Atomically Thin Mesoporous Co3O4 Layers Strongly Coupled with N-rGO Nanosheets as High-Performance Bifunctional Catalysts for 1D Knittable Zinc–Air Batteries

Abstract

Under development for next-generation wearable electronics are flexible, knittable, and wearable energy-storage devices with high energy density that can be integrated into textiles. Herein, knittable fiber-shaped zinc–air batteries with high volumetric energy density (36.1 mWh cm⁻³) are fabricated via a facile and continuous method with low-cost materials. Furthermore, a high-yield method is developed to prepare the key component of the fiber-shaped zinc–air battery, i.e., a bifunctional catalyst composed of atomically thin layer-by-layer mesoporous Co₃O₄/nitrogen-doped reduced graphene oxide (N-rGO) nanosheets. Benefiting from the high surface area, mesoporous structure, and strong synergetic effect between the Co₃O₄ and N-rGO nanosheets, the bifunctional catalyst exhibits high activity and superior durability for oxygen reduction and evolution reactions. Compared to a fiber-shaped zinc–air battery using state-of-the-art Pt/C + RuO₂ catalysts, the battery based on these Co₃O₄/N-rGO nanosheets demonstrates enhanced and stable electrochemical performance, even under severe deformation. Such batteries, for the first time, can be successfully knitted into clothes without short circuits under external forces and can power various electronic devices and even charge a cellphone.

Knittable fiber-shaped zinc–air batteries based on atomically thin mesoporous Co₃O₄ layers strongly coupled with nitrogen-doped reduced graphene oxide nanosheets as bifunctional catalysts of the air electrodes are developed and can be fabricated by a quick, facile, and continuous method. These high-energy-density batteries can be knitted into clothes and used as the power supply for wearable electronic devices.

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Realizing Over 13% Efficiency in Green-Solvent-Processed Nonfullerene Organic Solar Cells Enabled by 1,3,4-Thiadiazole-Based Wide-Bandgap Copolymers

Abstract

Two novel wide-bandgap copolymers, PBDT-TDZ and PBDTS-TDZ, are developed based on 1,3,4-thiadiazole (TDZ) and benzo[1,2-b:4,5-b′]dithiophene (BDT) building blocks. These copolymers exhibit wide bandgaps over 2.07 eV and low-lying highest occupied molecular orbital (HOMO) levels below −5.35 eV, which match well with the typical low-bandgap acceptor of ITIC, resulting in a good complementary absorption from 300 to 900 nm and a low HOMO level offset (≤0.13 eV). Compared to PBDT-TDZ, PBDTS-TDZ with alkylthio side chains exhibits the stronger optical absorption, lower-lying HOMO level, and higher crystallinity. By using a single green solvent of o-xylene, PBDTS-TDZ:ITIC devices exhibit a large open-circuit voltage (V_oc) up to 1.10 eV and an extremely low energy loss (E_loss) of 0.48 eV. At the same time, the desirable high short-circuit current density (J_sc) of 17.78 mA cm⁻² and fill factor of 65.4% are also obtained, giving rise to a high power conversion efficiency (PCE) of 12.80% without any additive and post-treatment. When adopting a homotandem device architecture, the PCE is further improved to 13.35% (certified as 13.19%) with a much larger V_oc of 2.13 V, which is the best value for any type of homotandem organic solar cells reported so far.

Two novel 1,3,4-thiadiazole-based wide-bandgap copolymers, PBDT-TDZ and PBDTS-TDZ, are developed for efficient nonfullerene organic solar cells. The single-junction devices processed by a green solvent of o-xylene exhibit a high power conversion efficiency (PCE) of 12.80% with a low energy loss of 0.48 eV. The PCE is finally improved to 13.35% when using a homotandem device architecture.

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Giampaolo Velo 1943–2017

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Factors influencing the fracture of dental implants

Abstract

Background

Implant fractures are rare but offer a challenging clinical situation.

Purpose

To determine the prevalence of implant fracture and the possible risk factors predisposing an implant to a higher fracture risk.

Materials and Methods

This retrospective study is based on 2670 patients consecutively treated with implant-supported prostheses. Anatomical-, patient-, and implant-related factors were collected. Descriptive statistics and survival analyses were performed. Generalized estimating equations (GEE) evaluated the effect of explanatory variables on implant fracture.

Results

Forty-four implants (out of 10 099; 0.44%) fractured. The mean ± standard deviation time for fracture to occur was 95.1 ± 58.5 months (min-max, 3.8-294.7). Half of the occurrences of fracture happened between 2 and 8 years after implantation. Five factors had a statistically significant influence on the fracture of implants (increase/decrease in fracture probability): use of higher grades of titanium (decrease 72.9%), bruxism (increase 1819.5%), direct adjacency to cantilever (increase 247.6%), every 1 mm increase in implant length (increase 22.3%), every 1 mm increase in implant diameter (decrease 96.9%).

Conclusions

It is suggested that 5 factors could influence the incidence of implant fractures: grade of titanium, implant diameter and length, cantilever, bruxism.

http://ift.tt/2zRI9C8

A retrospective study on clinical and radiological outcomes of oral implants in patients followed up for a minimum of 20 years

Abstract

Background

Very long-term follow-up of oral implants is seldom reported in the literature.

Purpose

To assess oral implant failure rates and marginal bone loss (MBL) of patients followed up for a minimum of 20 years.

Materials and Methods

Implants placed in patients followed up for 20+ years were included. Descriptive statistics, survival analyses, generalized estimating equations were performed. Three-hundred implants were randomly selected for MBL.

Results

1,045 implants (227 patients) were included. Implant location, irradiation, and bruxism affected the implant survival rate. Thirty-five percent of the failures occurred within the first year after implantation, and another 26.8% in the second/third year. There was a cumulative survival rate of 87.8% after 36 years of follow-up. In the last radiological follow up, 35 implants (11.7%) had bone gain, and 35 implants (11.7%) presented at least 3 mm of MBL. Twenty-six out of 86 failed implants with available radiograms presented severe MBL in the last radiological register before implant failure.

Conclusions

Most of the implant failures occurred at the first few years after implantation, regardless of a very long follow up. MBL can be insignificant in long-term observations, but it may, nevertheless, be the cause of secondary failure of oral implants in some cases.

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Intraoral versus extraoral cementation of implant-supported single crowns: Clinical, biomarker, and microbiological comparisons

Abstract

Objectives

Implant supported single metal-ceramic crowns cemented either extraorally or intraorally were comparatively evaluated by clinical, radiologic, biomarker, and microbiological parameters.

Materials and Methods

Twelve patients with bilateral single tooth gap in the maxillary posterior region received two locking-taper implants; 4.5 mm width, 8 mm length. Selection of intraoral (IOC) or extraoral cementation (EOC) using screwless titanium abutments was done randomly. Peri-implant crevicular fluid (PICF), gingival crevicular fluid (GCF) samples were collected from the implants, adjacent teeth, and bleeding on probing, soft tissue thickness, keratinized tissue width were recorded before starting the prosthetic procedures (baseline) and 3, 6 months after implant loading. Crestal bone loss was measured on radiographs taken immediately and 6 months after cementation. Cytokine levels, amounts of bacteria were determined in PICF/GCF samples. Data were tested by appropriate statistical analyses.

Results

Clinical findings were similar in the crowns cemented extraorally or intraorally at all times (P < .05). PICF and GCF data were similar. At 3 month, interleukin-17E and osteoprotegerin levels were lower in the intraorally cemented crowns.

Conclusion

Extraorally and intraorally cemented crowns exhibited similar crestal bone loss after loading. Higher amount of osteoprotegerin at 3 month at the EOC than the IOC sites might bode well for good osseointegration.

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Reduction of Skeletal Muscle Power in Adolescent Males Carrying H63D Mutation in the HFE Gene

Iron overload resulting from the mutation of genes involved in iron metabolism or excess dietary intake has been reported to negatively influence human physical performance. The aim of this study was to test the hypothesis that adolescents bearing a hemochromatosis gene (HFE) mutation in contrast to adults with the same mutation will not experience iron accumulation and their aerobic capacity will be similar to that of age-matched controls. Thirteen boys participated in the study. Seven of them are carriers of H63D mutation in the HFE gene and six were wild type. Fitness levels were assessed using the cardiopulmonary exercise test. In addition, iron status and inflammatory markers were determined. We observed that cardiovascular fitness was significantly lower in the group bearing the HFE mutation compared to the control group. Moreover, the HFE mutation group achieved lower maximal power output compared to the control group. There were no differences in blood ferritin concentrations between the two groups which indicates similar amounts of stored iron. Obtained data do not confirm our hypothesis. On the contrary, it was demonstrated that HFE mutation is associated with a lower level of aerobic capacity, even in the absence of iron accumulation.

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Potential therapeutic effects of N-butylidenephthalide from Radix Angelica Sinensis (Danggui) in human bladder cancer cells

N-butylidenephthalide (BP) isolated from Radix Angelica Sinensis (Danggui) exhibits anti-tumorigenic effect in various cancer cells both in vivo and in vitro. The effect of BP in bladder cancer treatment is still...

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Prognostic Factors for Immune Thrombocytopenia Outcome in Greek Children: A Retrospective Single-Centered Analysis

Immune thrombocytopenia (ITP) in children has a varied course and according to duration is distinguished as newly diagnosed (12) types. Several studies have evaluated the prognostic factors for the progression of the disease, but similar works have yet to be performed in Greece. We aimed to identify prognostic markers for the three forms of the disease in 57 Greek children during a 13-year period. Information regarding age, gender, preceding infection, bleeding type, duration of symptoms and platelets at diagnosis, treatment, disease course, and immunological markers was recorded. 39 children had newly diagnosed, 4 persistent, and 14 chronic disease. Chronic ITP children were more likely to be of age > 10 years and have gradual initiation of the disease , platelets > 10 × 109/L , and impaired immunological markers compared to newly diagnosed/persistent groups. Recent history of infection was found mainly in the newly diagnosed/persistent group . None of the children exhibited severe spontaneous bleeding. Conclusion. Even though ITP in children usually has a self-limited course, with rare serious bleeding complications, the chronic form of the disease is characterized by different predictive parameters, which can be used in clinical practice.

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The Turkish validation of the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) battery

Cognitive impairment may be seen in as many as 43–70% of patients with multiple sclerosis (MS) and may be observed in all MS subtypes. The Brief International Cognitive Assessment in Multiple Sclerosis (BICAMS...

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Joubert’s syndrome and related disorders and home-based peritoneal dialysis in East Africa: a case report

Joubert's syndrome is a rare condition affecting an estimated 1:80,000–1:100,000 individuals. There is underdevelopment of the cerebellar vermis resulting in a characteristic molar tooth sign on cross sectiona...

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Unpublished systematic reviews and financial support: a meta-epidemiological study

PROSPERO, an international prospective register of systematic reviews, was launched in February 2011 to reduce publication bias of systematic reviews (SRs). A questionnaire survey of SR researchers conducted i...

