The authors reply

No abstract available

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Should Hyperoxia Be Avoided During Sepsis? An Experimental Study in Ovine Peritonitis*

Objectives: Optimizing oxygen delivery is an important part of the hemodynamic resuscitation of septic shock, but concerns have been raised over the potentially deleterious effects of hyperoxia. We evaluated the impact of hyperoxia on hemodynamics, the microcirculation, and cerebral and renal metabolism in an ovine model of septic shock. Design: Randomized animal study. Setting: University hospital animal research laboratory. Subjects: Fourteen adult female sheep. Interventions: After induction of fecal peritonitis, sheep were randomized to ventilation with an FIO2 of 100% (n = 7) or an FIO2 adjusted to maintain PaO2 between 90 and 120 mm Hg (n = 7, control). All animals were fluid resuscitated and observed until death. Measurements and Main Results: In addition to hemodynamic measurements, we assessed the sublingual microcirculation, renal and cerebral microdialysis and microvascular perfusion, and brain tissue oxygen pressure. Hyperoxic animals initially had a higher mean arterial pressure than control animals. After onset of shock, hyperoxia blunted the decrease in stroke volume index observed in the control group. Hyperoxia was associated with a higher sublingual microcirculatory flow over time, with higher cerebral perfusion and brain tissue oxygen pressure and with a lower cerebral lactate-to-pyruvate ratio than in control animals. Hyperoxia was also associated with preserved renal microvascular perfusion, lower renal lactate-to-pyruvate ratio, and higher PaO2/FIO2 ratio. Conclusions: In this acute peritonitis model, hyperoxia induced during resuscitation provided better hemodynamics and peripheral microvascular flow and better preserved cerebral metabolism, renal function, and gas exchange. These observations are reassuring with recent concerns about excessive oxygen therapy in acute diseases.

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Patterns and Outcomes Associated With Timeliness of Initial Crystalloid Resuscitation in a Prospective Sepsis and Septic Shock Cohort*

Objectives: The objectives of this study were to 1) assess patterns of early crystalloid resuscitation provided to sepsis and septic shock patients at initial presentation and 2) determine the association between time to initial crystalloid resuscitation with hospital mortality, mechanical ventilation, ICU utilization, and length of stay. Design: Consecutive-sample observational cohort. Setting: Nine tertiary and community hospitals over 1.5 years. Patients: Adult sepsis and septic shock patients captured in a prospective quality improvement database inclusion criteria: suspected or confirmed infection, greater than or equal to two systemic inflammatory response criteria, greater than or equal to one organ-dysfunction criteria. Interventions: The primary exposure was crystalloid initiation within 30 minutes or lesser, 31–120 minutes, or more than 120 minutes from sepsis identification. Measurements and Main Results: We identified 11,182 patients. Crystalloid initiation was faster for emergency department patients (β, –141 min; CI, –159 to –125; p

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Single-Operator Ultrasound-Guided Central Venous Catheter Insertion Verifies Proper Tip Placement*

Objectives: To evaluate whether a single-operator ultrasound-guided, right-sided, central venous catheter insertion verifies proper placement and shortens time to catheter utilization. Design: Prospective observational study with historical controls. Setting: Adult ICUs. Patients: Sixty-four consecutive patients undergoing ultrasound-assisted right-sided central venous catheterization compared with 92 serial historic controls who had unassisted central catheter insertion at the same sites. Interventions: Subcostal transthoracic echocardiography during catheter insertion. Measurements and Main Results: The primary outcome was the correct placement of the catheter tip determined by postprocedural chest radiography. The subclavian site was used in 41 patients (64%) (inserted without ultrasound guidance) in the ultrasound-assisted group and 62 (67%) in the control group, whereas the jugular vein was used in the remaining patients. The tip was accurately positioned in 59 of 68 patients (86.7%) in the ultrasound-assisted group compared with 51 of 94 (54.8%) in the control group (p

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Identifying Distinct Subgroups of ICU Patients: A Machine Learning Approach*

Objectives: Identifying subgroups of ICU patients with similar clinical needs and trajectories may provide a framework for more efficient ICU care through the design of care platforms tailored around patients' shared needs. However, objective methods for identifying these ICU patient subgroups are lacking. We used a machine learning approach to empirically identify ICU patient subgroups through clustering analysis and evaluate whether these groups might represent appropriate targets for care redesign efforts. Design: We performed clustering analysis using data from patients' hospital stays to retrospectively identify patient subgroups from a large, heterogeneous ICU population. Setting: Kaiser Permanente Northern California, a healthcare delivery system serving 3.9 million members. Patients: ICU patients 18 years old or older with an ICU admission between January 1, 2012, and December 31, 2012, at one of 21 Kaiser Permanente Northern California hospitals. Interventions: None. Measurements and Main Results: We used clustering analysis to identify putative clusters among 5,000 patients randomly selected from 24,884 ICU patients. To assess cluster validity, we evaluated the distribution and frequency of patient characteristics and the need for invasive therapies. We then applied a classifier built from the sample cohort to the remaining 19,884 patients to compare the derivation and validation clusters. Clustering analysis successfully identified six clinically recognizable subgroups that differed significantly in all baseline characteristics and clinical trajectories, despite sharing common diagnoses. In the validation cohort, the proportion of patients assigned to each cluster was similar and demonstrated significant differences across clusters for all variables. Conclusions: A machine learning approach revealed important differences between empirically derived subgroups of ICU patients that are not typically revealed by admitting diagnosis or severity of illness alone. Similar data-driven approaches may provide a framework for future organizational innovations in ICU care tailored around patients' shared needs.

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The authors reply

No abstract available

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Molecular Adsorbent Recirculating System Can Reduce Short-Term Mortality Among Patients With Acute-on-Chronic Liver Failure—A Retrospective Analysis*

Objectives: Acute-on-chronic liver failure is associated with numerous consecutive organ failures and a high short-term mortality rate. Molecular adsorbent recirculating system therapy has demonstrated beneficial effects on the distinct symptoms, but the associated mortality data remain controversial. Design: Retrospective analysis of acute-on-chronic liver failure patients receiving either standard medical treatment or standard medical treatment and molecular adsorbent recirculating system. Secondary analysis of data from the prospective randomized Recompensation of Exacerbated Liver Insufficiency with Hyperbilirubinemia and/or Encephalopathy and/or Renal Failure trial by applying the recently introduced Chronic Liver Failure-criteria. Setting: Medical Departments of University Hospital Muenster (Germany). Patients: This analysis was conducted in two parts. First, 101 patients with acute-on-chronic liver failure grades 1–3 and Chronic Liver Failure-C-Organ Failure liver subscore equals to 3 but stable pulmonary function were identified and received either standard medical treatment (standard medical treatment, n = 54) or standard medical treatment and molecular adsorbent recirculating system (n = 47) at the University Hospital Muenster. Second, the results of this retrospective analysis were tested against the Recompensation of Exacerbated Liver Insufficiency with Hyperbilirubinemia and/or Encephalopathy and/or Renal Failure trial. Interventions: Standard medical treatment and molecular adsorbent recirculating system. Measurements and Main Results: Additionally to improved laboratory variables (bilirubin and creatinine), the short-term mortality (up to day 14) of the molecular adsorbent recirculating system group was significantly reduced compared with standard medical treatment. A reduced 14-day mortality rate was observed in the molecular adsorbent recirculating system group (9.5% vs 50.0% with standard medical treatment; p = 0.004), especially in patients with multiple organ failure (acute-on-chronic liver failure grade 2–3). Concerning the affected organ system, this effect of molecular adsorbent recirculating system on mortality was particularly evident among patients with increased kidney, brain, or coagulation Chronic Liver Failure-C-Organ Failure subscores. Subsequent reanalysis of the Recompensation of Exacerbated Liver Insufficiency with Hyperbilirubinemia and/or Encephalopathy and/or Renal Failure dataset with adoption of the Chronic Liver Failure-classification resulted in similar findings. Conclusions: Molecular adsorbent recirculating system treatment was associated with an improved short-term survival of patients with acute-on-chronic liver failure and multiple organ failure. Among these high-risk patients, molecular adsorbent recirculating system treatment might bridge to liver recovery or liver transplantation.

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Central Venous Catheter Insertion and Bedside Ultrasound: Building a New Standard of Care?*

No abstract available

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Determinants of Receiving Palliative Care and Ventilator Withdrawal Among Patients With Prolonged Mechanical Ventilation*

Objectives: Increasing numbers of patients with prolonged mechanical ventilation generates a tremendous strain on healthcare systems. Patients with prolonged mechanical ventilation suffer from long-term poor quality of life. However, no study has ever explored the willingness to receive palliative care or terminal withdrawal and the factors influencing willingness. Design: Cross-sectional study. Setting: Five different hospitals of Taipei City Hospital system. Patients: Adult patients with ventilatory support for more than 60 days. Interventions: None. Measurements and Main Results: We identified the family members of 145 consecutive patients with prolonged mechanical ventilation in five hospitals of Taipei City Hospital system and enrolled family members for 106 patients (73.1%). We collected information from patient families' regarding concepts (knowledge, attitude, and experiences) of palliative care, caregiver burden, family function, patient quality of life, and physician-family communications. From the medical record, we obtained duration of hospitalization, consciousness level, disease severity, medical cost, and the presence of do-not-resuscitate orders. The vast majority of family members agreed with the concept of palliative care (90.4%) with 17.3% of the family members agreeing to ventilator withdrawal currently and 67.5% terminally in anticipation of death. Approximately half of the family members regretted having chosen prolonged mechanical ventilation (56.7%). Reduced patient quality of life and increased family understanding of palliative care significantly associated with increased caregiver willingness to endorse palliative care and withdraw life-sustaining agents in anticipation of death. Longer duration of ventilator usage and hospitalization was associated with increased feelings of regret about choosing prolonged mechanical ventilation. Conclusions: During prolonged mechanical ventilation, physicians should thoroughly discuss its benefits and burdens. Families should be given the opportunity to discuss the circumstances under which they might request the implementation of palliative care or withdrawal of mechanical ventilation in order to avoid prolonging the dying process.

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Diabetes Is Not Associated With Increased 90-Day Mortality Risk in Critically Ill Patients With Sepsis

Objectives: To determine the association of pre-existing diabetes, hyperglycemia, and hypoglycemia during the first 24 hours of ICU admissions with 90-day mortality in patients with sepsis admitted to the ICU. Design: We used mixed effects logistic regression to analyze the association of diabetes, hyperglycemia, and hypoglycemia with 90-day mortality (n = 128,222). Setting: All ICUs in the Netherlands between January 2009 and 2014 that participated in the Dutch National Intensive Care Evaluation registry. Patients: All unplanned ICU admissions in patients with sepsis. Interventions: The association between 90-day mortality and pre-existing diabetes, hyperglycemia, and hypoglycemia, corrected for other factors, was analyzed using a generalized linear mixed effect model. Measurements and Main Results: In a multivariable analysis, diabetes was not associated with increased 90-day mortality. In diabetes patients, only severe hypoglycemia in the absence of hyperglycemia was associated with increased 90-day mortality (odds ratio, 2.95; 95% CI, 1.19–7.32), whereas in patients without pre-existing diabetes, several combinations of abnormal glucose levels were associated with increased 90-day mortality. Conclusions: In the current retrospective large database review, diabetes was not associated with adjusted 90-day mortality risk in critically ill patients admitted with sepsis.

