Blood donation practice and associated factors among health professionals in Tigray regional state public hospitals, northern Ethiopia

The demand for blood and blood products are increasing in all part of the globe, especially in the developing nations. However, there is limited information on the level of blood donation practice and their re...

https://ift.tt/2Oa2uNn

Determinants of drug-related problems among ambulatory type 2 diabetes patients with hypertension comorbidity in Southwest Ethiopia: a prospective cross sectional study

The aim of this study was to assess drug-related problems and its determinants in type 2 diabetes patients with hypertension co-morbidity.

https://ift.tt/2Q66qMD

Is nodding syndrome in northern Uganda linked to consumption of mycotoxin contaminated food grains?

Nodding syndrome (NS) is a type of epilepsy characterized by repeated head-nodding seizures that appear in previously healthy children between 3 and 18 years of age. In 2012, during a WHO International Meeting...

https://ift.tt/2O7Cu5q

Kalman inversion stress microscopy

Although mechanical cues are crucial to tissue morphogenesis and development, the tissue mechanical stress field remains poorly characterized. Given traction force timelapse movies, as obtained by traction force microscopy of in vitro cellular sheets, we show that the tissue stress field can be estimated by Kalman filtering. After validation using numerical data, we apply Kalman inversion stress microscopy to experimental data. We combine the inferred stress field with velocity and cell shape measurements to quantify the rheology of epithelial cell monolayers in physiological conditions, found to be close to that of an elastic and active material.

https://ift.tt/2QWOIMM

The differential diagnosis of Helicobacter pylori negative gastritis

Abstract

Gastric biopsies are often submitted with as clinical question Helicobacter pylori (HP) infection. Regularly, the morphology suggests a HP infection but the organism is not detected in special stains. This review presents a practical approach to deal with such biopsies. The first step is to exclude a false negative result of the search for HP, by ensuring that both antral and oxyntic mucosa are present, by the use of sensitive stains, identification of marked reactive changes, such as intestinal, pseudo-pyloric, pancreatic metaplasia that may suggest a diagnosis of (HP associated or autoimmune) atrophic gastritis, and finally identification of signs of the use of proton pump inhibitors (PPI) as in such biopsies, HP may sometimes be found only within parietal cells. The differential diagnosis should include lymphocytic gastritis, other diseases affecting the stomach, such as inflammatory bowel disease (IBD), vasculitis, granulomatous disease, viral infection, such as cytomegalovirus (CMV) or more rarely Epstein-Barr virus (EBV) infection, or other bacterial infections, such as Enterococcus and Treponema pallidum. Clinical input may be required to ensure the patient is not taking medication that may cause gastritis, such as antibiotics used for HP eradication or common medications that cause a form of gastropathy. When these have been excluded, a known cause has not been found and in such a case, the term idiopathic focal/diffuse gastritis can be used.

https://ift.tt/2Q5e9ul

Regulatory effect of Phikud Navakot extract on HMG-CoA reductase and LDL-R: potential and alternate agents for lowering blood cholesterol

For decades, various cardiovascular symptoms have been relieved by the use of Ya-Hom Navakot, which is a formulation comprising 54 herbal medicines. The Thailand Ministry of Public Health listed Ya-Hom Navakot...

https://ift.tt/2zsq5kl

Use of biologically-based complementary medicine in breast and gynecological cancer patients during systemic therapy

Biologically-based complementary medicines (BB-CAM) including herbs and nutritional supplements are frequently taken by breast- and gynecological cancer patients undergoing systemic therapy. The aim of this st...

https://ift.tt/2OOrV4l

Cost Effectiveness of Quadrivalent Influenza Vaccines Compared with Trivalent Influenza Vaccines in Young Children and Older Adults in Korea

Abstract

Introduction

Trivalent influenza vaccines (TIVs) are currently reimbursed for subjects aged ≥ 65 years and children between 6 and 59 months of age under a national immunization program in South Korea. Quadrivalent influenza vaccines (QIVs) are expected to address the potential problem of influenza B-lineage mismatch for TIVs.

Objective

The objective of this analysis was to compare the cost effectiveness of QIV versus TIV in children aged 6–59 months and older adults ≥ 65 years of age in South Korea.

Methods

A 1-year static population model was employed to compare the costs and outcomes of a QIV vaccination program compared with TIV in children aged 6–59 months and older adults ≥ 65 years of age in South Korea. Influenza-related parameters (probabilities, health resource use, and costs) were derived from an analysis of the National Health Insurance System claims database between 2010 and 2013 under a broad and narrow set of International Classification of Diseases, Tenth Revision (ICD-10) codes used to identify influenza. Other inputs were extracted from published literature. Incremental cost-effectiveness ratios (2016 South Korean Won [KRW] per quality-adjusted life-year [QALY] gained) were estimated using a 'limited' societal perspective as per the Korean pharmacoeconomic guidelines. QALYs lost due to premature mortality were discounted at 5% annually.

Results

For both age groups combined, under the narrow definition of influenza, QIV is expected to prevent nearly 16,000 (2923 in children and 13,011 in older adults) medically attended influenza cases, nearly 8000 (672 in children, 7048 in older adults) cases of complications, and over 230 (0 in children, 238 in older adults) deaths annually compared with TIV. The impact of using QIV versus TIV in this setting translates into savings of KRW 24 billion (KRW 0.6 billion in children, KRW 23.4 billion in older adults) in annual medical costs, and over 2100 (18 in children, 2084 in older adults) QALYs. Under the broad definition, the corresponding results are over 190,000 (50,697 in children, 140,644 in older adults) influenza cases, over 37,000 (12,623 in children, 24,526 in older adults) complications, 270 deaths (0 in children, 270 in older adults), KRW 94.22 billion (KRW 16 billion in children, KRW 78.2 billion in older adults), and over 3500 QALYs saved (316 in children, 3260 in older adults).

Conclusion

The use of QIV over TIV was estimated to not be cost effective in children 6–59 months of age, but cost saving in older adults, using the narrow definition of influenza; however, QIV use was cost saving in both age groups using the broad definition. QIV is expected to yield more benefits in older adults ≥ 65 years of age than in children aged 6–59 months due to higher influenza-related mortality and costs among the older adults. Further analyses considering the indirect effects of influenza vaccination in children are required.

https://ift.tt/2OP5bB8

Carrie Owen Benefits from a New Minimally Invasive In-office Treatment for Nasal Polyposis

By the time she arrived in the office of rhinologist Martin J. Citardi, MD, Carrie Owen had lost her senses...

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Breathing Better After Surgery and a Novel Implant

Former Houstonian Kelly Krohn was among the first to benefit from a relatively new solution for nasal airway obstruction symptoms...

https://ift.tt/2NEI3ss

Six ORL Specialists Named Houstonia Top Doctors for 2018

Six members of the Department of Otorhinolaryngology-Head and Neck Surgery have been selected as Houstonia Top Doctors by physicians, physician...

https://ift.tt/2DrS9YZ

Dr. Amber Luong Selected Faculty Member of the Year by ORL Residents

Each year, otorhinolaryngology residents of the Department of Otorhinolaryngology-Head and Neck Surgery at McGovern Medical School at UTHealth have the...

https://ift.tt/2NzflJA

Changes in heart rate variability with respect to exercise intensity and time during treadmill running

Heart rate variability (HRV) arises from the complex interplay of sympathetic and parasympathetic autonomic regulation of heart rate. Ultra-low frequency (ULF) and very-low frequency (VLF) components of HRV pl...

https://ift.tt/2IbgwZC

Prevalence of Chlamydia trachomatis and Neisseria gonorrhoeae infections among pregnant women and eye colonization of their neonates at birth time, Shiraz, Southern Iran

Chlamydia trachomatis and Neisseria gonorrhoeae are the two common transmissible pathogens from pregnant women to their neonates. Given the lack of routine screening and treatment of pregnant women in some areas,...

https://ift.tt/2OM9Wv9

Ade2 Functions in the Drosophila Fat Body To Promote Sleep

Metabolic state is a potent modulator of sleep and circadian behavior and animals acutely modulate their sleep in accordance with internal energy stores and food availability. Across phyla, hormones secreted from adipose tissue act in the brain to control neural physiology and behavior to modulate sleep and metabolic state. Growing evidence suggests the fat body is a critical regulator of complex behaviors, but little is known about the genes that function within the fat body to regulate sleep. To identify molecular factors functioning in non-neuronal tissues to regulate sleep, we performed an RNAi screen selectively knocking down genes in the fat body. We found that knockdown of Phosphoribosylformylglycinamidine synthase/Pfas (Ade2), a highly conserved gene involved the biosynthesis of purines, sleep regulation and energy stores. Flies heterozygous for multiple Ade2 mutations are also short sleepers and this effect is partially rescued by restoring Ade2 to the Drosophila fat body. Targeted knockdown of Ade2 in the fat body does not alter arousal threshold or the homeostatic response to sleep deprivation, suggesting a specific role in modulating baseline sleep duration. Together, these findings suggest Ade2 functions within the fat body to promote both sleep and energy storage, providing a functional link between these processes.

https://ift.tt/2NFZiKd

Design, Synthesis and Biological Evaluation of Quinazoline Derivatives as Dual HDAC1 and HDAC6 Inhibitors for the Treatment of Cancer

Chemical Biology &Drug Design, Volume 0, Issue ja, -Not available-.


https://ift.tt/2IbLH75

Modified T Cells Home to Brain Tumors [News in Brief]

Reengineered immune cells could improve CAR T-cell therapies for glioblastoma, medulloblastoma.

https://ift.tt/2xAF22v

Net Benefit of Anticoagulants for A-Fib Varies With Stroke Rate

MONDAY, Sept. 24, 2018 -- There is variation in the net clinical benefit of anticoagulants based on variation in published atrial fibrillation (AF) stroke rates, according to a study published online Sept. 25 in the Annals of Internal...

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Gender Nonconformity Linked to Students' Mental Distress

MONDAY, Sept. 24, 2018 -- Gender nonconformity (GNC) is associated with mental distress for female and male students, according to a study published online Sept. 24 in JAMA Pediatrics. Richard Lowry, M.D., from the U.S. Centers for Disease Control...

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Participation Up With Online Diabetes Prevention Program

MONDAY, Sept. 24, 2018 -- For overweight/obese veterans with prediabetes, participation is higher for online Diabetes Prevention Programs (DPPs), but weight loss is similar for online and in-person DPPs, according to a study published online Sept....