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Short form version of the Quality of Trauma Care Patient-Reported Experience Measure (SF QTAC-PREM)

To enable the valid and reliable measurement of patient experiences we previously published a multicenter multi-center validation of the Quality of Trauma Care Patient-Reported Experience Measure (QTAC-PREM). ...

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Animations designed to raise patient awareness of prudent antibiotic use: patient recall of key messages and their immediate effect on patient attitude

This study aimed to determine if patients recalled key messages from antibiotic animations shown on digital displays in General Practice waiting rooms, and if watching them changed patients' immediate intentio...

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An outbreak of acute haemorrhagic conjunctivitis associated with coxsackievirus A24 variant in The Gambia, West Africa

An outbreak of acute haemorrhagic conjunctivitis occurred in The Gambia, West Africa in 2011. Affected individuals presented with conjunctival haemorrhages, swelling and ocular discharge. In an effort to ident...

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Improved Efficiency and Stability of Perovskite Solar Cells Induced by CO Functionalized Hydrophobic Ammonium-Based Additives

Abstract

Because of the rapid rise of the efficiency, perovskite solar cells are currently considered as the most promising next-generation photovoltaic technology. Much effort has been made to improve the efficiency and stability of perovskite solar cells. Here, it is demonstrated that the addition of a novel organic cation of 2-(6-bromo-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)ethan-1-ammonium iodide (2-NAM), which has strong Lewis acid and base interaction (between CO and Pb) with perovskite, can effectively increase crystalline grain size and reduce charge carrier recombination of the double cation FA_0.83MA_0.17PbI_2.51Br_0.49 perovskite film, thus boosting the efficiency from 17.1 ± 0.8% to 18.6 ± 0.9% for the 0.1 cm² cell and from 15.5 ± 0.5% to 16.5 ± 0.6% for the 1.0 cm² cell. The champion cell shows efficiencies of 20.0% and 17.6% with active areas of 0.1 and 1.0 cm², respectively. Moreover, the hysteresis behavior is suppressed and the stability is improved. The result provides a promising route to further elevate efficiency and stability of perovskite solar cells by the fine tuning of triple organic cations.

A new organic additive (2-NAM) is introduced into the perovskite film. The introduction of this additive boosts the efficiency from 17.1 ± 0.8% to 18.6 ± 0.9% for the 0.1 cm² area cells and from 15.5 ± 0.5% to 16.5 ± 0.6% for the 1.0 cm² area cells. Moreover, the hydrophobic nature of this additive effectively reduces the influence from moisture, thus enhancing the solar cell stability.

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Highly Deformable and See-Through Polymer Light-Emitting Diodes with All-Conducting-Polymer Electrodes

Abstract

Despite the high expectation of deformable and see-through displays for future ubiquitous society, current light-emitting diodes (LEDs) fail to meet the desired mechanical and optical properties, mainly because of the fragile transparent conducting oxides and opaque metal electrodes. Here, by introducing a highly conductive nanofibrillated conducting polymer (CP) as both deformable transparent anode and cathode, ultraflexible and see-through polymer LEDs (PLEDs) are demonstrated. The CP-based PLEDs exhibit outstanding dual-side light-outcoupling performance with a high optical transmittance of 75% at a wavelength of 550 nm and with an excellent mechanical durability of 9% bending strain. Moreover, the CP-based PLEDs fabricated on 4 µm thick plastic foils with all-solution processing have extremely deformable and foldable light-emitting functionality. This approach is expected to open a new avenue for developing wearable and attachable transparent displays.

Deformable and see-through polymer light-emitting diodes (PLEDs) are developed by using a highly conductive nanofibrillated conducting polymer (CP) as both ultraflexible transparent anode and cathode. The CP-based PLEDs fabricated on plastic foils with all-solution processing exhibit outstanding dual-side light-outcoupling performance and rollable/foldable light-emitting functionality with a high optical transmittance of 75% at a wavelength of 550 nm.

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Massive cortical reorganization is reversible following bilateral transplants of the hands: evidence from the first successful bilateral pediatric hand transplant patient

Abstract

In this repeated measures case study, we show that sensory deafferentation after limb amputation leads to changes in cortical somatotopic maps which are reversible after restoration of sensory input. Using magnetoencephalography (MEG), we observed in a child with bilateral hand transplants large-scale shifts in somatosensory lip cortical representation from anatomic hand area to anatomic face region. After recovery of tactile sensation in the digits, responses to finger stimulation were localized to orthotopic sensory cortex, but with atypical electrophysiologic features (amplitude and frequencies).

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Regional gastrointestinal contractility parameters using the wireless motility capsule: inter-observer reproducibility and influence of age, gender and study country

Summary

Background

The wireless motility capsule concurrently measures temperature, pH and pressure as it traverses the gastrointestinal tract.

Aims

To describe normative values for motility/contractility parameters across age, gender and testing centres.

Methods

Healthy participants underwent a standardised wireless motility capsule assessment following an overnight fast and consumption of a meal of known nutritional content. Traces were divided into regions of interest and analysed using 2 software packages (MotiliGI and GIMS Data Viewer). Inter-observer agreement was independently assessed by 2 investigators.

Results

Normative data for motility/contractility parameters (maximum amplitude, mean peak amplitude, contraction frequency and motility index) are presented for 107 individuals (62 male, median age 40 years, range 18-78). MotiliGI-Gastric, small bowel and colonic maximal contraction amplitude correlated with age (r = .24, P = .01; r = .22, P = .02; and r = .2, P = .04 respectively). Small bowel motility index was higher in females than males (150.4 ± 12 vs 122 ± 7.6, P = .04). Inter-observer agreement was excellent for transit times, pH and contractility/motility parameters. GIMS Data viewer-Gastric, small bowel and colonic log_e motility index correlated with the respective area under the contraction curve, total contractions, sum of amplitudes and contraction frequency (all r>.35, P < .0003) but not with transit times.

Conclusions

Our analysis provides normative data for motility/contractility parameters. Log motility index summarises a number of measures. In future, the measurement of contractile activity with the wireless motility capsule may potentially aid in the diagnosis of disease states such as visceral myopathic disorders.

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Parotid gland: an unusual site of breast cancer metastasis

Parotid gland metastases from breast cancer are an extremely rare and unusual event with a limited number of cases recorded in the literature. A 71-year-old woman with a history of ductal adenocarcinoma of the left breast presented to the maxillofacial clinic with an asymptomatic swelling of the left parotid gland. The presentation occurred 21 years after she underwent treatment for recurrent breast cancer. Investigations led to the diagnosis of a breast cancer metastasis which was oestrogen receptor and progesterone receptor positive and negative. Positron emission tomography scan confirmed this as a solitary metastasis. She was treated with aromatase inhibitors and a stable clinical response was observed on follow-up. Surgical intervention was avoided with its potential complications such as facial nerve injury. Metastasis from breast cancer to the parotid gland is a very rare phenomenon. However, in a patient with previous breast cancer, it should be considered as a possible differential diagnosis.

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Nerve abscess in pure neural leprosy mistaken for peripheral nerve sheath tumour with disastrous consequence: what can we learn?

A 34-year-old Indian man presented to an orthopaedician with gradually progressive hypoesthesia affecting his right lower limb and an ipsilateral common peroneal nerve swelling around the knee. The nerve swelling was diagnosed as a peripheral nerve sheath tumour based on MRI findings and was excised, only to be revealed as leprous nerve abscess on histopathology later. The patient developed right foot drop as a result of common peroneal nerve biopsy. This case presents several learning points in the diagnosis of pure neural leprosy.

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Gastric liposarcoma resected by laparoscopic total gastrectomy to achieve a wide surgical margin

Gastric liposarcoma is an extremely rare tumour that usually affects the extremities and retroperitoneum. Preoperative diagnosis is difficult, and operative procedures are not well standardised. A 61-year-old woman presented with melaena, epigastric discomfort and palpitations. Upper endoscopy revealed a submucosal tumour at the posterior gastric fundus with an actively bleeding ulcer on the top. Our preoperative diagnosis was lipoma, and we performed laparoscopic intragastric surgery. However, the histopathological diagnosis was liposarcoma. Laparoscopic total gastrectomy was performed to achieve a wide surgical margin. Several recent series have shown that a positive microscopic margin is associated with a higher rate of local recurrence than a negative margin. We have added a staged operation to obtain a wide margin in cases involving a positive surgical margin. Preoperative diagnosis of liposarcoma is still challenging. Gastric lipoma-like tumours should be resected with a wide margin because of their possibility of malignancy.

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Pathological ECG that seemed normal following electrode misplacement

We report the case of a 57-year-old woman found at home who received an ECG after having recovered from a seizure, without any clinical cardiac anomaly. The ECG revealed an elevation of the ST segment from the V1 to V5 leads and negative T waves from V1 to V5 leads. At her hospital admission, the emergency care unit (ECU) nurse performed another ECG. It no longer showed any repolarisation anomaly. However, the ECU nurse had put the precordial electrodes 3 cm too low, probably due to the patient's voluminous breasts. In the end, the pathological trace reappeared after we returned the electrodes to their initial positions. Malpositioning of the electrodes caused a seemingly normal ECG result with life-threatening consequences.

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Lentiform fork sign due to severe metabolic acidosis

Description

An 11-month-old, developmentally normal, female infant presented with acute-onset fever, vomiting, shallow breathing and gradually progressive lethargy for the past 2 days. There was no history of seizures, neck stiffness, focal motor deficits, cranial nerve palsies, tone changes, rash, diarrhoea, recurrent encephalopathies, abnormal body odour, recurrent infections or hospitalisations, drug or toxin ingestion. Her past and family history was not contributory. On examination, anthropometric parameters were normal for age. She had mild pallor, angular cheilitis, wrist widening, tachypnea (respiratory rate 58/min) with acidotic breathing. She was conscious with fluctuations in alertness (Glasgow Coma Scale (GCS) E4M5V2) and irritability with reduced spontaneous activity, mild hypotonia, preserved antigravity movements, brisk muscle stretch reflexes, bilateral extensor plantar response, absence of oculomotor abnormalities, cranial nerve palsies or bulbar signs and normal fundi. Rest of the systemic examination was unremarkable. A clinical diagnosis of acute febrile encephalopathy was considered.

Laboratory investigations showed...

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Dysphagia lusoria presenting as epigastric pain

Description

A 36-year-old African–American woman with medical history of systemic lupus erythematosus, lupus nephritis, protein S deficiency and recurrent deep venous thrombosis presented to outpatient clinic complaining of epigastric pain associated with nausea, vomiting and unintentional weight loss. Esophagogastroduodenoscopy (EGD) was performed; however, mucosal tear was noted following severe retching. Subsequently, the procedure was terminated. EGD was significant for distal oesophageal obstruction. CT of the chest with contrast was significant for pneumomediastinum. Moreover it demonstrated an aberrant right subclavian artery compressing on the posterior part of the oesophagus (figure 1). The patient was diagnosed with dysphagia lusoria. This patient's symptoms were moderate and managed with dietary modifications. Thus, surgical intervention was not recommended. There was no further progression of symptoms at 1-year follow-up.

Figure 1

Aberrant right subclavian artery compressing on the posterior part of the oesophagus.

