Neoadjuvant treatment of pancreatic adenocarcinoma: a systematic review and meta-analysis of 5520 patients

Abstract

Background

Recent years have seen standardization of the anatomic definitions of pancreatic adenocarcinoma, and increasing utilization of neoadjuvant therapy (NAT). The aim of the current review was to summarize the evidence for NAT in pancreatic adenocarcinoma since 2009, when consensus criteria for resectable (R), borderline resectable (BR), and locally advanced (LA) disease were endorsed.

Methods

PubMed search was undertaken along with extensive backward search of the references of published articles to identify studies utilizing NAT for pancreatic adenocarcinoma. Abstracts from ASCO-GI 2014 and 2015 were also searched.

Results

A total of 96 studies including 5520 patients were included in the final quantitative synthesis. Pooled estimates revealed 36% grade ≥ 3 toxicities, 5% biliary complications, 21% hospitalization rate and low mortality (0%, range 0–16%) during NAT. The majority of patients (59%) had stable disease. On an intention-to-treat basis, R0-resection rates varied from 63% among R patients to 23% among LA patients. R0 rates were > 80% among all patients who were resected after NAT. Among R and BR patients who underwent resection after NAT, median OS was 30 and 27.4 months, respectively.

Conclusions

The current study summarizes the recent literature for NAT in pancreatic adenocarcinoma and demonstrates improving outcomes after NAT compared to those historically associated with a surgery-first approach for pancreatic adenocarcinoma.

http://ift.tt/2g7MDjl

Unraveling the Mystery of the Blue Fog: Structure, Properties, and Applications of Amorphous Blue Phase III

Abstract

The amorphous blue phase III of cholesteric liquid crystals, also known as the "blue fog," are among the rising stars in materials science that can potentially be used to develop next-generation displays with the ability to compete toe-to-toe with disruptive technologies like organic light-emitting diodes. The structure and properties of the practically unobservable blue phase III have eluded scientists for more than a century since it was discovered. This progress report reviews the developments in this field from both fundamental and applied research perspectives. The first part of this progress report gives an overview of the 130-years-long scientific tour-de-force that very recently resulted in the revelation of the mysterious structure of blue phase III. The second part reviews progress made in the past decade in developing electrooptical, optical, and photonic devices based on blue phase III. The strong and weak aspects of the development of these devices are underlined and criticized, respectively. The third- and-final part proposes ideas for further improvement in blue phase III technology to make it feasible for commercialization and widespread use.

The structure and properties of the amorphous blue phase III of cholesteric liquid crystals have been a topic of intense debate among scientists in the soft matter community for more than a century. This progress report provides an update on the current status of materials and electrooptical, optical, and photonic devices based on this hitherto mysterious phase of matter.

http://ift.tt/2g8sLNc

Cover

The cover image, by Tim Joda et al., is based on the Original Article Time efficiency, difficulty, and operator's preference comparing digital and conventional implant impressions: a randomized controlled trial, DOI: 10.1111/clr.12982.

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The fine print behind the big picture

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Ogilvies syndrome treated with an emergency laparotomy, right hemicolectomy and end ileostomy

Acute colonic pseudo-obstruction (ACPO), or Ogilvie's syndrome, is a rare clinical entity in which there is massive non-toxic colonic dilatation in the absence of a mechanically obstructing lesion. It is an important yet poorly recognised cause of surgical morbidity and mortality occurring typically in elderly patients with multiple comorbidities. ACPO can often be reversed conservatively with colonoscopic or nasogastric decompression. Surgical intervention is seldom necessary. We present a case of Ogilvie's syndrome in which a healthy 76-year-old man developed life-threatening pseudo-obstruction following rib polytrauma after a mechanical fall. Pneumatosis coli was evident radiologically, prompting emergency exploratory laparotomy. Operative findings of serosal tearing and ischaemic colitis necessitated treatment with right hemicolectomy and ileostomy formation. Microbiological and histopathological analyses proved negative for inflammatory, obstructive and infectious colitides. The case emphasises the importance of early recognition and timely intervention in the management of this rare yet potentially fatal cause of megacolon.

http://ift.tt/2hYaN0n

Knee upside down

We present a case of a 19-year-old woman with a forced hyperextension trauma of the knee causing a posteromedial fracture, a medial meniscus root tear and rupture of the posterior cruciate ligament. The posteromedial fracture of the tibial plateau was treated operatively with open reduction and internal fixation. Anatomical reconstruction was achieved. Postoperative treatment included unlimited flexion and minimal weight bearing. After 3 months, the patient had minimal pain after weight bearing and returned to preoperative range of motion.

http://ift.tt/2g7cRlZ

Reviving a national prevention agenda is key to sustainability of health care in Canada [Commentary]

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Oral morphine versus ibuprofen administered at home for postoperative orthopedic pain in children: a randomized controlled trial [Research]

BACKGROUND:

Oral morphine for postoperative pain after minor pediatric surgery, while increasingly popular, is not supported by evidence. We evaluated whether oral morphine was superior to ibuprofen for at-home management of children's postoperative pain.

