidity and mortality: tuberculosis, severe bacterial infections, cryptococcal meningitis, toxoplasmosis, and Pneumocystis jirovecii pneumonia. A package of targeted interventions to reduce mortality and morbidity was recommended, based on results of 2 recent randomized trials that both showed a mortality reduction associated with delivery of a simplified intervention package. Taking these results and existing recommendations into consideration, WHO recommends that a package of care be offered to those presenting with advanced HIV disease; depending on age and CD4 cell count, the package may include opportunistic infection screening and prophylaxis, including fluconazole preemptive therapy for those who are cryptococcal antigen positive and without evidence of meningitis. Rapid ART initiation and intensified adherence interventions should also be proposed to everyone presenting with advanced HIV disease.

http://ift.tt/2H1YnvE

Causes and Timing of Mortality and Morbidity Among Late Presenters Starting Antiretroviral Therapy in the REALITY Trial

Abstract

Background

In sub-Saharan Africa, 20%–25% of people starting antiretroviral therapy (ART) have severe immunosuppression; approximately 10% die within 3 months. In the Reduction of EArly mortaLITY (REALITY) randomized trial, a broad enhanced anti-infection prophylaxis bundle reduced mortality vs cotrimoxazole. We investigate the contribution and timing of different causes of mortality/morbidity.

Methods

Participants started ART with a CD4 count <100 cells/µL; enhanced prophylaxis comprised cotrimoxazole plus 12 weeks of isoniazid + fluconazole, single-dose albendazole, and 5 days of azithromycin. A blinded committee adjudicated events and causes of death as (non–mutually exclusively) tuberculosis, cryptococcosis, severe bacterial infection (SBI), other potentially azithromycin-responsive infections, other events, and unknown.

Results

Median pre-ART CD4 count was 37 cells/µL. Among 1805 participants, 225 (12.7%) died by week 48. Fatal/nonfatal events occurred early (median 4 weeks); rates then declined exponentially. One hundred fifty-four deaths had single and 71 had multiple causes, including tuberculosis in 4.5% participants, cryptococcosis in 1.1%, SBI in 1.9%, other potentially azithromycin-responsive infections in 1.3%, other events in 3.6%, and unknown in 5.0%. Enhanced prophylaxis reduced deaths from cryptococcosis and unknown causes (P < .05) but not tuberculosis, SBI, potentially azithromycin-responsive infections, or other causes (P > .3); and reduced nonfatal/fatal tuberculosis and cryptococcosis (P < .05), but not SBI, other potentially azithromycin-responsive infections, or other events (P > .2).

Conclusions

Enhanced prophylaxis reduced mortality from cryptococcosis and unknown causes and nonfatal tuberculosis and cryptococcosis. High early incidence of fatal/nonfatal events highlights the need for starting enhanced-prophylaxis with ART in advanced disease.

Clinical Trials Registration

ISRCTN43622374.

http://ift.tt/2F9ct1G

Persistent High Burden of Advanced HIV Disease Among Patients Seeking Care in South Africa’s National HIV Program: Data From a Nationwide Laboratory Cohort

Abstract

Background

The South African national HIV program has increased antiretroviral therapy (ART) coverage over the last decade, supported by policy changes allowing for earlier ART initiation. However, many patients still enter care with advanced (<200 cells/μL) and very advanced (<100 cells/μL) HIV disease. We assessed disease progression at entry to care using nationwide laboratory data.

Methods

We constructed a national HIV cohort using laboratory records containing HIV RNA loads and CD4 counts from 2004 to 2016 to determine entry into care. We estimated numbers and proportions of adults with the first CD4 count <100 cells/ μL or 100–199 cells/μL. We calculated relative risks of presenting with advanced disease associated with male sex.

Results

8.04 million first CD4 results were identified. From 2005 to 2011, the proportion of patients entering into care with CD4 count <200 cells/μL declined from 46.8% to 35.6%. From 2011 onward, the proportion of patients entering ART with advanced HIV disease has remained relatively unchanged. In 2016, we estimated that of 654 868 patients entering care, 32.9% had advanced HIV disease, and 16.8% had very advanced HIV disease. Men were almost twice as likely as women (23.1% vs 12.6% ) to enter care with very advanced HIV disease.

Conclusions

The proportion of patients presenting with advanced HIV disease in South Africa remains consistently high despite ART scale-up, representing a large and avoidable burden of morbidity. Early HIV diagnosis, rapid linkage to ART and approaches to attract men into early ART initiation should be prioritized.

http://ift.tt/2CYncGl

The Persistent Challenge of Advanced HIV Disease and AIDS in the Era of Antiretroviral Therapy

advanced HIV diseaseAIDScryptococcal meningitistuberculosis

http://ift.tt/2F9VcWr

The Continuing Burden of Advanced HIV Disease Over 10 Years of Increasing Antiretroviral Therapy Coverage in South Africa

Abstract

Background

Antiretroviral treatment (ART) has been massively scaled up to decrease human immunodeficiency virus (HIV)–related morbidity, mortality, and HIV transmission. However, despite documented increases in ART coverage, morbidity and mortality have remained substantial. This study describes trends in the numbers and characteristics of patients with very advanced HIV disease in the Western Cape, South Africa.

Methods

Annual cross-sectional snapshots of CD4 distributions were described over 10 years, derived from a province-wide cohort of all HIV patients receiving CD4 cell count testing in the public sector. Patients with a first CD4 count <50 cells/µL in each year were characterized with respect to prior CD4 and viral load testing, ART access, and retention in ART care.

Results

Patients attending HIV care for the first time initially constituted the largest group of those with CD4 count <50 cells/µL, dropping proportionally over the decade from 60.9% to 26.7%. By contrast, the proportion who were ART experienced increased from 14.3% to 56.7%. In patients with CD4 counts <50 cells/µL in 2016, 51.8% were ART experienced, of whom 76% could be confirmed to be off ART or had recent viremia. More than half who were ART experienced with a CD4 count <50 cells/µL in 2016 were men, compared to approximately one-third of all patients on ART in the same year.

Conclusions

Ongoing HIV-associated morbidity now results largely from treatment-experienced patients not being in continuous care or not being fully virologically suppressed. Innovative interventions to retain ART patients in effective care are an essential priority for the ongoing HIV response.

http://ift.tt/2CUx0RD

Late Presentation With HIV in Africa: Phenotypes, Risk, and Risk Stratification in the REALITY Trial

Abstract

Background

Severely immunocompromised human immunodeficiency virus (HIV)–infected individuals have high mortality shortly after starting antiretroviral therapy (ART). We investigated predictors of early mortality and "late presenter" phenotypes.

Methods

The Reduction of EArly MortaLITY (REALITY) trial enrolled ART-naive adults and children ≥5 years of age with CD4 counts <100 cells/µL initiating ART in Uganda, Zimbabwe, Malawi, and Kenya. Baseline predictors of mortality through 48 weeks were identified using Cox regression with backwards elimination (exit P > .1).

Results

Among 1711 included participants, 203 (12%) died. Mortality was independently higher with older age; lower CD4 count, albumin, hemoglobin, and grip strength; presence of World Health Organization stage 3/4 weight loss, fever, or vomiting; and problems with mobility or self-care at baseline (all P < .04). Receiving enhanced antimicrobial prophylaxis independently reduced mortality (P = .02). Of five late-presenter phenotypes, Group 1 (n = 355) had highest mortality (25%; median CD4 count, 28 cells/µL), with high symptom burden, weight loss, poor mobility, and low albumin and hemoglobin. Group 2 (n = 394; 11% mortality; 43 cells/µL) also had weight loss, with high white cell, platelet, and neutrophil counts suggesting underlying inflammation/infection. Group 3 (n = 218; 10% mortality) had low CD4 counts (27 cells/µL), but low symptom burden and maintained fat mass. The remaining groups had 4%–6% mortality.

Conclusions

Clinical and laboratory features identified groups with highest mortality following ART initiation. A screening tool could identify patients with low CD4 counts for prioritizing same-day ART initiation, enhanced prophylaxis, and intensive follow-up.

Clinical Trials Registration

ISRCTN43622374.

http://ift.tt/2F9Vahh

High Proportions of Patients With Advanced HIV Are Antiretroviral Therapy Experienced: Hospitalization Outcomes From 2 Sub-Saharan African Sites

Abstract

Background

Human immunodeficiency virus (HIV) remains an important cause of hospitalization and death in low- and middle- income countries. Yet morbidity and in-hospital mortality patterns remain poorly characterized, with prior antiretroviral therapy (ART) exposure and treatment failure status largely unknown.

Methods

We studied HIV-infected inpatients aged ≥13 years from cohorts in Kenya and the Democratic Republic of Congo (DRC), assessing clinical and demographic characteristics and hospitalization outcomes. Kenyan inpatients were prospectively enrolled during hospitalization; identical retrospective data were extracted for Congolese patients meeting the study criteria using routine medical information.

Results

Among 338 HIV-infected patients in Kenya and 411 in DRC, 83.7% (95% confidence interval [CI], 79.4%–87.3%) and 97.3% (95% CI, 95.2%–98.5%), were admitted with advanced disease (defined as CD4 <200 cells/µL or World Health Organization stage 3/4 illness). Among inpatients with advanced HIV, 35.4% and 21.7% were ART-naive at admission. Patients under care had a median time of 44.1 (interquartile range [IQR], 18.4–90.5) months and 55.9 (IQR, 28.1–99.6) months on treatment; 17.2% (95% CI, 13.5%–21.6%) and 29.6% (95% CI, 25.4%–34.3%) died, 25.9% (95% CI, 16.0%–39.0%) and 22.5% (95% CI, 15.8%–31.0%) of these within 48 hours.

Conclusions

Across 2 diverse clinical contexts in sub-Saharan Africa, advanced HIV inpatients were frequently admitted with low CD4 counts, often failing first-line ART. Earlier identification of treatment failure and rapid switching to second-line ART are needed.

http://ift.tt/2H2fBt1

CD4 Cell Count Threshold for Cryptococcal Antigen Screening of HIV-Infected Individuals: A Systematic Review and Meta-analysis

Abstract

Background

Current guidelines recommend screening all people living with human immunodeficiency virus (PLHIV) who have a CD4 count ≤100 cells/µL for cryptococcal antigen (CrAg) to identify those patients who could benefit from preemptive fluconazole treatment prior to the onset of meningitis. We conducted a systematic review to assess the prevalence of CrAg positivity at different CD4 cell counts.