Dysphagia lusoria is a condition...

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Painful testicular metastasis from prostate adenocarcinoma

A 60-year-old man presented with unilateral testicular pain and urinary frequency. His presenting prostate-specific antigen (PSA) was 100 ng/mL, and a biopsy revealed Gleason 4+4 prostate adenocarcinoma. The significance of his initial PSA was somewhat complicated by possible prostatitis and early initiation of bicalutamide. PSA rose on two occasions prior to radiotherapy but coincided with a flare of testicular pain on one of these. Whole-body staging diffusion-weighted MRI scan was negative. He was treated with 3 years of androgen deprivation therapy (ADT) and radical radiotherapy. PSA fell to undetectable levels on ADT. Twelve months following completion of ADT, PSA rose to 3.6 ng/mL. No disease recurrence was noted on restaging MRI pelvis. The patient was well, except for persistent testicular symptoms, which failed to resolve following multiple antibiotics. Testicular tumour markers were negative. Ultrasound findings were consistent with chronic epididymitis. A right orchidectomy was performed for symptomatic relief, confirming metastatic prostate adenocarcinoma.

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The effect of Opuntia ficus-indica juice supplementation on oxidative stress, cardiovascular parameters, and biochemical markers following yo-yo Intermittent recovery test

Abstract

The aim of the study was to investigate the effect of a flavonoid-rich fresh fruit juice on cardiovascular, oxidative stress, and biochemical parameters during the yo-yo intermittent recovery test (YYIRT). Twenty-two healthy males subjects participated in this study divided into two groups: An experimental group (EG: n = 11) who consumed the antioxidant supplement and a control group (CG: n = 11). All participants performed two test sessions at 07:00 hr before and after 2 weeks of supplementation with Opuntia ficus-indica juice. Blood samples were taken before (P1) and immediately (P2) after the YYIRT. Our results showed that following the 2,2-diphenyl-1- picrylhydrazyl (DPPH^●) test, the Opuntia ficus-indica juice has an antioxidant capacity for capturing free radicals (p < .05) and reducing oxidative stress related to exercise. Concerning biochemical and cardiovascular parameters, our results showed a significant increase on total cholesterol (TC) (p < .01), triglycerides (TG) (p < .05), high-density lipoprotein (HDL) (p < .01), low-density lipoprotein (LDL) (p < .01), creatine kinase (CK) (p < .01), lactate deshydrogenase (LDH) (p < .01), glucose (GLC) (p < .01), systolic (SBP), and diastolic blood pressure (DBP) (p < .01) immediately after exercise. However, TC (p < .05), TG (p < .05) and LDL (p < .05), the maximal heart rate (HRmax), the CK (p < .05), and LDH (p < .01) as well as the malondialdehyde (MDA) (p < .01) demonstrated a significant decrease after supplementation of Opuntia ficus-indica juice before and immediately after YYIRT. However, no significant effect on HDL (p > .05), GLC (p > .05) levels nor the SBP and DBP (p > .05) was observed after supplementation with Opuntia ficus-indica juice. The supplementation leads to an improvement on YYIRT performance (The total distance covered during the YYIRT, VO_2max, VMA) and the rating of perceived exertion (RPE). Opuntia ficus-indica juice has a potent antioxidant activity that reduces total and LDL-cholesterol with only a moderate lowering of HDL-cholesterol and oxidative stress. Moreover, supplementation decreases muscle damage caused by the endurance exercise.

The Opuntia ficus-indica juice has a potent antioxidant activity. The supplementation Juice decrease muscle damage and oxidative stress caused by the endurance exercise.

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Antimicrobial peptides sourced from post-butter processing waste yak milk protein hydrolysates

Yak butter is one of the most important foods for the Tibetan people. Of note, its production yields waste yak milk as a by-product. In this work, waste yak milk protein hydrolysates made via Pepsin hydrolysis...

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Correction to: Effect of incubation duration, growth temperature, and abiotic surface type on cell surface properties, adhesion and pathogenicity of biofilm-detached Staphylococcus aureus cells

Following publication of the original article (Khelissa et al. 2017), the authors reported that the legend for Fig. 3 contained an error. Instead of "Adhesion of planktonic and biofilm-detached Staphylococcus aur...

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Bloodstream infections at a tertiary level paediatric hospital in South Africa

Bloodstream infection (BSI) in children causes significant morbidity and mortality. There are few studies describing the epidemiology of BSI in South African children.

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Identification by mass spectrometry and automated susceptibility testing from positive bottles: a simple, rapid, and standardized approach to reduce the turnaround time in the management of blood cultures

Speeding up identification and antimicrobial susceptibility testing (AST) is of foremost importance in the management of blood cultures. Here, we describe a simple, rapid, and standardized approach based on a ...

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Time trend of clinical cases of Lyme disease in two hospitals in Belgium, 2000–2013

As several studies indicated an increase in Lyme disease (LD), notably in neighbouring countries, concerns have arisen regarding the evolution of Lyme disease in Belgium. In order to confirm or infirm the incr...

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Economic burden of preemptive treatment of CMV infection after allogeneic stem cell transplantation: a retrospective study of 208 consecutive patients

Cytomegalovirus (CMV) infection and disease (CMV episodes) are global concerns after allogeneic hematopoietic stem cell transplantation (HSCT). They affect survival, both by direct and indirect effects. Due to...

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Normothermic machine perfusion for the assessment and transplantation of declined human kidneys from donation after circulatory death donors

Background

A significant proportion of donation after circulatory death (DCD) kidneys are declined for transplantation because of concerns over their quality. Ex vivo normothermic machine perfusion (NMP) provides a unique opportunity to assess the quality of a kidney and determine its suitability for transplantation.

Methods

In phase 1 of this study, declined human DCD kidneys underwent NMP assessment for 60 min. Kidneys were graded 1–5 using a quality assessment score (QAS) based on macroscopic perfusion, renal blood flow and urine output during NMP. In phase 2 of the study, declined DCD kidneys were assessed by NMP with an intention to transplant them.

Results

In phase 1, 18 of 42 DCD kidneys were declined owing to poor in situ perfusion. After NMP, 28 kidneys had a QAS of 1–3, and were considered suitable for transplantation. In phase 2, ten of 55 declined DCD kidneys underwent assessment by NMP. Eight kidneys had been declined because of poor in situ flushing in the donor and five of these were transplanted successfully. Four of the five kidneys had initial graft function.

Conclusion

NMP technology can be used to increase the number of DCD kidney transplants by assessing their quality before transplantation.

http://ift.tt/2iqJ5WS

99m Tc-rituximab as a tracer for sentinel lymph node biopsy in breast cancer patients: a single-center analysis

Abstract

Purpose

This study aimed to determine the long-term prognosis of breast cancer patients with ^99mTc-rituximab for sentinel lymph node biopsy (SLNB).

Methods

A total of 2947 patients with negative sentinel lymph nodes (SLNs) omitting axillary lymph node dissection (ALND), treated between June 2005 and December 2013, were retrospectively analyzed. SLNB was performed prior to adjuvant therapy.

Results

After a median follow-up of 62 months, 22 cases of axillary recurrence (AR) were observed. The 5-year AR rate (ARR) was 0.7% [95% confidence interval (CI) 0.3–1.1%] and the 5-year relapse-free survival (RFS) was 95.2% (95% CI 94.4–96.0%). Multivariate analysis showed that abnormal axillary ultrasound with negative fine-needle aspiration (FNA) [hazard ratio (HR) 3.79, 95% CI 1.55–9.28; P = 0.004], not receiving radiotherapy (HR 4.38, 95% CI 1.47–13.05; P = 0.008), and age ≤ 40 years (HR 2.93, 95% CI 1.19–7.20; P = 0.020) were independent risk factors for AR.

Conclusions

ARR of SLNB-negative patients with ^99mTc-rituximab is low. Abnormal axillary ultrasound with negative FNA, not receiving radiotherapy, and age ≤ 40 years were prognostic factors for higher ARRs.

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Calpain-2 inhibitor treatment preferentially reduces tumor progression for human colon cancer cells expressing highest levels of this enzyme

Abstract

Calpain-2 levels are higher in colorectal tumors resistant to chemotherapy and previous work showed calpain-2 inhibitor therapy reduced inflammation-driven colorectal cancer, but direct effects of the inhibitor on colon cancer cells themselves were not demonstrated. In the present study, five human colon cancer cell lines were directly treated with a calpain-2 inhibitor and results showed increased cell death in 4 of 5 cell lines and decreased anchorage-independent growth for all cell five lines. When tested for levels of calpain-2, three cell lines exhibited increasing levels of this enzyme: HCT15 (low), HCC2998 (medium), and HCT116 (significantly higher). This was consistent with gel shift assays showing that calpain-2 inhibitor reduced of NF-κB nuclear translocation most effectively in HCT116 cells. Ability of calpain-2 inhibitor to impede tumor progression in vivo was evaluated using intrarectal transplant of luciferase-expressing cells for these three cell lines. Results showed that calpain-2 inhibitor therapy reduced tumor growth and increased survival only in mice injected with HCT116 cells. These data suggest calpain-2 inhibitor treatment may be most effective on colorectal tumors expressing highest levels of calpain-2.

Calpain-2 inhibitor therapy reduces inflammation in the colon, but its direct effects on colon cancer cells are unknown. This study shows in vitro and in vivo that calpain-2 inhibitor has the strongest therapeutic effects on colon cancer cells expressing the highest levels of calpain-2.

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Table of Contents

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In This Issue

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Editorial board

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Masthead

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[ 18 F]-BMS-747158-02PET imaging for evaluating hepatic mitochondrial complex 1dysfunction in a mouse model of non-alcoholic fatty liver disease

Abstract

Background

Mitochondrial dysfunction is one of the main causes of non-alcohol fatty liver disease (NAFLD). [¹⁸F]-BMS-747158-02 (¹⁸F-BMS) which was originally developed as a myocardial perfusion imaging agent was reported to bind mitochondrial complex-1 (MC-1). The aim of this study was to investigate the potential use of ¹⁸F-BMS for evaluating hepatic MC-1 activity in mice fed a methionine- and choline-deficient (MCD) diet.

Male C57BL/6J mice were fed a MCD diet for up to 2 weeks. PET scans with ¹⁸F-BMS were performed after 1 and 2 weeks of the MCD diet. ¹⁸F-BMS was intravenously injected into mice, and the uptake (standardized uptake value (SUV)) in the liver was determined. The binding specificity for MC-1 was assessed by pre-administration of rotenone, a specific MC-1 inhibitor. Hepatic MC-1 activity was measured using liver homogenates generated after each positron emission tomography (PET) scan. Blood biochemistry and histopathology were also assessed.

Results

In control mice, hepatic ¹⁸F-BMS uptake was significantly inhibited by the pre-injection of rotenone. The uptake of ¹⁸F-BMS was significantly decreased after 2 weeks of the MCD diet. The SUV at 30–60 min was well correlated with hepatic MC-1 activity (r = 0.73, p < 0.05). Increases in plasma ALT and AST levels were also noted at 1 and 2 weeks. Mild hepatic steatosis with or without minimal inflammation was histopathologically observed at 1 and 2 weeks in mice liver on the MCD diet. However, inflammation was observed only at 2 weeks in mice on the MCD diet.