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No Impact of Preadmission Anti-Inflammatory Drug Use on Risk of Depression and Anxiety After Critical Illness*

Objectives: Risk of depression and anxiety is elevated after intensive care. Drugs with anti-inflammatory properties may have antidepressant and anxiolytic effects. The aim of this study was to investigate the association between preadmission use of drugs with anti-inflammatory effects and risk of new-onset depression and anxiety among adult patients admitted to an ICU. Design: Propensity score–matched, population-based cohort study. Setting: All ICUs in Denmark from 2005 to 2013. Patients: Adults receiving mechanical ventilation in an ICU. Interventions: None. Measurements and Main Results: A total of 48,207 ICU patients were included. Exposures were preadmission single-agent or combined use of statins, nonsteroidal anti-inflammatory drugs, or glucocorticoids. Outcomes were cumulative incidence (risk) and risk ratio of new-onset psychiatrist-diagnosed depression or anxiety or prescriptions for antidepressants or anxiolytics. Propensity score matching yielded 6,088 statin user pairs, 2,886 nonsteroidal anti-inflammatory drug user pairs, 1,440 glucocorticoid user pairs, and 1,743 combination drug user pairs. The cumulative incidence of anxiety and depression during the 3 years following intensive care was 18.0% (95% CI, 17.0–19.0%) for statin users, 21.3% (95% CI, 19.8–22.9%) for nonsteroidal anti-inflammatory drug users, 17.4% (95% CI, 15.4–19.5%) for glucocorticoid users, and 19.0% (95% CI, 16.3–20.2%) for combination users. The cumulative incidence was similar in nonusers compared with users in all drug groups. The risk ratio of depression and anxiety 3 years after admission to ICU was 1.04 (95% CI, 0.96–1.13) for statin users, 1.00 (95% CI, 0.90–1.11) for nonsteroidal anti-inflammatory drug users, 0.97 (95% CI, 0.82–1.14) for glucocorticoid users, and 1.05 (95% CI, 0.90–1.21) for combination users, compared with nonusers. Results were consistent across subgroups (gender, age, preadmission diseases, type of admission) and sensitivity analyses (depression and anxiety separately). Conclusions: Preadmission use of statins, nonsteroidal anti-inflammatory drugs, glucocorticoids, or combinations did not alter the risk of depression and anxiety after critical illness.

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Acute Respiratory Distress Syndrome Due To Tuberculosis in a Respiratory ICU Over a 16-Year Period

Objective: Whether tuberculosis-related acute respiratory distress syndrome is associated with worse outcomes when compared with acute respiratory distress syndrome secondary to other causes remains unknown. Herein, we compare the outcomes between the two groups. Design: Retrospective analysis of all subjects admitted with acute respiratory distress syndrome over the last 16 years. Setting: Respiratory ICU of a tertiary care hospital in North India. Subjects: Consecutive subjects with acute respiratory distress syndrome. Intervention: Subjects were categorized as tuberculosis-related acute respiratory distress syndrome and acute respiratory distress syndrome-others and were managed with mechanical ventilation using the low tidal volume strategy as per the Acute Respiratory Distress Syndrom Network protocol. Measurements and Main Results: The baseline clinical and demographic characteristics, lung mechanics, and mortality were compared between the two groups. Factors predicting ICU survival were analyzed using multivariate logistic regression analysis. During the study period, 469 patients (18 tuberculosis-related acute respiratory distress syndrome and 451 acute respiratory distress syndrome-others) with acute respiratory distress syndrome were admitted. The mean (SD) age of the study population (52.9% women) was 33.6 years (14.8 yr). The baseline parameters and the lung mechanics were similar between the two groups. There were 132 deaths (28.1%) with no difference between the two groups (tuberculosis-related acute respiratory distress syndrome vs acute respiratory distress syndrome-others; 27.7% vs 28.2%; p = 0.71). There was also no significant difference in the ventilator-free days, ICU, and the hospital length of stay. On multivariate logistic regression analysis, the factors predicting survival were the admission Acute Physiology and Chronic Health Evaluation II score and baseline driving pressure after adjusting for PaO2:FIO2 ratio, gender, and the etiology of acute respiratory distress syndrome. Conclusions: Tuberculosis is an uncommon cause of acute respiratory distress syndrome even in high tuberculosis prevalence countries. Acute respiratory distress syndrome due to tuberculosis behaves like acute respiratory distress syndrome due to other causes and does not affect the ICU survival.

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Severe Respiratory Failure, Extracorporeal Membrane Oxygenation, and Intracranial Hemorrhage*

Objectives: For patients supported with veno-venous extracorporeal membrane oxygenation, the occurrence of intracranial hemorrhage is associated with a high mortality. It is unclear whether intracranial hemorrhage is a consequence of the extracorporeal intervention or of the underlying severe respiratory pathology. In a cohort of patients transferred to a regional severe respiratory failure center that routinely employs admission brain imaging, we sought 1) the prevalence of intracranial hemorrhage; 2) survival and neurologic outcomes; and 3) factors associated with intracranial hemorrhage. Design: A single-center, retrospective, observational cohort study. Setting: Tertiary referral severe respiratory failure center, university teaching hospital. Patients: Patients admitted between December 2011 and February 2016. Intervention: None. Measurements and Main Results: Three hundred forty-two patients were identified: 250 managed with extracorporeal support and 92 managed using conventional ventilation. The prevalence of intracranial hemorrhage was 16.4% in extracorporeal membrane oxygenation patients and 7.6% in conventionally managed patients (p = 0.04). Multivariate analysis revealed factors independently associated with intracranial hemorrhage to be duration of ventilation (d) (odds ratio, 1.13 [95% CI, 1.03–1.23]; p = 0.011) and admission fibrinogen (g/L) (odds ratio, 0.73 [0.57–0.91]; p = 0.009); extracorporeal membrane oxygenation was not an independent risk factor (odds ratio, 3.29 [0.96–15.99]; p = 0.088). In patients who received veno-venous extracorporeal membrane oxygenation, there was no significant difference in 6-month survival between patients with and without intracranial hemorrhage (68.3% vs 76.0%; p = 0.350). Good neurologic function was observed in 92%. Conclusions: We report a higher prevalence of intracranial hemorrhage than has previously been described with high level of neurologically intact survival. Duration of mechanical ventilation and admission fibrinogen, but not exposure to extracorporeal support, are independently associated with intracranial hemorrhage.

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The authors reply

No abstract available

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Quality Improvement Initiatives in Sepsis in an Emerging Country: Does the Institution’s Main Source of Income Influence the Results? An Analysis of 21,103 Patients*

Objective: We aimed to assess the results of a quality improvement initiative in sepsis in an emerging setting and to analyze it according to the institutions' main source of income (public or private). Design: Retrospective analysis of the Latin American Sepsis Institute database from 2005 to 2014. Settings: Brazilian public and private institutions. Patients: Patients with sepsis admitted in the participant institutions. Interventions: The quality improvement initiative was based on a multifaceted intervention. The institutions were instructed to collect data on 6-hour bundle compliance and outcomes in patients with sepsis in all hospital settings. Outcomes and compliance was measured for eight periods of 6 months each, starting at the time of the enrollment in the intervention. The primary outcomes were hospital mortality and compliance with 6-hour bundle. Measurements and Main Results: We included 21,103 patients; 9,032 from public institutions and 12,071 from private institutions. Comparing the first period with the eigth period, compliance with the 6-hour bundle increased from 13.5% to 58.2% in the private institutions (p

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Optimal Sampling Frequency of Serum Cortisol Concentrations After Cardiac Surgery

No abstract available

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Effectiveness and Safety of an Extended ICU Visitation Model for Delirium Prevention: A Before and After Study*

Objectives: To evaluate the effect of an extended visitation model compared with a restricted visitation model on the occurrence of delirium among ICU patients. Design: Prospective single-center before and after study. Setting: Thirty-one–bed medical-surgical ICU. Patients: All patients greater than or equal to 18 years old with expected length of stay greater than or equal to 24 hours consecutively admitted to the ICU from May 2015 to November 2015. Interventions: Change of visitation policy from a restricted visitation model (4.5 hr/d) to an extended visitation model (12 hr/d). Measurements and Main Results: Two hundred eighty-six patients were enrolled (141 restricted visitation model, 145 extended visitation model). The primary outcome was the cumulative incidence of delirium, assessed bid using the confusion assessment method for the ICU. Predefined secondary outcomes included duration of delirium/coma; any ICU-acquired infection; ICU-acquired bloodstream infection, pneumonia, and urinary tract infection; all-cause ICU mortality; and length of ICU stay. The median duration of visits increased from 133 minutes (interquartile range, 97.7–162.0) in restricted visitation model to 245 minutes (interquartile range, 175.0–272.0) in extended visitation model (p

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Hyperoxia in Septic Shock: Crafty Therapeutic Weapon or Double-Edged Sword?*

No abstract available

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Anisodamine inhibits endoplasmic reticulum stress-associated TXNIP/NLRP3 inflammasome activation in rhabdomyolysis-induced acute kidney injury

Abstract

Anisodamine protects against free radical-induced cellular damage. This study aimed to investigate the protective effect of anisodamine on rhabdomyolysis-induced acute kidney injury (RIAKI). C57BL/6 J mice, TXNIP^−/− and NLRP3 ^−/− (both were C57BL/6 J background) mice were used to construct RIAKI model. Anisodamine administration was performed on RIAKI mice only. Mice were divided into control, TXNIP-KD (knock down), LNPR3-KD, and anisodamine group (n = 15 in each group). The renal injury, renal function, renal tubular cells apoptosis and expression of Caspase-1, ASC, endoplasmic reticulum (ER) stress markers IRE-1α, CHOP, and ATF4, and interleukin (IL-1α, IL-1β, and IL-18) were detected. The knock down of TXNIP or NLRP3 expression in mice showed protective effect against RIAKI pathogenesis, as compared with the RIAKI mice. The expression of Caspase-1, ASC, and interleukins, renal injury, renal tubular cells apoptosis in TXNIP-KD and LNPR3-KD mice were significantly inhibited in comparison with the RIAKI mice. Moreover, anisodamine treatment reduced expression of ER stress markers IRE-1α, CHOP, and ATF4, TXNIP and NLRP3, as well as ACS, Caspase-1, IL-1α, IL-1β, and IL-18, showing moderate protective effect on the changes of above factors comparing with TXNIP or NLRP3 knock down. This study declared that anisodamine showed protective effect on RIAKI model may by inhibiting ER stress associated TXNIP/NLRP3 inflammasome.

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The muscle regulatory transcription factor MyoD participates with p53 to directly increase the expression of the pro-apoptotic Bcl2 family member PUMA

Abstract

The muscle regulatory transcription factor MyoD is a master regulator of skeletal myoblast differentiation. We have previously reported that MyoD is also necessary for the elevated expression of the pro-apoptotic Bcl2 family member PUMA, and the ensuing apoptosis, that occurs in a subset of myoblasts induced to differentiate. Herein, we report the identification of a functional MyoD binding site within the extended PUMA promoter. In silico analysis of the murine PUMA extended promoter revealed three potential MyoD binding sites within 2 kb of the transcription start site. Expression from a luciferase reporter construct containing this 2 kb fragment was enhanced by activation of MyoD in both myoblasts and fibroblasts and diminished by silencing of MyoD in myoblasts. Experiments utilizing truncated versions of this promoter region revealed that the potential binding site at position − 857 was necessary for expression. Chromatin immunoprecipitation (ChIP) analysis confirmed binding of MyoD to the DNA region encompassing position − 857. The increase in MyoD binding to the PUMA promoter as a consequence of culture in differentiation media (DM) was comparable to the increase in MyoD binding at the myogenin promoter and was diminished in myoblasts silenced for MyoD expression. Finally, ChIP analysis using an antibody specific for the transcription factor p53 demonstrated that, in myoblasts silenced for MyoD expression, p53 binding to the PUMA promoter was diminished in response to culture in DM. These data indicate that MyoD plays a direct role in regulating PUMA expression and reveal functional consequences of MyoD expression on p53 mediated transcription of PUMA.