Methods

We searched 4 databases and abstracts from 3 conferences up to 1 September 2017 for studies reporting prevalence of CrAg positivity according to CD4 cell count strata. Prevalence estimates were pooled using random effects models.

Results

Sixty studies met our inclusion criteria. The pooled prevalence of cryptococcal antigenemia was 6.5% (95% confidence interval [CI], 5.7%–7.3%; 54 studies) among patients with CD4 count ≤100 cells/µL and 2.0% (95% CI, 1.2%–2.7%; 21 studies) among patients with CD4 count 101–200 cells/µL. Twenty-one studies provided sufficient information to compare CrAg prevalence per strata; overall, 18.6% (95% CI, 15.4%–22.2%) of the CrAg-positive cases identified at ≤200 cells/µL (n = 11823) were identified among individuals with a CD4 count 101–200 cells/µL. CrAg prevalence was higher among inpatients (9.8% [95% CI, 4.0%–15.5%]) compared with outpatients (6.3% [95% CI, 5.3%–7.4%]).

Conclusions

The findings of this review support current recommendations to screen all PLHIV who have a CD4 count ≤100 cells/µL for CrAg and suggest that screening may be considered at CD4 cell count ≤200 cells/µL.

http://ift.tt/2F82ZUB

Quantitative Proteomics Identify the Possible Tumor Suppressive Role of Protease-Activated Receptor-4 in Esophageal Squamous Cell Carcinoma Cells

Abstract

Exposure to carcinogens of tobacco smoke may result in methylation of protease-activated receptors-4 (PAR4) gene and further induces the loss of PAR4 expression, which is considered to be involved in carcinogenesis of esophageal squamous cell carcinoma (ESCC). Here we employed a TMT-based quantitative proteomic approach to identify PAR4-regulated changes of proteomic profiles in ESCC cells and to identify potentially therapeutic value. A total of 33 proteins were found significantly changed with 15 up-regulated and 18 down-regulated in PAR4-activating peptide (PAR4-AP) treated ESCC cells compared with controls. Bioinformatics analysis showed that key higher expressed proteins included those associated with apoptosis and tumor suppressor (e.g. CASP9), and lower expressed proteins included those associated with anti-apoptosis, autophagy and promoting cell proliferation (e.g. CHMP1B, PURA, PARG and HIST1H2AH). Western blot verified changes in five representative proteins including CASP9, CHMP1B, PURA, PARG and HIST1H2AH. Immunohistochemistry analysis showed that CHMP1B, PURA, PARG and HIST1H2AH expression in ESCC tissues were significantly higher than those in adjacent nontumorous tissues. Our findings will be helpful in further investigations into the functions and molecular mechanisms of PAR4 in ESCC.

http://ift.tt/2FQbnoN

Combined Diagnosis of Systemic Lupus Erythematosus and Tuberculosis in an Irish Adolescent Female

Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown aetiology, which can affect any organ system. Tuberculosis (TB) is a common infection in SLE because of immune dysregulation associated with the latter. We report a case of an adolescent female who presented with a year's history of polyarticular arthralgia and fever. Physical examination revealed a large left effusion that needed drainage. Investigations revealed a combined diagnosis of SLE and TB. Management comprised quadruple anti-TB therapy and SLE treatment. She made a steady recovery and has maintained a stable state from the lupus perspective.

http://ift.tt/2FQNEon

Development and Characterization of an In Vitro Model for Radiation-Induced Fibrosis

Radiation Research, Volume 189, Issue 3, Page 326-336, March 2018.


http://ift.tt/2oCSGO8

Biophysics Model of Heavy-Ion Degradation of Neuron Morphology in Mouse Hippocampal Granular Cell Layer Neurons

Radiation Research, Volume 189, Issue 3, Page 312-325, March 2018.


http://ift.tt/2H0MENN

AZD9291 Increases Sensitivity to Radiation in PC-9-IR Cells by Delaying DNA Damage Repair after Irradiation and Inducing Apoptosis

Radiation Research, Volume 189, Issue 3, Page 283-291, March 2018.


http://ift.tt/2oIs5Pq

Whole-Body Oxygen (16O) Ion-Exposure-Induced Impairments in Social Odor Recognition Memory in Rats are Dose and Time Dependent

Radiation Research, Volume 189, Issue 3, Page 292-299, March 2018.


http://ift.tt/2FdncV7

Role of Infiltrating Monocytes in the Development of Radiation-Induced Pulmonary Fibrosis

Radiation Research, Volume 189, Issue 3, Page 300-311, March 2018.


http://ift.tt/2oEYbMi

Roles of Hydration for Inducing Decomposition of 2-Deoxy-d-ribose by Ionization of Oxygen K-Shell Electrons

Radiation Research, Volume 189, Issue 3, Page 264-272, March 2018.


http://ift.tt/2FeeR3u

Radiation-Induced Long Noncoding RNAs in a Mouse Model after Whole-Body Irradiation

Radiation Research, Volume 189, Issue 3, Page 251-263, March 2018.


http://ift.tt/2oF4Xl4

Impaired Attentional Set-Shifting Performance after Exposure to 5 cGy of 600 MeV/n 28Si Particles

Radiation Research, Volume 189, Issue 3, Page 273-282, March 2018.


http://ift.tt/2FaFiqz

The Sequence Preference of Gamma-Radiation-Induced Damage in End-Labeled DNA after Heat Treatment

Radiation Research, Volume 189, Issue 3, Page 238-250, March 2018.


http://ift.tt/2oFyXgt

Synergy Theory in Radiobiology

Radiation Research, Volume 189, Issue 3, Page 225-237, March 2018.


http://ift.tt/2H1vf7O

Cross Talk between Radiation and Immunotherapy: The Twain Shall Meet

Radiation Research, Volume 189, Issue 3, Page 219-224, March 2018.


http://ift.tt/2oFkIIv

Profiling of Germline Mutations in Major Hotspot Codons of TP53 Using PCR-RFLP

Abstract

Tumor suppressor protein, TP53 also known as the "guardian of the genome" plays a key role in preventing malignant transformation. Almost 50% of human tumors carry mutations in this gene; in the remaining tumors, the TP53 network is functionally inoperative. The majority of TP53 mutations are missense mutations and more than 90% of the missense mutations affect specific codons in the DNA-binding domain, called "hotspot codons." The present study was aimed at analyzing the germline mutation status of four hotspot codons in TP53 namely, codon 175, codon 245, codon 248 (within the DNA binding domain) and codon 72 (outside the DNA binding domain) in cancer cases encountered in a tertiary care hospital in South India by PCR-RFLP. The case-control study included 85–10 subjects respectively. The results of the study indicated that majority of the cancer cases did not harbor germline mutations in the four hot spot codons of TP53. The study further highlights the usefulness of PCR-RFLP as a simple and cost effective tool for checking gene mutations.

http://ift.tt/2HXiTPb

Efficacy and safety of concurrent immunoradiotherapy in patients with metastatic melanoma after progression on nivolumab

Abstract

Background

The objective of this study was to evaluate the efficacy and safety of concurrent immune checkpoint inhibitor therapy and radiotherapy (immunoradiotherapy) in patients with metastatic melanoma after progression on nivolumab.

Patients and methods

A retrospective review was performed on 16 consecutive patients with metastatic melanoma treated with concurrent immunoradiotherapy after progression on nivolumab. Best responses to immunoradiotherapy were assessed either inside or outside of the radiation fields. The target lesions ratio (the sum of the diameters of the target lesions inside the irradiated fields/all target lesions) was also assessed.

Results

Among the patients, seven received ipilimumab and radiotherapy (Ipi-RT), six received nivolumab and radiotherapy (Nivo-RT), and three sequentially received Ipi-RT and Nivo-RT. The overall response rate (all patients regardless of inside or outside radiation fields) was 30%. The response rate inside the radiation fields was 68.8% for all patients combined. The response rates of Ipi-RT and Nivo-RT inside the radiation fields were 37.5 and 100% (P = 0.03), respectively. Grade 3 adverse events were observed in three patients treated with Ipi-RT. The target lesions ratio was a predictive marker of disease control rate among patients treated with Nivo-RT.

Conclusions

This study showed that concurrent immunoradiotherapy is an option for patients with metastatic melanoma after progression on nivolumab.

http://ift.tt/2Fcq0By

Phase I study of chemoradiotherapy using gemcitabine plus nab-paclitaxel for unresectable locally advanced pancreatic cancer

Abstract

Purpose

For unresectable locally advanced (UR-LA) pancreatic cancer, chemoradiotherapy has been recommended by the NCCN guidelines. We designed a chemoradiotherapy protocol using nab-paclitaxel combined with gemcitabine (GnP) for patients with UR-LA pancreatic cancer. The purpose of this phase I study was to determine a recommended dose (RD) for this novel regimen.

Methods

Patients with UR-LA pancreatic cancer were eligible. The frequency of dose-limiting toxicities (DLTs) was evaluated, and the RD was determined. Patients were classified according to the designated dose levels of chemoradiotherapy using the GnP regimen. After additional 6 cycles of the GnP regimen were administered, surgery was considered if the patients had stable disease and tumor marker levels had normalized.

Results

DLT (grade 4 thrombocytopenia) was observed only in 1 of 12 patients, and the RD was set at level 3. Grade 3–4 leukopenia was observed in 9 (75.0%) patients, and neutropenia in 7 (58.3%). The response rate was 41.7%, and the disease control rate was 100%. Conversion surgery was performed in 6 (50%) patients, and curative resection (R0) was performed in all 6 patients (100%). Stratification according to the Evans classification system demonstrated one patient with grade 1b, one with grade 2, two with grade 3, and two with grade 4 disease.

Conclusion

The RD for weekly administration was 800 mg/m² for gemcitabine and 100 mg/m² for nab-paclitaxel with a 50.4 Gy radiation. The GnP regimen at this dosage was promising with 6 of 12 patients proceeding to conversion surgery, and should be evaluated further in a phase II trial.

http://ift.tt/2FPmlL8

Addition of bevacizumab to gemcitabine for platinum-resistant recurrent ovarian cancer: a retrospective analysis

Abstract

Purpose

To compare a cohort of patients with platinum-resistant recurrent ovarian cancer (PROC) treated with bevacizumab and gemcitabine (Bev–Gem) to that of patients treated only with gemcitabine (Gem).