Conclusions

The present study demonstrated that ¹⁸F-BMS is a potential PET probe for quantitative imaging of hepatic MC-1 activity and its mitochondrial dysfunction induced by steatosis and inflammation, such as in NAFLD.

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Concordance of FDG PET/CT metabolic tumour volume versus DW-MRI functional tumour volume with T2-weighted anatomical tumour volume in cervical cancer

Abstract

Background

¹⁸F–fluoro-deoxyglucose positron emission tomography with computed tomography (FDG PET/CT) has been employed to define radiotherapy targets using a threshold based on the standardised uptake value (SUV), and has been described for use in cervical cancer. The aim of this study was to evaluate the concordance between the metabolic tumour volume (MTV) measured on FDG PET/CT and the anatomical tumour volume (ATV) measured on T2-weighted magnetic resonance imaging (T2W-MRI); and compared with the functional tumour volume (FTV) measured on diffusion-weighted MRI (DW-MRI) in cervical cancer, taking the T2W-ATV as gold standard.

Methods

Consecutive newly diagnosed cervical cancer patients who underwent FDG PET/CT and DW-MRI were retrospectively reviewed from June 2013 to July 2017.

Volumes of interest was inserted to the focal hypermetabolic activity corresponding to the cervical tumour on FDG PET/CT with automated tumour contouring and manual adjustment, based on SUV 20%–80% thresholds of the maximum SUV (SUVmax) to define the MTV_20–80, with intervals of 5%.

Tumour areas were manually delineated on T2W-MRI and multiplied by slice thickness to calculate the ATV.

FTV were derived by manually delineating tumour area on ADC map, multiplied by the slice thickness to determine the FTV_(manual). Diffusion restricted areas was extracted from b0 and ADC map using K-means clustering to determine the FTV_{(semi-automated)}.

The ATVs, FTVs and the MTVs at different thresholds were compared using the mean and correlated using Pearson's product-moment correlation.

Results

Twenty-nine patients were evaluated (median age 52 years). Paired difference of mean between ATV and MTV was the closest and not statistically significant at MTV₃₀ (−2.9cm³, −5.2%, p = 0.301). This was less than the differences between ATV and FTV_{(semi-automated)} (25.0cm³, 45.1%, p < 0.001) and FTV_(manual) (11.2cm³, 20.1%, p = 0.001). The correlation of MTV₃₀ with ATV was excellent (r = 0.968, p < 0.001) and better than that of the FTVs.

Conclusions

Our study demonstrated that MTV₃₀ was the only parameter investigated with no statistically significant difference with ATV, had the least absolute difference from ATV, and showed excellent positive correlation with ATV, suggesting its superiority as a functional imaging modality when compared with DW-MRI and supporting its use as a surrogate for ATV for radiotherapy tumour contouring.

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Overexpression of Cullin7 is associated with hepatocellular carcinoma progression and pathogenesis

Abstract

Background

Overexpression of Cullin7 is associated with some types of malignancies. However, the part of Cullin7 in hepatocellular carcinoma remains unclear. The aim of this study was to investigate the role of Cullin7 in pathogenesis and the progression of hepatocellular carcinoma.

Methods

In the present study, the expression of Cullin7 in hepatocellular carcinoma cell lines and five surgical hepatocellular carcinoma specimens was detected with quantitative reverse transcription PCR and western blotting. In addition, the protein expression of Cullin7 was examined in 162 cases of archived hepatocellular carcinoma using immunohistochemistry.

Results

We found elevated expression of both mRNA and protein levels of Cullin7 in hepatocellular carcinoma cell lines, and Cullin7 protein was significantly upregulated in hepatocellular carcinoma compared with paired normal hepatic tissues. The immunohistochemistry analysis revealed that overexpression of Cullin7 occurred in 69.1% of hepatocellular carcinoma samples, which was a significantly higher rate than that in adjacent normal hepatic tissue (P < 0.01). Statistical analysis found that overexpression of Cullin7 was significantly associated with lymph node metastasis, tumor thrombus of the portal vein and advanced clinical stage (P < 0.05). Furthermore, by overexpressing Cullin7 in hepatocellular carcinoma HepG2 cells, we revealed that Cullin7 could significantly enhance cell proliferation, growth, migration and invasion. Conversely, knocking down Cullin7 expression with short hairpin RNAi in hepatocellular carcinoma HepG2 cells inhibited cell proliferation, growth, migration and invasion.

Conclusion

Our studies provide evidence that overexpression of Cullin7 plays an important role in the pathogenesis and progression of hepatocellular carcinoma and may be a valuable marker for hepatocellular carcinoma management.

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Study protocol for a cluster-randomized trial to compare human papillomavirus based cervical cancer screening in community-health campaigns versus health facilities in western Kenya

Abstract

Background

Despite guidelines for cervical cancer prevention in low-resource countries, a very small proportion of women in these settings undergo screening, and even fewer women are successfully treated. Using pilot data from western Kenya and World Health Organization recommendations, we developed a protocol to implement evidence-based cervical cancer screening and linkage to treatment strategies to the rural communities. We describe the protocol for a cluster-randomized trial to compare two implementation strategies for human-papillomavirus (HPV)-based cervical cancer screening program using metrics described in the RE-AIM (reach, efficacy, adaption, implementation and maintenance) framework.

Methods

The study is a three-year, two-phase cluster-randomized trial in 18 communities in western Kenya. During Phase 1, six control communities were offered screening in health facilities; and six intervention communities were offered screening in community health campaigns. Screening was done with human-papillomavirus testing through self-collected specimens. Phase 1 ended and we are working in partnership with communities to further contextualize the implementation strategy for screening, and develop an enhanced linkage to treatment plan. This plan will be tested in an additional six communities in Phase 2 (enhanced intervention). We will compare the reach, efficacy, cost-effectiveness and adaptability of the implementation strategies.

Discussion

Effective low-cost cervical cancer prevention technologies are becoming more widely available in low- and middle-income countries. Despite increasing government support for cervical cancer prevention, there remains a sizeable gap in service availability. We will use implementation science to identify the most effective strategies to fill this gap through development of context-specific evidence-based solutions. This protocol design and results can help guide implementation of cervical cancer screening in similar settings, where women are most underserved and at highest risk for disease.

Trial registration

This trial is registered at ClinicalTrials.gov, NCT02124252.

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Decreased expression of the β 2 integrin on tumor cells is associated with a reduction in liver metastasis of colorectal cancer in mice

Abstract

Background

Lymphocyte Function-Associated Antigen-1 (LFA-1; CD18/CD11a) is one of the main adhesion molecules used by immune cells to infiltrate the liver under inflammatory conditions. Recently, the expression of this integrin has also been reported on several solid tumors, including colorectal cancer. However, its functional role in the metastatic progression to the liver remains unknown. Using in vitro assays and an experimental orthotopic in vivo model of liver metastasis, we aimed to elucidate the role of tumor LFA-1 in the metastatic progression by means of the partial depletion of the β₂ subunit of LFA-1, required for integrin activation, firm adhesion and signaling.

Methods

To do so, we evaluated the effects of β₂ reduction on the murine colon carcinoma C26 cell line on their pro-metastatic features in vitro and their metastatic potential in vivo in a mouse model of colon carcinoma metastasis to the liver.

Results

The reduction in β₂ integrin expression correlated with a slower proliferation, and a reduced adhesion and migration of C26 cells in an in vitro setting. Additionally, tumor cells with a reduced in β₂ integrin expression were unable to activate the liver sinusoidal endothelial cells (LSECs). This resulted in a recovery of the cytotoxic potential of liver lymphocytes which is compromised by LSECs activated by C26 cells. This was related to the abrogation of RNA expression of inflammatory and angiogenic cytokines by C26 cells after their activation with sICAM-1, the main ligand of β₂α_L. Furthermore, in vivo tumor cell retention and metastasis were profoundly reduced, along with a decrease in the recruitment and infiltration of myeloid derived suppressor cells (MDSCs) and lymphocytes to the liver.

Conclusion

Taken together, our findings uncovered the modulatory role for the tumor β₂ subunit of the LFA-1 integrin in the metastatic progression of colorectal cancer to the liver by impairing activation of liver endothelium and thus, the local immune response in the liver. Besides, this integrin also showed to be critical in vivo for tumor cell retention, cytokine release, leukocyte recruitment and metastasis development. These data support a therapeutical potential of the integrin LFA-1 as a target for the treatment of colorectal liver metastasis.

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JCAR015 in ALL: A Root-Cause Investigation [News in Brief]

Early CAR T-cell expansion, inflammatory cytokine surge among factors linked with fatal cerebral edema.

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Cell-Type Transcriptomes of the Multicellular Green Alga Volvox carteri Yield Insights into the Evolutionary Origins of Germ and Somatic Differentiation Programs

Germ-soma differentiation is a hallmark of complex multicellular organisms, yet its origins are not well understood. Volvox carteri is a simple multicellular green alga that has recently evolved a simple germ-soma dichotomy with only two cell types: large germ cells called gonidia and small terminally differentiated somatic cells. Here, we provide a comprehensive characterization of the gonidial and somatic transcriptomes of Volvox to uncover fundamental differences between the molecular and metabolic programming of these cell types. We found extensive transcriptome differentiation between cell types, with somatic cells expressing a more specialized program overrepresented in younger, lineage-specific genes and gonidial cells expressing a more generalist program overrepresented in more ancient genes that shared striking overlap with stem-cell-specific genes from animals and land plants. Directed analyses of metabolic pathways revealed a strong dichotomy between cell types with gonidial cells expressing growth-related genes and somatic cells expressing an altruistic metabolic program geared towards the assembly of flagella, which support organismal motility, and the conversion of storage carbon to sugars, which act as donors of extracellular matrix glycoproteins whose secretion enables massive organismal expansion. Volvox orthologs of Chlamydomonas diurnally controlled genes were analyzed for cell-type distribution and found to be strongly partitioned, with expression of dark-phase genes overrepresented in somatic cells and light-phase genes overrepresented in gonidial cells, a result that is consistent with cell type programs in Volvox arising by cooption of temporal regulons in a unicellular ancestor. Together our findings reveal fundamental molecular, metabolic, and evolutionary mechanisms that underlie the origins of germ-soma differentiation in Volvox and provide a template for understanding the acquisition of germ-soma differentiation in other multicellular lineages.