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New Risk Factors Identified for Varicose Vein Disease

MONDAY, Sept. 24, 2018 -- New risk factors have been identified for varicose vein disease, including height, according to a study published online Sept. 24 in Circulation. Eri Fukaya, M.D., Ph.D., from the Stanford University School of Medicine in...

https://ift.tt/2xVXt11

Effects of Hemodialysis on Thiol-Disulphide Homeostasis in Critically Ill Pediatric Patients with Acute Kidney Injury

Aim. To evaluate thiol/disulphide homeostasis as a new indicator of oxidative stress in AKI patients and to determine the effect of HD on antioxidant balance and oxidative stress through plasma thiols. Methods. This study was performed in patients aged between 12 months and 18 years prospectively who underwent hemodialysis due to AKI and were followed up for a year in a 22-bed tertiary pediatric intensive care unit. 20 patients and 39 controls were included. Results. No difference was present between the groups in terms of age and gender. Median values of plasma native thiol, total thiol, and percent thiol were significantly lower in AKI group both before and after dialysis when compared to control group. The median dynamic disulphide values were significantly lower in the AKI group of predialysis compared to the controls. When pre- and postdialysis values were compared, disulphide values were statistically higher after dialysis. When pre- and postdialysis native thiol, dynamic disulphide, total thiol, and percent thiol median values were compared, postdialysis values were significantly higher than the predialysis values. There was a positive correlation between albumin, total thiol, and native thiol values before dialysis in the patient group. Conclusion. AKI patients have low levels of thiol species showing the presence of oxidative stress and hemodialysis has a positive effect on thiol/disulphide balance. This new method may be an inexpensive and simple tool suitable for clinical studies and can be used in routine screening as a useful indicator to show oxidative stress.

https://ift.tt/2O68bvH

Speech Understanding and Sound Localization with a New Nonimplantable Wearing Option for Baha

Objective. To measure the audiological benefit of the Baha SoundArc, a recently introduced nonimplantable wearing option for bone conduction sound processor, and to compare it with the known softband wearing option in subjects with normal cochlear function and a purely conductive bilateral hearing loss. Methods. Both ears of 15 normal hearing subjects were occluded for the time of the measurement, yielding an average unaided threshold of 49 dB HL (0.5 – 4 kHz). Soundfield thresholds, speech understanding in quiet and in noise, and sound localization were measured in unaided conditions and with 1 or 2 Baha 5 sound processors mounted on either a softband or a SoundArc device. Results. Soundfield thresholds and speech reception thresholds were improved by 19.5 to 24.8 dB (p<.001 when compared to the unaided condition. speech reception thresholds in noise were improved by db using sound processors rather than one understanding for from direction of device and localization error no statistically significant difference was found between soundarc softband wearing options any tests. conclusions. bone conduction processor mounted on a or resulted considerable improvements hearing subjects with simulated purely conductive bilateral loss. found. improves certain spatial settings.>

https://ift.tt/2Q2iP3T

New insights into the pathophysiology of fasciculations in amyotrophic lateral sclerosis: an ultrasound study

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects the upper (UMN) and lower motor neurons (LMN). Fasciculations are involuntary twitches due to spontaneous contraction of muscle fascicles, originating from motor unit depolarizations as recorded by electromyography (EMG) (de Carvalho et al., 2017). Widespread fasciculations are characteristic of ALS and, therefore, have been incorporated to the diagnostic criteria (de Carvalho et al. 2008).

https://ift.tt/2xCEngJ

Laryngeal Adductor Reflex And Future Projections for Brainstem Monitoring. Reply to “A method for intraoperative recording of the laryngeal adductor reflex during lower brainstem surgery in children”

In their Letter to the Editor, Costa et al. (2018) report on using the laryngeal adductor reflex (LAR), along with standard, methodologies, to monitor vagus nerve pathways in three pediatric patients during the removal of large 4th ventricle tumors. Preservation of LAR correlated with the absence of X cranial nerve neurological deficits.

https://ift.tt/2xzSF1Y

A method for intraoperative recording of the laryngeal adductor reflex during lower brainstem surgery in children

The recently published study Sinclair et al. (2017) presented a nice method for the intraoperative recording of the laryngeal adductor reflex (LAR) during thyroid and cervical spine surgeries.

https://ift.tt/2N0hKHS

Automated EEG source imaging: a retrospective, blinded clinical validation study

Approximately 1/3 of patients with epilepsy are drug-resistant (Kwan et al. 2000). In this patient group, epilepsy surgery of the presumed epileptogenic focus is currently the treatment option with highest efficacy (Dwivedi et al. 2017; Engel et al. 2012; Wiebe et al. 2001). However, accurate localization of the epileptic focus is often challenging. Since there is no single-modality that reliably can localize the area that needs to be resected in order to render the patient seizure-free (EZ, epileptogenic zone), the presurgical evaluation is based on a multimodal approach (Rosenow and Lüders 2001).

https://ift.tt/2xAZfF9

Electrooculogram and submandibular montage to distinguish different eye, eyelid, and tongue movements in electroencephalographic studies

Different types of ictal eye and eyelid movements have been described in the literature. In some generalized epilepsies, such as Jeavons Syndrome, eyelid myoclonia is a cardinal symptom (Jeavons, 1977). In focal epilepsies, eye and head version have an important lateralizing value regarding the epileptogenic zone (Rasmussen and Penfield, 1948; Wyllie et al., 1986). Eyelid flutter, forced rapid blinking, oculoclonic seizures, or epileptic nystagmus have all been described as having localizing value pointing to a posterior quadrant epileptogenic zone (Bancaud et al., 1965; Foerster and Penfield, 1930; Gastaut, 1960; Gastaut and Roger, 1954; Salanova et al., 1992; Williamson et al., 1992).

https://ift.tt/2N0iFIx

Identifying mild-moderate Parkinson’s disease using whole-brain functional connectivity

Parkinson's disease (PD) is the second most common progressive neurodegenerative disease and is associated predominantly with motor symptoms, such as bradykinesia, in combination with rigidity and resting tremors. Moreover, PD is related to numerous non-motor symptoms, such as mood disorders and cognitive changes (Chaudhuri et al., 2009), some of which precede the motor dysfunction by more than a decade. The current diagnosis of PD is largely based on self-reported symptoms and clinical assessments (Jankovic, 2008) and has a high rate of misdiagnosis (Hughes et al., 1992).

https://ift.tt/2MZIQiG

Indications for Neuromuscular Ultrasound: Expert Opinion and Review of the Literature

For much of the last fifty years, there has been remarkable uniformity in electrodiagnostic practice. Aside from the rare patient who might need referral to a specialized center for a single fiber EMG study, patients have been able to receive consistent diagnostic evaluations with comparable results regardless of the size of the laboratory or its geographic location. However, now a number of laboratories provide advanced ultrasound imaging in addition to standard electrophysiological assessment of nerve and muscle, a trend that appears to be accelerating, and this is creating an unprecedented gap between ultrasound enhanced and standard clinical neurophysiology practice.

https://ift.tt/2xAZe43

Passive Functional Mapping of Receptive Language Areas Using Electrocorticographic Signals

Resective brain surgery for the treatment of tumors or intractable epilepsy often requires localizing "eloquent" cortical regions involved in production and comprehension of language to minimize post-surgical deficits. Among the techniques to identify these eloquent regions, electrical cortical stimulation (ECS) has become the gold standard, perhaps because of its relatively low cost and procedural simplicity (see Borchers et al., 2012 for review).

https://ift.tt/2MYScer

Predictors of survival in patients with influenza pneumonia-related severe acute respiratory distress syndrome treated with prone positioning

Patients with influenza complicated with pneumonia are at high risk of rapid progression to acute respiratory distress syndrome (ARDS). Prone positioning with longer duration and lung-protective strategies mig...

https://ift.tt/2PX0Hsm

Endoscopic magnet placement into sub-adventitial tunnels for augmenting lower esophageal sphincter using submucosal endoscopy: ex vivo and in vivo study in a porcine model (with video)

Endolumenal therapies serve as a treatment option for gastroesophageal reflux disease (GERD). This study aimed to determine if magnets could be placed endoscopically using the adventitial layer creating a sub-adventitial space near the esophagogastric junction to augment the lower esophageal sphincter using the submucosal endoscopy.

https://ift.tt/2N4H7ss

Which heart rate variability index is an independent predictor of mortality in cirrhosis

Liver cirrhosis is associated with reduced heart rate variability (HRV), which indicates impaired integrity of cardiovascular control in this patient population. There are several different indices for HRV quantification. The present study was designed to: 1) determine which of the HRV indices is best at predicting mortality in patients with cirrhosis; 2) verify if such ability to predict mortality is independent of the severity of hepatic failure.

https://ift.tt/2IcOeOF

BILIARY STONE DISEASE IN PATIENTS RECEIVING SOMATOSTATIN ANALOGS FOR NEUROENDOCRINE NEOPLASMS. A RETROSPECTIVE OBSERVATIONAL STUDY

Somatostatin analogs are the backbone of neuroendocrine neoplasms treatment. Biliary stone disease is a potentially severe adverse event of somatostatin analogs: an increased incidence has been reported in somatostatin analogs-treated acromegalic patients, but studies on patients with neuroendocrine neoplasms are lacking.

https://ift.tt/2pAkpPu

A Phase II Clinical Trial of Molecular Profiled Neoadjuvant Therapy for Localized Pancreatic Ductal Adenocarcinoma

Objectives: One facet of precision medicine is the use of tumor molecular profiling to guide chemotherapeutic selection. We conducted the first prospective clinical trial of molecular profiling to guide neoadjuvant therapy in patients with operable pancreatic ductal adenocarcinoma (PDAC). We hypothesized that more effective systemic therapy would prevent disease progression during neoadjuvant therapy and, therefore, allow more patients to undergo surgery. Methods: In patients with resectable and borderline resectable (BLR) PDAC, molecular profiling consisted of immunocytochemical staining of pretreatment endoscopic ultrasound-guided fine needle aspiration tumor biopsies using 6 biomarkers. Neoadjuvant systemic therapy was selected based on the molecular profiling results. The primary endpoint was the completion of all intended neoadjuvant therapy and surgery. Results: The trial enrolled 130 patients; 61 (47%) resectable and 69 (53%) BLR. Molecular profiling was reported within a median of 5 business days (IQR: 3). Of the 130 patient samples, 95 (73%) had adequate cellularity for molecular profiling and 92 (71%) patients received molecular profile-directed therapy. Of the 92 patients who had predictive profiling, 74 (80%) received fluoropyrimidine-based therapy and 18 (20%) received gemcitabine-based therapies. Of the 130 patients, 107 (82%) completed all intended neoadjuvant therapy and surgery; 56 (92%) of the 61 with resectable PDAC and 51 (74%) of 69 with BLR PDAC. Conclusions: We report the first prospective clinical trial that utilized molecular profiling to select neoadjuvant therapy in patients with operable PDAC. Such high resectability rates have not been observed in prior neoadjuvant trials, suggesting that molecular profiling may improve the efficacy of chemotherapy in these patients.

https://ift.tt/2Qr6wPY

3 ways telemedicine can increase the reach of your EMS agency

Improve access to care and triage less urgent calls for more efficient use of healthcare resources

https://ift.tt/2xJ8xPN

A Phase1b Dose Escalation Study of Recombinant Circularly Permuted TRAIL in Patients With Relapsed or Refractory Multiple Myeloma

Objectives: Circularly permuted tumor necrosis factor-related apoptosis-inducing ligand (CPT), or CPT, is a novel antitumor drug candidate. This phase 1b study evaluated the safety, tolerability, pharmacokinetics (PK), and efficacy of single-agent CPT in patients with relapsed or refractory multiple myeloma (RRMM), and aimed to identify the recommended dose for the phase 2 study. Materials and Methods: Patients received single or multiple doses (once daily for 5 consecutive days per 21-d cycle) of CPT intravenous infusion at doses of 5, 6.5, 8, 10, and 15 mg/kg, to determine the maximum tolerated dose, dose-limiting toxicities, safety, and tolerability. PK were evaluated. Preliminary efficacy was assessed after each treatment cycle. Results: Twenty-nine RRMM patients received CPT. Neither the dose-limiting toxicity nor the maximum tolerated dose were identified. The most common treatment-related adverse events were liver enzyme elevations (eg, elevation of aspartate aminotransferase and alanine aminotransferase), hematological abnormalities (eg, leukopenia and neutropenia), fever, fatigue, and vomiting. CPT had a terminal half-life of 0.90 to 1.27 hours at the 5 dose levels, and no accumulation was observed with repeated doses. Safety and PK profiles were similar across the 5 dose cohorts. The overall response rate (complete and partial response) was 18.5%. The clinical benefit rate (complete, partial, and minimal response) was 33.3%. Sixteen patients did not respond to CPT (no change and progressive disease). Patients treated with higher doses of CPT appeared to have better responses. Conclusions: CPT was safe and well tolerated by RRMM patients, and doses between 8 and 15 mg/kg were recommended for the phase 2 study.