Methods

Between 2011 and 2017, we identified the Bev–Gem and Gem PROC groups. The regimen included 1000 mg/m² of Gem on days 1, 8, and 15, and 15 mg/m² of Bev on day 1, every 4 weeks. Progression-free survival (PFS) and overall survival (OS) were calculated from the date of the administration of Bev–Gem or Gem until disease progression or death.

Results

The Bev–Gem and Gem groups included 18 and 29 patients, respectively. More patients had advanced stage disease in the Bev–Gem group (p = 0.048); no other characteristics differed between the groups. The response rates [ratio of complete remission (CR) to partial remission (PR)] of Bev–Gem and Gem were 38.9 and 3.4%, respectively (p < 0.01). The clinical benefit rates [combined percentages of CR, PR, and stable disease] of the Bev–Gem and Gem groups were 88.9 and 41.4%, respectively (p = 0.04). PFS and OS of the Bev–Gem group were superior (p < 0.01, p = 0.03, respectively). Bev–Gem was the better prognostic factor of both PFS [hazard ratio (HR) 0.17, p < 0.01] and OS (HR 0.31, p = 0.01). The frequency of hematologic and non-hematologic adverse effects was similar in each group.

Conclusion

Bev–Gem regimens improved PFS and OS for PROC. Furthermore, the adverse effects of Bev–Gem were tolerable. Thus, Bev–Gem could be a candidate treatment strategy for PROC.

http://ift.tt/2FcrGez

S-1 (Teysuno) and gemcitabine in Caucasian patients with unresectable pancreatic adenocarcinoma

Abstract

Purpose

Gemcitabine has been standard of care in advanced pancreatic adenocarcinomas (PC) for almost two decades. Randomized, primarily Japanese, studies have shown promising efficacy when combined with S-1 (GemS-1); however, no data are published in Caucasian patients. We report the first study with a combination of GemS-1 in an unselected cohort of Caucasian PC patients.

Methods

In this observational cohort study, we analyzed efficacy and toxicity prospectively.

Results

From July 2012 to July 2014, 64 patients received at least one cycle of GemS-1. 16 patients started therapy with gemcitabine and capecitabine (GemCap) but switched to GemS-1 after median 3 cycles of GemCap due to toxicity (hand-foot syndrome). 48 patients received GemS-1 as initial therapy. For the complete cohort, median age was 68 years (range 44–80); 22 patients (34%) had locally advanced PC; 42 patients (66%) had metastatic disease. Five patients had received prior adjuvant therapy with gemcitabine and 9 pts had received prior first-line therapy. The most common adverse event was fatigue (86%), however, only grade 3 in 3%. Five patients (8%) developed febrile neutropenia. Median PFS was 8.1 (95% CI 6.9–9.0) months and median OS was 11.7 (95% CI 10.7–13.1) months in the whole GemS-1 population. In the 48 patients starting with GemS-1, median PFS was 7.7 (95% CI 6.7–8.9) months and median OS was 11.5 (95% CI 9.7–12.3) months.

Conclusions

The combination of gemcitabine and S-1 is safe and associated with promising efficacy in a Caucasian population; however, this needs to be confirmed in prospective clinical trials.

http://ift.tt/2FPmgXQ

Phase 1 summary of plasma concentration–QTc analysis for idasanutlin, an MDM2 antagonist, in patients with advanced solid tumors and AML

Abstract

Purpose

Idasanutlin, a selective small-molecule MDM2 antagonist in phase 3 testing for refractory/relapsed AML, is a non-genotoxic oral p53 activator. The aim of this analysis is to examine the potential of idasanutlin to prolong the corrected QT (QTc) interval by evaluating the relationship between plasma idasanutlin concentration and QTc interval.

Method

Intensive plasma concentration QTc interval data were collected at the same timepoints, from three idasanutlin (RO5503781) phase 1 studies in patients with solid tumors and AML. QTc data in absolute values and changes from baseline (Δ) were analyzed for a potential association with plasma idasanutlin concentrations with a linear mixed effect model. Categorical analysis was also performed.

Results

A total of 282 patients were exposed to idasanutlin and had at least one observation of QTc and idasanutlin plasma concentration. There was no apparent increase of QTcF or ΔQTcF in a wide idasanutlin plasma concentration range, even at concentrations exceeding the exposure matching the dose adopted in the ongoing phase 3 study (300-mg BID). Categorical analysis did not detect a potential signal of QT prolongation.

Conclusion

The concentration–QTc analysis indicates that idasanutlin does not prolong the QT interval within the targeted concentration range currently in consideration for clinical development.

http://ift.tt/2F9Z6KQ

Role of TPMT and ITPA variants in mercaptopurine disposition

Abstract

Purpose

To explore the levels of thioguanine incorporated into DNA (DNA-TG), and erythrocyte levels of 6-thioguanine nucleotides (Ery-TGN) and methylated metabolites (Ery-MeMP) during 6-mercaptopurine (6MP)/Methotrexate (MTX) therapy of childhood acute lymphoblastic leukemia (ALL) and the relation to inosine triphosphatase (ITPA) and thiopurine methyltransferase (TPMT) gene variants.

Methods

Blood samples were drawn during 6MP/MTX maintenance therapy from 132 children treated for ALL at Rigshospitalet, Copenhagen. The samples were analysed for thiopurine metabolites and compared to TPMT (rs1800460 and rs1142345) and ITPA (rs1127354) genotypes.

Results

Median DNA-TG (mDNA-TG) levels were higher in TPMT and ITPA low-activity patients as compared to wildtype patients (TPMT^LA 549 vs. 364 fmol/µg DNA, p = 0.007, ITPA^LA 465 vs. 387 fmol/µg DNA, p = 0.04). mDNA-TG levels were positively correlated to median Ery-TGN (mEry-TGN)(r_s = 0.37, p = 0.001), but plateaued at higher mEry-TGN levels. DNA-TG indices (mDNA-TG/mEry-TGN) were 42% higher in TPMT^WT patients as compared to TPMT^LA patients but no difference in DNA-TG indices was observed between ITPA^WT and ITPA^LA patients (median 1.7 vs. 1.6 fmol/µg DNA/ nmol/mmol Hb, p = 0.81). DNA-TG indices increased with median Ery-MeMP (mEry-MeMP) levels (r_s = 0.25, p = 0.001).

Conclusions

TPMT and ITPA genotypes significantly influence the metabolism of 6MP. DNA-TG may prove to be a more relevant pharmacokinetic parameter for monitoring 6MP treatment intensity than cytosolic metabolites. Prospective trials are needed to evaluate the usefulness of DNA-TGN for individual dose adjustments in childhood ALL maintenance therapy.

http://ift.tt/2FQUMRM

Long-term results of S-1 plus cisplatin with concurrent thoracic radiotherapy for locally advanced non-small-cell lung cancer

Abstract

Purpose

The purpose of this phase I/II study was to evaluate the feasibility and efficacy of S-1 plus cisplatin at the recommended schedule with concurrent thoracic radiotherapy for locally advanced non-small cell lung cancer (LA-NSCLC).

Methods

Eligible patients with LA-NSCLC were treated with cisplatin intravenously at a dose of 60 mg/m² on day 8 plus oral S-1 at a dosage of 40 mg/m² twice per day for two different treatment schedules for up to 4 cycles. Patients also concurrently received 60 Gy of thoracic radiation in 30 fractions. The primary endpoint of the phase II study was the proportion of patients who survived for more than 2 years.

Results

Between August 2005 and October 2010, a total of 45 patients were enrolled in this phase I/II study; their long-term survival was then followed for a median period of 5.8 years. Nineteen of the 39 patients in the phase II study survived for more than 2 years and met the primary endpoint of the study. The median overall survival period was 24.9 months [95% confidence interval (CI) 17.4–74.5 months], and the 2- and 5-year overall survival rates were 51.0 and 43.0%, respectively. The response rate was 85%, and the median progression-free survival period was 13.8 months (95% CI 9.5–27.1 months). Hematological toxicity was mild. Grade 3 febrile neutropenia and pneumonitis was observed in 5 and 5%, respectively.

Conclusion

Our study indicated that S-1 plus cisplatin with concurrent thoracic radiotherapy yielded encouraging survival outcomes and an acceptable safety profile for LA-NSCLC.

http://ift.tt/2CWlWnj

A phase I dose escalation trial of nab-paclitaxel and fixed dose radiation in patients with unresectable or borderline resectable pancreatic cancer

Abstract

Purpose

Patients with locally advanced pancreatic cancer typically have poor outcomes, with a median survival of approximately 16 months. Novel methods to improve outcomes are needed. Nab-paclitaxel (Abraxane) has shown efficacy in pancreatic cancer and is FDA-approved for metastatic disease in combination with gemcitabine. Nab-paclitaxel is also a promising radiosensitizer based on laboratory studies, but it has never been clinically tested with definitive radiotherapy for locally advanced pancreatic carcinoma.

Methods

We performed a phase 1 study using a 3 + 3 dose escalation strategy to determine the safety and tolerability of dose-escalated nab-paclitaxel with fractionated radiotherapy for patients with unresectable or borderline resectable pancreatic cancer. Following induction chemotherapy with two cycles of nab-paclitaxel and gemcitabine, patients were treated with weekly nab-paclitaxel and daily radiotherapy to a dose of 52.5 Gy in 25 fractions. Final dose-limiting toxicity (DLT) determination was performed at day 65 after the start of radiotherapy.

Results

Nine patients received nab-paclitaxel at a dose level of either 100 mg/m² (n = 3) or 125 mg/m² (n = 6). There were no observed grade 3 gastrointestinal toxicities. One DLT (grade 3 neuropathy) was observed in a patient who received 125 mg/m² of nab-paclitaxel. Other grade 3 toxicities included fatigue (11%), anemia (11%) and neutropenia (11%). No grade 4 toxicities were observed. Following chemoradiotherapy, four patients (borderline resectable, n = 2 and unresectable, n = 2) underwent surgical resection, all with negative margins and with significant treatment effect with limited tumor viability.