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Transcriptional Profiling of Saccharomyces cerevisiae Reveals the Impact of Variation of a Single Transcription Factor on Differential Gene Expression in 4NQO, Fermentable, and Non-fermentable Carbon Sources

Cellular metabolism can change the potency of a chemical's tumorigenicity. 4-nitroquinoline-1-oxide (4NQO) is a tumorigenic drug widely used on animal models for cancer research. Polymorphisms of the transcription factor, Yrr1, confer different levels of resistance to 4NQO in Saccharomyces cerevisiae. To study how different Yrr1 alleles regulate gene expression leading to resistance, transcriptomes of three isogenic S. cerevisiae strains carrying different Yrr1 alleles were profiled via RNA sequencing (RNA-Seq) and chromatin immunoprecipitation coupled with sequencing (ChIP-Seq) in presence and absence of 4NQO. In response to 4NQO, all alleles of Yrr1 drove the expression of SNQ2 (multidrug transporter), which was the highest in the presence of 4NQO resistance conferring alleles, and overexpression of SNQ2 alone was sufficient to overcome 4NQO sensitive growth. Using shape metrics to refine the ChIP-seq peaks, Yrr1 strongly associated with three loci including SNQ2. In addition to a known Yrr1 target, SNG1, Yrr1 also bound upstream of RPL35B; however, overexpression of these genes did not confer 4NQO resistance. RNA-seq data also implicated nucleotide synthesis pathways including the de novo purine pathway, and the ribonuclease reductase pathways were downregulated in response to 4NQO. Conversion of a 4NQO sensitive allele to a 4NQO resistant allele by a single point mutation mimicked the 4NQO resistant allele in phenotype and while the 4NQO resistant allele increased the expression of the ADE genes in the de novo purine biosynthetic pathway, the mutant Yrr1 increased expression of ADE genes even in the absence of 4NQO. These same ADE genes were only increased in the wild-type alleles in the presence of 4NQO, indicating the point mutation activated Yrr1 to upregulate a pathway normally only activated in response to stress. The various Yrr1 alleles also influenced growth on different carbon sources by altering the function of the mitochondria. Hence, the complement to 4NQO resistance was poor growth on non-fermentable carbon sources, which in turn varied depending on the allele of Yrr1 expressed in the isogenic yeast. The oxidation state of the yeast affected the 4NQO toxicity by altering the reactive oxygen species (ROS) generated by cellular metabolism. The integration of RNA-Seq and ChIP-Seq elucidated how Yrr1 regulates global gene transcription in response to 4NQO and how various Yrr1 alleles confer differential resistance to 4NQO. This study provides guidance for further investigation into how Yrr1 regulates cellular responses to 4NQO, as well as transcriptomic resources for further analysis of transcription factor variation on carbon source utilization.

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Whole Genome Sequencing of Hulunbuir Short-Tailed Sheep for Identifying Candidate Genes Related to the Short-Tail Phenotype

The Hulunbuir short-tailed sheep (Ovis aries) is a breed native to China, in which the short-tail phenotype is the result of artificial and natural selection favoring a specific set of genetic mutations. Here, we analyzed the genetic differences between short-tail and normal-tail phenotypes at the genomic level. Selection signals were identified in genome-wide sequences. From 16 sheep, we identified 72,101,346 single nucleotide polymorphisms. Selection signals were detected based on the fixation index and heterozygosity. Seven genomic regions under putative selection were identified, and these regions contained nine genes. T was related to vertebral development; however, a non-synonymous mutation at c.G334T resulted in p.G112W substitution. We inferred that the c.G334T mutation in T leads to functional changes in Brachyury-encoded by this gene-resulting in the short-tail phenotype. Our findings provide a valuable insight into the development of the short-tail phenotype in sheep and other short-tailed animals.

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DNA damage signaling and polyploid macrophages in chronic inflammation

Veronika Horn | Antigoni Triantafyllopoulou

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Immunoresolvents signaling molecules at intersection between the brain and immune system

Jesmond Dalli | Charles N Serhan

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New roles and controls of mast cells

Eric Espinosa | Salvatore Valitutti

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Recent advances in inflammasome biology

David E Place | Thirumala-Devi Kanneganti

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A ravenous defense: canonical and non-canonical autophagy in immunity

Payel Sil | Ginger Muse | Jennifer Martinez

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Control of innate-like B cell location for compartmentalised IgM production

Lucy H Jackson-Jones | Cécile Bénézech

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Heme and hemolysis in innate immunity: adding insult to injury

Rui Martins | Sylvia Knapp

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Innate sensing of cancer's non-immunologic hallmarks

Ruth Seelige | Stephen Searles | Jack D Bui

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Type I interferon-mediated autoinflammation and autoimmunity

Stefanie Kretschmer | Min Ae Lee-Kirsch

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Negative selection, epitope mimicry and autoimmunity

Noel R Rose

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Monogenic lupus: it's all new!

Patricia Costa-Reis | Kathleen E Sullivan

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What's up in the ALPS

Frédéric Rieux-Laucat

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Molecular control of regulatory T cell development and function

Yohko Kitagawa | Shimon Sakaguchi

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Insights into immune tolerance from AIRE deficiency

Irina Proekt | Corey N Miller | Michail S Lionakis | Mark S Anderson

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Biomarker-guided stratification of autoimmune patients for biologic therapy

Sabine Ivison | Christine Des Rosiers | Sylvie Lesage | John D Rioux | Megan K Levings

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Have we pushed the needle for treatment of Type 1 diabetes?

Nida Naushad | Ana Luisa Perdigoto | Jinxiu Rui | Kevan C Herold

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Hemophagocytic syndrome: primary forms and predisposing conditions

Fernando E Sepulveda | Geneviève de Saint Basile

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Leveraging blood and tissue CD4+ T cell heterogeneity at the single cell level to identify mechanisms of disease in rheumatoid arthritis

Chamith Y Fonseka | Deepak A Rao | Soumya Raychaudhuri

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Lessons from CTLA-4 deficiency and checkpoint inhibition

Bernice Lo | Ussama M Abdel-Motal

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Psoriasis: a mixed autoimmune and autoinflammatory disease

Yun Liang | Mrinal K Sarkar | Lam C Tsoi | Johann E Gudjonsson

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The interictal mesial temporal lobe epilepsy network

Summary

Objective

Identification of patient-specific epileptogenic networks is critical to designing successful treatment strategies. Multiple noninvasive methods have been used to characterize epileptogenic networks. However, these methods lack the spatiotemporal resolution to allow precise localization of epileptiform activity. We used intracranial recordings, at much higher spatiotemporal resolution, across a cohort of patients with mesial temporal lobe epilepsy (MTLE) to delineate features common to their epileptogenic networks. We used interictal rather than seizure data because interictal spikes occur more frequently, providing us greater power for analyzing variances in the network.

Methods

Intracranial recordings from 10 medically refractory MTLE patients were analyzed. In each patient, hour-long recordings were selected for having frequent interictal discharges and no ictal events. For all possible pairs of electrodes, conditional probability of the occurrence of interictal spikes within a 150-millisecond bin was computed. These probabilities were used to construct a weighted graph between all electrodes, and the node degree was estimated. To assess the relationship of the highly connected regions in this network to the clinically identified seizure network, logistic regression was used to model the regions that were surgically resected using weighted node degree and number of spikes in each channel as factors. Lastly, the conditional spike probability was normalized and averaged across patients to visualize the MTLE network at group level.

Results

We generated the first graph of connectivity across a cohort of MTLE patients using interictal activity. The most consistent connections were hippocampus to amygdala, anterior fusiform cortex to hippocampus, and parahippocampal gyrus projections to amygdala. Additionally, the weighted node degree and number of spikes modeled the brain regions identified as seizure networks by clinicians.

Significance

Apart from identifying interictal measures that can model patient-specific epileptogenic networks, we also produce a group map of network connectivity from a cohort of MTLE patients.

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CXCR4 is a potential target for diagnostic PET/CT imaging in Barrett's dysplasia and esophageal adenocarcinoma

Introduction: Barrett's Esophagus (BE) represents an early stage in carcinogenesis leading to esophageal adenocarcinoma (EAC). Considerable evidence supports a major role for chronic inflammation and diverse chemokine pathways in the development of BE and EAC. Methods: Here we utilized a IL-1b transgenic mouse model of BE and EAC and human patient imaging to analyse the importance of CXCR4 expressing cells during esophageal carcinogenesis. Results: IL-1b overexpression induces chronic esophageal inflammation and recapitulates the progression to BE and EAC. CXCR4 expression is increased in both epithelial and immune cells during disease progression in pL2-IL1b mice, and also elevated in EAC patient biopsy samples. Specific recruitment of CXCR4-positive (CXCR4+) immune cells correlated with dysplasia progression, suggesting that this immune population may be a key contributor to esophageal carcinogenesis. Similarly, with progression to dysplasia, there were increased numbers of CXCR4+ columnar epithelial cells at the squamocolumnar junction (SCJ). These findings were supported by stronger CXCR4-related signal intensity in ex vivo fluorescence imaging and autoradiography with advanced dysplasia. Pilot CXCR4-directed PET/CT imaging studies in esophageal cancer patients demonstrate the potential utility of CXCR4 imaging for the diagnosis and staging of esophageal cancer. Discussion: In conclusion, the recruitment of CXCR4+ immune cells and expansion of CXCR4+ epithelial cells in esophageal dysplasia and cancer highlight the potential of CXCR4 as a biomarker and molecular target for diagnostic imaging of the tumor microenvironment in EAC. 

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Inhibition of ID1-BMPR2 intrinsic signaling sensitizes glioma stem cells to differentiation therapy

Purpose: Normal stem cells tightly control self-renewal and differentiation during development, but their neoplastic counterparts, cancer stem cells (CSCs), sustain tumorigenicity both through aberrant activation of stemness and evasion of differentiation. Although regulation of CSC stemness has been extensively studied, the molecular mechanisms suppressing differentiation remain unclear. Experimental Design: We performed in silico screening and in vitro validation studies through western blotting, q-RT-PCR for treatment of WNT and SHH signaling inhibitors and BMP signaling inducer with control and ID1-overexpressing cells. We also performed in vivo drug treatment assays with Balb/c nude mice. Results: Inhibitor of differentiation 1 (ID1) abrogated differentiation signals from bone morphogenetic protein receptor (BMPR) signaling in glioblastoma stem cells (GSCs) to promote self-renewal. ID1 inhibited BMPR2 expression through microRNAs, miR-17 and miR-20a, which are transcriptional targets of MYC. ID1 increases MYC expression by activating WNT and SHH signaling. Combined pharmacological blockade of WNT and SHH signaling with BMP treatment significantly suppressed GSC self-renewal and extended survival of tumor-bearing mice. Conclusions: Collectively, our results suggested that ID1 simultaneously regulates stemness through WNT and SHH signaling and differentiation through BMPR-mediated differentiation signaling in GSCs, informing a novel therapeutic strategy of combinatorial targeting of stemness and differentiation.