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Approximate equiangular tight frames for compressed sensing and CDMA applications

Performance guarantees for recovery algorithms employed in sparse representations, and compressed sensing highlights the importance of incoherence. Optimal bounds of incoherence are attained by equiangular uni...

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Reconnecting with Joseph and Augusta Dejerine: 100 hundred years on

Bajada et al. mark the centenary of Joseph Dejerine's death by demonstrating the continuing relevance of his research with his long-standing collaborator, Augusta Dejerine-Klumpke, on the white matter pathways of the brain to modern-day connectional anatomy. A first English translation of the original work is provided in the Supplementary Materials.

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Exposure rate of VZV among women attending antenatal care clinic in Sri Lanka - a cross sectional study

Varicella or chickenpox was not a notifiable disease until 2005 in Sri Lanka and only a few studies have been conducted on the epidemiology of VZV infection in the country. The anti­VZV IgG sero-prevalence amo...

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Future complications of chronic hepatitis C in a low-risk area: projections from the hepatitis c study in Northern Norway

Hepatitis C (HCV) infection causes an asymptomatic chronic hepatitis in most affected individuals, which often remains undetected until cirrhosis and cirrhosis-related complications occur. Screening of high-ri...

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Correlates of isoniazid preventive therapy failure in child household contacts with infectious tuberculosis in high burden settings in Nairobi, Kenya – a cohort study

Sub-Saharan Africa continues to document high pediatric tuberculosis (TB) burden, especially among the urban poor. One recommended preventive strategy involves tracking and isoniazid preventive therapy (IPT) f...

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Impact of UGT1A1 gene polymorphisms on plasma dolutegravir trough concentrations and neuropsychiatric adverse events in Japanese individuals infected with HIV-1

Dolutegravir (DTG) is metabolized mainly by uridine diphosphate (UDP)-glucuronosyltransferase 1A1 (UGT1A1), and partly by cytochrome P450 3A (CYP3A). Therefore, we focused on UGT1A1 gene polymorphisms (*6 and *28...

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Treatment options and barriers to case management of neonatal pneumonia in India: a protocol for a scoping review

Introduction

India contributes to the highest neonatal deaths globally. Case management is said to be the cornerstone of pneumonia control. Much of the published evidence focuses on children aged 1 to 59 months. This scoping review, thus, aims to identify the treatment options for and barriers to case management of neonatal pneumonia in India.

Methods and analysis

This protocol is part of a series of three reviews on neonatal pneumonia in India. Studies addressing treatment of or barriers to case management of neonatal pneumonia in Indian context, published in English in peer-reviewed and indexed journals will be eligible for inclusion. Electronic search will be conducted on nine databases. Hand searching and snowballing will be done for published and grey literature. Selection of studies will be done in title, abstract and full-text stages. A narrative summary will be performed to summarise the details of evidence.

Ethics and dissemination

As this is a review involving analysis of secondary data which is available in the public domain and does not involve human participants, ethical approval was not required. The findings of the study will be shared with all stakeholders of this research. Knowledge dissemination workshops will be conducted with relevant stakeholders to ultimately transfer the evidence tailored to the stakeholder (eg, policy briefs, publications, information booklets and so on).

PROSPERO 2016

CRD42016045449

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'Just like a normal pain, what do people with diabetes mellitus experience when having a myocardial infarction: a qualitative study recruited from UK hospitals

Objective

The objective of the study was to investigate the symptoms people with diabetes experience when having a myocardial infarction (MI), their illness narrative and how they present their symptoms to the health service.

Setting

Three London (UK) hospitals (coronary care units and medical wards).

Participants

Patients were recruited with diabetes mellitus (DM) (types 1 and 2) with a clinical presentation of MI (ST elevated MI (STEMI), non-ST elevated MI (NSTEMI), acute MI unspecified and cardiac arrest). A total of 43 participants were recruited, and 39 interviews met the study criteria and were analysed. They were predominantly male (n=30), aged 40–90 years and white British (18/39), and just over a half were from other ethnic groups. The majority had type 2 DM (n=35), 24 had an NSTEMI, 10 had an STEMI and five had other cardiac events.

Definitions of selection/exclusion criteria

A diagnosis of MI and DM and the ability to communicate enough English to complete the interview. Ward staff made a clinical judgement that the participant was post-treatment, clinically stable and well enough to participate.

Methods

A qualitative study using taped and transcribed interviews analysed using a thematic analysis.

Results

While most participants did experience chest pain, it was often not their most striking symptom. As their chest pain did not match their expectations of what a 'heart attack' should be, participants developed narratives to explain these symptoms, including the symptoms being effects of their DM ('hypos'), side effects of medication (oral hypoglycaemics) or symptoms (such as breathlessness and indigestion) related to other comorbidities, often leading to delays in seeking care.

Conclusions

While truly absent chest pain during MI among people with DM was rare in this study, patients' attenuated symptoms often led to delay in seeking attention, and this may result in delays in receiving treatment.

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Burden of non-adherence to latent tuberculosis infection drug therapy and the potential cost-effectiveness of adherence interventions in Canada: a simulation study

Objective

Pharmaceutical treatment of latent tuberculosis infection (LTBI) reduces the risk of progression to active tuberculosis (TB); however, poor adherence tempers the protective effect. We aimed to estimate the health burden of non-adherence, the maximum allowable cost of hypothetical new adherence interventions to be cost-effective and the potential value of existing adherence interventions for patients with low-risk LTBI in Canada.

Design

A microsimulation model of LTBI progression over 25 years.

Setting

General practice in Canada.

Participants

Individuals with LTBI who are initiating drug therapy.

Interventions

A hypothetical intervention with a range of effectiveness was evaluated. Existing drug adherence interventions including peer support, two-way text messaging support, enhanced adherence counselling and adherence incentives were also evaluated.

Primary and secondary outcome measures

Simulation outcomes included healthcare costs, TB incidence, TB deaths and quality-adjusted life years (QALYs). Base case results were interpreted against a willingness-to-pay threshold of $C50 000/QALY.

Results

Compared with current adherence levels, full adherence to LTBI drug therapy could reduce new TB cases from 90.3 cases per 100 000 person-years to 35.9 cases per 100 000 person-years and reduce TB-related deaths from 7.9 deaths per 100 000 person-years to 3.1 deaths per 100 000 person-years. An intervention that increases relative adherence by 40% would bring the population near full adherence to drug therapy and could have a maximum allowable annual cost of approximately $C450 per person to be cost-effective. Based on estimates of effect sizes and costs of existing adherence interventions, we found that they yielded between 900 and 2400 additional QALYs per million people, reduced TB deaths by 5%–25% and were likely to be cost-effective over 25 years.

Conclusion

Full adherence could reduce the number of future TB cases by nearly 60%, offsetting TB-related costs and health burden. Several existing interventions are could be cost-effective to help achieve this goal.

http://ift.tt/2wiihBB

Effectiveness, cost-utility and implementation of a decision aid for patients with localised prostate cancer and their partners: study protocol of a stepped-wedge cluster randomised controlled trial

Introduction

Patient decision aids (PDAs) have been developed to help patients make an informed choice for a treatment option. Despite proven benefits, structural implementation falls short of expectations. The present study aims to assess the effectiveness and cost-utility of the PDA among newly diagnosed patients with localised prostate cancer and their partners, alongside implementation of the PDA in routine care.

Methods/analysis

A stepped-wedge cluster randomised trial will be conducted. The PDA will be sequentially implemented in 18 hospitals in the Netherlands, over a period of 24 months. Every 3 or 6 months, a new cluster of hospitals will switch from usual care to care including a PDA.

The primary outcome measure is decisional conflict experienced by the patient. Secondary outcomes comprise the patient's quality of life, treatment preferences, role in the decision making, expectations of treatment, knowledge, need for supportive care and decision regret. Furthermore, societal cost-utility will be valued. Other outcome measures considered are the partner's treatment preferences, experienced participation to decision making, quality of life, communication between patient, partner and health care professional, and the effect of prostate cancer on the relationship, social contacts and their role as caregiver. Patients and partners receiving the PDA will also be asked about their satisfaction with the PDA.

Baseline assessment takes place after the treatment choice and before the start of a treatment, with follow-up assessments at 3, 6 and 12 months following the end of treatment or the day after deciding on active surveillance. Outcome measures on implementation include the implementation rate (defined as the proportion of all eligible patients who will receive a PDA) and a questionnaire for health care professionals on determinants of implementing an innovation.

Ethics and dissemination

This study will be conducted in accordance with local laws and regulations of the Medical Ethics Committee of VU University Medical Center, Amsterdam, The Netherlands. The results from this stepped-wedge trial will be presented at scientific meetings and published in peer-reviewed journals.

Trial registration

Nederlands Trial Register NTR TC5177, registration date: May 28^th 2015.Pre-results.

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Combining CD4 recovery and CD4: CD8 ratio restoration as an indicator for evaluating the outcome of continued antiretroviral therapy: an observational cohort study

Objectives

Immune recovery following highly active antiretroviral therapy (HAART) is commonly assessed by the degree of CD4 reconstitution alone. In this study, we aimed to assess immune recovery by incorporating both CD4 count and CD4:CD8 ratio.

Design

Observational cohort study

Setting and participants

Clinical data from Chinese HIV-positive patients attending the largest HIV service in Hong Kong and who had been on HAART for ≥4 years were accessed.

Main outcome measures

Optimal immune outcome was defined as a combination of a CD4 count ≥500/μL and a CD4:CD8 ratio ≥0.8.

Results

A total of 718 patients were included for analysis (6353 person-years). At the end of year 4, 318 out of 715 patients achieved CD4 ≥500/μL, of which only 33% (105 out of 318) concurrently achieved CD4:CD8 ratio ≥0.8. Patients with a pre-HAART CD8 ≤800/μL (428 out of 704) were more likely to be optimal immune outcome achievers with CD4 ≥500/μL and CD4:CD8 ratio ≥0.8, the association of which was stronger after adjusting for pre-HAART CD4 counts. In a multivariable logistic model, optimal immune outcome was positively associated with male gender, younger pre-HAART age and higher pre-HAART CD4 count, longer duration of HAART and pre-HAART CD8 ≤800/μL. Treatment regimen and cumulative viral loads played no significant role in the pattern of immune recovery.

Conclusions

A combination of CD4 count and CD4:CD8 ratio could be a useful approach for the characterisation of treatment outcome over time, on top of monitoring CD4 count alone.

http://ift.tt/2wiFaoJ

Qualitative interview study of parents perspectives, concerns and experiences of the management of lower respiratory tract infections in children in primary care

Objective

To explore parents' perspectives, concerns and experiences of the management of lower respiratory tract infections (LRTIs) in children in primary care.