Conclusions

The combination of fractionated radiation and weekly full dose nab-paclitaxel was safe and well-tolerated.

http://ift.tt/2FPDqor

Total Plasma Exchange in Hypertriglyceridemia-Induced Pancreatitis: Case Report and Literature Review

Objective. To emphasize the role of apheresis in management of pancreatitis. Methods. The clinical course of a patient admitted for hypertriglyceridemia-induced pancreatitis (HTGP) complicated by multiorgan dysfunction is described, who demonstrated dramatic improvement in his clinical status after total plasma exchange (TPE). In addition, the current guidelines for TPE and the alternative treatment options for HTGP are also presented. Results. A patient presenting with pancreatitis associated with severe systemic inflammatory response was admitted to our hospital with an initial triglyceride level of 1181 mg/dL. Given the patient's worsening clinical condition, he was started on TPE with a rapid fall in his serum TG levels, in turn leading to early clinical recovery. Conclusion. Though various therapeutic options for the treatment of HTGP are described in literature, there are no set guidelines available to tackle this difficult clinical situation. TPE, albeit not very well known in this context, is one of the many therapies available. Though it leads to a rapid, precipitous fall in the TG levels and early symptom resolution, the data about the long-term morbidity as well as the effectiveness of this therapy is still lacking.

http://ift.tt/2teSlFT

Infective Endocarditis in a Young Adult due to Lactococcus lactis: A Case Report and Review of the Literature

Infective endocarditis (IE) is a condition mainly associated with valvular disease or prosthetic valve and intravenous drug use as a risk factor. Here, we describe a rare case of a previously healthy patient with endocarditis due to Lactococcus lactis associated with cattle contact, where antibiotic treatment resulted in full recovery.

http://ift.tt/2FhIiVx

A Seizure and Hemiplegia following Contrast Exposure: Understanding Contrast-Induced Encephalopathy

Contrast-induced encephalopathy is a rare, reversible phenomenon known to occur after intravenous or intra-arterial contrast exposure. This report describes a case involving a 73-year-old female admitted for an elective thoracic aortic aneurysm repair. During the procedure, a large volume of nonionic iodinated contrast was necessary for arteriography. Postoperatively, the patient developed seizure activity followed by left-sided hemiplegia. Computed tomography (CT) of the brain without contrast and magnetic resonance imaging (MRI) were negative for acute stroke but did show residual contrast surrounding the brain. Antiepileptic medications were administered with resolution of the seizure activity. The patient was treated with supportive management and improved to baseline over the next seven days. This case demonstrates a rare, nonionic iodinated contrast-induced encephalopathy with seizure activity and transient hemiplegia. The unique imaging findings differentiate it from other neurologic conditions.

http://ift.tt/2taIXTI

Development of Irritable Bowel Syndrome Features Over a 5-year Period

There are few data from longitudinal studies of the gastrointestinal and psychologic features of irritable bowel syndrome (IBS). We studied within-person correlations among features of IBS, along with progression of gastrointestinal (GI) symptoms and quality of life, and factors associated with changes over time.

http://ift.tt/2I0QNm9

Virtual Histology in Everyday Gastrointestinal Endoscopy

Advances in imaging technologies have demonstrated promise in the early detection of dysplasia and cancer. They have also provided the ability to assess submucosal and vascular structures, helping differentiate neoplastic from non-neoplastic tissue. The aim of this concise case-based review is to discuss how optical imaging can impact patient management decisions during endoscopy, using real- life scenarios.

http://ift.tt/2oN7wAB

Factor Analysis Defines Distinct Upper and Lower Gastrointestinal Symptom Groups Compatible With Rome IV Criteria in a Population-based Study

The Rome IV criteria define functional gastrointestinal (GI) disorders by specific combinations of symptoms. It is possible to empirically evaluate these symptom combinations by factor analysis (a statistical procedure that groups variables that correlate). However, this analysis has not been performed for the Rome IV criteria, and factor analyses based on the previous versions of the Rome criteria did not use population-based data. We therefore investigated symptom grouping by the Rome IV questionnaire using factor analysis of a population-based sample.

http://ift.tt/2I0QI1P

The naked fat sign: a signature finding in colonic lipoma

http://ift.tt/2oN7ysd

Efficacy of Stereotactic Body Radiotherapy for Recurrent or Residual Hepatocellular Carcinoma after Transcatheter Arterial Chemoembolization

Aim. To evaluate the efficacy and toxicity of hypofractionated stereotactic body radiotherapy (SBRT) for patients with recurrent or residual hepatocellular carcinoma (HCC) after transcatheter arterial chemoembolization (TACE). Methods. Between June 2008 and July 2015, thirty-three patients with HCC were treated by SBRT. There were 63 lesions in 33 patients. A total dose of 39–45 Gy/3–5 fractions was delivered to the 70–80% isodose line. Results. Objective response rate (CR + PR) was 84.8% at 6 months. The overall survival rate was 87.9%, 75.8%, 57.6%, and 45.5% at 6, 12, 18, and 24 months, respectively. Median overall survival was 19 months. At 3 months, AFP decreased by more than 75% in 51.5% of patients (17/33). Overall survival was significantly different () between the group of patients for whom AFP decreased more than 75% and the group for whom AFP decreased by less than 75%. The AFP-negative rate was 48.5% (16/33) after 6 months. Eight patients (24.2%) had grade 1-2 transient fatigue, and 11 patients (33.3%) had grade 1-2 gastrointestinal reactions within 1 month. Conclusion. SBRT is a promising noninvasive and palliative treatment with acceptable toxicity for recurrent or residual HCC after TACE.

http://ift.tt/2I0QAiR

Quintupling Inhaled Glucocorticoids to Prevent Childhood Asthma Exacerbations

New England Journal of Medicine, Ahead of Print.


http://ift.tt/2FQv9jV

Individualized colorectal cancer screening based on the clinical risk factors: beyond family history of colorectal cancer

Individuals without a family history of colorectal cancer (CRC) are screened uniformly despite interpersonal risk. To assess individual risk, we examined the age-specific prevalence of advanced colorectal neoplasia (ACRN) according to clinical risk factors and fecal immunochemical test (FIT) results.

http://ift.tt/2tcz1sV

Visceral obesity as a risk factor for colorectal adenoma occurrence in surveillance colonoscopy

The aim of this study was to examine the prospective association between visceral obesity and the incidence and recurrence of colorectal adenoma.

http://ift.tt/2FhAcw7

Feasibility and safety of micro-forceps biopsy in the diagnosis of pancreatic cysts

The tissue acquisition and diagnostic yield of cyst fluid cytology is low-to-moderate and rarely provides a specific diagnosis. The aim of this study was to compare the tissue acquisition and diagnostic tissue yield of micro-forceps biopsy (MFB) with cyst fluid cytology.

http://ift.tt/2tfrPvZ

Palliative Care Disincentives in CKD: Changing Policy to Improve CKD Care

The dominant health delivery model for advanced chronic kidney disease (CKD) and end-stage renal disease (ESRD) in the United States, which focuses on provision of dialysis, is ill-equipped to address many of the needs of seriously ill patients. Although palliative care may address some of these gaps in care, its integration into advanced CKD care has been suboptimal due to several health system barriers. These barriers include uneven access to specialty palliative care services, underdeveloped models of care for seriously ill patients with advanced CKD, and misaligned policy incentives.

http://ift.tt/2Fb76zd

Changes in Blood Pressure During Young Adulthood and Subsequent Kidney Function Decline: Findings From the Coronary Artery Risk Development in Young Adulthood (CARDIA) Study

Many studies have focused on the association between a single blood pressure (BP) measurement and risk for adverse outcomes. However, the association of BP trajectories during young adulthood with subsequent decline in kidney function has not been well defined.

http://ift.tt/2H0dUMp

Improving Incident ESRD Care Via a Transitional Care Unit

Dialysis care in the United States continues to move toward an emphasis on continuous quality improvement and performance benchmarking. Government- and industry-sponsored programs have evolved to assess and incentivize outcomes for many components of end-stage renal disease care. One aspect that remains largely unaddressed at a systemic level is the high-risk transition period from chronic kidney disease and acute kidney injury to permanent dialysis dependence. Incident dialysis patients experience disproportionately high mortality and hospitalization rates coupled with high costs.

http://ift.tt/2FdzhNK

Low Heteroplasmy Rates of the m.8993T>G Variant May Not Be Pathogenic

We read with interest the article by Lemoine et al1 about an 11-year-old boy with neuropathy, ataxia, and retinitis pigmentosa (NARP) syndrome due to the m.8993T>G variant in the MT-ATP6 gene who developed progressive renal involvement after age 12 years. We have a number of comments and concerns.

http://ift.tt/2H0wtjx

The Clinical and Immunologic Features of Patients With Combined Anti-GBM Disease and Castleman Disease

Patients with both anti–glomerular basement membrane (anti-GBM) disease and Castleman disease have been rarely reported. In this study, we report 3 patients with this combination. They had immunologic features similar to patients with classic anti-GBM disease. Sera from the 3 patients recognized the noncollagenous (NC) domain of the α3 chain of type IV collagen (α3(IV)NC1) and its 2 major epitopes, EA and EB. All 4 immunogloblin G (IgG) subclasses against α3(IV)NC1 were detectable, with predominance of IgG1.

http://ift.tt/2H1uNGK

Quintupling Inhaled Glucocorticoids to Prevent Childhood Asthma Exacerbations

New England Journal of Medicine, Ahead of Print.


http://ift.tt/2FQv9jV

Escalating Inhaled Glucocorticoids to Prevent Asthma Exacerbations

Inhaled glucocorticoids are pivotal to achieve asthma control and disease stability in both children and adults; despite their use, with or without other treatments, many patients with asthma have ongoing episodic disease exacerbations. Often, these are linked to provocative factors such as viral…

http://ift.tt/2CWRwBc

Quadrupling Inhaled Glucocorticoid Dose to Abort Asthma Exacerbations

Asthma is one of the most common chronic diseases, with an estimated 300 million people affected worldwide. Acute exacerbations of asthma are frightening for patients, cause considerable illness and death, and account for a large proportion of the overall costs related to asthma. Although plans for…

http://ift.tt/2FQ9FDX

A Simple Non-invasive Method for Temporary Knockdown of Upper Limb Proprioception

The goal of this protocol is to demonstrate a practical method to temporarily interfere with proprioception in the upper limb of healthy humans.

http://ift.tt/2I2zvVI

A Neural Network-Based Identification of Developmentally Competent or Incompetent Mouse Fully-Grown Oocytes

Here, we present a protocol for non-invasive assessment of oocyte developmental competence performed during their in vitro maturation from the germinal vesicle to the metaphase II stage. This method combines time-lapse imaging with particle image velocimetry (PIV) and neural network analyses.

http://ift.tt/2FP8F2R

iSepsis- SEP-1: Conspiracy Theories and Fake News!