https://ift.tt/2zrvA2P

Hypoalbuminemia is a Predictive Factor for Fistula Formation in Recurrent Cervical Cancer

Objective: Antivascular endothelial growth factor monoclonal antibodies inhibit tumor angiogenesis, consequently impeding the recruitment of new vasculature to existing and new tumor lesions. We sought to evaluate toxicities in women with recurrent cervical cancer after receiving bevacizumab combination chemotherapy. Methods: A review was conducted of women with recurrent and metastatic cervical cancer who were treated with salvage chemotherapy with or without bevacizumab between 2005 and 2015. Clinicopathologic data and reasons for treatment discontinuation were recorded. Patients that were excluded had other histology than squamous or adenocarcinoma, received 1 cycle of salvage chemotherapy, single agent bevacizumab, currently on treatment, or noncompliant. Statistical analysis was performed using the Fishers Exact Test, logistic regression, and Kaplan-Meier Survival Analysis. Results: A total of 74 patients were included in analysis. Twenty-six patients were treated with bevacizumab (BEV) and chemotherapy and 48 patients with chemotherapy alone (chemotherapy). The progression free survival was significant with median 12 months versus 7 months for the BEV cohort (P

https://ift.tt/2ONCwfH

Clinical Characteristics of Patients Experiencing Pathologic Complete Response Following Neoadjuvant Therapy for Borderline Resectable/Locally Advanced Pancreatic Adenocarcinoma

Objectives: The purpose of this study is to describe clinical characteristics and outcomes of patients with borderline resectable pancreatic cancer (BRPC) or locally advanced pancreatic cancer (LAPC) who achieved pathologic complete response (pCR) following neoadjuvant therapy. Materials and Methods: A single institution clinical database for patients with pancreatic ductal adenocarcinoma was queried. Between 2008 and 2014 patients were identified with BRPC and LAPC, who underwent surgical resection after receiving neoadjuvant treatment. Clinical and pathologic features of the patients who achieved pCR were acquired retrospectively. Results: Six patients were identified to have pCR on pathology of the postoperative specimen. On the basis of pretreatment clinical staging, 2 patients were considered to have BRPC and 4 LAPC. Four patients received gemcitabine-based chemotherapy and 2 patients received FOLFIRINOX (5-fluorouracil, oxaliplatin, irinotecan, and leucovorin). Five of 6 patients received radiation therapy before operative resection. Operative procedures included distal pancreatectomy (n=3) and pancreatoduodenectomy (n=3). Pancreatic intraepithelial neoplasia 1 to 2 was present in 3 cases, and pancreatic intraepithelial neoplasia 3 in 1 case. During a median follow-up of 21.3 months, 2 patients died, with a median survival of 11.0 months (range, 10.4 to 11.6 mo). Four patients are alive and continue to follow-up with median survival of 28.7 months (range, 20.1 to 42.4 mo). Conclusions: Multimodality neoadjuvant therapy may lead to complete pathologic response in a small number of patients with borderline resectable/locally advanced pancreatic adenocarcinoma. pCR to neoadjuvant therapy does not lead to cure in most cases, and the majority of patients appear to relapse locally or systemically.

https://ift.tt/2zqF8uD

Improving Patient-reported Pain During Radiotherapy Through Nurse Involvement and Patient Education

Objectives: Pain management during radiotherapy helps assess quality of care. By establishing an intervention to address pain during on-treatment visits (OTVs), we aim to lower patient-reported pain scores. Methods: A total of 171 patients were included in the analysis: 58 were retrospectively reviewed to provide a control and 113 were prospectively enrolled and evaluated after the intervention. The intervention included (1) a pain management in-service performed with the resident physician and nurses, (2) distribution of pain management educational materials, and (3) nurse consultation for patients with a pain score ≥5 within 2 days of the in-service. Study aims were to reduce the number of pain scores ≥5 by 30% and increase the number of pain scores documented during every OTV to >90%. Results: Median patient age was 65 years. Before the intervention, the average DVPRS score at initial consultation was 2 (range, 0 to 9) and 98% of patients had scores documented during OTVs. Overall, 26% (44/171) of OTV scores measured ≥5. Following the intervention, average DVPRS score at initial consultation was 2 (range, 0 to 10) and 99% of scores were documented during OTVs. About 14% (49/341) of patient-reported scores were ≥5, representing an ~50% relative reduction (P=0.023). The number of patients with 2+ pain scores ≥5 was reduced from 21% (12/58) before the intervention to 11% (12/109) after the intervention (P=0.1068). Conclusion: Involving nursing staff in the education and follow-up of patients with uncontrolled pain during radiotherapy led to an ~50% relative reduction in patient-reported DVPRS scores of 5+ during weekly OTVs.

https://ift.tt/2zs509B

Impact of Concomitant Urologic Intervention on Clinical Outcomes After Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy

Introduction: The impact of concomitant urologic procedures (UPs) on perioperative and long-term outcomes after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) is uncertain. Methods: In total, 935 consecutive CRS/HIPEC procedures were performed between 1996 and 2016 in Sydney, Australia. Among these, 73 (7.8%) involved concomitant UP. The association of concomitant UP with 21 perioperative outcomes and overall survival was assessed using univariate and multivariate analyses. Results: In-hospital mortality was 1.8%. Patients requiring UP were more likely to require transfusion of ≥5 units of red blood cells (P=0.031) and have a complete cytoreduction (79% vs. 60%, P

https://ift.tt/2OJl5wF

Quantifying Decreased Radiation Exposure From Modern CT Scan Technology and Surveillance Programs of Germ Cell Tumors

Introduction: Upgrading computerized tomography (CT) scanners to iterative reconstruction techniques (IRT) decreases radiation dose. This reduction, combined with changes in surveillance protocols in clinical stage I testicular cancer (CS1TC) measurably decrease the lifetime attributable risk (LAR) of dying of radiation-associated cancer. Materials and Methods: This IRB-approved study enrolled 24 CS1TC patients who had CT scans on the same Toshiba Aquilion 64 CT before and after IRT software installation. Dose-length product and CT dose index volume were recorded. A physicist calculated effective doses. Radiation doses were compared using the Wilcoxon signed rank test. Median effective dose per scan was multiplied by scan number based on 16 versus 7 scans in 5-year AS protocols to calculate estimated cumulative dose (ECD). LAR of dying of radiation-associated solid tumor was estimated using ECD for a single exposure at age 35 with the excess absolute risk transport model from the BEIR VII analysis of long-term atomic bomb survivors. Results: Median preupgrade and postupgrade effective doses were 12.5 and 7.7 mSv, respectively (P

https://ift.tt/2OS7h3n

Travel Distance as a Barrier to Receipt of Adjuvant Radiation Therapy After Radical Prostatectomy

Objectives: Following radical prostatectomy (RP), adjuvant radiation therapy (RT) decreases biochemical recurrence and potentially improves metastasis-free and overall survival for patients with high-risk pathologic features. Since adjuvant RT typically occurs daily over several weeks, the logistical challenges of extensive traveling may be a significant barrier to its use. We examined the association between distance to treatment facility and use of adjuvant RT. Materials and Methods: We identified 97,568 patients in the National Cancer Database diagnosed from 2004 through 2011 with cT1-4N0-xM0-x prostate cancer and found to have high-risk pathologic features (pT3-4 stage and/or positive surgical margins) at RP. Multivariable logistic regression adjusting for sociodemographic and clinicopathologic factors was used to examine the association between travel distance and receipt of adjuvant RT, defined as radiotherapy initiated within 12 months after RP. Results: Overall, 10.6% (10,346) of the study cohort received adjuvant RT. On multivariable analysis, increasing travel distance was significantly associated with decreased use of adjuvant RT, with adjusted odds ratios of 1.0 (reference), 0.67, 0.46, 0.39, and 0.32 (all P100.0 miles away, respectively. Conclusions: Increasing travel distance was strongly associated with decreased use of adjuvant RT in this national cohort of postprostatectomy patients with high-risk pathologic features. These results strongly suggest that the logistical challenges of extensive travel are a significant barrier to the use of adjuvant RT. Efforts aimed at improving access to radiotherapy and reducing treatment time are urgently needed.

https://ift.tt/2OS7gMR

Patterns of Adjuvant Therapy Utilization in Uterine Carcinosarcoma Stages I to III: A National Cancer Database Analysis

Objective: The objective of this study is to characterize patterns of utilization of adjuvant chemotherapy (CT) and radiotherapy (RT) in the posthysterectomy management of uterine carcinosarcoma (UCS) in the United States. Materials and Methods: We queried the National Cancer Database for women diagnosed with UCS between 2004 and 2012 and undergoing hysterectomy. Logistic regression was performed to identify sociodemographic, facility-specific, and treatment-related predictors of receiving multiagent chemotherapy, external beam radiotherapy (EBRT), or brachytherapy (BT). Results: In total 4272 patients were included, with 2 in 5 (40.5%) receiving no adjuvant therapy. Regarding RT, 2357 (55.1%) received neither EBRT nor BT, 929 (21.7%) received EBRT alone, 518 (12.1%) received BT alone, and 468 (11.0%) received EBRT+BT. Most women (70.8%) received no CT, a minority (1.5%) received single-agent CT, and the rest (27.8%) received multiagent chemotherapy. Logistic regression demonstrated disparities in receipt of adjuvant therapies by age, diagnosis year, insurance, facility volume, facility type, stage, and margin status, with patients with positive surgical margins less likely to receive BT. Conclusions: Following hysterectomy for UCS, a large proportion of women receives no CT and no RT in the United States. Multispecialty evaluation is critical for individualization of therapy and may address disparities in this aggressive disease.

https://ift.tt/2zrj3Mt

Oligorecurrent Nodal Prostate Cancer: Long-term Results of an Elective Nodal Irradiation Approach

Objectives: The objective of this study was to report long-term results of elective nodal radiotherapy (ENRT) in prostate cancer (PCa) patients with oligorecurrent nodal disease after primary treatment. Methods: Data of 53 oligorecurrent PCa patients (N1 and/or M1a) with ≤5 nodal metastases (n=108) treated with ENRT combined with androgen deprivation therapy (ADT) between 2004 and 2016 were retrospectively reviewed. Median prostate-specific antigen (PSA) and PSA doubling time (DT) were 3.4 ng/mL and 5 months, respectively. At restaging, 45% of the patients presented single nodal metastases, mainly located in the pelvis (n=38). All patients underwent ENRT between 45 and 50.4 Gy with a boost on positive nodes (median 64.4 Gy; 54 to 69 Gy) using mainly VMAT (n=24) or IMRT (n=21) techniques. Concomitant ADT was administered to all patients for a median time of 6 months. Results: After a median follow-up after ENRT of 44 months (range, 2 to 133), the 5-year biochemical disease-free and distant progression-free survival (DPFS) rates were 43% and 58%, respectively, with worse DPFS observed in patients with a PSA-doubling time

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Six-Year Results From a Phase I/II Trial for Hypofractionated Accelerated Partial Breast Irradiation Using a 2-Day Dose Schedule