Design

Qualitative semistructured interview study.

Setting

UK primary care.

Participants

23 parents of children aged 6 months to 10 years presenting with LRTI in primary care.

Method

Thematic analysis of semistructured interviews (either in person or by telephone) conducted with parents to explore their experiences and views on their children being prescribed antibiotics for LRTI.

Results

Four major themes were identified and these are perspectives on: (1) infection, (2) antibiotic use, (3) the general practitioner (GP) appointment and (4) decision making around prescribing. Symptomatic relief was a key concern: the most troublesome symptoms were cough, breathing difficulty, fever and malaise. Many parents were reluctant to use self-care medication, tended to support antibiotic use and believed they are effective for symptoms, illness duration and for preventing complications. However, parental expectations varied from a desire for reassurance and advice to an explicit preference for an antibiotic prescription. These preferences were shaped by: (1) the age of the child, with younger children perceived as more vulnerable because of their greater difficulty in communicating, and concerns about rapid deterioration; (2) the perceived severity of the illness; and (3) disruption to daily routine. When there was disagreement with the GP, parents described feeling dismissed, and they were critical of inconsistent prescribing when they reconsult. When agreement between the parent and the doctor featured, parents described a feeling of relief and legitimation for consulting, feeling reassured that the illness did indeed warrant a doctor's attention.

Conclusion

Symptomatic relief is a major concern for parents. Careful exploration of expectations, and eliciting worries about key symptoms and impact on daily life will be needed to help parents understand when a no antibiotic recommendation or delayed antibiotic recommendation is made.

http://ift.tt/2wikqNG

Post-traumatic growth and its relationship to quality of life up to 9 years after liver transplantation: a cross-sectional study in Spain

Objective

Little is known concerning post-traumatic growth (PTG) after liver transplantation. Against this backdrop the current study analysed the relationship between PTG and time since transplantation on quality of life. Furthermore, it compared PTG between liver transplant recipients and their caregivers.

Design

Cross-sectional case–control study.

Setting

University Hospital in Spain.

Participants

240 adult liver transplant recipients who had undergone only one transplantation, with no severe mental disease, were the participants of the study. Specific additional analyses were conducted on the subset of 216 participants for whom caregiver data were available. Moreover, results were compared with a previously recruited general population sample.

Outcome measures

All participants completed the Posttraumatic Growth Inventory, and recipients also filled in the 12-Item Short-Form Health Survey. Relevant sociodemographic and clinical parameters were also assessed.

Results

In the sample of 240 recipients, longer time since transplantation (>9 years) was associated with more pain symptoms (p=0.026). Regardless of duration, recipients showed lower scores on most quality of life dimensions than the general population. However, high PTG was associated with a significantly higher score on the vitality quality of life dimension (p=0.021). In recipients with high PTG, specific quality of life dimensions, such as bodily pain (p=0.307), vitality (p=0.890) and mental health (p=0.353), even equalled scores in the general population, whereas scores on general health surpassed them (p=0.006). Furthermore, liver transplant recipients (n=216) compared with their caregivers showed higher total PTG (p<0.001) and higher scores on the subscales relating to others (p<0.001), new possibilities (p<0.001) and appreciation of life (p<0.001).

Conclusions

Our findings highlight the protective role of PTG in the long-term outcome of liver transplant recipients. Future studies should analyse and develop psychosocial interventions to strengthen PTG in transplant recipients and their caregivers.

http://ift.tt/2jy5wwH

Prediction of early unplanned intensive care unit readmission in a UK tertiary care hospital: a cross-sectional machine learning approach

Objectives

Unplanned readmissions to the intensive care unit (ICU) are highly undesirable, increasing variance in care, making resource planning difficult and potentially increasing length of stay and mortality in some settings. Identifying patients who are likely to suffer unplanned ICU readmission could reduce the frequency of this adverse event.

Setting

A single academic, tertiary care hospital in the UK.

Participants

A set of 3326 ICU episodes collected between October 2014 and August 2016. All records were of patients who visited an ICU at some point during their stay. We excluded patients who were ≤16 years of age; visited ICUs other than the general and neurosciences ICU; were missing crucial electronic patient record measurements; or had indeterminate ICU discharge outcomes or very early or extremely late discharge times. After exclusion, 2018 outcome-labelled episodes remained.

Primary and secondary outcome measures

Area under the receiver operating characteristic curve (AUROC) for prediction of unplanned ICU readmission or in-hospital death within 48 hours of first ICU discharge.

Results

In 10-fold cross-validation, an ensemble predictor was trained on data from both the target hospital and the Medical Information Mart for Intensive Care (MIMIC-III) database and tested on the target hospital's data. This predictor discriminated between patients with the unplanned ICU readmission or death outcome and those without this outcome, attaining mean AUROC of 0.7095 (SE 0.0260), superior to the purpose-built Stability and Workload Index for Transfer (SWIFT) score (AUROC=0.6082, SE 0.0249; p=0.014, pairwise t-test).

Conclusions

Despite the inherent difficulties, we demonstrate that a novel machine learning algorithm based on transfer learning could achieve good discrimination, over and above that of the treating clinicians or the value added by the SWIFT score. Accurate prediction of unplanned readmission could be used to target resources more efficiently.

http://ift.tt/2jz1QuH

Rare cause of colonic intussusception in an adult

Colonic intussusception is an uncommon phenomenon in adults. Advanced imaging has facilitated the increase in awareness of this rare disease. When present, the lead point is most often secondary to a malignancy with primary adenocarcinoma being the most frequent cause. Current surgical management involves oncologic resections for this reason. This is a report of the third ever-reported case of colonic intussusception secondary to an angiolipoma and the first in the western hemisphere. We also demonstrate that these masses are amenable to minimally invasive resection for definitive management.

http://ift.tt/2jzNtqj

Successful twice interrupted therapy of HCV infection in patients with cirrhosis with hepatocellular carcinoma before and after liver transplantation

We are presenting the case study of the patient diagnosed at the age of 37 with liver cirrhosis due to genotype 1b hepatitis C virus infection. At the age of 46, he was diagnosed with hepatocellular carcinoma with subsequent resection of the tumour in May 2015. In December 2015, the treatment was started with ombitasvir, paritaprevir/ritonavir and dasabuvir (3D) with ribavirin (RBV) 1000 mg per day. After 24 days of this treatment, the patient received a deceased donor liver transplantation, followed by 18-day interruption of 3D therapy. Due to the anaemia, RBV dose was reduced to 600 mg per day for the rest of the treatment. At the 11th week of 3D+RBV treatment, there was another 8-day long discontinuation of therapy due to the postoperative wound infection. In total, the patient received 24 weeks of 3D+RBV treatment, achieving sustained virological response at week 24 post-treatment.

http://ift.tt/2xGuEI1

Combined caesarean with splenectomy in pregnancy with portal hypertension: defining plausibility

24-year-old woman at 28 weeks gestation was referred from peripheral hospital with diagnosis of pregnancy with portal hypertension. She had received multiple transfusion for pancytopaenia in the past and had undergone endoscopic sclerotherapy for oesophageal varices. Initially, she was admitted in our hospital at 28 weeks gestation for blood transfusion and was evaluated by multispecialty team of doctors. She was advised splenectomy for transfusion-dependent pancytopaenia secondary to hypersplenism in non-cirrhotic portal hypertension. She was readmitted at 36 weeks gestation. A decision for caesarean was taken owing to failed induction of labour at 38 weeks gestation. She underwent combined caesarean with splenectomy. Mother and child had an uneventful postoperative recovery and were discharged on ninth postoperative day. Preconceptional counselling, treatment of oesophageal varices and multispecialty approach was paramount in the management. Combined caesarean with splenectomy is feasible and cost-effective treatment associated with improved quality of life. Prospective clinical trials are essential to prove safety and efficacy of treatment.

http://ift.tt/2jw2E3w

Renal cell carcinoma with isolated metastasis to sigmoid mesentery: a rare resectable combination

Renal cell carcinoma accounts for 2%–3% of all malignancies in adults. It spreads via direct extension, lymphatic route as well as haematogenous route. Lymph nodes, lungs, bone, liver and brain are the usual sites for its metastatic spread. In the presence of limited metastatic disease with potentially resectable metastases, surgery offers the best chances of cure. In the present case, we describe a case of renal cell carcinoma with a solitary metastasis to the sigmoid mesentery in a patient with Von Hippel-Lindau syndrome. There was no retroperitoneal lymphadenopathy or tumour thrombus in the renal vein. The patient was managed with laparoscopic radical nephrectomy and excision of the sigmoid mesentery mass. At 6 months of follow-up, there is no evidence of recurrent disease.

http://ift.tt/2xGiwXC

Rare case of primary leiomyosarcoma of sigmoid mesocolon

We experienced a rare case of primary leiomyosarcoma of sigmoid mesentery. A 45-year-old woman was presented to us with left iliac fossa mass and discomfort for 4-month duration. CT scan of abdomen and pelvis revealed a huge mass 14 cmx14 cmx16 cm occupying left iliac fossa mimicked having a large left ovarian carcinoma. She was subsequently planned for elective total abdominal hysterectomy and bilateral salpingo-oophorectomy by gynaecology team. During laparotomy, a huge mass was revealed arising from sigmoid mesentery invaded to the left lower ureter. Curative resection was done and pathological findings show the tumour being leiomyosarcoma with immunohistochemistry tests on caldesmon, desmin, smooth muscle actin and CD34 reagent all positive. Clinicopathological and literature review of this rare primary leiomyosarcoma of mesocolon was discussed in our case presentation

http://ift.tt/2jvqSel

Hot off the Press: Embedded Clinical Decision Support in Electronic Health Record Decreases Use of High-cost Imaging in the Emergency Department: EmbED study

Abstract

This longitudinal before/after study of embedded CDRs assessed the effects of clinical decision support on use of common imaging studies. Among high users, rates of CT-brain and CT c-spine were reduced after implementation of embedded clinical decision instruments, while in low users, rates increased. This article summarizes the manuscript and the Skeptics Guide to Emergency Medicine podcast, as well as the ensuing social media/online discussion.

This article is protected by copyright. All rights reserved.

http://ift.tt/2fpXUZ0

Early assessment of response to induction therapy in acute myeloid leukemia using 18 F-FLT PET/CT

Abstract

Background

We evaluated the suitability of ¹⁸F-fluorodeoxythymidine (¹⁸F-FLT) positron emission tomography (PET)/computed tomography (CT) for assessment of the early response to induction therapy and its value for predicting clinical outcome in patients with acute myeloid leukemia (AML). Adult patients who had histologically confirmed AML and received induction therapy were enrolled. All patients underwent ¹⁸F-FLT PET/CT after completion of induction. PET/CT images were visually and quantitatively assessed. Cases with intensely increased bone marrow uptake in more than one third of the long bones and throughout the central skeleton were interpreted as PET-positive for resistant disease (RD). PET results were compared to the clinical response and outcome.

Results

In visual PET analysis of 10 eligible patients (7 male, 3 female; median age 58 years), 5 patients were interpreted as being PET-positive and 5 as PET-negative. Standardized uptake values were significantly different between PET-positive and PET-negative groups. Eight of 10 patients achieved clinical complete remission (CR)/CR with incomplete blood count recovery (CRi). Five CR/CRi patients had PET-negative findings, but 3 CR patients had PET-positive findings. Both of the RD patients had PET-positive findings. During follow-up, 2 CR patients with PET-positive findings relapsed, or were strongly suspected of relapse, 4 months after consolidation.