The systematic review by Pepper et al demonstrates that SEP-1 may be harmful to patients.

EMCrit Project by Paul Marik.

http://ift.tt/2oNzxIk

Is sorafenib an optimal treatment for hepatocellular carcinoma with macrovascular invasion or metastatic disease?

http://ift.tt/2FkmEA0

Letter to the editor: Growth factor therapy for decompensated cirrhosis – Much ado about nothing?

http://ift.tt/2tduarw

New biomarkers for drug-induced liver injury

http://ift.tt/2FkmCrS

Macrophages come on Tap for Liver Fibrosis Therapy

http://ift.tt/2ti74A4

Reply to Philips et al.

http://ift.tt/2FfCcoH

Flicker electroretinograms of eyes with cataract recorded with RETeval system before and after mydriasis

http://ift.tt/2CW9XpF

Correlation between glycemic control and peripapillary retinal nerve fiber layer thickness in Saudi type II diabetics

http://ift.tt/2FdktxO

Integrated neurodegenerative disease autopsy diagnosis

http://ift.tt/2FPkl5Q

Novel t(1;2)(p36.1;q23) and t(7;19)(q32;q13.3) chromosomal translocations in ischemic fasciitis: expanding the spectrum of pseudosarcomatous lesions with clonal pathogenetic link

Ischemic fasciitis is a distinctive pseudosarcomatous entity with a marked predilection for elderly and physically debilitated or immobilized patients. The etiology of these lesions is unknown but felt to be r...

http://ift.tt/2CXjOeJ

Prediabetes in pregnancy, can early intervention improve outcomes? A feasibility study for a parallel randomised clinical trial

Objective

Measurement of glycated haemoglobin (HbA1c) in early pregnancy is routine in New Zealand to identify women with diabetes and prediabetes. However, the benefit of early intervention in women with prediabetes is inconclusive. Our aim was to test the feasibility of a two-arm parallel randomised controlled trial of standard care versus early intervention in pregnancies complicated by prediabetes.

Setting

Two tertiary referral centres in New Zealand.

Participants

Women <14 weeks' gestation and HbA1c ≥5.9%–6.4% (41–46 mmol/mol) measured at booking, without pre-existing diabetes.

Interventions

Randomisation was done by remote web-based allocation into one of two groups. Women in the early intervention group attended an antenatal diabetes clinic, commenced daily home blood glucose monitoring, and medication was prescribed if lifestyle measures failed to maintain target blood glucose levels. Controls received lifestyle education, continued standard care with their midwife and/or obstetrician, and were asked to perform a 75 g oral glucose tolerance test at 24 weeks' gestation with a referral to clinic if this test was positive. Both groups received lifestyle questionnaires at recruitment and in late pregnancy.

Outcome measures

Recruitment rate, adherence to protocol and validation of potential primary outcomes.

Results

Recruitment rates were lower than expected, especially in Māori and Pacific women. Non-adherence to allocated treatment protocol was significant, 42% (95% CI 24% to 61%) in the early intervention group and 30% (95% CI 16% to 51%) in controls. Caesarean section and pre-eclampsia were signalled as potential primary outcomes, due to both the high observed incidence in the control group and ease of measurement.

Conclusions

For a future definitive trial, extending the gestation of eligibility and stepped-wedge cluster randomisation may overcome the identified feasibility issues. Consistent with published observational data, pre-eclampsia and emergency caesarean section could be included as primary outcome measures, both of which have a significant impact on maternal and neonatal morbidity and healthcare costs.

Trial registration number

ACTRN12615000904572; Pre-results.

http://ift.tt/2FaZSXZ

Diagnostic study on an immunochromatographic rapid test for schistosomiasis: comparison between use on serum and on blood spot from fingerprick

Background

An immunochromatographic rapid test (ICT; Schistosoma ICT IgG-IgM, LDBIO Diagnostics) demonstrated high sensitivity (96%) in the diagnosis of Schistosoma mansoni and S. haematobium. To date, the test has been validated for use on serum only, but in the absence of lab equipment, blood drop from fingerprick could be a useful option. This method is acquiring more interest because of the high flow of migrants rapidly moving across Italy and other European countries.

Objective

The aim of this prospective study was to evaluate the use of ICT on whole blood obtained from fingerprick.

Setting

Centre for Tropical Diseases (CTD), Sacro Cuore Don Calabria Hospital, Negrar, Verona, Italy.

Participants

The inclusion criteria were African migrants aged ≥18 years with epidemiological risk of infection. The exclusion criteria were refusal to participate in the study and impossibility of execution of one of the two study methods, for any reason. Seventy of the 72 eligible patients completed the study, 79% of whom were male.

Interventions

The ICT was performed twice for each included patient: one on blood drop (by the research nurses, in the ward) and one on serum (by staff of CTD lab). The primary outcome was the concordance between the two methods, assessed by Cohen's kappa.

Results

Cohen's kappa was 0.45 (95% CI 27.0 to 63.6), indicating moderate agreement between the ICT on serum and the ICT on blood drop. Assuming the results on serum as reference standard for diagnosis, the sensitivity and specificity of ICT on blood drop were 55% (95% CI 40 to 69) and 93% (95% CI 79 to 98), respectively.

Conclusions

The agreement between the two diagnostic methods is too low to support the alternative one. Implementation of the kit for using blood drop instead of the serum and/or further studies aimed to identify easy-to-use tests for schistosomiasis feasible outside referral centres for tropical diseases are needed.

http://ift.tt/2oBJVDV

Economic burden of cirrhosis in Catalonia: a population-based analysis

Background

Cirrhosis is a chronic disease with high morbidity and mortality. Few studies have evaluated healthcare resource use in patients with cirrhosis.

Objective

We aimed to describe the point prevalence of cirrhosis on 31 December 2012 and the population-level distribution of healthcare resource use and expenditures in a non-selected population of patients with cirrhosis, stratified by whether their disease was compensated or decompensated, and by comorbidity burden.

Methods

This population study included all known patients aged >18 years with cirrhosis (according to International Classification of Diseases, ninth revision) in Catalonia, Spain, on 31 December 2012. We evaluated healthcare resource use and expenditure during 2013, taking into account the presence of decompensation before or during 2012.

Results

We documented 34 740 patients diagnosed with cirrhosis (58.7% men; mean age 61.8±14 years), yielding a point prevalence of 460 per 100 000 inhabitants on 31 December 2012. Annual mortality was 9.1%. During 2013, healthcare expenditures on patients with cirrhosis totalled 142.1 million (4234 per patient), representing 1.8% of the total 2013 healthcare budget of Catalonia. Hospitalisation costs accounted for 35.1% of the total expenditure and outpatient care accounted for 22.4%. MultivariateMultivariate logistic regression identified morbidity burden, HIV infection, hospitalisation and emergency room visits during 2012 as independent predictors of expenditure above the 85th centile (area under the receiver operating curve, 0.88 (95% CI 0.883 to 0.893, P<0.001)).

Conclusions

Cirrhosis accounts for a high proportion of healthcare resource usage and expenditures; hospitalisation accounted for the highest expenditures.

http://ift.tt/2FaZRTV

Factors affecting decisions to extend access to primary care: results of a qualitative evaluation of general practitioners views

Objectives

To report general practitioners' (GPs') views and experiences of an Enhanced Primary Care programme (EPCP) funded as part of the Prime Minister's Challenge Fund (second wave) for England which aimed to extend patient access to primary care.

Setting

Primary care in Sheffield, England.

Participants

Semi-structured interviews with a purposive sample of GPs working in 24 practices across the city.

Results

Four core themes were derived: GPs' receptivity to the aims of the EPCP, their capacity to support integrated care teams, their capacity to manage urgent care and the value of some new community-based schemes to enhance locality-based primary care. GPs were aware of the policy initiatives associated with out-of-hours access that aimed to reduce emergency department and hospital admissions. Due to limited capacity to respond to the programme, they selected elements that directly related to local patient demand and did not increase their own workload.

Conclusions

The variation in practice engagement and capacity to manage changes in primary care services warrants a subtle and specialist approach to programme planning. The study makes the case for enhanced planning and organisational development with GPs as stakeholders within individual practices and groups. This would ensure that policy implementation is effective and sustained at local level. A failure to localise implementation may be associated with increased workloading in primary care without the sustained benefits to patients and the public. To enable GPs to become involved in systems transformation, further research is needed to identify the best methods to engage GPs in programme planning and evaluation.

http://ift.tt/2oDRJoG

An electronic health records cohort study on heart failure following myocardial infarction in England: incidence and predictors

Objectives

To investigate the incidence and determinants of heart failure (HF) following a myocardial infarction (MI) in a contemporary cohort of patients with MI using routinely collected primary and hospital care electronic health records (EHRs).

Methods

Data were used from the CALIBER programme, linking EHRs in England from primary care, hospital admissions, an MI registry and mortality data. Subjects were eligible if they were 18 years or older, did not have a history of HF and survived a first MI. Factors associated with time to HF were examined using Cox proportional hazard models.

Results

Of the 24 479 patients with MI, 5775 (23.6%) developed HF during a median follow-up of 3.7 years (incidence rate per 1000 person-years: 63.8, 95% CI 62.2 to 65.5). Baseline characteristics significantly associated with developing HF were: atrial fibrillation (HR 1.62, 95% CI 1.51 to 1.75), age (per 10 years increase: 1.45, 1.41 to 1.49), diabetes (1.45, 1.35 to 1.56), peripheral arterial disease (1.38, 1.26 to 1.51), chronic obstructive pulmonary disease (1.28, 1.17 to 1.40), greater socioeconomic deprivation (5th vs 1st quintile: 1.27, 1.13 to 1.41), ST-segment elevation MI at presentation (1.19, 1.11 to 1.27) and hypertension (1.16, 1.09 to 1.23). Results were robust to various sensitivity analyses such as competing risk analysis and multiple imputation.

Conclusion

In England, one in four survivors of a first MI develop HF within 4 years. This contemporary study demonstrates that patients with MI are at considerable risk of HF. Baseline patient characteristics associated with time until HF were identified, which may be used to target preventive strategies.

http://ift.tt/2FbPK1f

Factors influencing career progress for early stage clinician-scientists in emerging Asian academic medical centres: a qualitative study in Singapore

Objectives

To explore the factors that influence career progress for early stage clinician-scientists and to identify ways to mitigate these factors in the context of emerging Asian academic medical centres (AMCs).