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CD271 Confers an Invasive and Metastatic Phenotype of Head and Neck Squamous Cell Carcinoma Through the Upregulation of Slug

Purpose: Head and neck squamous cell carcinoma (HNSCC) is comprised of heterogeneous populations of cells, and CD271 (NGFR; p75NTR) has been associated with a tumor-initiating cell subpopulation. This study assessed the role of CD271 in modulating metastatic behavior in HNSCC. Experimental Design: CD271 was overexpressed in murine and human oral squamous cell carcinoma cells to assess the impact of CD271 activation on the invasive and metastatic phenotype of these cells, using in vitro and orthotopic in vivo modeling. Treatment with human nerve growth factor (NGF) to activate CD271, as well as shRNA knockdown of the CD271-upregulated Snai2 expression, was used to assess the mechanism of the CD271-induced invasive phenotype. Relevance of CD271 expression in human HNSCC was evaluated in patient derived xenografts (PDXs) and primary human oral cancers, annotated with clinical behavior characteristics and survival data. Results: Forced expression of CD271 resulted in a more invasive and metastatic phenotype. Slug, an epithelial-to-mesenchymal transition (EMT)-related transcription factor, encoded by Snai2, was highly expressed in MOC2-CD271 and HSC3-CD271, compared to respective parental cells. CD271 activation by NGF conferred enhanced invasiveness in CD271-overexpressing cells, which was abrogated by Snai2 knockdown. In PDXs and primary human HNSCC, CD271 expression correlated with higher Snai2 expression, greater nodal metastasis, and shorter disease-free survival. Conclusions: Activation of CD271 results in upregulation of Snai2/Slug, which, in turn, results in a more invasive phenotype and an enhanced capacity for metastasis to regional lymph nodes. These findings point to CD271 as a promising, therapeutic target for oral cancer metastasis.

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Biomarkers of primary resistance to trastuzumab in HER2-positive metastatic gastric cancer patients: the AMNESIA case-control study

Purpose: Refining the selection of HER2 positive metastatic gastric cancer patients candidates for trastuzumab is a challenge of precision oncology. Preclinical studies have suggested several genomic mechanisms of primary resistance, leading to activation of tyrosine kinase receptors other than HER2 or downstream signaling pathways. Experimental design: We carried out this multicenter, prospective, case-control study to demonstrate the negative predictive impact of a panel of candidate genomic alterations (AMNESIA panel), including EGFR/MET/KRAS/PI3K/PTEN mutations and EGFR/MET/KRAS amplifications. Hypothesizing a prevalence of candidate alterations of 30% and 0% in resistant and sensitive HER2-positive patients, respectively, 20 patients per group were needed. Results: AMNESIA panel alterations were significantly more frequent in resistant (11 out of 20, 55%) as compared to sensitive (0% of 17) patients (p<0.001), and in HER2 IHC 2+ (7 out of 13, 53.8%) than 3+ (4 out of 24, 16.7%) tumors (p=0.028). Patients with tumors bearing no candidate alterations had a significantly longer median progression-free (5.2 versus 2.6 months, HR: 0.34 [95%CI: 0.07-0.48]; p=0.001) and overall survival (16.1 versus 7.6 months, HR: 0.38 [95%CI: 0.09-0.75], p=0.015). The predictive accuracy of AMNESIA panel and HER2 IHC was 76% and 65%, respectively. The predictive accuracy of the combined evaluation of AMNESIA panel and HER2 IHC was 84%. Conclusions: Our panel of candidate genomic alterations may be clinically useful to predict primary resistance to trastuzumab in HER2-positive metastatic gastric cancer patients, and should be further validated with the aim of molecularly stratifying HER2 addicted cancers for the development of novel treatment strategies.

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Vimentin is required for lung adenocarcinoma metastasis via heterotypic tumor cell-cancer-associated fibroblast interactions during collective invasion

Purpose: Vimentin is an epithelial to mesenchymal transition (EMT) biomarker and intermediate filament protein that functions during cell migration to maintain structure and motility. Despite the abundance of clinical data linking vimentin to poor patient outcome, it is unclear if vimentin is required for metastasis or is a correlative biomarker. We developed a novel genetically engineered mouse model (GEMM) to probe vimentin in lung adenocarcinoma metastasis. Experimental Design: We used the LSL-Kras G12D/Lkb1 fl/fl/Vim-/-model (KLV-/-), which incorporates a whole-body knockout of vimentin and is derived from the Cre-dependent LSL-Kras G12D/Lkb1 fl/fl model (KLV+/+). We compared the metastatic phenotypes of the GEMMs and analyzed primary tumors from the KLV models and lung adenocarcinoma patients to assess vimentin expression and function. Results: Characterization of KLV^+/+ and KLV-/- mice, show that vimentin is not required for primary lung tumor growth but is required for metastasis and vimentin loss generates lower grade primary tumors. Interestingly, in the KLV+/+ mice, vimentin was not expressed in tumor cells but in cancer-associated fibroblasts (CAFs) surrounding collective invasion packs (CIPs) of epithelial tumor cells, with significantly less CIPs in KLV-/- mice. CIPs correlate with tumor grade, and are vimentin-negative and E-cadherin-positive, indicating a lack of cancer cell EMT. Similar heterotypic staining pattern was observed in human lung adenocarcinoma samples. In vitro studies show that vimentin is required for CAF-led tumor cell invasion, supporting a vimentin-dependent model of collective invasion. Conclusions: These data show that vimentin is required for lung adenocarcinoma metastasis by maintaining heterotypic tumor cell-CAF interactions during collective invasion.

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Etk interaction with PFKFB4 modulates chemoresistance of small cell lung cancer by regulating autophagy

Purpose: Epithelial and endothelial tyrosine kinase (Etk), also known as bone marrow X kinase (Bmx), was found to be critical in modulating the chemoresistance of small cell lung cancer (SCLC) in our preliminary study. However, the molecular mechanisms of Etk in SCLC chemoresistance remain poorly understood. The present study investigated the downstream factor and pathway involved. Experimental Design: We demonstrated first that knockdown of Etk by siRNAs suppressed autophagy in chemoresistant SCLC cells, and that direct inhibition of autophagy sensitized cells to chemotherapy. Our subsequent microarray, co-immunoprecipitation (co-IP) and GST-pull down experiments identified 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 (PFKFB4) as a downstream target of Etk and an Etk-interacting protein. We demonstrated knockdown of PFKFB4 suppressed autophagy in SCLC cells. Our in vitro and in vivo gain or loss-of-function analyses of PFKFB4 revealed PFKFB4 plays a critical role in SCLC chemoresistance. Our analysis of PFKFB4 expression in SCLC specimens demonstrated that high levels of PFKFB4 are associated with poor therapeutic response and prognosis. Furthermore, as Etk shares conserved domains with Btk (Bruton's tyrosine kinase) family, we explored the potential of Ibrutinib, a Btk inhibitor clinically effective in treating leukemia, in targeting Etk and found that Ibrutinib exhibited a synergistic anti-tumor effect with chemotherapy in SCLC preclinical models including a PDX model. Results: Described above Conclusions:Our results demonstrated for the first time that Etk interacts with PFKFB4 to promote SCLC chemoresistance through regulation of autophagy. Aberrant Etk and PFKFB4 can be predictive factors for the chemotherapy response as well as potential therapeutic targets in SCLC.

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Emerging Role of CRISPR/Cas9 Technology for MicroRNAs Editing in Cancer Research

MicroRNAs (miRNA) are small, noncoding RNA molecules with a master role in the regulation of important tasks in different critical processes of cancer pathogenesis. Because there are different miRNAs implicated in all the stages of cancer, for example, functioning as oncogenes, this makes these small molecules suitable targets for cancer diagnosis and therapy. RNA-mediated interference has been one major approach for sequence-specific regulation of gene expression in eukaryotic organisms. Recently, the CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 system, first identified in bacteria and archaea as an adaptive immune response to invading genetic material, has been explored as a sequence-specific molecular tool for editing genomic sequences for basic research in life sciences and for therapeutic purposes. There is growing evidence that small noncoding RNAs, including miRNAs, can be targeted by the CRISPR/Cas9 system despite their lacking an open reading frame to evaluate functional loss. Thus, CRISPR/Cas9 technology represents a novel gene-editing strategy with compelling robustness, specificity, and stability for the modification of miRNA expression. Here, I summarize key features of current knowledge of genomic editing by CRISPR/Cas9 technology as a feasible strategy for globally interrogating miRNA gene function and miRNA-based therapeutic intervention. Alternative emerging strategies for nonviral delivery of CRISPR/Cas9 core components into human cells in a clinical context are also analyzed critically. Cancer Res; 77(24); 1–6. ©2017 AACR.

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International Medical Graduates in Nephrology: Roles, Rules, and Future Risks

International medical graduates (IMGs) have become an increasingly essential part of many residency and fellowship programs in the United States. IMGs, who may be of either US or non-US citizenship, contribute significantly to the physician workforce across this country, particularly in underserved areas, as well as in their home countries on their return after training. Approximately 65% of nephrology fellows are IMGs, with most of these being non-US citizens. Non-US IMG applications for nephrology fellowship have been declining, exacerbating an ongoing shortage of nephrology trainees.

http://ift.tt/2knMOsH

Population Health for CKD and Diabetes: Lessons From the Indian Health Service

Despite extensive clinical guidelines, innovative efforts to improve care, and well-funded efforts to raise awareness, limited progress has been made in reducing the burden of kidney disease in the United States, and the prevalence continues to increase worldwide. The Indian Health Service and the Centers for Disease Control and Prevention recently reported a 54% decrease in the incidence of kidney failure among American Indian and Alaska Native people with diabetes. This decrease in end-stage renal disease incidence was associated with a population health approach to diabetes care based in the community and the primary clinical setting.

http://ift.tt/2BLxPwO

A Novel In Situ Simulation Intervention Used to Mitigate an Outbreak of Methicillin-Resistant Staphylococcus aureus in a Neonatal Intensive Care Unit

To describe the successful implementation of an in situ simulation program to diagnose and correct latent safety threats in a level 4 neonatal intensive care unit (NICU) to mitigate a methicillin-resistant Staphylococcus aureus (MRSA) outbreak.

http://ift.tt/2AyuIYQ

Proinflammatory Diets during Pregnancy and Neonatal Adiposity in the Healthy Start Study

To evaluate the association between dietary inflammatory index (DII) scores during pregnancy and neonatal adiposity.

http://ift.tt/2AuPiLZ

Prolonged Time Lag to Final Diagnosis of Fragile X Syndrome

To evaluate the diagnostic process in children ultimately diagnosed with fragile X syndrome (FXS), with an emphasis on the time lag between initial presentation and on diagnosis in female vs male children.

http://ift.tt/2Ay1R73

Human mitochondrial MTHFD2 is a dual redox cofactor-specific methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase

Abstract

Background

Folate-dependent one-carbon metabolism provides one-carbon units for several biological processes. This pathway is highly compartmentalized in eukaryotes, with the mitochondrial pathway producing formate for use in cytoplasmic processes. The mitochondrial enzyme MTHFD2 has been reported to use NAD⁺ as a cofactor while the isozyme MTHFD2L utilizes NAD⁺ or NADP⁺ at physiologically relevant conditions. Because MTHFD2 is highly expressed in many cancer types, we sought to determine the cofactor preference of this enzyme.

Results

Kinetic analysis shows that purified human MTHFD2 exhibits dual redox cofactor specificity, utilizing either NADP⁺ or NAD⁺ with the more physiologically relevant pentaglutamate folate substrate.