Conclusion

¹⁸F-FLT PET/CT after induction therapy showed good sensitivity and negative-predictive value for evaluating RD in patients with AML. This preliminary study suggests that ¹⁸F-FLT PET/CT may be valuable as a noninvasive tool for early assessment of the response to treatment and may provide prognostic value for survival in patients with AML.

http://ift.tt/2whA8IW

Histological healing beyond endoscopic healing in ulcerative colitis: Shall we target the “ultra-deep” remission?

http://ift.tt/2wwUsRW

Mitogen and Stress Signal Memory Regulates Daughter Cell Proliferation [Research Watch]

CCND1 and p53 transmitted to daughter cells in mitosis determine if cells are proliferative or quiescent.

http://ift.tt/2h6QDRl

Melanoma Risk Variants Prevent MC1R Palmitoylation and Activation [Research Watch]

Palmitoylation-deficient MC1R variants accelerate BRAF^V60E-driven melanomagenesis.

http://ift.tt/2h6Ikoz

ACTRT1 Inhibits Hedgehog Signaling to Suppress Basal Cell Carcinoma [Research Watch]

Coding or enhancer mutations in ACTRT1 reduce its expression to drive basal cell carcinoma.

http://ift.tt/2h90piq

Targeting the c-Rel Subunit of NF-{kappa}B Inhibits Treg Function in Melanoma [Research Watch]

Specific inhibition of c-Rel impairs activated Tregs to suppress melanoma growth in vivo.

http://ift.tt/2h5NeSW

Monoclonal antibodies directed against cadherin RGD exhibit therapeutic activity against melanoma and colorectal cancer metastasis

Purpose: New targets are required for the control of advanced metastatic disease. We investigated the use of cadherin RGD motifs, which activate the α2β1integrin pathway, as targets for the development of therapeutic monoclonal antibodies (mAbs). Experimental Design: CDH17 fragments and peptides were prepared and used for immunization and antibody development. Antibodies were tested for inhibition of β1 integrin and cell adhesion, proliferation and invasion assays using cell lines from different cancer types: colorectal, pancreatic, melanoma and breast cancer. Effects of the mAbs on cell signaling were determined by Western blot. Nude mice were used for survival analysis after treatment with RGD-specific mAbs and metastasis development. Results: Antibodies against full-length CDH17 failed to block the binding to α2β1 integrin. However, CDH17 RGD peptides generated highly selective RGD mAbs that blocked (CDH17 and VE-cadherin)-mediated β1 integrin activation in melanoma, breast, pancreatic and colorectal cancer cells. Antibodies provoked a significant reduction in cell adhesion and proliferation of metastatic cancer cells. Treatment with mAbs impaired the integrin signaling pathway activation of FAK in colorectal cancer, of JNK and ERK kinases, in colorectal and pancreatic cancers, and of JNK, ERK, Src and AKT in melanoma and breast cancers. In vivo, RGD-specific mAbs increased mouse survival after inoculation of melanoma and colorectal cancer cell lines to cause lung and liver metastasis, respectively. Conclusions: Blocking the interaction between RGD cadherins and α2β1 integrin with highly selective mAbs constitutes a promising therapy against advanced metastatic disease in colon cancer, melanoma and, potentially, other cancers.

http://ift.tt/2x8Q1A7

Demethylation therapy as a targeted treatment for human papilloma virus-associated head and neck cancer

Purpose:DNA methylation in human papillomavirus-associated (HPV+) head and neck squamous cell carcinoma (HNSCC) may have importance for continuous expression of HPV oncogenes, tumor cell proliferation and survival. Here, we determined activity of a global DNA demethylating agent, 5-azacytidine (5-aza), against HPV+ HNSCC in pre-clinical models and explored it as a targeted therapy in a window trial enrolling patients with HPV+ HNSCC. Experimental Design: Sensitivity of HNSCC cells to 5-aza treatment was determined, then 5-aza activity was tested in vivo using xenografted tumors in a mouse model. Finally, tumor samples from patients enrolled in a window clinical trial were analyzed to identify activity of 5-aza therapy in patients with HPV+ HNSCC. Results: Clinical trial and experimental data show that 5-aza induced growth inhibition and cell death in HPV+ HNSCC. 5-aza reduced expression of HPV genes, stabilized p53, and induced p53-dependent apoptosis in HNSCC cells and tumors. 5-aza repressed expression and activity of matrix metalloproteinases (MMPs) in HPV+ HNSCC, activated interferon response in some HPV+ head and neck cancer cells, and inhibited the ability of HPV+ xenografted tumors to invade mouse blood vessels. Conclusions: 5-aza may provide effective therapy for HPV-associated HNSCC as an alternative or complement to standard cytotoxic therapy.

http://ift.tt/2x75RtG

Dosimetric comparison of different treatment modalities for stereotactic radiotherapy

Abstract

Background

The modalities for performing stereotactic radiotherapy (SRT) on the brain include the cone-based linear accelerator (linac), the flattening filter-free (FFF) volumetric modulated arc therapy (VMAT) linac, and tomotherapy. In this study, the cone-based linac, FFF-VMAT linac, and tomotherapy modalities were evaluated by measuring the differences in doses delivered during brain SRT and experimentally assessing the accuracy of the output radiation doses through clinical measurements.

Methods

We employed a homemade acrylic dosimetry phantom representing the head, within which a thermoluminescent dosimeter (TLD) and radiochromic EBT3 film were installed. Using the conformity/gradient index (CGI) and Paddick methods, the quality of the doses delivered by the various SRT modalities was evaluated. The quality indicators included the uniformity, conformity, and gradient indices. TLDs and EBT3 films were used to experimentally assess the accuracy of the SRT dose output.

Results

The dose homogeneity indices of all the treatment modalities were lower than 1.25. The cone-based linac had the best conformity for all tumors, regardless of the tumor location and size, followed by the FFF-VMAT linac; tomography was the worst-performing treatment modality in this regard. The cone-based linac had the best gradient, regardless of the tumor location and size, whereas the FFF-VMAT linac had a better gradient than tomotherapy for a large tumor diameter (28 mm). The TLD and EBT3 measurements of the dose at the center of tumors indicated that the average difference between the measurements and the calculated dose was generally less than 4%. When the 3% 3-mm gamma passing rate metric was used, the average passing rates of all three treatment modalities exceeded 98%.

Conclusions

Regarding the dose, the cone-based linac had the best conformity and steepest dose gradient for tumors of different sizes and distances from the brainstem. The results of this study suggest that SRT should be performed using the cone-based linac on tumors that require treatment plans with a steep dose gradient, even as the tumor is slightly irregular, we should also consider using a high dose gradient of the cone base to treat and protect the normal tissue. If normal tissues require special protection exist at positions that are superior or inferior to the tumor, we can consider using tomotherapy or Cone base with couch at 0° for treatment.

http://ift.tt/2xHbjX2

T cells deficient in diacylglycerol kinase-{zeta} are resistant to PD-1 inhibition and help create persistent host immunity to leukemia

Efforts to improve the efficacy of adoptive T cell therapies and immune checkpoint therapies in myelogenous leukemia are desired. In this study, we evaluated the anti-leukemia activity of adoptively transferred polyclonal cancer antigen-reactive T cells deficient in the regulator diacylglycerol kinase-zeta (DGKζ) with or without PD-1/PD-L1 blockade. In the C1498 mouse model of myeloid leukemia, we showed that leukemia was eradicated more effectively in DGKζ-deficient (DGKζ-/-) mice than wild-type mice. T cells transferred from DGKζ-deficient mice to wild-type tumor-bearing recipients conferred this benefit. Leukemia clearance was similar to mice treated with anti-PD-L1. Strikingly, we found that the activity of adoptively transferred DGKζ-/- T cells relied partly on induction of sustainable host T cell immunity. Transferring DGKζ-deficient T cells increased the levels of IFN-γ and other cytokines in recipient mice, especially with co-administration of anti-PD-L1. Overall, our results offered evidence that targeting DGKζ may leverage the efficacy of adoptive T cell and immune checkpoint therapies in leukemia treatment. Further, they suggest that DGKζ targeting might decrease risks of antigen escape or resistance to immune checkpoint blockade.

http://ift.tt/2xpDMjl

Tenascin-C and integrin {alpha}9 mediate interactions of prostate cancer with the bone microenvironment

Deposition of the extracellular matrix protein tenascin-C is part of the reactive stroma response, which has a critical role in prostate cancer progression. Here we report that tenascin-C is expressed in the bone endosteum and involved associated with formation of prostate bone metastases. Metastatic cells cultured on osteo-mimetic surfaces coated with tenascin-C exhibited enhanced adhesion and colony formation as mediated by integrin α9β1. Additionally, metastatic cells preferentially migrated and colonized tenascin-C-coated trabecular bone xenografts in a novel system that employed chorioallantoic membranes of fertilized chicken eggs as host. Overall, our studies deepen knowledge about reactive stroma responses in the bone endosteum that accompany prostate cancer metastasis to trabecular bone, with potential implications to therapeutically target this process in patients.

http://ift.tt/2fbfYc7

Tethering IL2 to its receptor IL2R{beta} enhances anti-tumor activity and expansion of natural killer NK92 cells

Interleukin-2 (IL2) is an immunostimulatory cytokine for key immune cells including T cells and natural killer (NK) cells. Systemic IL2 supplementation could enhance NK-mediated immunity in a variety of diseases ranging from neoplasms to viral infection. However, its systemic use is restricted by its serious side effects and limited efficacy due to activation of T regulatory cells (Tregs). IL2 signaling is mediated through interactions with a multi-subunit receptor complex containing IL2Rα, IL2Rβ and IL2Rγ. Adult natural killer (NK) cells express only IL2Rβ and IL2Rγ subunits and are therefore relatively insensitive to IL2. To overcome these limitations, we created a novel chimeric IL2-IL2Rβ fusion protein of IL2 and its receptor IL2Rβ joined via a peptide linker (CIRB). NK92 cells expressing CIRB (NK92CIRB) were highly activated and expanded indefinitely without exogenous IL2. When compared to an IL2-secreting NK92 cell line, NK92CIRB were more activated, cytotoxic and resistant to growth inhibition. Direct contact with cancer cells enhanced the cytotoxic character of NK92CIRB cells, which displayed superior in vivo antitumor effects in mice. Overall, our results showed how tethering IL2 to its receptor IL2Rβ eliminates the need for IL2Rα and IL2Rβ, offering a new tool to selectively activate and empower immune therapy.

http://ift.tt/2xpawck

YAP suppresses lung squamous cell carcinoma progression via deregulation of the DNp63-GPX2 axis and ROS accumulation

Lung squamous cell carcinoma (SCC), accounting for approximately 30% of non-small cell lung cancer, is often refractory to therapy. Screening a small molecule library, we identified digitoxin as a high potency compound for suppressing human lung SCC growth in vitro and in vivo. Mechanistic investigations revealed that digitoxin attenuated YAP phosphorylation and promoted YAP nuclear sequestration. YAP activation led to excessive accumulation of reactive oxygen species (ROS) by downregulating the antioxidant enzyme GPX2 in a manner related to p63 blockade. In patient-derived xenograft (PDX) models, digitoxin treatment efficiently inhibited lung SCC progression in correlation with reduced expression of YAP. Collectively, our results highlight a novel tumor suppressor function of YAP via downregulation of GPX2 and ROS accumulation, with potential implications to improve precision medicine of human lung SCC.