Design

Qualitative interviews and thematic data analysis based on grounded theory.

Setting and participants

Five focus group interviews comprising 29 early career clinician-scientists who have received their first national-level career development award in Singapore.

Results

Clinical priorities represented an overarching concern with many reporting the difficulty in delineating responsibilities between clinical care and research. Additionally, there was a prevailing perception of the lack of support for research at the institutional level. Participants tended to identify mentors through their own efforts in a relatively haphazard manner, often owing to the dearth of role models and perceived inadequacy of reward systems for mentoring. Support from mentors was thought to be limited in terms of targeted scientific guidance and long-term commitments to the relationship. Most of the participants expressed concerns about how they could secure the next level of funding with diminishing confidence. Notably, the work-life balance was neither conceptualised as a 'barrier' to successful pursuit of research career nor was it translated into the reason for leaving the dual clinical-research career pathway.

Conclusions

Results revealed specific limitations presented by the research environment in newly emerging Asian AMCs. To retain a vibrant clinician-scientist workforce, additional measures are needed, aiming to improve institutional culture of research, build mentoring networks, adopt effective tools for tracking career progress and provide a clear and viable career progression path for clinician-scientist. Further research might explore the cross-cultural differences in managing work-life balance in academic medicine.

http://ift.tt/2oDRvOm

Prevalence of xenobiotic substances in first-trimester blood samples from Danish pregnant women: a cross-sectional study

Objective

The aim of this study was to investigate the prevalence of xenobiotic substances, such as caffeine, nicotine and illicit drugs (eg, cannabis and cocaine), in blood samples from first-trimester Danish pregnant women unaware of the screening.

Design

A cross-sectional study examined 436 anonymised residual blood samples obtained during 2014 as part of the nationwide prenatal first-trimester screening programme. The samples were analysed by ultra performance liquid chromatography with high-resolution time-of-flight mass spectrometry.

Setting

An antenatal clinic in a Danish city with 62 000 inhabitants, where >95% of pregnant women joined the screening programme.

Primary and secondary outcome measures

The prevalence and patterns of caffeine, nicotine, medication and illicit drug intake during the first trimester of pregnancy.

Results

The prevalence of prescription and over-the-counter drug detection was 17.9%, including acetaminophen (8.9%) and antidepressants (3.0%), of which citalopram (0.9%) was the most frequent. The prevalence of illegal drugs, indicators of smoking (nicotine/cotinine) and caffeine was 0.9%, 9.9%, and 76.4%, respectively. Only 17.4% of women had no substance identified in their sample.

Conclusions

This study emphasises the need for further translational studies investigating lifestyle habits during pregnancy, as well as the underlying molecular mechanisms through which xenobiotic substances may affect placental function and fetal development.

http://ift.tt/2FbdylD

Risk of pyogenic liver abscess and endoscopic sphincterotomy: a population-based cohort study

Objectives

To evaluate the risk of pyogenic liver abscess (PLA) in patients receiving endoscopic sphincterotomy (ES).

Setting

A population-based cohort study using data from Taiwans' National Health Insurance Research Database was conducted. Patients aged 20 or older who had undergone an ES were considered as the ES cohort. The dates for the first hospitalisation of the patients receiving ES were defined as the index dates.

Participants

Patients in the ES and non-ES cohorts were selected by 1:1 matching ratio based on a propensity score. A total of 8174 sex-matched, age-matched and index year-matched (1:1) pairs of patients receiving ES and 8174 patients without ES served as controls. Cox proportional hazards regression was employed to calculate the HRs and 95% CIs for the association between PLA and ES.

Results

The overall incidence of PLA was significantly higher in the ES cohort than in the non-ES cohort (4.20 vs 0.94, respectively, per 1000 person-year) with the adjusted HR (aHR) 4.50 (95% CI 3.38 to 6.58) A stratified analysis during the follow-up years revealed that when the ES cohort was compared with the non-ES cohort, they displayed a higher risk of PLA during the first follow-up year (aHR 4.35, 95% CI 2.26 to 8.39) which continued significantly over the next 4–5 years of follow-up.

Conclusions

Patients receiving ES are associated with having a higher risk of PLA.

http://ift.tt/2oBJnxR

Prevalence of coronary artery calcification in a non-specific chest pain population in emergency and cardiology departments compared with the background population: a prospective cohort study in Southern Denmark with 12-month follow-up of cardiac endpoints

Objectives

To examine and compare the prevalence of coronary artery calcification (CAC) and the frequency of cardiac events in a background population and a cohort of patients with non-specific chest pain (NSCP) who present to an emergency or cardiology department and are discharged without an obvious reason for their symptom.

Design

A double-blinded, prospective, observational cohort study that measures both CT-determined CAC scores and cardiac events after 1 year of follow-up.

Setting

Emergency and cardiology departments in the Region of Southern Denmark.

Subjects

In total, 229 patients with NSCP were compared with 722 patients from a background comparator population.

Main outcomes measures

Prevalence of CAC and incidence of unstable angina (UAP), acute myocardial infarction (MI), ventricular tachycardia (VT), coronary revascularisation and cardiac-related mortality 1 year after index contact.

Results

There was no significant difference in the prevalence of CAC (OR 0.9 (95% CI 0.6 to 1.3), P=0.546) or the frequency of cardiac endpoints (P=0.64) between the studied groups. When compared with the background population, the OR for patients with NSCP for a CAC >100 Agatston units (AU) was 1.0 (95% CI 0.6 to 1.5), P=0.826. During 1 year of follow-up, two (0.9%) patients with NSCP underwent cardiac revascularisation, while none experienced UAP, MI, VT or death. In the background population, four (0.6%) participants experienced a clinical cardiac endpoint; two had an MI, one had VT and one had a cardiac-related death.

Conclusion

The prevalence of CAC (CAC >0 AU) among patients with NSCP is comparable to a background population and there is a low risk of a cardiac event in the first year after discharge. A CAC study does not provide notable clinical utility for risk-stratifying patients with NSCP.

Trial registration number

NCT02422316; Pre-results.

http://ift.tt/2GZ8bX9

Cost-effectiveness of a complex workplace dietary intervention: an economic evaluation of the Food Choice at Work study

Objective

To evaluate the costs, benefits and cost-effectiveness of complex workplace dietary interventions, involving nutrition education and system-level dietary modification, from the perspective of healthcare providers and employers.

Design

Single-study economic evaluation of a cluster-controlled trial (Food Choice at Work (FCW) study) with 1-year follow-up.

Setting

Four multinational manufacturing workplaces in Cork, Ireland.

Participants

517 randomly selected employees (18–65 years) from four workplaces.

Interventions

Cost data were obtained from the FCW study. Nutrition education included individual nutrition consultations, nutrition information (traffic light menu labelling, posters, leaflets and emails) and presentations. System-level dietary modification included menu modification (restriction of fat, sugar and salt), increase in fibre, fruit discounts, strategic positioning of healthier alternatives and portion size control. The combined intervention included nutrition education and system-level dietary modification. No intervention was implemented in the control.

Outcomes

The primary outcome was an improvement in health-related quality of life, measured using the EuroQoL 5 Dimensions 5 Levels questionnaire. The secondary outcome measure was reduction in absenteeism, which is measured in monetary amounts. Probabilistic sensitivity analysis (Monte Carlo simulation) assessed parameter uncertainty.

Results

The system-level intervention dominated the education and combined interventions. When compared with the control, the incremental cost-effectiveness ratio (101.37/quality-adjusted life-year) is less than the nationally accepted ceiling ratio, so the system-level intervention can be considered cost-effective. The cost-effectiveness acceptability curve indicates there is some decision uncertainty surrounding this, arising from uncertainty surrounding the differences in effectiveness. These results are reiterated when the secondary outcome measure is considered in a cost–benefit analysis, whereby the system-level intervention yields the highest net benefit (56.56 per employee).

Conclusions

System-level dietary modification alone offers the most value per improving employee health-related quality of life and generating net benefit for employers by reducing absenteeism. While system-level dietary modification strategies are potentially sustainable obesity prevention interventions, future research should include long-term outcomes to determine if improvements in outcomes persist.

Trial registration number

ISRCTN35108237; Post-results.

http://ift.tt/2oBJhpZ

Intertester reliability of clinical shoulder instability and laxity tests in subjects with and without self-reported shoulder problems

Objective

First, to investigate the intertester reliability of clinical shoulder instability and laxity tests, and second, to describe the mutual dependency of each test evaluated by each tester for identifying self-reported shoulder instability and laxity.

Methods

A standardised protocol for conducting reliability studies was used to test the intertester reliability of the six clinical shoulder instability and laxity tests: apprehension, relocation, surprise, load-and-shift, sulcus sign and Gagey. Cohen's kappa () with 95% CIs besides prevalence-adjusted and bias-adjusted kappa (PABAK), accounting for insufficient prevalence and bias, were computed to establish the intertester reliability and mutual dependency.

Results

Forty individuals (13 with self-reported shoulder instability and laxity-related shoulder problems and 27 normal shoulder individuals) aged 18–60 were included. Fair (relocation), moderate (load-and-shift, sulcus sign) and substantial (apprehension, surprise, Gagey) intertester reliability were observed across tests ( 0.39–0.73; 95% CI 0.00 to 1.00). PABAK improved reliability across tests, resulting in substantial to almost perfect intertester reliability for the apprehension, surprise, load-and-shift and Gagey tests ( 0.65–0.90). Mutual dependencies between each test and self-reported shoulder problem showed apprehension, relocation and surprise to be the most often used tests to characterise self-reported shoulder instability and laxity conditions.

Conclusions

Four tests (apprehension, surprise, load-and-shift and Gagey) out of six were considered intertester reliable for clinical use, while relocation and sulcus sign tests need further standardisation before acceptable evidence. Furthermore, the validity of the tests for shoulder instability and laxity needs to be studied.

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Management of haemothoraces in blunt thoracic trauma: study protocol for a randomised controlled trial

Introduction

Haemothorax following blunt thoracic trauma is a common source of morbidity and mortality. The optimal management of moderate to large haemothoraces has yet to be defined. Observational data have suggested that expectant management may be an appropriate strategy in stable patients. This study aims to compare the outcomes of patients with haemothoraces following blunt thoracic trauma treated with either chest drainage or expectant management.