Conclusion

These results show that the mitochondrial folate pathway isozymes MTHFD2 and MTHFD2L both exhibit dual redox cofactor specificity. Our kinetic analysis clearly supports a role for MTHFD2 in mitochondrial NADPH production, indicating that this enzyme is likely responsible for mitochondrial production of both NADH and NADPH in rapidly proliferating cells.

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Treatment of sporadic Burkitt lymphoma in adults, a retrospective comparison of four treatment regimens

Abstract

Burkitt lymphoma is an aggressive B cell malignancy accounting for 1–2% of all adult lymphomas. Treatment with dose-intensive, multi-agent chemotherapy is effective but associated with considerable toxicity. In this observational study, we compared real-world efficacy, toxicity, and costs of four frequently employed treatment strategies for Burkitt lymphoma: the Lymphome Malins B (LMB), the Berlin-Frankfurt-Münster (BFM), the HOVON, and the CODOX-M/IVAC regimens. We collected data from 147 adult patients treated in eight referral centers. Following central pathology assessment, 105 of these cases were accepted as Burkitt lymphoma, resulting in the following treatment groups: LMB 36 patients, BFM 19 patients, HOVON 29 patients, and CODOX-M/IVAC 21 patients (median age 39 years, range 14–74; mean duration of follow-up 47 months). There was no significant difference between age, sex ratio, disease stage, or percentage HIV-positive patients between the treatment groups. Five-year progression-free survival (69%, p = 0.966) and 5-year overall survival (69%, p = 0.981) were comparable for all treatment groups. Treatment-related toxicity was also comparable with only hepatotoxicity seen more frequently in the CODOX/M-IVAC group (p = 0.004). Costs were determined by the number of rituximab gifts and the number of inpatients days. Overall, CODOX-M/IVAC had the most beneficial profile with regards to costs, treatment duration, and percentage of patients completing planned treatment. We conclude that the four treatment protocols for Burkitt lymphoma yield nearly identical results with regards to efficacy and safety but differ in treatment duration and costs. These differences may help guide future choice of treatment.

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Paeoniflorin, the Main Active Ingredient of Shuyu Capsule, Inhibits Cav1.2 and Regulates Calmodulin/Calmodulin-Dependent Protein Kinase II Signalling

The aim of this study was to explore the mechanism underlying the antidepression activity of paeoniflorin, the main active ingredient of paeony extract and Shuyu capsules, and determine its effect on the calmodulin/calmodulin-dependent protein kinase II (CaM/CaMKII) signalling pathway and on the possible target, the voltage-gated calcium channel (). Rats at the nonacceptance stage were selected for premenstrual syndrome (PMS) depression modelling. Behavioural assays were used for model testing. Rats were given Shuyu capsules, paeony extract, and bupleurum. Western blot analysis was used to assess the expression levels of calcium voltage-gated channel subunit alpha 1 C (CACNA1C), brain-derived neurotrophic factor, and CaM/CaMKII signalling pathway proteins. Intracellular Ca2+ concentration in CHO cell line was measured using Fluo-4-AM and whole-cell patch clamps. The PMS depression model was successfully established and demonstrated that Shuyu can mitigate depressive behaviour in a rat PMS model. Paeony extract did not affect CACNA1C protein expression in rat hippocampi but did affect 1.2-mediated CaM/CaMKII signalling pathways. Paeoniflorin significantly inhibited KCl-induced increases in intracellular Ca2+ concentration and 1.2 current density. Further, it may function via the CaM/CaMKII pathway and its downstream signalling molecules by regulating 1.2, thus playing an important role in the treatment and alleviation of affective disorders.

http://ift.tt/2BAZjoc

Association between Fluorescent Advanced Glycation End-Products and Vascular Complications in Type 2 Diabetic Patients

Objectives. Diabetes is a major health problem associated with hyperglycemia and chronically increased oxidative stress and enhanced formation of advanced glycation end-products (AGEs). The aim of this study was to determine whether oxidative plasma biomarkers in diabetic patients could be evidenced and associated with vascular complications. Methods. Oxidative stress biomarkers such as thiols, ischemia-modified albumin (IMA), glycated albumin (GA), fructosamine, and AGEs were measured in 75 patients with poorly controlled type 2 diabetes (HbA1c > 7.5%) with (44) or without (31) vascular disease and in 31 nondiabetic controls. Results. Most biomarkers of oxidation and glycation were significantly increased in diabetic patients in comparison with nondiabetics. Fructosamines, GA, IMA, and AGEs were positively correlated and levels of fluorescent AGEs were significantly increased in the plasma from patients presenting vascular complication. Conclusions. These results bring new evidence for the potential interest of glycated albumin, oxidative stress, and glycoxidation parameters in the monitoring of type 2 diabetic patients. Furthermore, it emphasizes fluorescent AGEs as a putative indicator for vascular event prediction in diabetic patients.

http://ift.tt/2BAysbE

Mechanisms of inactivation of the tumour suppressor gene RHOA in colorectal cancer

Mechanisms of inactivation of the tumour suppressor gene RHOA in colorectal cancer

Mechanisms of inactivation of the tumour suppressor gene RHOA in colorectal cancer, Published online: 05 December 2017; doi:10.1038/bjc.2017.420

Mechanisms of inactivation of the tumour suppressor gene RHOA in colorectal cancer

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Prevailing Ethical Dilemmas Encountered by Physicians in Terminal Cancer Care Changed after the Enactment of the Natural Death Act: Fifteen Years Follow up Survey

Advance directive laws have influences on ethical dilemmas encountered by physicians caring for terminal cancer patients.

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Gabapentin as an adjuvant therapy for prevention of acute phantom-limb pain in pediatric patients undergoing amputation for malignant bone tumors: a prospective double-blind randomized controlled trial

Gabapentin is reported to have an analgesic effect of reducing phantom-limb pain(PLP) in adult patients. There's no study on preoperative use of gabapentin in pediatric population in term of PLP prevention.

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Outpatient Pain Medication Use: An Electronic Daily Diary Study in Metastatic Breast Cancer

Understanding cancer patients' everyday pain experiences and their concomitant use of pain medication may help identify ways to improve pain management among outpatients.

http://ift.tt/2BBKKAA

Menopausal-related Symptoms in Women One Year After Breast Cancer Surgery

Approximately 60% to 100% of women with breast cancer experience at least one menopausal-related symptom. Little is known about associations between menopausal status and symptoms in women 12 months after breast cancer surgery.

http://ift.tt/2jhHbsH

Characterizing the Role of U.S. Surgeons in the Provision of Palliative Care: A Systematic Review and Mixed-Methods Meta-Synthesis

The provision of palliative care varies appropriately by clinical factors such as patient age and severity of disease, but also varies by provider practice and specialty. Surgical patients are persistently less likely to receive palliative care than their medical counterparts for reasons that aren't clear.

http://ift.tt/2BCmFcO

A Comparison of the Accuracy of Clinician Prediction of Survival versus the Palliative Prognostic Index

Survival predictions for advanced cancer patients impact many aspects of care, but the accuracy of clinician prediction of survival (CPS) is low. Prognostic tools such as the Palliative Prognostic Index (PPI) have been proposed to improve accuracy of predictions. However, it is not known if PPI is better than CPS at discriminating survival.

http://ift.tt/2jhH2p9

Carotid Dosimetry and the Risk of Carotid Blowout Syndrome Following Re-irradiation with Head and Neck Stereotactic Body Radiation Therapy

Stereotactic body radiation therapy has emerged as a viable treatment option for recurrent head and neck cancers after prior irradiation, though carotid dose constraints are not defined. The maximum dose to 0.1cc, 1cc, 2cc of the carotid and the mean dose were analyzed for association with bleeding. No significant association was found between dose-volume parameters and risk of carotid bleeding, and no CBOS noted when D0.1cc was <47.6 Gy.

http://ift.tt/2nxuLl2

The New York Sepsis Severity Score: Development of a Risk-Adjusted Severity Model for Sepsis

Objectives: In accordance with Rory's Regulations, hospitals across New York State developed and implemented protocols for sepsis recognition and treatment to reduce variations in evidence informed care and preventable mortality. The New York Department of Health sought to develop a risk assessment model for accurate and standardized hospital mortality comparisons of adult septic patients across institutions using case-mix adjustment. Design: Retrospective evaluation of prospectively collected data. Patients: Data from 43,204 severe sepsis and septic shock patients from 179 hospitals across New York State were evaluated. Settings: Prospective data were submitted to a database from January 1, 2015, to December 31, 2015. Interventions: None. Measurement and Main Results: Maximum likelihood logistic regression was used to estimate model coefficients used in the New York State risk model. The mortality probability was estimated using a logistic regression model. Variables to be included in the model were determined as part of the model-building process. Interactions between variables were included if they made clinical sense and if their p values were less than 0.05. Model development used a random sample of 90% of available patients and was validated using the remaining 10%. Hosmer-Lemeshow goodness of fit p values were considerably greater than 0.05, suggesting good calibration. Areas under the receiver operator curve in the developmental and validation subsets were 0.770 (95% CI, 0.765–0.775) and 0.773 (95% CI, 0.758–0.787), respectively, indicating good discrimination. Development and validation datasets had similar distributions of estimated mortality probabilities. Mortality increased with rising age, comorbidities, and lactate. Conclusions: The New York Sepsis Severity Score accurately estimated the probability of hospital mortality in severe sepsis and septic shock patients. It performed well with respect to calibration and discrimination. This sepsis-specific model provides an accurate, comprehensive method for standardized mortality comparison of adult patients with severe sepsis and septic shock. Mr. Phillips and Dr. Osborn contributed equally as cofirst authors. Mr. Philips is retired from the Center for Biostatistics, Department of Biomedical Infomatics, Ohio State University, Columbus, OH. Dr. Gesten is retired from the Office of Quality and Patient Safety, New York State Department of Health, New York State Department of Health, Albany, NY. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://ift.tt/29S62lw). Mr. Phillips and Dr. Lemeshow received funding from IPRO. Dr. Gesten disclosed government work, and he disclosed that the New York State Department of Health (NYSDOH) has an existing contract with IPRO for an extensive scope of work which includes, but is not limited to, the implementation of the statewide sepsis initiative. This initiative is the source for the data used in the development of the model, and the contract with IPRO paid statistical consultant services. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: osbornt@wustl.edu Copyright © by 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