Background: To report 6-year outcomes from a phase I/II trial using balloon-based brachytherapy to deliver APBI in 2 days. Methods: A total of 45 patients with early-stage breast cancer received adjuvant APBI in 2 days with high-dose rate (HDR) brachytherapy totaling 2800 cGy in 4 fractions (700 cGy BID) using a balloon-based applicator as part of a prospective phase I/II clinical trial. All patients had negative margins and skin spacing ≥8 mm. We evaluated toxicities (CTCAE v3) as well as ipsilateral breast tumor recurrence (IBTR), regional nodal failure (RNF), distant metastasis, disease-free survival, cause-specific survival, and overall survival. Results: Median age and tumor size were 66 years old (48 to 83) and 0.8 cm (0.2 to 2.3 cm), respectively. Four percent of patients were N1 (n=2) and 73% were estrogen receptor (ER) positive (n=32). Median follow-up was 6.2 years (2.4 to 8.0 y). Nearly all toxicities at 6 years were grade 1 to 2 except 1 instance of grade 3 telangiectasia (2%). Eleven percent (n=5) of patients had chronic asymptomatic fat necrosis whereas asymptomatic seromas were noted on mammogram in 13% of cases (n=6). Cosmesis at last follow-up was good or excellent in 91% of cases (n=40) and fair in 9% (n=4). Two of the previously reported rib fractures healed with conservative measures. There were no IBTR or RNF (6 y IBTR/RNF rate 0%); however, 2 patients experienced distant metastasis (4% at 6 y). The 6-year actuarial disease-free survival, cause-specific survival, and overall survival were 96%, 100%, and 93%, respectively. Conclusions: Hypofractionated 2-day APBI using brachytherapy resulted in excellent clinical outcomes with acceptable chronic toxicities.

https://ift.tt/2zrZB2w

Capecitabine and Celecoxib as a Promising Therapy for Thymic Neoplasms

Objectives: For patients with unresectable or metastatic thymic epithelial neoplasms, few therapy options are available and outcomes are poor. This case series demonstrates that the combination of capecitabine and celecoxib may be a promising therapeutic option for these patients. Materials and Methods: The current report describes the outcomes of 5 patients with thymic neoplasms treated on a drug-drug interaction study of capecitabine and celecoxib in patients with advanced solid malignancies (NCT01705106) conducted at the University of Chicago, plus a sixth patient treated with the same regimen outside of the protocol. Results: Six patients with thymic neoplasms were treated with capecitabine 1000 mg/m2 twice daily and celecoxib 200 mg twice daily, day 1 to day 14 on a 21-day cycle. This included 3 patients with thymic carcinoma, 1 with thymic neuroendocrine tumor, and 2 with thymomas. Objective response rates were noted in 3 of 6 patients. Two of the 3 thymic carcinoma patients had complete responses, and the third had a partial response. Best response for the other patients included stable disease for both thymoma patients and progressive disease for the thymic neuroendocrine patient. Other than grade 3 palmar-plantar erythrodysesthesia, which developed in 4 of 6 patients and required dose reductions, the regimen was well tolerated. Conclusions: This case series suggests that capecitabine plus celecoxib may be an effective and well-tolerated treatment option for patients with thymic carcinoma. Further studies should be carried out to establish the efficacy of capecitabine plus celecoxib in thymic carcinoma, and to determine whether monotherapy with capecitabine would be similarly effective.

https://ift.tt/2OO1JGY

Treatment Patterns Among Women Diagnosed With Stage I-III Triple-negative Breast Cancer

Objective: To examine contemporary treatment patterns for women diagnosed with stage I-III triple-negative breast cancer (TNBC) in the United States. Methods: We identified 48,961 patients diagnosed with stage I-III TNBC from 2010 to 2013 in the National Cancer Data Base and created 3 treatment subcohorts (definitive locoregional therapy [appropriate local therapy, including surgery/radiation], adjuvant chemotherapy [stage II-III disease or stage I tumors with tumor size ≥1 cm], and adjuvant chemotherapy for small tumors [stage I tumors with tumor size

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Dose Escalation Study of Concurrent Chemoradiotherapy With the Use of Involved-field Conformal Radiotherapy and Accelerated Hyperfractionation in Combination With Cisplatin and Vinorelbine Chemotherapy for Stage III Non–small Cell Lung Cancer: The Final Report

Objectives: A phase I study to determine a recommended dose of thoracic radiotherapy using accelerated hyperfractionation for unresectable non–small cell lung cancer was conducted. Materials and Methods: We used chemotherapy of a cisplatin doublet and 2 dose levels of radiation with accelerated hyperfractionation. The radiation dose levels were: a total dose of 60 Gy in 40 fractions at level 1, and 66 Gy in 44 fractions at level 2. Eligible patients with unresectable stage III non–small cell lung cancer received cisplatin and vinorelbine. Radiation therapy started on day 2 of chemotherapy and was delivered twice daily for 5 days a week. Results: Total 12 patients were enrolled, with 6 patients each at dose levels 1 and 2. Dose-limiting toxicity was noted in 2 patients at level 1; one patient had grade 3 febrile neutropenia and the other patient had grade 3 esophagitis. No dose-limiting toxicity was noted in the 6 patients at level 2. Grade 3 to 4 leukopenia, neutropenia, and anemia were noted in 11 (92%), 9 (75%), and 8 (67%) of the total 12 patients, respectively. Grade 3 anorexia and infection were noted in 2 patients (17%) at each level. Grade 3 nausea, fatigue, esophagitis, and febrile neutropenia were noted in 1 patient (8%) at each level. The response rate in the total 12 patients was 83.3%. The median progression-free survival time and the median overall survival time were 10.7 and 24.2 months, respectively. Conclusions: Sixty-six gray in 44 fractions is the recommended dose for the following phase II study.

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Patterns of Failure in Patients With Adult Medulloblastoma Presenting Without Extraneural Metastasis

Objectives: The objective of this study is to evaluate long-term outcomes, specifically patterns of tumor recurrence, in patients with adult medulloblastoma treated with radiotherapy. Methods: We recorded outcomes of 28 (median age, 25 y) patients 18 years old or above with M0 to M3 medulloblastoma treated between 1971 and 2012. Among them, 61% had standard-risk disease. All received craniospinal irradiation with a posterior fossa boost. Median dose to the craniospinal axis was 36 Gy. Median total dose to the primary site was 55.9 Gy and 46% received chemotherapy. Results: Median follow-up among survivors was 14.2 years. At 5 and 10 years, local control was 80% and 73%, overall survival was 71% and 59%, cause-specific survival was 71% and 63%, and freedom from progression was 68% and 59%. Tumors recurred in 11 patients (39%); median time to recurrence was 2.4 years, and 82% of recurrences developed in patients with standard-risk disease. Of the recurrences, 55% involved the primary site; 36% were bone metastases without neural axis recurrence. There were no isolated recurrences in the spinal canal or ventricular system outside of the posterior fossa. Conclusion: The primary site is the main site of medulloblastoma recurrence, with isolated bone metastases more common in adults than children. Our results prompt us to consider 4 modifications to our treatment approach with adults who present with medulloblastoma: (1) initial staging to include PET or bone scan; (2) radiotherapy dose to the primary site of 59.4 Gy; (3) chemotherapy during and/or following radiotherapy in medically fit patients; (4) follow-up to include PET or bone scan twice a year for 3 years.

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A Phase I Clinical Trial of the Phosphatidylserine-targeting Antibody Bavituximab in Combination With Radiation Therapy and Capecitabine in the Preoperative Treatment of Rectal Adenocarcinoma

Objectives: There is interest in improving the tumoricidal effects of preoperative radiotherapy for rectal carcinoma by studying new radiosensitizers. The safety and toxicity profile of these combination regimens needs rigorous clinical evaluation. The primary objective of this study was to evaluate the toxicity of combining bavituximab, an antibody that targets exposed phosphatidylserine, with capecitabine and radiation therapy. Materials and Methods: Patients with stage II or III rectal adenocarcinoma were enrolled on a phase I study combining radiation therapy, capecitabine, and bavituximab. A standard 3+3 trial designed was used. Results: In general, bavituximab was safe and well tolerated in combination with radiation therapy and capecitabine in the treatment of rectal adenocarcinoma. One patient at the highest dose level experienced a grade III infusion reaction related to the bavituximab. One tumor demonstrated a complete pathologic response to the combination treatment. Conclusions: Bavituximab is safe in combination with capecitabine and radiation therapy at the doses selected for the study. Further clinical investigation would be necessary to better define the efficacy of this combination.

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“Lost to Follow-up” Among Adult Cancer Survivors

Background: Follow-up cancer care is important for patients who have received IV chemotherapy but some patients discontinue their care and are lost to follow-up (LFU) at the cancer center where they were treated. The purpose of this study was to determine what proportion of cancer survivors are LFU at 5 years after treatment, the timing of LFU, and the characteristics of those who do not continue survivorship care. Methods: Adult patients with cancer who were treated with chemotherapy at a large community teaching hospital in 2006 and 2007 were identified and linked with State tumor registry data. Hospital medical records were reviewed to obtain information on demographics, diagnosis, treatment, and date of last follow-up visit. Characteristics of patients with ≥5 years of follow-up care were compared with those who were LFU. Results: In total, 487 patients received chemotherapy and 304 died (62%) during the 5-year follow-up period. Among the 183 cancer patients who were known to be alive at 5 years, 92 (50%) were LFU and 50% (46/92) of this LFU group were LFU within 1 year of diagnosis. At 5 years, follow-up care was continuing for 55% of women, compared with 39% of men. The highest proportion of follow-up was observed among lung cancer patients (84%), followed by patients with breast cancers (63%) and gastrointestinal cancers (40%). Patients with hematological cancers had the lowest follow-up proportion at 5 years (29%) (P

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Phase I/II Study of S-1 Plus Cisplatin Alternating With S-1 Plus Docetaxel in Patients With Advanced Gastric Cancer

Objectives: To investigate the usefulness of S-1 plus cisplatin alternating with S-1 plus docetaxel as first-line treatment in patients with advanced gastric cancer, we conducted a phase I/II study to determine the maximum tolerated dose and recommended dose, and evaluate efficacy and toxicity. Materials and Methods: Patients with histologically confirmed unresectable and recurrent gastric cancer were enrolled in this study. Cisplatin was administered on day 1 and the dose escalated by 10 mg/m2 from a starting dose of 40 mg/m2 in the phase I part. S-1 was given orally at 80 mg/m2 on days 1 to 14 and docetaxel at 40 mg/m2 on day 22 in combination with S-1 80 mg/m2 on days 22 to 35. The treatment was repeated every 6 weeks. The primary endpoint of the phase II analysis was the response rate. Results: Nine patients entered the phase I and 24 the phase II part. Because 50% of patients (3/6) developed dose-limiting toxicities in the phase I part, the maximum tolerated dose of cisplatin was presumed to be 50 mg/m2. Therefore, the estimated recommended dose of cisplatin was 40 mg/m2; 27 patients received that dose. The response rate was 59.3% (95% confidence interval, 40.8-77.8) and the median follow-up 26.2 months. The median progression-free survival was 7.9 months and the median overall survival 18.6 months. The most common grade 3/4 toxicities were neutropenia (59.3%), leucopenia (37.0%), and anemia (29.6%). These toxicities were tolerable and manageable. Conclusion: This alternating treatment seems to have promising activity with tolerable toxicities in the first-line treatment of patients with advanced gastric cancer.

https://ift.tt/2OOpvm0

Effect of Variation in Published Stroke Rates on the Net Clinical Benefit of Anticoagulation for Atrial Fibrillation

Background:

Stroke rates in patients with nonvalvular atrial fibrillation (AF) who are not receiving anticoagulant therapy vary widely across published studies; the resulting effect on the net clinical benefit of anticoagulation in AF is unknown.