Methods and analysis

This is a single-centre, dual-arm randomised controlled trial. Patients presenting with a moderate to large sized haemothorax following blunt thoracic trauma will be assessed for eligibility. Eligible patients will then undergo an informed consent process followed by randomisation to either (1) chest drainage (tube thoracostomy) or (2) expectant management. These groups will be compared for the rate of additional thoracic interventions, major thoracic complications, length of stay and mortality.

Ethics and dissemination

This study has been approved by the institution's research ethics board and registered with ClinicalTrials.gov. All eligible participants will provide informed consent prior to randomisation. The results of this study may provide guidance in an area where there remains significant variation between clinicians. The results of this study will be published in peer-reviewed journals and presented at national and international conferences.

Trial registration number

NCT03050502.

http://ift.tt/2oDReuO

Cushings sign and severe traumatic brain injury in children after blunt trauma: a nationwide retrospective cohort study in Japan

Objective

We tested whether Cushing's sign could predict severe traumatic brain injury (TBI) requiring immediate neurosurgical intervention (BI-NSI) in children after blunt trauma.

Design

Retrospective cohort study using Japan Trauma Data Bank.

Setting

Emergency and critical care centres in secondary and tertiary hospitals in Japan.

Participants

Children between the ages of 2 and 15 years with Glasgow Coma Scale motor scores of 5 or less at presentation after blunt trauma from 2004 to 2015 were included. A total of 1480 paediatric patients were analysed.

Primary outcome measures

Patients requiring neurosurgical intervention within 24 hours of hospital arrival and patients who died due to isolated severe TBI were defined as BI-NSI. The combination of systolic blood pressure (SBP) and heart rate (HR) on arrival, which were respectively divided into tertiles, and its correlation with BI-NSI were investigated using a multiple logistic regression model.

Results

In the study cohort, 297 (20.1%) exhibited BI-NSI. After adjusting for sex, age category and with or without haemorrhage shock, groups with higher SBP and lower HR (SBP ≥135 mm Hg; HR ≤92 bpm) were significantly associated with BI-NSI (OR 2.84, 95% CI 1.68 to 4.80, P<0.001) compared with the patients with normal vital signs. In age-specific analysis, hypertension and bradycardia were significantly associated with BI-NSI in a group of 7–10 and 11–15 years of age; however, no significant association was observed in a group of 2–6 years of age.

Conclusions

Cushing's sign after blunt trauma was significantly associated with BI-NSI in school-age children and young adolescents.

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Identifying research priorities for patient safety in mental health: an international expert Delphi study

Objective

Physical healthcare has dominated the patient safety field; research in mental healthcare is not as extensive but findings from physical healthcare cannot be applied to mental healthcare because it delivers specialised care that faces unique challenges. Therefore, a clearer focus and recognition of patient safety in mental health as a distinct research area is still needed. The study aim is to identify future research priorities in the field of patient safety in mental health.

Design

Semistructured interviews were conducted with the experts to ascertain their views on research priorities in patient safety in mental health. A three-round online Delphi study was used to ascertain consensus on 117 research priority statements.

Setting and participants

Academic and service user experts from the USA, UK, Switzerland, Netherlands, Ireland, Denmark, Finland, Germany, Sweden, Australia, New Zealand and Singapore were included.

Main outcome measures

Agreement in research priorities on a five-point scale.

Results

Seventy-nine statements achieved consensus (>70%). Three out of the top six research priorities were patient driven; experts agreed that understanding the patient perspective on safety planning, on self-harm and on medication was important.

Conclusions

This is the first international Delphi study to identify research priorities in safety in the mental field as determined by expert academic and service user perspectives. A reasonable consensus was obtained from international perspectives on future research priorities in patient safety in mental health; however, the patient perspective on their mental healthcare is a priority. The research agenda for patient safety in mental health identified here should be informed by patient safety science more broadly and used to further establish this area as a priority in its own right. The safety of mental health patients must have parity with that of physical health patients to achieve this.

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Impact and acceptability of self-consent procedures for the school-based human papillomavirus vaccine: a mixed-methods study protocol

Introduction

The human papillomavirus (HPV) vaccine, administered in early adolescence, can substantially reduce cervical cancer incidence and mortality. However, lack of written parental consent is a key reason why some young women do not receive the vaccine. The national legal framework allows girls to be vaccinated without parental consent provided they are deemed Gillick competent, but there is some reticence about vaccinating without written parental consent. Self-consent procedures are being implemented in Bristol and South Gloucestershire. This study will examine the implementation, acceptability and impact of these new procedures.

Methods and analysis

Statistical analyses of routine data from Public Health England and the Child Health Information System will test if there has been an increase in HPV vaccination uptake in two ways: (a) Is there an increase when comparing before and after the change in our intervention sites? and (b) Does the percentage change in our intervention sites differ from comparison sites (similar to our intervention sites in terms of initial HPV uptake, ethnicity and deprivation levels) in England where no such intervention took place and how? For the process evaluation, we will develop a logic model and use questionnaires, observations and audio-recorded interviews with young women, school nurses, school staff and parents to examine the context, implementation of self-consent and response to the new procedures.

Ethics and dissemination

The University of Bristol Faculty of Health Sciences Research Ethics Committee and the National Health Service Health Research Authority provided approvals for the study. We will produce a report with recommendations about self-consent procedures in conjunction with key stakeholders. At least two papers will be written for publication in peer-reviewed journals and for conference presentations. A summary of results will be shared with participating immunisation nurses, school staff, young people and parents as requested.

Trial registration number

ISRCTN49086105; Pre-results.

http://ift.tt/2FbB6XC

A new model of exercise referral scheme in primary care: is the effect on adherence to physical activity sustainable in the long term? A 15-month randomised controlled trial

Introduction

Studies had not yet overcome the most relevant barriers to physical activity (PA) adherence. An exercise referral scheme (ERS) with mechanisms to promote social support might enhance adherence to PA in the long term.

Setting

A randomised controlled trial in 10 primary care centres in Spain.

Objective

To assess the effectiveness of a primary care-based ERS linked to municipal resources and enhancing social support and social participation in establishing adherence to PA among adults over a 15-month period.

Participants

422 insufficiently active participants suffering from at least one chronic condition were included. 220 patients (69.5 (8.4) years; 136 women) were randomly allocated to the intervention group (IG) and 202 (68.2 (8.9) years; 121 women) to the control group (CG).

Interventions

The IG went through a 12-week standardised ERS linked to community resources and with inclusion of mechanisms to enhance social support. The CG received usual care from their primary care practice.

Outcomes

The main outcome measure was self-report PA with the International Physical Activity Questionnaire and secondary outcomes included stages of change and social support to PA practice.

Data collection

Participant-level data were collected via questionnaires at baseline, and at months 3, 9 and 15.

Blinding

The study statistician and research assessors were blinded to group allocation.

Results

Compared with usual care, follow-up data at month 15 for the ERS group showed a significant increase of self-reported PA (IG: 1373±1845 metabolic equivalents (MET) min/week, n=195; CG: 919±1454 MET min/week, n=144; P=0.009). Higher adherence (in terms of a more active stage of change) was associated with higher PA level at baseline and with social support.

Conclusions

Prescription from ordinary primary care centres staff yielded adherence to PA practice in the long term. An innovative ERS linked to community resources and enhancing social support had shown to be sustainable in the long term.

Trial registration number

NCT00714831; Results.

http://ift.tt/2oEu4EG

Towards personalized therapy for multiple sclerosis: limitations of observational data

Sir,

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Reply: Towards personalized therapy for multiple sclerosis: limitations of observational data

Sir,

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Ultrasound waves increase the yield and carotenoid content of lipid extracted from cephalothorax of Pacific white shrimp (Litopenaus vannamei)

Abstract

Lipids from cephalothorax of Pacific white shrimp (Litopenaus vannamei) were obtained using solvent extraction and ultrasonic assisted extraction (UAE). Among all solvents used, the mixture of hexane:isopropane (1:1) provided the highest yield (25.32% dry weight basis) and carotenoid content (1.97 mg/g lipid). When ultrasonication with different amplitudes (50-90%) was used for 25 min, the highest yield was obtained at 80% amplitude (p < 0.05). With the same ultrasonication time, UAE with continous mode rendered the higher yield than pulse mode (p < 0.05). Lipid extracted with hexane:isopropanol mixture with UAE process had the yield of 49.81%. Phospholipids were major constituents of lipids extracted by solvent extraction. However, more free fatty acids, mono and diglycerides were found in lipids extracted by UAE process, indicating increased hydrolysis. UAE process resulted in higher oxidation of lipids as evidenced by increased peroxide values (PVs) and thiobarbituric acid reactive substances (TBARS). Those alterations were more pronounced in lipids extracted using UAE with continuous mode than pulsed mode as confirmed by fourier transform infrared (FTIR) spectra. Overall, UAE process markedly increased the yield of lipids from shrimp cephalothorax, but oxidation and hydrolysis took place to some degree.

Practical applications: Cephalothorax of Pacific white shrimp contains high value products, especially lipids rich in polyunsaturated fatty acids (PUFAs) and astaxanthin. These value-added products could serve as excellent source of nutrients as well as bioactive compounds with proven health benefits. The extraction yield of lipid and carotenoid was significantly higher when UAE was implemented, compared to the conventional solvent extraction method. The lipids extracted by UAE process were found to have high free fatty acids (FFAs). The lipids rich in FFAs can be used as alternative raw material for manufacturing of biodiesel or other marketable products.

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Issue Information

Cover of this issue. Cladogran of taxa of microbiota in the mice in the model and Bifico group. See also Song et al. (pp. 666–677 of this issue).

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In this Issue

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Phytochemical profiling and in vitro screening for anticholinesterase, antioxidant, antiglucosidase and neuroprotective effect of three traditional medicinal plants for Alzheimer’s Disease and Diabetes Mellitus dual therapy

Extensive epidemiological and clinical studies revealed that Alzheimer's Disease (AD) and Type 2 Diabetes Mellitus (T2D) are most likely to appear simultaneously in aged people as T2D is a major risk factor fo...

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Chronic kidney disease and poor outcomes in ischemic stroke: is impaired cerebral autoregulation the missing link?

Chronic kidney disease increases stroke incidence and severity but the mechanisms behind this cerebro-renal interaction are mostly unexplored. Since both vascular beds share similar features, microvascular dys...

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Biological conversion of aromatic monolignol compounds by a Pseudomonas isolate from sediments of the Baltic Sea

Bacterial strains were isolated from the sediments of the Baltic Sea using ferulic acid, guaiacol or a lignin-rich softwood waste stream as substrate. In total nine isolates were obtained, five on ferulic acid...