http://ift.tt/2BBGWPO

Hospital Variation in Renal Replacement Therapy for Sepsis in the United States

Objectives: Acute renal replacement therapy in patients with sepsis has increased dramatically with substantial costs. However, the extent of variability in use across hospitals—and whether greater use is associated with better outcomes—is unknown. Design: Retrospective cohort study. Setting: Nationwide Inpatient Sample in 2011. Patients: Eighteen years old and older with sepsis and acute kidney injury admitted to hospitals sampled by the Nationwide Inpatient Sample in 2011. Interventions: We estimated the risk- and reliability-adjusted rate of acute renal replacement therapy use for patients with sepsis and acute kidney injury at each hospital. We examined the association between hospital-specific renal replacement therapy rate and in-hospital mortality and hospital costs after adjusting for patient and hospital characteristics. Measurements and Main Results: We identified 293,899 hospitalizations with sepsis and acute kidney injury at 440 hospitals, of which 6.4% (n = 18,885) received renal replacement therapy. After risk and reliability adjustment, the median hospital renal replacement therapy rate for patients with sepsis and acute kidney injury was 3.6% (interquartile range, 2.9–4.5%). However, hospitals in the top quintile of renal replacement therapy use had rates ranging from 4.8% to 13.4%. There was no significant association between hospital-specific renal replacement therapy rate and in-hospital mortality (odds ratio per 1% increase in renal replacement therapy rate: 1.03; 95% CI, 0.99–1.07; p = 0.10). Hospital costs were significantly higher with increasing renal replacement therapy rates (absolute cost increase per 1% increase in renal replacement therapy rate: $1,316; 95% CI, $157–$2,475; p = 0.03). Conclusions: Use of renal replacement therapy in sepsis varied widely among nationally sampled hospitals without associated differences in mortality. Improving renal replacement standards for the initiation of therapy for sepsis may reduce healthcare costs without increasing mortality. This article does not necessarily represent the views of the U.S. Government or the Department of Veterans Affairs. Dr. Valley had full access to all of the data in the study and takes full responsibility for the integrity of the data and the accuracy of the data analysis. Drs. Valley and Cooke contributed in study concept and design. Dr. Valley contributed in acquisition of data. Drs. Valley, Nallamothu, Heung, Iwashyna, and Cooke contributed in analysis and interpretation of data. Drs. Valley and Cooke contributed in drafting of the article. Drs. Valley, Nallamothu, Heung, Iwashyna, and Cooke contributed in critical revision of the article for important intellectual content. Drs. Valley and Cooke contributed in statistical analysis. Dr. Cooke obtained funding. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://ift.tt/29S62lw). Supported, in part, by National Institutes of Health T32HL007749 (to Dr. Valley), the Department of Veterans Affairs Health Services Research and Development Service grant 13–079 (to Dr. Iwashyna), and the Agency for Healthcare Research and Quality K08HS020672 (to Dr. Cooke). Dr. Valley received support for article research from the National Institutes of Health. Dr. Nallamothu received funding from United Healthcare and the American Heart Association. Dr. Iwashyna disclosed government work. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: valleyt@umich.edu Copyright © by 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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Prevention of Ventilator-Associated and Early Postoperative Pneumonia Through Tapered Endotracheal Tube Cuffs: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Objective: Microaspiration of subglottic secretions is considered a major pathogenic mechanism of hospital-acquired pneumonia, either early postoperative or ventilator-associated pneumonia. Tapered endotracheal tube cuffs have been proposed to provide a better seal of the extraluminal airway, thereby preventing microaspiration and possibly hospital-acquired pneumonia. We performed a systematic review and meta-analysis to assess the value of endotracheal tubes with tapered cuffs in the prevention of hospital-acquired pneumonia. Data Sources: A systematic search of MEDLINE, EMBASE, CENTRAL/CCTR, ClinicalTrials.gov, and ICTRP was conducted up to March 2017. Study Selection: Eligible trials were randomized controlled clinical trials comparing the impact of tapered cuffs versus standard cuffs on hospital-acquired pneumonia. Data Extraction: Random-effects meta-analysis calculated odds ratio and 95% CI for hospital-acquired pneumonia occurrence rate between groups. Secondary outcome measures included mortality, duration of mechanical ventilation, length of hospital and ICU stay, and cuff underinflation. Data Synthesis: Six randomized controlled clinical trials with 1,324 patients from intensive care and postoperative wards were included. Only two studies concomitantly applied subglottic secretion drainage, and no trial performed continuous cuff pressure monitoring. No significant difference in hospital-acquired pneumonia incidence per patient was found when tapered cuffs were compared with standard cuffs (odds ratio, 0.97; 95% CI, [0.73–1.28]; p = 0.81). There were likewise no differences in secondary outcomes. Conclusions: Application of tapered endotracheal tube cuffs did not reduce hospital-acquired pneumonia incidence among ICU and postoperative patients. Further research should examine the impact of concomitant use of tapered cuffs with continuous cuff pressure monitoring and subglottic secretion drainage. This work was performed at the Department of Internal Medicine, Ghent University, Ghent, Belgium. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://ift.tt/29S62lw). The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: stijn.blot@ugent.be Copyright © by 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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PET-CT in Critically Ill Patients: Diagnosing the Unsuspected

Objective: Quick identification of septic source is fundamental in patients with severe sepsis of unknown origin. The purpose of this case report was to assess the benefit and feasibility of an early PET-CT in critically ill patients with undiagnosed sepsis. Data Sources: Clinical observations of two patients. Study Selection: Case reports. Data Extraction: Data extracted from medical records, after patient's consent. Illustrations were collected from the imaging software. Data Synthesis: We admitted two critically ill patients for suspected sepsis and altered mental state. As all bacteriological samples were initially sterile, diagnostic workups in both patients led us to suspect underlying malignant hemopathy. In fact, the lumbar puncture of the first patient revealed a large B-cell lymphoma, and an acquired thrombotic thrombocytopenic purpura was suspected in the second patient. However, PET-CTs performed in both patients displayed infra-clinical underlying infectious foci. Within 48 hours, both patients developed a clearly identified sepsis linked to the described focus, and favorable outcome thanks to the precious information delivered by the PET-CT. Conclusions: PET-CT precisely detected the deep foci of infection about 48 hours prior to the diagnosis of sepsis. The cases reports suggested the use of this image technique in ICU for patients with sepsis of unknown origin. Dr. Friggeri received funding from Pfizer, MSD, and Sanofi. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: romain.fort@chu-lyon.fr Copyright © by 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

http://ift.tt/2BBGxNi

The perioperative significance of systemic arterial diastolic hypertension in adults

Purpose of review Hypertension affects approximately one third of the U.S. population and is the most common preventable medical reason that surgical cases are postponed or cancelled. However, subtypes of hypertension and their perioperative risks are poorly studied and understood. We will review the natural history and pathophysiology of essential hypertension and discuss the perioperative significance of diastolic blood pressure elevation. Recent findings There is evidence that elevated preoperative diastolic blood pressures are associated with an increased perioperative risk of cardiovascular and cerebrovascular events and increased postoperatively 30-day mortality. However, lower preoperative diastolic blood pressures were found, in one study, to be associated with renal injury. Summary Diastolic hypertension and hypotension both carry perioperative risk. Further study needs to be dedicated to elucidating the risks and developing strategies for acute and chronic management of diastolic blood pressure changes in order to improve perioperative safety. Correspondence to Edwin G. Avery IV, MD, Chief Anesthesia Officer, Harrington Heart and Vascular Institute, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA. Tel: +1 216 844 7334; fax: +1 216 844 3781; e-mail: edwin.avery@uhhospitals.org Copyright © 2017 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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Perioperative pulmonary thromboembolism: current concepts and treatment options

Purpose of review Anesthesiologists are familiar with pulmonary emboli prophylaxis paradigms and many have witnessed acute intraoperative embolization. Clinicians must balance conservative anticoagulation and aggressive intervention in perioperative submassive pulmonary emboli, yet the bulk of the literature excludes surgery as a relative contraindication. This review will summarize the current treatment options for acute pulmonary emboli, drawing attention to special considerations in perioperative submassive pulmonary emboli, and discuss right ventricular monitoring to improve assessment of intervention efficacy. Recent findings Recent reviews have identified the elevated risk and inadequacy of treatment of pulmonary embolism in intra and postoperative patients, in part because of the risks of systemic anticoagulation. Early studies of catheter-directed therapies have shown promising efficacy with a reduction in bleeding risk, which is especially important for perioperative patients. Success relies on defining endpoints, yet the practice of measuring mean pulmonary artery pressure alone to assess intervention efficacy is flawed. Summary Identifying submassive pulmonary emboli that requires treatment and optimizing therapy remains difficult. Researchers must consider avoiding systemic anticoagulation and focus on designing trials that evaluate intervention efficacy in surgical patients. The success of catheter-directed therapy in early trials warrants further investigation into using these therapies in the treatment of perioperative submassive pulmonary emboli. Correspondence to Paul M. Heerdt, MD, PhD, Division of Applied Hemodynamics, Department of Anesthesiology, Yale University School of Medicine, 333 Cedar Street B425, New Haven, CT 06520, USA. E-mail: paul.heerdt@yale.edu Copyright © 2017 YEAR Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2jUIZam

Surgery and discontinuation of angiotensin converting enzyme inhibitors: current perspectives

Purpose of review The current article reviews the current evidence for continuing or discontinuing angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) during the perioperative period. Recent findings In patients undergoing treatment of hypertension with ACEIs or ARBs, there are both benefits associated with continuing these medications during the perioperative period and higher risk for perioperative hypotension and its complications. Summary Since the introduction of ACEIs and ARBs into clinical practice, their use during the perioperative period has been controversial. Although these medications increase the risk of serious hypotension immediately after induction and maintenance of anesthesia, their use has numerous benefits, making it reasonable to continue them during perioperative period. Correspondence to Nikola Bradic, MD, Department of Cardiovascular Anesthesiology and Cardiac Intensive Medicine, Clinic of Anesthesiology, Resuscitation and Intensive Care Medicine, University Hospital Dubrava, Gojko Susak Avenue No. 6, 10000 Zagreb, Croatia. e-mail: nbradic@kbd.hr Copyright © 2017 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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Drug-induced sleep endoscopy: from obscure technique to diagnostic tool for assessment of obstructive sleep apnea for surgical interventions

Purpose of review Provide a practical update on drug-induced sleep endoscopy (DISE) for anesthesia providers, which can also serve as a reference for those preparing to establish a DISE program. Recent findings New developments in surgical approaches to OSA and the growing global incidence of the condition have stimulated increased interest and demand for drug-induced sleep endoscopy. New techniques include transoral robotic surgery and hypoglossal nerve stimulation. Recent DISE literature has sought to address numerous debates including relevance of DISE findings to those during physiologic sleep and the most appropriate depth and type of sedation for DISE. Propofol and dexmedetomidine have supplanted midazolam as the drugs of choice for DISE. Techniques based on pharmacokinetic models of propofol are superior to empiric dosing with regard to risk of respiratory compromise and the reliability of dexmedetomidine to achieve adequate conditions for a complete DISE exam is questionable. Summary The role of DISE in surgical evaluation and planning for treatment of OSA continues to develop. Numerous questions as to the optimal anesthetic approach remain unanswered. Multicenter studies that employ a standardized approach using EEG assessment, pharmacokinetic–pharmacodynamic modelling, and objectively defined clinical endpoints will be helpful. There may be benefit to undertaking DISE studies in non-OSA patients. Correspondence to Joshua H. Atkins, Associate Professor of Anesthesiology & Critical Care, Associate Professor of Otorhinolaryngology: Head & Neck Surgery, Department of Anesthesiology & Critical Care, Perelman School of Medicine at the University of Pennsylvania, 680 Dulles Building, 3400 Spruce Street, Philadelphia, PA 19104, USA. Tel: +1 215 203 4781; e-mail: Joshua.Atkins@uphs.upenn.edu Copyright © 2017 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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