Objective:

To determine the effect of variation in published AF stroke rates on the net clinical benefit of anticoagulation.

Design:

Markov model decision analysis. Warfarin was the base case, and non–vitamin K antagonist oral anticoagulants (NOACs) were modeled in a secondary analysis.

Setting:

Community-dwelling adults.

Patients:

33 434 adults with incident AF.

Measurements:

Quality-adjusted life-years (QALYs).

Results:

Of the 33 434 patients, 27 179 had a CHA₂DS₂-VASc (congestive heart failure, hypertension, age, diabetes, stroke, and vascular disease) score of 2 or more. The population benefit of warfarin anticoagulation for these patients was least using stroke rates from the ATRIA (AnTicoagulation and Risk Factors In Atrial Fibrillation) study and greatest using those from the Danish National Patient Registry (6290 QALYs [95% CI, ± 2.3%] vs. 24 110 QALYs [CI, ± 1.9%]; P < 0.001). The optimal CHA₂DS₂-VASc score threshold for anticoagulation was 3 or more using stroke rates from ATRIA, 2 or more using those from the Swedish AF cohort study, 1 or more using those from the SPORTIF (Stroke Prevention using ORal Thrombin Inhibitor in atrial Fibrillation) study, and 0 or more using those from the Danish National Patient Registry. Accounting for lower rates of NOAC-associated intracranial hemorrhage decreased optimal CHA₂DS₂-VASc score thresholds, but these thresholds still varied widely.

Limitation:

Measured benefit may not generalize to other populations.

Conclusion:

Variation in published AF stroke rates for patients not receiving anticoagulant therapy results in multifold variation in the net clinical benefit of anticoagulation. Guidelines should better reflect the uncertainty in current thresholds of stroke risk score for recommending anticoagulation.

Primary Funding Source:

None.

https://ift.tt/2IbVGcG

Stroke Rates, Atrial Fibrillation, and Drugs to Prevent Blood Clots

https://ift.tt/2pxbBtB

Oversight of Patient-Centered Outcomes Research: Recommendations From a Delphi Panel

A key aim of patient-centered outcomes research (PCOR) is to generate data that are important to patients by deliberately and extensively involving them in all aspects of research, from design to dissemination. However, certain elements of PCOR raise challenging and potentially novel ethical and regulatory issues for institutional review boards and oversight bodies. These challenges stem primarily from the engagement of patients in roles other than research subject, such as advisors, study personnel, and co-investigators, which gives rise to questions about appropriate levels of protection, training, and education, as well as identifying and managing conflicts of interest. This article presents and discusses recommendations from a Delphi expert panel that was convened to address these and other PCOR-related oversight challenges.

https://ift.tt/2Ihg6RP

Atrial Fibrillation and Anticoagulation: One Size Fits All?

In their article, Shah and colleagues demonstrate vulnerability in the assumption of a universal net benefit of anticoagulation for a specific CHA₂DS₂-VASc score by applying analytic models of the score to 4 cohorts. The editorialists discuss the findings and their implications.

https://ift.tt/2pz7flW

Dying Healthy: Public Health Priorities for Fixed Population Life Expectancies

Recent evidence suggests that the human lifespan has an unalterable biological limit of approximately 115 years and that virtually all humans will die before age 90 years. The authors suggest that it is time to shift our research priorities and resources toward identifying ways to improve quality of life throughout the lifespan and to delay illness to the shortest period possible near the end of life.

https://ift.tt/2IbVkCS

A Beginning to Principles of Ethical and Regulatory Oversight of Patient-Centered Research

This issue includes recommendations on ethical and regulatory issues related to the involvement of patients in the research process, which were produced by a panel funded by the Patient-Centered Outcomes Research Institute. The editorialist discusses the recommendations and explains why the direct and continuous involvement of patients in the design, conduct, and reporting of clinical research represents a notable improvement in clinical trial methodology.

https://ift.tt/2pxOor6

Single-Agent Immunotherapy for Two Types of Cancer in One Patient

https://ift.tt/2Iab5u1

Medicinal properties of Clerodendrum glaburum E may leaf extracts: phytochemical constituents, antioxidant, cytotoxicity, and carbohydrate-metabolizing enzyme inhibitory potentials

Abstract

The phytochemical constituents, antioxidant, and cytotoxicity as well as the inhibitory potentials of Clerodendrum glaburum on key carbohydrate metabolizing enzymes were investigated. The plant sample was extracted separately with hexane, EtOAc, MeOH, and water. The phytochemical analysis and antioxidant assays of the extracts were achieved using standard procedures; the antidiabetic capability of the extracts against the actions of α-amylase and α-glucosidase was examined while their cytotoxicity was tested against Vero cells. Highest quantity of phenol (65.97 mg gallic acid g⁻¹), flavonoid (47.02 mg quercetin g⁻¹), and flavanol (173.74 mg catechin g⁻¹) were observed in MeOH extract. Also, MeOH extract had the most potent ability (p < 0.05) to scavenge ABTS (0.05 mg/mL), DPPH (0.17 mg/mL), and superoxide anion (0.36 mg/mL) than other extracts and standards. Stronger inhibition (p < 0.05) against metal chelation (26.41 mg/mL) and FRAP (5.92 mg/mL) were observed in water extract compared to other extracts; it also competes favorably with the standard. EtOAc extract displayed best scavenging potentials (p < 0.05) against hydroxyl radical than other extracts. Methanol (0.71 mg/mL) and aqueous (0.19 mg/mL) extracts displayed more potent inhibition against the actions of α-amylase and α-glucosidase respectively compared to acarbose and other extracts. Hexane extract displayed better antidiabetic activities as revealed by its moderate α-amylase (2.54 mg/mL) and potent α-glucosidase (0.53 mg/mL) inhibitions compared to acarbose. The hexane, methanol, and aqueous extracts were non-toxic against Vero cells, with LC₅₀ of 0.11, 0.23, and 0.52 mg/mL respectively. C. glaburum leaves contain active phytochemicals that can be beneficial in managing diabetes and other oxidative stress-induced disorders.

https://ift.tt/2zraK3u

Actigraphy May Overestimate Sleep in ICU Setting

MONDAY, Sept. 24, 2018 -- Using actigraphy as a measure of sleep, critically ill patients in the intensive care unit (ICU) show wide ranges of sleep quality and quantity, and actigraphy may estimate higher sleep durations than other measures,...

https://ift.tt/2zrBEIq

Brain Iron on MRI Linked to Disability in Multiple Sclerosis

MONDAY, Sept. 24, 2018 -- Brain iron at quantitative magnetic resonance imaging (MRI) is associated with disability in multiple sclerosis (MS), according to a study recently published in Radiology. Robert Zivadinov, M.D., Ph.D., from the University...

https://ift.tt/2OPCZhl

Patients Report Poorer Dialysis Service in Certain Settings

MONDAY, Sept. 24, 2018 -- Patient-reported experiences at dialysis facilities vary by patient, facility, and geographic characteristics, according to a study published online Sept. 10 in JAMA Internal Medicine. Brian M. Brady, M.D., from Stanford...

https://ift.tt/2zr5ehb

Most Breast Cancer Diagnoses Given Over the Phone

MONDAY, Sept. 24, 2018 -- Currently, most patients receiving a breast cancer diagnosis receive the information over the phone, according to a study published online Aug. 7 in Supportive Care in Cancer. Jane A. McElroy, Ph.D., from the University of...

https://ift.tt/2ON5nkh

Multiple Pathways Explain Age-Linked Increase in Dementia Risk

MONDAY, Sept. 24, 2018 -- Multiple pathways account for the age-related increases in dementia risk, according to a study recently published in the Annals of Neurology. Melinda C. Power, Sc.D., from the George Washington University Milken Institute...

https://ift.tt/2zrBCQO

Simplifying Medicare Plan Finder Improves Plan Selection

MONDAY, Sept. 24, 2018 -- Simplifying an internet-based decision support tool provided by the Centers for Medicare & Medicaid Services to help older adults make good plan choices in the Medicare prescription drug (Part D) program could result in...

https://ift.tt/2ONJj9k

Heart Failure Patients Enrolled in Hospice Use Less Health Care

MONDAY, Sept. 24, 2018 -- Patients with advanced heart failure enrolled in hospice have fewer emergency department visits, hospital days, and intensive care unit (ICU) stays, according to a study published in the September issue of JACC: Heart...

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Mortality for Unintentional Drug Poisonings Up Since 1979

MONDAY, Sept. 24, 2018 -- Since at least 1979, there has been an exponential increase in the overall mortality rate for unintentional drug poisonings, according to a research article published online Sept. 21 in Science. Hawre Jalal, M.D., Ph.D.,...

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MRI Indicates Sacroiliitis in Some Healthy Individuals

MONDAY, Sept. 24, 2018 -- Magnetic resonance imaging (MRI) positive for sacroiliitis is seen in a considerable number of healthy individuals without back pain, according to a study recently published in Arthritis & Rheumatology. Janneke de...

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Prenatal, Postnatal Homelessness Tied to Poor Health in Children

MONDAY, Sept. 24, 2018 -- Homelessness is associated with an increased risk of adverse pediatric outcomes regardless of whether it occurs prenatally or postnatally, according to a study published online Sept. 3 in Pediatrics. Megan Sandel, M.D.,...

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Rifampin resistance in staphylococci after rifaximin intake for surgical prophylaxis in elective colorectal surgery. [Susceptibility]

The aim of our study was to determine whether rifampin-resistance emerges in human skin staphylococci after oral intake of rifaximin for surgical prophylaxis. Rifampin-resistant staphylococci appeared on the skin of 32 out of 74 patients (43.2%) two weeks after prophylactic treatment with rifaximin. In all cases the resistant strains were coagulase-negative staphylococci. The resistance was completely reverted after three months. This study shows the emergence of transient resistance to rifampin after rifaximin intake.

https://ift.tt/2O9pBHQ

In vivo efficacy of ellagic acid against Candida albicans in a Drosophila melanogaster infection model [Pharmacology]

The aim of this study was to evaluate the antifungal activity and the toxicity of ellagic acid (EA) using a Drosophila melanogaster model. Candida albicans was inoculated in Toll heterozygous flies. Survival curves were obtained for the evaluation of the antimicrobial effect and toxicity of EA. A protective effect of Drosophila melanogaster from fungal infection was observed at non-toxic concentrations. This study showed that EA is promising for the treatment of candidiasis.

https://ift.tt/2OM1xI5

Site-directed mutagenesis of the 1,3-{beta} glucan synthase catalytic subunit of Pneumocystis jirovecii and susceptibility assays suggest its sensitivity to caspofungin [Susceptibility]

The echinocandin caspofungin inhibits the catalytic subunit Gsc1 of the enzymatic complex synthetizing 1,3-β glucan, an essential compound of the fungal wall. Studies in rodents showed that caspofungin is effective against Pneumocystis asci. However, its efficacy against asci of Pneumocystis jirovecii, the species infecting exclusively humans, remains controversial. The aim of this study was to assess the sensitivity to caspofungin of the P. jirovecii Gsc1 subunit, as well as of those of Pneumocystis carinii and Pneumocystis murina infecting respectively rats and mice. In absence of an established in vitro culture method for Pneumocystis species, we used functional complementation of the Saccharomyces cerevisiae gsc1 deletant. In the fungal pathogen Candida albicans, mutations leading to amino acid substitutions in Gsc1 confer resistance to caspofungin. We introduced the corresponding mutations into the Pneumocystis gsc1 genes using site-directed mutagenesis. In spot dilution tests, the sensitivity to caspofungin of the complemented strains decreased with the number of mutations introduced, suggesting that the wild-type enzymes are sensitive. The minimum inhibitory concentrations of caspofungin determined by E-test and Yeastone for strains complemented with Pneumocystis enzymes (respectively 0.125 and 0.12 microg/ml) were identical to those upon complementation with the enzyme of C. albicans for which caspofungin presents low MICs. However, they were lower than the MICs upon complementation with the enzyme of the resistant species Candida parapsilosis (0.19 and 0.25). Sensitivity levels of Gsc1 enzymes of the three Pneumocystis species were similar. Our results suggest that P. jirovecii is sensitive to caspofungin during infections, as P. carinii and P. murina.

https://ift.tt/2O9pBaO

A large, refractory nosocomial outbreak of Klebsiella pneumoniae carbapenemase (KPC)-producing Escherichia coli demonstrates carbapenemase gene outbreaks involving sink sites require novel approaches to infection control [Epidemiology and Surveillance]

Carbapenem-resistant Enterobacteriaceae (CRE) are a health threat, but effective control interventions remain unclear. Hospital wastewater sites are increasingly highlighted as important potential reservoirs. We investigated a large Klebsiella pneumoniae carbapenemase (KPC)-producing E. coli (KPC-EC) outbreak and wider CRE incidence trends over eight years in the Central Manchester Foundation NHS Trust (CMFT), UK, to determine the impact of Infection Prevention and Control measures.