http://ift.tt/2fbfW3Z

Chemotherapy-induced macrophage infiltration into tumors enhances nanographene-based photodynamic therapy

Increased recruitment of tumor-associated macrophages (TAM) to tumors following chemotherapy promotes tumor resistance and recurrence and correlates with poor prognosis. TAM depletion suppresses tumor growth, but is not highly effective due to the effects of tumorigenic mediators from other stromal sources. Here we report that adoptive macrophage transfer led to a dramatically enhanced photodynamic therapy (PDT) effect of 2-(1-hexyloxyethyl)-2-devinyl pyropheophor-bide-alpha (HPPH)-coated polyethylene glycosylated nanographene oxide [GO(HPPH)-PEG] by increasing its tumor accumulation. Moreover, tumor treatment with commonly used chemotherapeutic drugs induced an increase in macrophage infiltration into tumors, which also enhanced tumor uptake and the PDT effects of GO(HPPH)-PEG, resulting in tumor eradication. Macrophage recruitment to tumors after chemotherapy was visualized noninvasively by near-infrared fluorescence and single-photon emission computed tomography imaging using F4/80-specific imaging probes. Our results demonstrate that chemotherapy combined with GO(HPPH)-PEG PDT is a promising strategy for the treatment of tumors, especially those resistant to chemotherapy. Furthermore, TAM-targeted molecular imaging could potentially be used to predict the efficacy of combination therapy and select patients who would most benefit from this treatment approach.

http://ift.tt/2xpast6

Biallelic Dicer1 loss mediated by aP2-Cre drives angiosarcoma

Angiosarcoma is an aggressive vascular sarcoma with an extremely poor prognosis. Due to the relative rarity of this disease, its molecular drivers and optimal treatment strategies are obscure. DICER1 is an RNase III endoribonuclease central to microRNA biogenesis, and germline DICER1 mutations result in a cancer predisposition syndrome, associated with an increased risk of many tumor types. Here we show that biallelic Dicer1 deletion with aP2-Cre drives aggressive and metastatic angiosarcoma independent of other genetically engineered oncogenes or tumor suppressor loss. Angiosarcomas in aP2-Cre;Dicer1Flox/- mice histologically and genetically resemble human angiosarcoma. MicroRNA-23 target genes including the oncogenes Ccnd1 as well as Adam19, Plau, and Wsb1 that promote invasiveness and metastasis were enriched in mouse and human angiosarcoma. These studies illustrate that Dicer1 can function as a traditional loss-of-function tumor suppressor gene, and they provide a fully penetrant animal model for the study of angiosarcoma development and metastasis.

http://ift.tt/2fbfVgr

Symptom intensity of hospice patients: A longitudinal analysis of concordance between patients’ and nurses’ outcomes

Nearing death, hospice patients are increasingly unable or unwilling to self-report their symptom intensity and rely on nurses' assessments.We hypothesized that concordance between patients' and nurses' assessments of symptom intensity improves over time.

http://ift.tt/2fp7hrA

Results of a Double-Blind, Randomized, Placebo-Controlled Study of Nabiximols Oromucosal Spray as Adjunctive Therapy in Advanced Cancer Patients With Chronic Uncontrolled Pain

Prior phase 2/3 studies found that cannabinoids might provide adjunctive analgesia in advanced cancer patients with uncontrolled pain.

http://ift.tt/2w066FB

Tumor associated macrophages are strongly related to vascular invasion, non-luminal subtypes and interval breast cancer

Tumor associated macrophages (TAM) resemble M2 macrophages, promote tumor invasion and show strong expression of CD163 in breast cancer. We here investigated the association between CD163 positive macrophages and vascular invasion, molecular subgroups, mode of detection, and patient outcome. We performed a population-based, retrospective study of invasive breast cancer from the Norwegian Breast Cancer Screening Programme in Vestfold County (2004–2009), including 200 screen-detected and 82 interval cancers.

http://ift.tt/2jy6ZmY

A Population-Based Study of Stereotactic Radiosurgery or Fractionated Stereotactic Radiotherapy for Vestibular Schwannoma: Long-Term Outcomes and Toxicities

The purpose of the study is to examine long-term local control of vestibular schwannoma (VS) and side effects in patients treated with stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (SRT) in XX-region.

http://ift.tt/2yerqIC

Evaluation of stopping-power prediction by dual- and single-energy computed tomography in an anthropomorphic ground-truth phantom

To determine the accuracy of particle range prediction for proton and heavier ion radiotherapy based on dual-energy computed tomography (DECT) in a realistic inhomogeneous geometry and to compare it to the state-of-the-art clinical approach.

http://ift.tt/2x9wijV

MiR-20a regulates fibroblast-like synoviocyte proliferation and apoptosis in rheumatoid arthritis

OBJECTIVE: STAT3 expression is elevated in the synovial tissue of patients with rheumatoid arthritis (RA). MiR-20a plays a role in mediating synovial inflammation in RA. Bioinformatics analysis has identified a binding site between miR-20 and the 3'-UTR of STAT3 mRNA. This study aimed to investigate the role of miR-20a in the regulation of STAT3 expression and synovial cell proliferation as well as apoptosis.

PATIENTS AND METHODS: Synovial tissues were collected from RA patients and osteoarthritis (OA) patients to measure miR-20a, STAT3, p-STAT3, and Ki-67 expressions. Fibroblast-like synoviocytes (FLS) were treated with IL-17 (10 ng/ml) and then Ki-67 expression and cell cycle were evaluated by flow cytometry. The targeting relationship between miR-20a and STAT3 was assessed by dual luciferase reporter gene assay. FLS cells were divided into five groups: miR-NC, miR-20a mimic, si-NC, si-STAT3, and miR-20a mimic + si-STAT3 groups.

RESULTS: In RA patients, significantly lower MiR-20a expression, and substantially higher STAT3, p-STAT3, and Ki-67 expression were found in the synovial tissues compared with those in OA patients. IL-17A treatment markedly promoted FLS cell proliferation, inhibited cell apoptosis, reduced miR-20a expression, as well as upregulated levels of STAT3, p-STAT3, and Bcl-2. MiR-20a played a regulatory function on the expression of STAT3. MiR-20a mimic and/or si-STAT3 transfection apparently downregulated STAT3, p-STAT3, and Bcl-2 expression, attenuated IL-17A-induced cell proliferation promotive and enhanced cell apoptosis in FLS cells.

CONCLUSIONS: The expression of miR-20a was reduced in synovial tissue of RA patients with the increased level of STAT3. Downregulation of miR-20a promoted the expression of STAT3, p-STAT3, and Bcl-2, facilitated FLS cell proliferation, reduced apoptosis and, thereby, played a critical role in RA.

L'articolo MiR-20a regulates fibroblast-like synoviocyte proliferation and apoptosis in rheumatoid arthritis sembra essere il primo su European Review.

http://ift.tt/2juC4rv

Correlation between IL-4 gene polymorphismas well as its mRNA expressionand rheumatoid arthritis

OBJECTIVE: This study sought to explore the correlation between IL-4-590C/T polymorphism as well as mRNA expression and the occurrence of rheumatoid arthritis (RA).

PATIENTS AND METHODS: IL-4-590C/T polymorphisms, detected by a TaqMan probe from 150 RA patients who were treated in Yantaishan Hospital from June 2014 to June 2016, and from 150 healthy people, all from the Han population, were selected for the study. Interleukin-4 (IL-4) mRNA expression was detected by Real-time Polymerase Chain Reaction (PCR), and the differences in IL-4mRNA expressions of different genotypes in RA patients were compared.

RESULTS: The difference in CC, CT and TT genotype distributions between the RA group and the healthy group were statistically significant (p<0.05). The mutation frequency of the T allele in IL-4 of the RA group was significantly higher than that of the healthy group (p<0.01). The mRNA expression of IL-4 in the RA group was significantly lower than that in the healthy group (p<0.01). The mRNA expression of IL-4 in RA patients was gradually decreased in the following order: CC, CT and TT, and the differences among these genotypes were significant (p<0.01).

CONCLUSIONS: IL-4-590C/T polymorphism may be correlated with the incidence of RA in the Chinese Han population. Carrying the T allele can significantly increase the risk of RA and reduce the mRNA expression of IL-4.

L'articolo Correlation between IL-4 gene polymorphismas well as its mRNA expressionand rheumatoid arthritis sembra essere il primo su European Review.

http://ift.tt/2xF3Mbp

Differential Expression of miRNAs in the Respiratory Tree of the Sea Cucumber Apostichopus japonicus Under Hypoxia Stress

Sea cucumber, an important economic species, has encountered high mortality since 2013 in northern China because of seasonal environmental stress such as hypoxia, high temperature, and low salinity. MicroRNAs (miRNAs) are important in regulating gene expression in marine organisms in response to environmental change. In the present study, high-throughput sequencing was used to investigate alterations in miRNA expression in the sea cucumber under different levels of dissolved oxygen (DO). Nine small RNA libraries were constructed from the sea cucumber respiratory trees. A total of 26 differentially expressed miRNAs, including 12 upregulated and 14 downregulated miRNAs were observed in severe hypoxia (DO 2 mg/L) compared with mild hypoxia (DO 4 mg/L) and normoxic conditions (DO 8 mg/L). Twelve differently expressed miRNAs were clustered in severe hypoxia. In addition, RT-qPCR revealed that 14 randomly selected differentially expressed miRNAs showed significantly increased expressions in severe hypoxia and the expressions of nine miRNAs, including key miRNAs such as Aja-miR-1, Aja-miR-2008 and Aja-miR-184, were consistent with the sequencing results. Moreover, GO and pathway analyses of putative target genes suggest that these miRNAs are important in redox, transport, transcription and hydrolysis under hypoxia stress. Notably, novel-miR-1, novel-miR-2, and novel-miR-3 were specifically clustered and upregulated in severe hypoxia, which may provide new insights into novel "hypoxamiR" identification. These results will provide a basis for future studies of miRNA regulation and molecular adaptive mechanisms in sea cucumbers under hypoxia stress.

http://ift.tt/2vZZzKW

Genome Dynamics of Hybrid Saccharomyces cerevisiae During Vegetative and Meiotic Divisions

Mutation and recombination are the major sources of genetic diversity in all organisms. In the baker's yeast, all mutation rate estimates are in homozygous background. We determined the extent of genetic change through mutation and loss of heterozygosity (LOH) in a heterozygous Saccharomyces cerevisiae genome during successive vegetative and meiotic divisions. We measured genome wide LOH and base mutation rates during vegetative and meiotic divisions in a hybrid (S288c/YJM789) S. cerevisiae strain. The S288c/YJM789 hybrid showed nearly complete reduction in heterozygosity within 31 generations of meioses and improved spore viability. LOH in the meiotic lines was driven primarily by the mating of spores within the tetrad. The S288c/YJM789 hybrid lines propagated vegetatively for the same duration as the meiotic lines, showed variable LOH (from 2-3% and up to 35%). Two of the vegetative lines with extensive LOH, showed frequent and large internal LOH tracts that suggest a high frequency of recombination repair. These results suggest significant LOH can occur in the S288c/YJM789 hybrid during vegetative propagation presumably due to return to growth events. The average base substitution rates for the vegetative lines (1.82 x 10^-10 per base per division) and the meiotic lines (1.22 x 10^-10 per base per division), are the first genome wide mutation rate estimates for a hybrid yeast. This study therefore provides a novel context for the analysis of mutation rates (especially in the context of detecting LOH during vegetative divisions), compared to previous mutation accumulation studies in yeast that used homozygous backgrounds.