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The prognostic value of bispectral index and suppression ratio monitoring after out-of-hospital cardiac arrest: a prospective observational study

We investigated the ability of bispectral index (BIS) monitoring to predict poor neurological outcome in out-of-hospital cardiac arrest (OHCA) patients fully treated according to guidelines.

http://ift.tt/2I2Khvu

Identification of inhibitors of Tartrate-resistant acid phosphatase (TRAP/ACP5) activity by small molecule screening

Abstract

Tartrate-resistant acid phosphatase (TRAP/ACP5) occurs as two isoforms- TRAP 5a with low enzymatic activity due to a loop interacting with the active site and the more active TRAP isoform 5b generated upon proteolytic cleavage of this loop. TRAP has been implicated in several diseases, including cancer. Thus this study set out identifying small molecule inhibitors of TRAP activity. A microplate-based enzymatic assay for TRAP 5b was applied in a screen of 30,315 compounds, resulting in the identification of 90 primary hits. After removal of promiscuous compounds, unwanted groups and false-positives by orthogonal assays and three-concentration validation, the properties of 52 compounds were further investigated to better understand their mechanism of action. Full concentration-response curves for these compounds were established under different enzyme concentrations and (pre-) incubation times to remove compounds with inconsistent results and low potencies. Full concentration-response curves were also performed for both isoforms, to examine isoform prevalence. Filtering led to six prioritized compounds, representing different clusters. One of these, CBK289001 or (6S)-6-[3-(2H-1,3-benzodioxol-5-yl)-1,2,4-oxadiazol-5-yl]-N-(propan-2-yl)-1H,4H,5H,6H,7H-imidazo[4,5-c]pyridine-5-carboxamide demonstrated efficacy in a migration assay and IC₅₀ values from 4-125 μM. Molecular docking studies and analog testing were performed around CBK289001 to provide openings for further improvement towards more potent blockers of TRAP activity.

This article is protected by copyright. All rights reserved.

TRAP has been implicated in several diseases, including cancer and well-characterized inhibitors are majorly missing. In this study isoform-specific inhibitors for TRAP enzyme activity were identified by small molecule screening of a library containing drug-like compounds. Filtered by orthogonal validation and liability assessments, full-concentration responses and isoform selectivity were assessed for a selection of hit compounds. Six potential lead structures were characterized for molecular docking modes. The compound CBK289001 rendered valid as inhibiting TRAP-dependent migration in a cell system.

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Issue Information

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Fertility preservation for female cancer patients

Abstract

An improvement in the survival rates of cancer patients and recent advancements in assisted reproductive technologies have led to remarkable progress in oncofertility and fertility preservation treatments. Currently, for adults and postpubertal girls, oocyte or embryo cryopreservation is an established method. If their cancer treatment cannot be postponed for 2 weeks, ovarian tissue cryopreservation is offered as an experimental technique. For prepubertal girls, ovarian tissue cryopreservation is the only option. As for ovarian protection, there is insufficient evidence regarding the effectiveness of GnRH agonist in fertility preservation. In the past decade, the concept of fertility preservation for cancer patients has been rapidly spreading, but at present only a small part of young cancer patients receive fertility preservation services. It is partly because of the lack of adequate provision of information on fertility preservation and the lack of referral from oncology to the fertility clinic. In Japan, the clinical practice guidelines for fertility preservation in childhood, adolescent and young adult cancer patients was issued last year by the Japan Society of Clinical Oncology (JSCO). It would help Japanese health care providers, including oncologists and reproductive specialists, to increase their knowledge on fertility preservation for cancer patients and move forward the fertility preservation services. For further progress, it is also needed to establish a national registration system of fertility preservation for cancer patients to evaluate the safety and efficacy of the current management.

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Brain-resident memory CD8+ T cells induced by congenital CMV infection prevent brain pathology and virus reactivation

Abstract

Congenital HCMV infection is a leading infectious cause of long-term neurodevelopmental sequelae. Infection of newborn mice with MCMV intraperitoneally is a well-established model of congenital HCMV infection, which best recapitulates the hematogenous route of virus spread to brain and subsequent pathology. Here we used this model to investigate the role, dynamics and phenotype of CD8⁺ T cells in the brain following infection of newborn mice. We show that CD8⁺ T cells infiltrate the brain and form a pool of tissue-resident memory T cells (T_RM cells) that persist for lifetime. Adoptively transferred virus-specific CD8⁺ T cells provide protection against primary MCMV infection in newborn mice, reduce brain pathology and remain in the brain as T_RM cells. Brain CD8⁺ T_RM cells were long-lived, slowly proliferating cells able to respond to local challenge infection. Importantly, brain CD8⁺ T_RM cells controlled latent MCMV and their depletion resulted in virus reactivation and enhanced inflammation in brain.

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On the response function and range dependence of manual estimation

Abstract

Manual estimates without vision of the hand are thought to constitute a form of cross-modal matching between stimulus size and finger opening. However, few investigations have systematically looked at how manual estimates relate a perceived size to the response across different ranges of stimuli. In two experiments (N = 18 and N = 14), we sought to map out the response properties for (1) manual estimates of visually presented stimuli as well as (2) visual estimates of proprioceptive stimuli, and to test whether these properties depend on the range of stimuli. We also looked at whether scalar variability is present in manual estimates, as predicted by Weber's Law for perceptual tasks. We found that manual estimates scale linearly and with a slope of close to 1 with object sizes up to 90 mm, before participants' hand size limited their responses. In contrast, we found a shallower response slope of about 0.7 when participants performed the inverse task, adjusting the size of a visual object to match a not actively chosen, induced finger opening. Our results were mixed with regards to scalar variability in large objects. We saw some indication of a plateau, but no evidence for an effect of mechanical constraints in the range studied (up to 90 mm). Participants also showed a clear tendency to overestimate small differences when a set of objects differed little in size, but not when stimulus differences were more pronounced.

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Does mammographic density mediate risk factor associations with breast cancer? An analysis by tumor characteristics

Abstract

Background

Though mammographic density (MD) has been proposed as an intermediate marker of breast cancer risk, few studies have examined whether the associations between breast cancer risk factors and risk are mediated by MD, particularly by tumor characteristics.

Methods

Our study population included 3392 cases (1105 premenopausal) and 8882 (3192 premenopausal) controls from four case–control studies. For established risk factors, we estimated the percent of the total risk factor association with breast cancer that was mediated by percent MD (secondarily, by dense area and non-dense area) for invasive breast cancer as well as for subtypes defined by the estrogen receptor (ER+/ER−), progesterone receptor (PR+/PR−), and HER2 (HER2+/HER2−). Analyses were conducted separately in pre- and postmenopausal women.

Results

Positive associations between prior breast biopsy and risk of invasive breast cancer as well as all subtypes were partially mediated by percent MD in pre- and postmenopausal women (percent mediated = 11–27%, p ≤ 0.02). In postmenopausal women, nulliparity and hormone therapy use were positively associated with invasive, ER+ , PR+ , and HER2− breast cancer; percent MD partially mediated these associations (percent mediated ≥ 31%, p ≤ 0.02). Further, among postmenopausal women, percent MD partially mediated the positive association between later age at first birth and invasive as well as ER+ breast cancer (percent mediated = 16%, p ≤ 0.05).

Conclusion

Percent MD partially mediated the associations between breast biopsy, nulliparity, age at first birth, and hormone therapy with risk of breast cancer, particularly among postmenopausal women, suggesting that these risk factors at least partially influence breast cancer risk through changes in breast tissue composition.

http://ift.tt/2GZOzCm

Tumor-associated myeloid cells promote tumorigenesis of non-tumorigenic human and murine prostatic epithelial cell lines

Abstract

The etiology of prostate cancer is poorly understood, but it is a multi-step process that has been linked to environmental factors that induce inflammation within the gland. Glands of prostate cancer patients frequently contain multiple zones of disease at various stages of progression. The factors that drive disease progression from an indolent benign stage to aggressive disease are not well-defined. Prostate inflammation and carcinoma are associated with high levels of myeloid cell infiltration; these cells are linked to disease progression in other cancers, but their role in prostate cancer is unclear. To determine whether myeloid cells contribute to prostate cancer progression, the ability of prostate tumor-associated CD11b⁺ cells (TAMC) to drive prostate epithelial cell tumorigenesis was tested. Co-culture of CD11b⁺ TAMC with non-tumorigenic genetically primed prostate epithelial cells resulted in stable transformation and induction of tumorigenesis. RNA sequencing identified the IL-1α pathway as a potential molecular mechanism responsible for tumor promotion by TAMC. Inhibition of IL-1α delayed growth of TAMC-induced tumors. Further analysis showed that IL-1α inhibition led to decreased angiogenesis within tumors, suggesting that IL-1α promotes prostate tumor progression, potentially through augmentation of angiogenesis.

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Differential α-synuclein expression contributes to selective vulnerability of hippocampal neuron subpopulations to fibril-induced toxicity

Abstract

The accumulation of misfolded α-synuclein (aSyn) and neuron loss define several neurodegenerative disorders including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). However, the precise relationship between pathology and neurotoxicity and why these processes disproportionately affect certain neuron subpopulations are poorly understood. We show here that Math2-expressing neurons in the hippocampal Cornu ammonis (CA), a region significantly affected by aSyn pathology in advanced PD and DLB, are highly susceptible to pathological seeding with pre-formed fibrils (PFFs), in contrast to dentate gyrus neurons, which are relatively spared. Math2⁺ neurons also exhibited more rapid and severe cell loss in both in vitro and in vivo models of synucleinopathy. Toxicity resulting from PFF exposure was dependent on endogenous aSyn and could be attenuated by N-acetyl-cysteine through a glutathione-dependent process. Moreover, aSyn expression levels strongly correlate with relative vulnerability among hippocampal neuron subtypes of which Math2⁺ neurons contained the highest amount. Consistent with this, antisense oligonucleotide (ASO)-mediated knockdown of aSyn reduced the neuronal pathology in a time-dependent manner. However, significant neuroprotection was observed only with early ASO intervention and a substantial reduction of aSyn pathology, indicating toxicity occurs after a critical threshold of pathological burden is exceeded in vulnerable neurons. Together, our findings reveal considerable heterogeneity in endogenous aSyn levels among hippocampal neurons and suggest that this may contribute to the selective vulnerability observed in the context of synucleinopathies.

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