Bacteriology and patient administration data (2009 to 2017) were linked; a subset of CMFT/regional KPC-EC isolates (n=268) was sequenced. Control interventions followed international guidelines and included cohorting, rectal screening (n=184,539 screens), environmental sampling, enhanced cleaning, and ward closure/plumbing replacement. Segmented regression of time trends of CRE detections was used to evaluate the impact of interventions on CRE incidence.

Genomic analysis (n=268 isolates) identified spread of a KPC-EC outbreak clone (ST216, strain-A; n=125) amongst patients and the environment, particularly on two cardiac wards (W3/W4), despite control measures. ST216 strain-A had caused an antecedent outbreak, and shared its KPC plasmids with other E. coli lineages and Enterobacteriaceae. CRE acquisition incidence declined after W3/W4 closure and plumbing replacement, suggesting an environmental contribution. However, W3/W4 wastewater sites were rapidly re-colonised with CRE and patient CRE acquisitions recurred, albeit at lower rates.

Patient relocation and plumbing replacement were associated with control of a clonal KPC-EC outbreak; however, environmental contamination with CRE and patient CRE acquisitions recurred rapidly following this intervention. The large numbers of cases and persistence of bla_KPC in E. coli, including pathogenic lineages, is a concern.

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Microbiological Analysis From a Phase 2 Randomized Study in Adults Evaluating Single Oral Doses of Gepotidacin in the Treatment of Uncomplicated Urogenital Gonorrhea Caused by Neisseria gonorrhoeae [Clinical Therapeutics]

We evaluated microbiological correlates of successful treatment of Neisseria gonorrhoeae isolates from a Phase 2 study of gepotidacin, a novel triazaacenaphthylene antibacterial, for therapy of uncomplicated urogenital gonorrhea. Culture, susceptibility testing, genotypic characterization, and frequency of resistance (FoR) were performed for selected isolates. Microbiological success was defined as culture-confirmed eradication of N. gonorrhoeae. Against 69 baseline urogenital isolates, gepotidacin MICs ranged from ≤0.06 to 1 µg/mL (MIC₉₀ = 0.5 µg/mL). For gepotidacin, the ratio of the area under the free-drug concentration-time curve to MIC (fAUC/MIC) was associated with therapeutic success. Success was 100% (61/61) at fAUC/MICs ≥48 and decreased to 63% (5/8) for fAUC/MICs ≤25. All 3 isolates from microbiological failures were ciprofloxacin-resistant, had a baseline gepotidacin MIC of 1 µg/mL, and carried a pre-existing ParC D86N mutation, a critical residue for gepotidacin binding. At test-of-cure, resistance to gepotidacin emerged in 2 isolates (MICs increased ≥32-fold) with an additional GyrA A92T mutation, also implicated in gepotidacin binding. Test-of-cure isolates had the same sequence type as the corresponding baseline isolates. For 5 selected baseline isolates, all carrying a ParC D86N mutation, in vitro FoR to gepotidacin was low (10^–9 to 10^–10); resistant mutants had the same A92T mutation as the 2 emergence of resistance isolates. Five participants with isolates with a ParC D86N mutation were successes. In summary, fAUC/MICs ≥48 predicted 100% microbiological success, including 3 isolates with the ParC D86N mutation (fAUC/MICs ≥97). Pharmacokinetic/pharmacodynamic determinations may help to evaluate new therapies for gonorrhea; further study of gepotidacin is warranted.

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The combination of fosfomycin plus meropenem is synergistic for Pseudomonas aeruginosa PA01 in a Hollow Fiber Infection Model (HFIM). [Experimental Therapeutics]

Treating high-density bacterial infections is a challenging clinical problem. We have a paucity of new agents that can address this problem. Pseudomonas aeruginosa is a particularly difficult pathogen to treat effectively because of the plethora of resistance mechanisms it carries.

Fosfomycin is an agent discovered circa 40 years ago. Recently it has been resurrected in the United States and studied for intravenous therapy. We hypothesized that to maximize its utility, it would require combination chemotherapy when used in a clinical circumstance in high bacterial burden infections.

We chose to examine the combination of meropenem plus fosfomycin. These agents were studied in the Hollow Fiber Infection Model. We utilized a fully factorial study design, looking at 2 doses of meropenem alone (1 and 2 g 8 hourly) and two doses of fosfomycin alone (6 and 8 g 8 hourly) as well as all possible combinations plus a no-treatment control.

We used a high dimensional model of 5 inhomogeneous differential equations with 5 system outputs to analyze all data simultaneously. Combination therapy outperformed all monotherapy regimens, with all combinations driving > 6 Log₁₀(CFU/ml) bacterial kill. Combination therapy was able to counterselect resistance emergence (meropenem mutants being killed by the combination as well as fosfomycin mutants being killed by the combination) in all regimens studied. The analysis demonstrated that the combination was significantly synergistic for bacterial cell kill and resistance suppression. Meropenem plus fosfomycin is a promising combination for therapy of high burden Pseudomonas aeruginosa infections and requires further study.

https://ift.tt/2OLkKJZ

AN ASSESSMENT OF QUALITY INDICATORS FOR APPROPRIATE ANTIBIOTIC USE [Epidemiology and Surveillance]

One of the critical elements of antimicrobial stewardship programs is the ability to measure the quality of antibiotic prescription. The aim of the present study was to evaluate the performance properties of a set of previously developed quality indicators (QIs) and to identify the potential room for improvement in antibiotic use in our setting. A monthly cross sectional point prevalence survey was conducted in a 400-bed acute care teaching hospital from June to November 2015. All adult patients treated at least 24 hours with antibiotic therapy for a suspected hospital or community-acquired bacterial infection were included. Performance scores (adherence, room for improvement, inter-observer reliability and applicability) were calculated for eight QIs.

Three hundred sixty two patients were evaluated. Adherence to the whole set of QIs was accomplished in 14.1% of evaluable patients. The QIs with a higher room for improvement were: adequate request of blood cultures (60.6%), therapeutic drug monitoring (TDM) (59.1%), sequential antibiotic therapy within 72 hours (48.2%) and empirical antibiotic therapy according to the local guideline (30.4%). The rate of patients under unnecessary antibiotic treatment in the absence of clinical or microbiological evidence of infection after 5 days was 12.2%. All indicators scored kappa's ≥ 0.6, suggesting good inter-observer reliability. Low applicability (6.1% of reviewed patients) only was found for the TDM QI. The QIs analyzed were found to be applicable, showed a good inter-observer reliability and were useful tools to identify areas with potential room for improvement in antibiotic use.

https://ift.tt/2O5EsTI

A hyperactive form of the zinc cluster transcription factor Stb5 causes YOR1 overexpression and beauvericin resistance in Candida albicans [Mechanisms of Resistance]

Gain-of-function mutations in the zinc cluster transcription factors Mrr1, Tac1, and Upc2, which result in constitutive overexpression of their target genes, are a frequent cause of fluconazole resistance in the pathogenic yeast Candida albicans. In this study, we show that an activated form of another zinc cluster transcription factor, Stb5, confers resistance to the natural compound beauvericin by overexpression of YOR1, encoding an efflux pump of the ATP-binding cassette transporter superfamily. Beauvericin has recently been shown to potentiate the activity of azole drugs against C. albicans. Although Yor1 did not contribute to fluconazole resistance when C. albicans cells were treated with the drug alone, Stb5-mediated YOR1 overexpression diminished the synergistic effect of the fluconazole/beauvericin combination, thereby enhancing fluconazole resistance in beauvericin-treated C. albicans cells. Stb5-mediated YOR1 overexpression also suppressed the inhibition of hyphal growth, an important virulence trait of C. albicans, by beauvericin. Therefore, activating mutations in Stb5, which result in constitutive YOR1 overexpression, may enable C. albicans to acquire resistance to beauvericin and thereby overcome both the sensitization to azole drugs and the inhibition of morphogenesis caused by this compound.

https://ift.tt/2ONHmK2

In silico investigation of the decline in clinical efficacy of artemisinin combination therapies due to increasing artemisinin and partner drug resistance [Mechanisms of Resistance]

Antimalarial treatment currently relies on an artemisinin derivative and a longer acting partner drug. With the emergence of resistance to the artemisinin derivatives and the potential pressure this exerts on the partner drugs, the impact of resistance to each drug on efficacy needs to be investigated. An in silico exploration of dihydroartemisinin-piperaquine and mefloquine-artesunate, two commonly used artemisinin-based combination therapies in Southeast Asia, was performed. The percentage of treatment failures was simulated from a within-host pharmacokinetic-pharmacodynamic (PKPD) model assuming parasites developed increasing levels of (i) artemisinin derivative resistance or (ii) concomitant resistance to both the artemisinin derivative and partner drug. Because the exact nature of how resistant Plasmodium falciparum parasites respond to treatment is unknown, we examined the impact on treatment failure rates of artemisinin resistance that either: (i) reduced the maximal killing rate (k_max); (ii) increased the concentration of drug required for 50% killing (EC50); or (iii) shortened the window of parasite stages that are susceptible to artemisinin derivatives until it has no effect on the ring stages. The loss of the ring stage activity of the artemisinin derivative caused the greatest increase in the treatment failure rate, and this result held irrespective of whether partner drug resistance was assumed present or not. To capture the uncertainty around how artemisinin derivative and partner drug resistance impact the assumed concentration-killing effect relationship, a variety of changes to this relationship should be considered when using within-host PKPD models to simulate clinical outcomes to guide treatment strategies for resistant infections.

https://ift.tt/2O5vjKV

Predicting the Outcomes of New Short-Course Regimens for Multi-Drug Resistant Tuberculosis Using Intrahost and Pharmacokinetic-Pharmacodynamic Modelling [Epidemiology and Surveillance]

Short-course regimens for multi-drug resistant tuberculosis (MDR-TB) are urgently needed. Limited data suggest that the new drug, bedaquiline (BDQ), may have the potential to shorten MDR-TB treatment to less than six months when used in conjunction with standard anti-TB drugs. However, the feasibility of BDQ in shortening MDR-TB treatment duration remains to be established. Mathematical modelling provides a platform to investigate different treatment regimens and predict their efficacy. We developed a mathematical model to capture the immune response to TB inside a human host environment. This model was then combined with a pharmacokinetic-pharmacodynamic model to simulate various short-course BDQ-containing regimens. Our modelling suggests that BDQ could reduce MDR-TB treatment duration to just 18 weeks (four months) while still maintaining a very high treatment success rate (100% for daily BDQ for two weeks, or 95% for daily BDQ for one week during the intensive phase). The estimated time to bacterial clearance of these regimens ranges from 27 to 33 days. Our findings provide the justification for empirical evaluation of short-course BDQ-containing regimens. If short-course BDQ-containing regimens are found to improve outcomes then we anticipate clear cost-savings and a subsequent improvement in the efficiency of national TB programs.

https://ift.tt/2OLQkaw

Enterobacter cloacae complex ST-171 Isolates Expressing KPC-4 Carbapenemase Recovered from Canine Patients in Ohio, USA [Epidemiology and Surveillance]

Companion animals are likely relevant in the transmission of antimicrobial resistant bacteria in the community. Enterobacter xiangfangensis ST171, a clone that has been implicated in clusters of infections in humans, was isolated from two dogs with clinical disease in Ohio, U.S. The canine isolates contained IncHI2 plasmids encoding bla_KPC-4. Whole genome sequencing was used to put the canine isolates in phylogenetic context with available human ST171 sequences, as well as characterize their bla_KPC-4 plasmids.

https://ift.tt/2O5ElYi

The Activity of Moxifloxacin against Acid-Phase and Non-Replicative Persister Phenotype Phase Mycobacterium tuberculosis in a Hollow Fiber Infection Model [Experimental Therapeutics]

A major goal for improving tuberculosis therapy is to identify drug regimens with improved efficacy and shorter treatment durations. Shorter therapies improve patient adherence to the antibiotic regimens that, in turn, decreases resistance emergence.