http://ift.tt/2f0NQ81

Genomic Prediction Within and Across Biparental Families: Means and Variances of Prediction Accuracy and Usefulness of Deterministic Equations

A major application of genomic prediction (GP) in plant breeding is the identification of superior inbred lines within families derived from biparental crosses. When models for various traits were trained within related or unrelated biparental families (BPFs), experimental studies found substantial variation in prediction accuracy (PA), but little is known about the underlying factors. We used SNP marker genotypes of inbred lines from either elite germplasm or landraces of maize (Zea mays L.) as parents to generate in silico 300 BPFs of doubled-haploid lines. We analyzed PA within each BPF for 50 simulated polygenic traits, using GBLUP models trained with individuals from either full-sib (FSF), half-sib (HSF) or unrelated families (URF) for various sizes (N_train) of the training set and different heritabilities (h²). In addition, we modified two deterministic equations for forecasting PA to account for inbreeding and genetic variance unexplained by the training set. Averaged across traits, PA was high within FSF (0.41 - 0.97) with large variation only for N_train<50 and h² <0.6. For HSF and URF, PA was on average ~40 to 60% lower and varied substantially among different combinations of BPFs used for model training and prediction as well as different traits. As exemplified by HSF results, PA of across-family GP can be very low if causal variants not segregating in the training set account for a sizeable proportion of the genetic variance among predicted individuals. Deterministic equations accurately forecast the PA expected over many traits, yet cannot capture trait-specific deviations. We conclude that model training within BPFs generally yields stable PA, whereas a high level of uncertainty is encountered in across-family GP. Our study shows the extent of variation in PA that must be at least reckoned with in practice and offers a starting point for the design of training sets composed of multiple BPFs.

http://ift.tt/2vZg2yX

The Effect of Common Inversion Polymorphisms In(2L)t and In(3R)Mo on Patterns of Transcriptional Variation in Drosophila melanogaster

Chromosomal inversions are an ubiquitous feature of genetic variation. Theoretical models describe several mechanisms by which inversions can drive adaptation and be maintained as polymorphisms. While inversions have been shown previously to be under selection, or contain genetic variation under selection, the specific phenotypic consequences of inversions leading to their maintenance remain unclear. Here we use genomic sequence and expression data from the Drosophila Genetic Reference Panel to explore the effects of two cosmopolitan inversions, In(2L)t and In(3R)Mo, on patterns of transcriptional variation. We demonstrate that each inversion has a significant effect on transcript abundance for hundreds of genes across the genome. Inversion affected loci (IAL) appear both within inversions as well as on unlinked chromosomes. Importantly, IAL do not appear to be influenced by the previously reported genome-wide expression correlation structure. We found that five genes involved with sterol uptake, four of which are Niemann-Pick Type 2 orthologs, are upregulated in flies with In(3R)Mo but do not have SNPs in LD with the inversion. We speculate that this upregulation is driven by genetic variation in mod(mdg4) that is in LD with In(3R)Mo. We find that there is little evidence for regional or position effect of inversions on gene expression at the chromosomal level but do find evidence for the distal breakpoint of In(3R)Mo interrupting one gene and possibly disassociating the two flanking genes from regulatory elements.

http://ift.tt/2f0NNcl

Pharmacodynamics and Pharmacokinetics of Ticagrelor Versus Clopidogrel in Patients with Acute Coronary Syndromes and Chronic Kidney Disease

Abstract

Background

Pivotal clinical trials found ticagrelor reduced ischemic complications to a greater extent than clopidogrel and what is more, the benefit gradually increased with the reduction on creatinine clearance. However, the underlying mechanisms remains poorly explored.

Methods

This is a single-center, prospective, randomized clinical trial involving 60 hospitalized P2Y12 inhibitor naïve patients with CKD (eGFR<60ml/min/1.73m²) and NSTE-ACS. Eligible patients were randomly assigned in a 1:1 ratio to receive ticagrelor(180 mg loading dose, then 90 mg twice daily followed) or clopidogrel(600 mg loading dose, then 75 mg qd followed). The primary endpoint was the P2Y12 reactive unit (PRU) tested by VerifyNow at 30 days. Plasma concentration of ticagrelor and clopidogrel and its active metabolite was measured in first 10 patients in each group at baseline, and 1h, 2h, 4h, 8h, 12h and 24h after loading does.

Results

Baseline characteristics were well matched between the two groups. Our results indicated a markedly lower PRU in patients treated with ticagrelor vs. clopidogrel at 30 days (32.6±11.29 vs 203.7±17.92, P<0.001) as well as 2, 8 and 24 hours after loading does (P<0.001). Ticagrelor and its active metabolite AR-C124910XX showed similar T_max(h) of 8h, with C_max(ng/ml) of 355(242.50-522.00) and 63.20(50.80-85.15), respectively. Both Clopidogrel and its active metabolite approached maximal plasma concentration at 2 hours, with close C_max(ng/ml) of 8.67(6.64-27.75) vs 8.53(6.94-15.93).

Conclusion

Ticagrelor showed much more potent platelet inhibition in comparison of clopidogrel in patients with NSTE-ACS and CKD.

http://ift.tt/2wvYgCO

Low threshold unmyelinated mechanoafferents can modulate pain

Human, hairy skin contains a subgroup of C-fibers, the C-low threshold mechanoreceptive afferents ((C-LTMR) C-tactile or C-touch (CT) fibers) that are linked with the signaling of affective aspects of human to...

http://ift.tt/2x3sDoI

Anatomic mapping of molecular subtypes in diffuse glioma

Tumor location served as an important prognostic factor in glioma patients was considered to postulate molecular features according to cell origin theory. However, anatomic distribution of unique molecular sub...

http://ift.tt/2f1m6Qx

A novel frameshift GRN mutation results in frontotemporal lobar degeneration with a distinct clinical phenotype in two siblings: case report and literature review

Progranulin gene (GRN) mutations are major causes of frontotemporal lobar degeneration. To date, 68 pathogenic GRN mutations have been identified. However, very few of these mutations have been reported in Asians...

http://ift.tt/2x3vI82

Application value of procalcitonin in patients with central nervous system infection

OBJECTIVE: To study the application value of procalcitonin (PCT) in patients with central nervous system (CNS) infection.

PATIENTS AND METHODS: A total of 66 patients, including 24 patients with suppurative meningitis, 20 patients with viral meningitis and 22 patients with tuberculous meningitis, were enrolled. 20 patients admitted to the hospital due to epilepsy or headache without infection in the same period were enrolled as the control group. PCT, high-sensitivity C-reactive protein (Hs-CRP), high-sensitivity C-reactive protein (Hs-CRP), protein quantification, chloride and glucose in serum and cerebrospinal fluid, were collected.

RESULTS: The serum PCT level in suppurative meningitis group was significantly higher than that in other three groups. The dynamic monitoring of suppurative meningitis group on admission, at 72 h and 1 week after treatment showed that the serum PCT level was significantly decreased. PCT levels in cerebrospinal fluid in suppurative meningitis group, viral meningitis group and tuberculous meningitis group were decreased successively, and the differences were statistically significant. The detection of PCT in cerebrospinal fluid was more valuable than serum PCT detection in distinguishing tuberculous meningitis from viral meningitis. Continuous monitoring of changes in PCT in cerebrospinal fluid showed that there was no statistically significant difference before and after treatment. PCT level in cerebrospinal fluid was positively correlated with the serum PCT, cerebrospinal fluid white blood cell (WBC), and protein content in cerebrospinal fluid.

CONCLUSIONS: The dynamic changes of serum PCT in patients with suppurative meningitis can be used to evaluate the disease, guide the clinical medication, and monitor the prognosis.

L'articolo Application value of procalcitonin in patients with central nervous system infection sembra essere il primo su European Review.

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Underserved populations and bacterial and protozoal sexually transmitted infections: a lost health-care opportunity

OBJECTIVE: The purpose of our review is an update about the burden of sexually transmitted infections (STIs) among various types of underserved populations, such as migrants, substance abusers, homeless and incarcerated inmates. First-line test and treatment based on the latest available evidence according to the revised guidelines of Centers for Disease Control and Prevention have also been considered.

MATERIALS AND METHODS: We performed a comprehensive research using scientific databases such as Medline and Pubmed, followed by a review of citations and reference list. A consultation with other experts in the management of the various subpopulations was also conducted.

RESULTS: Health-care is often influenced by social determinants, which play a vital role in the diffusion of STIs. The consequence is a socio-economical and ethnic disparity in the rate of STIs. Early screening and treatment of STIs should be implemented in clinical practice, starting from marginalized social groups, which are the most affected by this health problem.

CONCLUSIONS: In the literature, there are very few papers containing information on STIs prevalence in various types of underserved populations, such as migrants, substance abusers, homeless and incarcerated inmates. The availability of more accurate epidemiological data is needed. In these groups, the most relevant barrier is the lower perception of health-care need, with an underestimation of risk and symptoms of STIs, causing a retard of diagnosis and health-care provision and use. For these populations, targeted interventions are needed, particularly on unaware people, responsible for most STIs transmissions.

L'articolo Underserved populations and bacterial and protozoal sexually transmitted infections: a lost health-care opportunity sembra essere il primo su European Review.

http://ift.tt/2jtVzR0

Spotlight: MedixSafe strives to make first responders' jobs easier

The MS2 narcotics cabinet saves space in ambulances while providing triple authentication of users

http://ift.tt/2x6TMVo

Roles for RpoS in survival of Escherichia coli during protozoan predation and in reduced moisture conditions highlight its importance in soil environments

Abstract

The soil is a complex ecosystem where interactions between biotic and abiotic factors determine the survival and fate of microbial inhabitants of the system. Having previously shown that Escherichia coli requires the general stress response regulator, RpoS, to survive long-term in soil, it was important to determine what specific conditions in this environment necessitate a functional RpoS. This study investigated the susceptibility of soil-persistent E. coli to predation by the single-celled eukaryotes Acanthamoeba polyphaga and Tetrahymena pyriformis, and the role RpoS plays in resisting this predation. Strain-specific differences were observed in the predation of E. coli strains, with soil-persistent strain COB583 being the most resistant to predation by both protozoans. RpoS and curli, proteinaceous fibres used for attachment to biotic and abiotic surfaces, increased the ability of E. coli to resist predation by A. polyphaga and T. pyriformis. Furthermore, soil moisture content impacted the survival of E. coli BW25113 but wild type COB583 had similar survival irrespective of soil moisture content. Overall, this study confirmed that RpoS contributes to the resistance of E. coli to protozoan predation and that RpoS is crucial for the increased fitness of soil-persistent E. coli against predation and reduced moisture in soil.

http://ift.tt/2ycP9sO

Environmental parameters altered by climate change affect the activity of soil microorganisms involved in bioremediation