M. tuberculosis exists in multiple metabolic states. At the initiation of therapy, the bulk of the population is in Log-Phase growth. Consequently, it is logical to focus initial therapy on these organisms. Moxifloxacin has good early bactericidal activity against Log-Phase growth bacteria and is a logical component of initial therapy. It would be optimal if this agent also possessed activity against Acid-Phase and Non-Replicative Persister (NRP) Phenotype organisms. We studied multiple exposures to moxifloxacin (equivalent to 200 mg-800 mg daily) in our Hollow Fiber Infection Model against strain H37Rv in Acid-Phase and against strain 18b in streptomycin starvation, which is a model for NRP-Phase organisms.

Moxifloxacin possesses good activity against Acid-Phase organisms, generating from 3.75 Log₁₀(CFU/ml) cell kill (200 mg daily) to 5.16 Log₁₀(CFU/ml) cell kill (800 mg daily) over the 28 days of the experiment.

Moxifloxacin also has activity against the streptomycin-starved strain 18b. The 400 to 800 mg daily regimens achieved extinction at day 28, while the no-treatment control still had 1.96 Log₁₀(CFU/ml) culturable. The lowest dose (200 mg daily) still had 0.7 Log₁₀(CFU/ml) measurable at day 28, a net kill of 1.26 Log₁₀(CFU/ml).

Moxifloxacin is an attractive agent for early therapy, as it possesses activity against three metabolic states of M. tuberculosis.

https://ift.tt/2OOJilg

"Electrocardiographic safety of repeated monthly dihydroartemisinin-piperaquine as a candidate for mass drug administration" [Clinical Therapeutics]

Background: Mass drug administration (MDA) of sequential rounds of antimalarial drugs is being considered as a tool for malaria elimination. As an effective and long-acting antimalarial, Dihydroartemisinin-piperaquine (DHA/PQP) appears suitable as a candidate for MDA. However, absence of cardiac safety data following repeated administration hinders its use in the extended schedules proposed for MDA.

Methods: We conducted an interventional study in Lihir Island, Papua New Guinea, with healthy individuals aged 3 to 60 years who received a standard 3-day course of DHA/PQP on 3 consecutive months. Twelve-lead electrocardiography (ECG) readings were conducted pre-dose and 4h after the final dose of each month. The primary safety endpoint was QTc (using Fridericia's correction; QTcF) prolongation from baseline to 4h post-dosing. We compared the difference in prolongation between the third course post-dose and the first course post-dose.

Results: Of 84 enrolled participants, 69 (82%) completed all treatment courses and ECG measurements. The average increase in QTcF was 19.6 ms (SD 17.8) and 17.1 ms (SD 17.1) for the first-course and third-course post-dosing ECGs [risk difference -2.4 (95%CI - 6.9 to 2.1), p=0.285], respectively. We recorded QTcF prolongation >60 ms from baseline in 3 (4.3%) and 2 (2.9%) participants after the first course and third course (p=1.00), respectively. No participants had QTcF intervals >500 ms at any time point.

Conclusions: Three consecutive monthly courses of DHA/PQP were as safe as a single course. The absence of cumulative cardiotoxicity with repeated dosing support the use of monthly DHA/PQP as part of malaria elimination strategies.

https://ift.tt/2O9mX4M

In vitro activity of ceftazidime-avibactam and aztreonam-avibactam against OXA-48-carrying Enterobacteriaceae isolated as part of the International Network for Optimal Resistance Monitoring (INFORM) global surveillance program, 2012 to 2015 [Epidemiology and Surveillance]

Enterobacteriaceae producing the Ambler class D OXA-48 carbapenemase combined with additional resistance mechanisms, such as permeability defects or co-carriage of class A, B or C β-lactamases, can become highly resistant to most β-lactams currently in use, including carbapenems. A total of 45,872 Enterobacteriaceae clinical isolates collected in 39 countries as part of the International Network for Optimal Resistance Monitoring (INFORM) global surveillance study in 2012 to 2015 were tested for susceptibility to β-lactams and comparator agents by Clinical and Laboratory Standards Institute broth microdilution methodology and screened for the presence of β-lactamases. bla_OXA-48 and bla_OXA-48-like were detected in 333 isolates across 14 species of Enterobacteriaceae collected in 20 countries across the globe. Few agents tested were effective in vitro against the overall collection of OXA-48-producers (n=265), with tigecycline (MIC₉₀, 2 µg/mL; 92.5% susceptible), ceftazidime-avibactam (MIC₉₀, 4 µg/mL; 92.5% susceptible) and aztreonam-avibactam (MIC₉₀, 0.5 µg/mL; 99.6% of isolates testing with MIC ≤8 µg/mL) demonstrating the greatest activity. Similarly, colistin (MIC₉₀, 1 µg/mL; 94.2% susceptible), tigecycline (MIC₉₀, 2 µg/mL; 92.6% susceptible), ceftazidime-avibactam (MIC₉₀, >128 µg/mL; 89.7% susceptible), and aztreonam-avibactam (MIC₉₀, 4 µg/mL; 100% of isolates testing with MIC ≤8 µg/mL) were most active against OXA-48-like positive isolates (n=68). The in vitro activity of ceftazidime-avibactam was improved against the subset of metallo-β-lactamase (MBL)-negative, OXA-48- and OXA-48-like-positive isolates (99.2% and 100% susceptible, respectively). The data reported here support the continued investigation of ceftazidime-avibactam and aztreonam-avibactam for treatment of infections caused by carbapenem-resistant Enterobacteriaceae carrying OXA-48 and OXA-48-like β-lactamases in combination with serine- or metallo-β-lactamases.

https://ift.tt/2OUQqMY

Detection of carbapenemases-producing Enterobacteriaceae in positive blood culture using Immunochromatographic RESIST-4 O.K.N.V assay [Epidemiology and Surveillance]

We evaluated the performances of the RESIST-4.O.K.N.V assay (Coris®) on 98 isolates to detect OXA-48-like, KPC-, NDM- and VIM-type carbapenemases directly on positive human blood cultures. OXA-48-like and KPC-type isolates were correctly detected but detection of NDM and VIM-type was weak and variable. We show that repeating the test on a 4-hour subculture improves the detection of NDM- and VIM-type to 100%.

https://ift.tt/2O4auQ4

Investigating sulfoxide to sulfone conversion as a prodrug strategy for a PI4K inhibitor in a humanized mouse model of malaria [Experimental Therapeutics]

The in vivo antimalarial efficacies of two PI4K inhibitors, a 3,5-diaryl-2-aminopyrazine sulfoxide and its corresponding sulfone metabolite, were evaluated in the NOD-scid IL2R^null (NSG) murine malaria disease model of Plasmodium falciparum infection. We hypothesized that the sulfoxide would serve as a more soluble prodrug for the sulfone, which would lead to improved drug exposure on oral dosing. Both compounds had similar efficacy (ED₉₀ 0.1 mg.kg^–1) across a quadruple-dose regimen. Pharmacokinetic profiling revealed rapid sulfoxide clearance via conversion to the sulfone with the latter identified as the major active metabolite. When the sulfoxide was dosed, the exposure of the sulfone achieved was as much as 2.9-fold higher than when the sulfone was directly dosed, thereby demonstrating that the sulfoxide served as an effective prodrug for the treatment of malaria.

https://ift.tt/2ORyTWl

TRPM2 modulates neutrophil attraction to murine tumor cells by regulating CXCL2 expression

Abstract

In recent years, immune cells were shown to play critical roles in tumor growth and metastatic progression. In this context, neutrophils were shown to possess both pro- and anti-tumor properties. To exert their anti-tumor effect, neutrophils need to migrate towards, and form physical contact with tumor cells. Neutrophils secrete H₂O₂ in a contact-dependent mechanism, thereby inducing a lethal Ca²⁺ influx via the activation of the H₂O₂-dependent TRPM2 Ca²⁺ channel. Here, we explored the mechanism regulating neutrophil chemoattraction to tumor cells. Interestingly, we found that TRPM2 plays a role in this context as well, since it regulates the expression of potent neutrophil chemoattractants. Consequently, cells expressing reduced levels of TRPM2 are not approached by neutrophils. Together, these observations demonstrate how tumor cells expressing reduced levels of TRPM2 evade neutrophil cytotoxicity in two interrelated mechanisms—downregulation of neutrophil chemoattractants and blocking of the apoptotic Ca²⁺-dependent cascade. These observations demonstrate a critical role for TRPM2 in neutrophil-mediated immunosurveillance and identify cells expressing low levels of TRPM2, as a potential target for cancer therapy.

https://ift.tt/2PX8Ixk

TRPM2 modulates neutrophil attraction to murine tumor cells by regulating CXCL2 expression

Abstract

In recent years, immune cells were shown to play critical roles in tumor growth and metastatic progression. In this context, neutrophils were shown to possess both pro- and anti-tumor properties. To exert their anti-tumor effect, neutrophils need to migrate towards, and form physical contact with tumor cells. Neutrophils secrete H₂O₂ in a contact-dependent mechanism, thereby inducing a lethal Ca²⁺ influx via the activation of the H₂O₂-dependent TRPM2 Ca²⁺ channel. Here, we explored the mechanism regulating neutrophil chemoattraction to tumor cells. Interestingly, we found that TRPM2 plays a role in this context as well, since it regulates the expression of potent neutrophil chemoattractants. Consequently, cells expressing reduced levels of TRPM2 are not approached by neutrophils. Together, these observations demonstrate how tumor cells expressing reduced levels of TRPM2 evade neutrophil cytotoxicity in two interrelated mechanisms—downregulation of neutrophil chemoattractants and blocking of the apoptotic Ca²⁺-dependent cascade. These observations demonstrate a critical role for TRPM2 in neutrophil-mediated immunosurveillance and identify cells expressing low levels of TRPM2, as a potential target for cancer therapy.

https://ift.tt/2PX8Ixk

Long noncoding RNA HOTAIR is upregulated in an aggressive subgroup of gastrointestinal stromal tumors (GIST) and mediates the establishment of gene‐specific DNA methylation patterns

Genes, Chromosomes and Cancer, EarlyView.


https://ift.tt/2I9Glt2

Clonal architecture in patients with myelodysplastic syndromes and double or minor complex abnormalities: Detailed analysis of clonal composition, involved abnormalities, and prognostic significance

Genes, Chromosomes and Cancer, EarlyView.


https://ift.tt/2pyKNsT

Decoupling between sulfate reduction and the anaerobic oxidation of methane in the shallow methane seep of the Black sea.