Abstract

Bioremediation, based on the use of microorganisms to break down pollutants, can be very effective at reducing soil pollution. But the climate change we are now experiencing is bound to have an impact on bioremediation performance, since the activity and degrading abilities of soil microorganisms are dependent on a series of environmental parameters which are themselves being altered by climate change, such as soil temperature, moisture, amount of root exudates, etc. Many climate-induced effects on soil microorganisms occur indirectly through changes in plant growth and physiology derived from increased atmospheric CO₂ concentrations and temperatures, the alteration of precipitation patterns, etc., with a concomitant effect on rhizoremediation performance (i.e. the plant-assisted microbial degradation of pollutants in the rhizosphere). But these effects are extremely complex and mediated by processes such as acclimation and adaptation. Besides, soil microorganisms form complex networks of interactions with a myriad of organisms from many taxonomic groups which will also be affected by climate change, further complicating data interpretation.

http://ift.tt/2wgAGyJ

Identification and characterization of a CI binding operator at a distant location in the temperate staphylococcal phage ф11

Abstract

Bacteriophage ф11 encodes repressors CI and Cro for executing its growth in Staphylococcus aureus, a human pathogen. There are three homologous operators O1, O2, and O3 between the repressor-expressing genes. While CI binds to O1 and O2, Cro interacts only with O3. To locate additional CI binding operators in ф11, we searched its genome using the O1/O2 sequence as a probe. The results show the presence of a putative CI binding operator (O4) at the 3' end of the cro. O4 differs from O2 and O1 by one base and five bases, respectively. A specific interaction was noticed between O4 and rCI, a recombinant CI. However, O4 shows no interaction with rCro, a chimeric Cro. Additionally, six guanine bases, situated in and around O4, have interacted with rCI. Interestingly, the rCI binding affinity of O4 or O1 is about fifteen times higher than that of O2. A comparative study indicates that some bases and structural alteration, unique to O1 and O4, may contribute to their enhanced rCI binding affinity. Collectively, the study has not only broadened the distinct gene regulatory circuit of ф11 but also suggested that it possibly employs a complex mechanism for its development in S. aureus.

http://ift.tt/2ycXkpd

Changes in DNA methylation in naïve T helper cells regulate the pathophysiological state in minimal-change nephrotic syndrome

DNA methylation plays a crucial role in regulating transcription, and changes in DNA methylation affect gene expression and disease development. Minimal change nephrotic syndrome (MCNS) has been reported to in...

http://ift.tt/2xEKl2s

Touchscreen Sustained Attention Task (SAT) for Rats

Sustained attention, or continuously monitoring situations for intermittent and unpredictable events, is a critical aspect of cognition. Here we detail how to test sustained attention in rats using touchscreen operant chambers. We demonstrate comparable performance in male and female rats, making this task useful for studying attention in both sexes.

http://ift.tt/2wipGRG

Sequential estimation of intrinsic activity and synaptic input in single neurons by particle filtering with optimal importance density

This paper deals with the problem of inferring the signals and parameters that cause neural activity to occur. The ultimate challenge being to unveil brain's connectivity, here we focus on a microscopic vision...

http://ift.tt/2x34SgB

Controlling Molecular Doping in Organic Semiconductors

The field of organic electronics thrives on the hope of enabling low-cost, solution-processed electronic devices with mechanical, optoelectronic, and chemical properties not available from inorganic semiconductors. A key to the success of these aspirations is the ability to controllably dope organic semiconductors with high spatial resolution. Here, recent progress in molecular doping of organic semiconductors is summarized, with an emphasis on solution-processed p-type doped polymeric semiconductors. Highlighted topics include how solution-processing techniques can control the distribution, diffusion, and density of dopants within the organic semiconductor, and, in turn, affect the electronic properties of the material. Research in these areas has recently intensified, thanks to advances in chemical synthesis, improved understanding of charged states in organic materials, and a focus on relating fabrication techniques to morphology. Significant disorder in these systems, along with complex interactions between doping and film morphology, is often responsible for charge trapping and low doping efficiency. However, the strong coupling between doping, solubility, and morphology can be harnessed to control crystallinity, create doping gradients, and pattern polymers. These breakthroughs suggest a role for molecular doping not only in device function but also in fabrication—applications beyond those directly analogous to inorganic doping.

Strong interactions between molecular dopants and organic semiconductor morphology are often responsible for charge trapping and low doping efficiency. This study reviews how solution-processing techniques can control these interactions and render them useful for engineering diffusion rates, doping gradients, and film topography. These breakthroughs suggest new roles for molecular doping in device fabrication as well as function.

http://ift.tt/2foAqTV

Increased Level of Interleukin 6 Associates With Increased 90-day and 1-year Mortality in Patients With End-stage Liver Disease

Organ allocation for liver transplantation is based on prognosis, using the model for end-stage liver disease (MELD) or MELD-Na score. These scores do not consider systemic inflammation and septic complications. Blood level of C-reactive protein (CRP), in addition to the MELD score, associates with mortality in patients with end-stage liver disease, whereas levels of interleukin 6 (IL6) have not been systematically studied.

http://ift.tt/2wfLiy5

Patterning Bioactive Proteins or Peptides on Hydrogel Using Photochemistry for Biological Applications

In this method, we use photopolymerization and click chemistry techniques to create protein or peptide patterns on the surface of polyethylene glycol (PEG) hydrogels, providing immobilized bioactive signals for the study of cellular responses in vitro.

http://ift.tt/2xEWILR

Fragile Y Chromosomes (retrospective on DOI 10.1002/bies.201500040)

http://ift.tt/2vZhstt

Screening Assays to Characterize Novel Endothelial Regulators Involved in the Inflammatory Response

Vascular endothelium tightly controls leukocyte recruitment. Inadequate leukocyte extravasation contributes to human inflammatory diseases. Therefore, searching for novel regulatory elements of endothelial activation is necessary to design improved therapies for inflammatory disorders. Here, we describe a comprehensive methodology to characterize novel endothelial regulators that can modify leukocyte trafficking during inflammation.

http://ift.tt/2xEOC6a

A Novel Method: Super-selective Adrenal Venous Sampling

'Super-selective' adrenal venous sampling (ssAVS, also called segmental adrenal venous sampling: sAVS) was performed using a micro-catheter to identify adrenal segment(s) that produce excessive amounts of hormones. The ssAVS technique was described, cases in which adrenal segmental lesion(s) were identified by ssAVS were presented, and the usefulness of ssAVS in future adrenal research was discussed.

http://ift.tt/2xEOofk

Monitoring the response of urothelial precancerous lesions to Bacillus Calmette-Guerin at the proteome level in an in vivo rat model

Abstract

Intravesical Bacillus Calmette-Guerin (BCG) is the best treatment modality for progression of non-muscle invasive bladder cancer. We aimed to monitor changes at the proteome level to identify putative protein biomarkers associated with the response of urothelial precancerous lesions to intravesical BCG treatment. The rats were divided into three groups (n = 10/group): control, non-treated, and BCG-treated groups. The non-treated and BCG-treated groups received N-methyl-N-nitrosourea intravesically. BCG Tice-strain was instilled into bladder in BCG-treated group. At the endpoint of experiment, all surviving rat bladders were collected and equally divided into two portions vertically from dome to neck. Half of each bladder was assessed immunohistopathologically and the other half was used for 2D-based comparative proteomic analysis. Differentially expressed proteins were validated by Western blot analysis. Precancerous lesions of bladder cancer were more common in non-treated group (77.8%) than in BCG-treated group (50%) and the control group (0%). Greater than twofold changes occurred in the expression of a number of proteins. Among them, Rab-GDIβ, aldehyde dehydrogenase 2 (ALDH2) and 14-3-3 zeta/delta were important since they were previously reported to be associated with cancer and their expression levels were found to be lower in BCG-treated group in comparison to the non-treated group. ALDH2 and 14-3-3 zeta/delta were also found to be highly expressed in the non-treated group compared to the control group. The down-regulation of these proteins and Rab-GDIβ was achieved with BCG; this result indicates that they may be used as putative biomarkers for monitoring changes in bladder carcinogenesis in response to BCG immunotherapy.

http://ift.tt/2juGdvF

Monitoring the response of urothelial precancerous lesions to Bacillus Calmette-Guerin at the proteome level in an in vivo rat model

Abstract

Intravesical Bacillus Calmette-Guerin (BCG) is the best treatment modality for progression of non-muscle invasive bladder cancer. We aimed to monitor changes at the proteome level to identify putative protein biomarkers associated with the response of urothelial precancerous lesions to intravesical BCG treatment. The rats were divided into three groups (n = 10/group): control, non-treated, and BCG-treated groups. The non-treated and BCG-treated groups received N-methyl-N-nitrosourea intravesically. BCG Tice-strain was instilled into bladder in BCG-treated group. At the endpoint of experiment, all surviving rat bladders were collected and equally divided into two portions vertically from dome to neck. Half of each bladder was assessed immunohistopathologically and the other half was used for 2D-based comparative proteomic analysis. Differentially expressed proteins were validated by Western blot analysis. Precancerous lesions of bladder cancer were more common in non-treated group (77.8%) than in BCG-treated group (50%) and the control group (0%). Greater than twofold changes occurred in the expression of a number of proteins. Among them, Rab-GDIβ, aldehyde dehydrogenase 2 (ALDH2) and 14-3-3 zeta/delta were important since they were previously reported to be associated with cancer and their expression levels were found to be lower in BCG-treated group in comparison to the non-treated group. ALDH2 and 14-3-3 zeta/delta were also found to be highly expressed in the non-treated group compared to the control group. The down-regulation of these proteins and Rab-GDIβ was achieved with BCG; this result indicates that they may be used as putative biomarkers for monitoring changes in bladder carcinogenesis in response to BCG immunotherapy.

http://ift.tt/2juGdvF

Neurocognitive, psychosocial, and quality-of-life outcomes in adult survivors of childhood non-Hodgkin lymphoma

BACKGROUND

Children with non-Hodgkin lymphoma (NHL) undergo treatment with central nervous system–directed therapy, the potentially neurotoxic effects of which have not been reported in NHL survivors.

METHODS

NHL survivors (n = 187) participating in the St. Jude Lifetime Cohort who were 10 or more years from their diagnosis and were 18 years old or older underwent neurocognitive, emotional distress (Brief Symptom Inventory 18), and health-related quality of life (HRQOL) assessments (36-Item Short Form Health Survey). Age-adjusted z scores were compared with community controls (n = 181) and normative data. Treatment exposures were abstracted from medical records. Models adjusted for the age, sex, and time from diagnosis were used to calculate the risk of impairment.

RESULTS

The mean ages at evaluation were similar for the survivors and the controls (35.7 ± 8.9 vs 35.5 ± 11.0 years; P = .86). Survivors were 25.2 ± 8.8 years from their diagnosis: 43 (23%) received cranial radiation, 70 (37%) received high-dose methotrexate, 40 (21%) received high-dose cytarabine, and 151 (81%) received intrathecal chemotherapy. Survivors' intelligence and attention were within normal limits; however, their memory, executive function, processing speed, and academics were impaired in comparison with both population norms and community controls (P values < .05). Treatment-related exposures were not associated with neurocognitive function; however, neurocognitive impairment was associated with lower educational attainment, unemployment, and occupational status (P values < .03). Slower processing speed and worse self-reported executive function were associated with symptoms of depression (P values ≤ .003) and poorer HRQOL (P values < .05).

CONCLUSIONS

Adult survivors of childhood NHL experience impaired neurocognitive function, which is associated with lower social attainment and poor HRQOL. Early-detection and intervention strategies are recommended. Cancer 2017. © 2017 American Cancer Society.

http://ift.tt/2x7Iba0