Abstract

Methane seepages are widespread in the Black Sea. However, microbiological research has been carried out only at the continental shelf seeps. The present work dealt with coastal gas seepages of the Kalamit Bay (Black Sea). High-throughput 16S rRNA gene sequencing and radiotracer analysis (¹⁴С and ³⁵S) were used to determine the composition of the microbial community and the rates of microbial sulfate reduction and methane oxidation. The phylum Proteobacteria, represented mainly by sulfate reducers of the class Deltaproteobacteria, was the predominant in sequence dataset. Bacteroidetes and Planctomycetes were other numerous phyla. Among archaea, the phylum Woesearchaeota and Marine Benthic Group B were predominant in the upper horizons. Relative abundance of Euryarchaeota of the families Methanomicrobiacea and Methanosarcinaceae (including ANME-3 archaea) increased in deeper sediment layers. Sulfate reduction rate (up to 2.9 mmol/L×day) was considerably higher than the rate of anaerobic methane oxidation (up to 43.4 μmol/L×day), which indicated insignificant contribution of anaerobic methane oxidation to the total sulfide production.

https://ift.tt/2xLugpe

Improving control in microbial cell factories: from single cell to large-scale bioproduction

Abstract

Bioprocess deviations are likely to occur at different operating scales, leading in most of the case to substrate deviation from main metabolic routes and impact product synthesis. Correlating q_S and q_P is of outmost importance for bioprocess observability and control and can be modeled actually by advanced metabolic flux models. However, if most of these models are able to make prediction about metabolic switches, they still do not incorporate deviation due to biological noise, i.e. phenotypic and genotypic heterogeneity. These limitations impair observability and thus the use of fundamental knowledge about biological network for practical application, i.e. metabolic engineering or bioprocess scale-up.

https://ift.tt/2QTlHBv

A novel sucrose based expression system for heterologous proteins expression in thermotolerant methylotrophic yeast Ogataea thermomethanolica

Abstract

The thermotolerant methylotrophic yeast Ogataea thermomethanolica TBRC656 is a potential host for heterologous protein expression. In this study, a novel expression system was developed for O. thermomethanolica based on the maltase (mal) gene promoter from this organism. The OtMal promoter function was tested for expression of fungal enzymes as reporter genes. Measurement of xylanase reporter enzyme activity showed that the OtMal promoter was repressed during growth on glucose and was activated by sucrose. When sucrose was used as a carbon source, the OtMal promoter was approximately twice as strong as the constitutive OtGAP promoter. Comparison of the OtMal promoter with the methanol-inducible OtAOX promoter showed that OtMal promoter drove 1.2 and 1.7 fold higher expression of xylanase and phytase reporter, respectively than OtAOX promoter under inducing conditions at 24 hr. Our results indicated that this novel expression system could be useful for the production of heterologous proteins from sucrose in yeast O. thermomethanolica.

https://ift.tt/2xUV9HB

The Escherichia coli bcsB gene is a conditional essential gene in the context of functional cellulose synthesis.

Abstract

The understanding of why a gene is essential for a bacterium has implications in different research areas, such as bacterial evolution, synthetic biology, and biotechnology, making the identification of essential genes a very active research field. Bacterial essential genes have been defined, among other criteria, by the inability to obtain viable mutants in such genes. In the case of Escherichia coli this approach led to the construction of the Keio collection of single-gene knockout mutants that contains deletions of all the open reading frames present in the genome with the exception of 303 genes that were found to be essential for the growth of this bacterium. One of the genes that was identified as essential is bcsB, which is involved in synthesis of extracellular cellulose. However, the reason for the essential nature of BcsB for E. coli viability has not been determined. In this work we show that bcsB is essential only in strains that have a functional capacity to synthesize cellulose, presumably due to the activity of BcsB in the translocation of this polymer across the periplasm. Thus we propose that bcsB is a conditionally essential gene in E. coli.

https://ift.tt/2QTlz4Z

Effectiveness and acceptability of myo-inositol nutritional supplement in the prevention of gestational diabetes (EMmY): a protocol for a randomised, placebo-controlled, double-blind pilot trial

Introduction

Gestational diabetes increases maternal and offspring complications in pregnancy and cardiovascular complications in the long term. The nutritional supplement myo-inositol may prevent gestational diabetes; however, further evaluation is required, especially in multiethnic high-risk mothers. Our pilot trial on myo-inositol to prevent gestational diabetes will evaluate trial processes, assess acceptability to mothers and obtain preliminary estimates of effect and cost data prior to a large full-scale trial.

Methods and analysis

EMmY is a multicentre, placebo-controlled, double-blind, pilot, randomised trial, with qualitative evaluation. We will recruit pregnant women at 12–15⁺⁶ weeks' gestation, with gestational diabetes risk factors, from five maternity units in England between 2018 and 2019. We will randomise 200 women to take either 2 g of myo-inositol powder (intervention) or placebo, twice daily until delivery. We will assess rates of recruitment, randomisation, adherence to intervention and follow-up. Gestational diabetes will be diagnosed at 24–28 weeks as per the National Institute for Health and Care Excellence (NICE) criteria (fasting plasma glucose: ≥5.6 mmol/L and 2-hour plasma glucose: ≥7.8 mmol/L). We will assess the effects of myo-inositol on glycaemic indices at 28 weeks and on other maternal, fetal and neonatal outcomes at postnatal discharge. Qualitative evaluation will explore the acceptability of the trial and the intervention among women and healthcare professionals. Cost data and health-related quality of life measures will be captured. We will summarise feasibility outcomes using standard methods for proportions and other descriptive statistics, and where appropriate, report point estimates of effect sizes (eg, mean differences and relative risks) and associated 95% CIs.

Ethics and dissemination

Ethical approval was obtained through the London Queen Square Research Ethics Committee (17/LO/1741). Study findings will be submitted for publication in peer-reviewed journals. Newsletters will be made available to participants, healthcare professionals and members of Katie's Team (a patient and public advisory group) to disseminate.

Trial registration number

ISRCTN48872100.

Protocol version and date

Version 4.0, 15 January 2018.

https://ift.tt/2xPJqd0

AIDS Therapy Evaluation in the Netherlands (ATHENA) national observational HIV cohort: cohort profile

Purpose

In 1998, the AIDS Therapy Evaluation in the Netherlands (ATHENA) national observational HIV cohort was established to demonstrate the lifesaving effectiveness of triple combination antiretroviral therapy, including HIV-protease inhibitors, that had recently been made available for clinical use. Subsequently, the HIV Monitoring Foundation was established by the Dutch Ministry of Health, Welfare and Sport to continue ATHENA as an open cohort in order to continue the registration and monitoring of all HIV-positive people as an integral part of HIV care in all 26 HIV treatment centres in the Netherlands.

Participants

To date, a total of 25 036 participants have been enrolled in the cohort, with 263 600 person-years of follow-up. As of 1 January 2017, 19 035 HIV-1-positive participants were known to be in care: 18 824 adults (81% men and 19% women) and 211 children (47% boys and 53% girls). The remaining 6001 participants had either died (46%), were lost to care (29%) or had moved abroad (25%).

Findings to date

Today, with over 20 years of follow-up, the ATHENA cohort has provided extensive knowledge on HIV treatment, comorbidities and coinfections and created insight into the transmission dynamics of the HIV epidemic.

Future plans

ATHENA continues to enrol and monitor HIV positive people entering HIV care in the Netherlands. Future research will continue to provide tangible input into HIV care and prevention policies in the Netherlands and internationally.

https://ift.tt/2xJ0520

Acceptability of a German multicentre healthcare research study: a survey of research personnels attitudes, experiences and work load

Objectives

The DACAPO study as a multicentre nationwide observational healthcare research study investigates the influence of quality of care on the quality of life in patients with acute respiratory distress syndrome. The aim of this study was to investigate the acceptability to the participating research personnels by assessing attitudes, experiences and workload associated with the conduct of the DACAPO study.

Design, setting and participants

A prospective anonymous online survey was sent via email account to 169 participants in 65 study centres. The questionnaire included six different domains: (1) training for performing the study; (2) obtaining informed consent; (3) data collection; (4) data entry using the online documentation system; (5) opinion towards the study and (6) personal data. Descriptive data analysis was carried out.

Results

A total of 78 participants took part (46%) in the survey, 75 questionnaires (44%) could be evaluated. 51% were senior medical specialists. 95% considered the time frame of the training as appropriate and the presentation was rated by 93% as good or very good. Time effort for obtaining consent, data collection and entry was considered by 41% as a burden. Support from the coordinating study centre was rated as good or very good by more than 90% of respondents. While the DACAPO study was seen as scientifically relevant by 81%, only 45% considered the study results valuable for improving patient care significantly.

Conclusion

Collecting feedback on the acceptability of a large multicentre healthcare research study provided important insights. Recruitment and data acquisition was mainly performed by physicians and often regarded as additional time burden in clinical practice. Reducing the amount of data collection and simplifying data entry could facilitate the conduct of healthcare research studies and could improve motivation of researchers in intensive care medicine.

Trial registration number

NCT02637011; Pre-results.

https://ift.tt/2QRon2J

Efficacy and tolerability of novel triple combination therapy in drug-naïve patients with type 2 diabetes from the TRIPLE-AXEL trial: protocol for an open-label randomised controlled trial

Introduction

Patients with type 2 diabetes are at risk of microvascular and macrovascular complications. Intensive glycaemic control, especially in patients with short duration of diabetes, is the mainstay of management of type 2 diabetes to lower the risk of complications. However, despite the improvement in the understanding of the pathophysiology of type 2 diabetes and development of novel glucose-lowering agents, long-term durable glycaemic control remains a difficult goal to achieve. Several challenging clinical trials proved that an early combination therapy with a variety of glucose-lowering agents had a more favourable effect than conventional stepwise therapy in terms of glycaemic control. We aim to evaluate the efficacy and tolerability of a novel, initial triple combination therapy with metformin, sodium glucose cotransporter 2 inhibitor (dapagliflozin) and dipeptidyl peptidase-4 inhibitor (saxagliptin) compared with conventional stepwise add-on therapy in drug-naïve patients with recent-onset type 2 diabetes.

Methods and analysis

This study is a multicentre, prospective, randomised, open-label, parallel group, comparator-controlled trial. A total of 104 eligible participants will be randomised to either the initial combination therapy group or the conventional stepwise add-on therapy group for 104 weeks. The primary endpoint is the proportion of patients who achieved haemoglobin A1c level<6.5% without hypoglycaemia, weight gain or discontinuation due to adverse events at 104 weeks. This trial will determine whether a novel triple combination therapy with metformin, dapagliflozin and saxagliptin has a beneficial effect on durable glycaemic control compared with conventional therapy in drug-naïve patients with type 2 diabetes.

Ethics and dissemination

This study protocol was approved by the local institutional review boards and independent ethics committees over the recruitment sites. Results of this study will be disseminated in scientific journals and scientific conferences.

Trial registration number

NCT02946632; Pre-results.

https://ift.tt/2xPJGJ0