METHODS:

We conducted a randomized superiority trial comparing oral morphine (0.5 mg/kg) with ibuprofen (10 mg/kg) in children 5 to 17 years of age who had undergone minor outpatient orthopedic surgery (June 2013 to September 2016). Participants took up to 8 doses of the intervention drug every 6 hours as needed for pain at home. The primary outcome was pain, according to the Faces Pain Scale – Revised, for the first dose. Secondary outcomes included additional analgesic requirements, adverse effects, unplanned health care visits and pain scores for doses 2 to 8.

RESULTS:

We analyzed data for 77 participants in each of the morphine and ibuprofen groups. Both interventions decreased pain scores with no difference in efficacy. The median difference in pain score before and after the first dose of medication was 1 (interquartile range 0–1) for both morphine and ibuprofen (p = 0.2). For doses 2 to 8, the median differences in pain score before and after the dose were not significantly different between groups. Significantly more participants taking morphine reported adverse effects (45/65 [69%] v. 26/67 [39%], p < 0.001), most commonly drowsiness (31/65 [48%] v. 15/67 [22%] in the morphine and ibuprofen groups, respectively; p = 0.003).

INTERPRETATION:

Morphine was not superior to ibuprofen, and both drugs decreased pain with no apparent difference in efficacy. Morphine was associated with significantly more adverse effects, which suggests that ibuprofen is a better first-line option after minor surgery.

Trial registration:

ClinicalTrials.gov, no. NCT01686802.

http://ift.tt/2xsSrvr

Medical-legal concerns over prescribing opioids on the rise [News]

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Bitot spot: early marker for avoidable blindness [Practice]

http://ift.tt/2xuzp7N

Hundreds of doctors support controversial tax reforms [News]

http://ift.tt/2xtaJwv

Sepsis kills one million newborns a year: WHO [News]

http://ift.tt/2xuzo3J

FAT1 modulates EMT and stemness genes expression in hypoxic glioblastoma

Abstract

Glioblastoma (GBM) is characterized by the presence of hypoxia, stemness and local invasiveness. We have earlier demonstrated that FAT1 promotes invasiveness, inflammation and upregulates HIF-1α expression and its signalling in hypoxic GBM. Here, we have identified the role of FAT1 in regulating EMT (Epithelial-Mesenchymal Transition) and stemness characteristics in GBM. The expression of FAT1, EMT (Snail/LOX/Vimentin/N-cad), stemness (SOX2/OCT4/Nestin/REST) and hypoxia markers (HIF-1α/VEGF/PGK1/CA9) was upregulated in ≥39% of GBM tumors (n=31) with significant positive correlation (p≤0.05) of the expression of FAT1 with LOX/Vimentin/SOX2/HIF-1α/PGK1/VEGF/CA9. Furthermore, positive correlation (p≤0.01) of FAT1 with Vimentin/N-cad/SOX2/REST/HIF-1α has been observed in TCGA GBM-dataset (n=430). Analysis of cells (U87MG/A172) exposed to severe hypoxia (0.2%O₂) revealed elevated mRNA expression of FAT1, EMT (Snail/LOX/Vimentin/N-cad), stemness (SOX2/OCT4/Nestin/REST) and hypoxia markers (HIF-1α/PGK1/VEGF/CA9) as compared to their normoxic (20%O₂) counterparts. FAT1 knockdown in U87MG/A172 maintained in severe hypoxia and in normoxic primary glioma cultures led to significant reduction of EMT/stemness markers as compared to controls. HIF-1α knockdown in U87MG cells markedly reduced the expression of all the EMT/stemness markers studied except for nestin and SOX2 which were more under the influence of FAT1. This indicates FAT1 has a novel regulatory effect on EMT/stemness markers both via or independent of HIF-1α. The functional relevance of our study was corroborated by significant reduction in the number of soft-agar colonies formed in hypoxic-siFAT1 treated U87MG cells. Hence, this study for the first time reveals FAT1 as a novel regulator of EMT/stemness in hypoxic GBM and suggests FAT1 as a potential therapeutic candidate. This article is protected by copyright. All rights reserved.

http://ift.tt/2fXyGAL

Systematic review and meta-analysis: assessment of factors affecting disability in inflammatory bowel disease and the reliability of the inflammatory bowel disease disability index

Summary

Background

The Inflammatory Bowel Disease Disability Index (IBD-DI) has recently been developed for patients with Crohn's disease (CD) and ulcerative colitis (UC).

Aim

To assess the severity of disability and associated factors using the IBD-DI, and review the validity of the IBD-DI as a tool.

Method

Systematic review of cross-sectional studies. Patients included had UC or CD and were classified as active, in remission, or needing surgery, biological and/or steroid treatment. We included studies assessing disability using the IBD-DI and that were captured by electronic and manual searches (January 2017). The possibility of bias was evaluated with the Newcastle-Ottawa Scale.

Results

Nine studies were included with 3167 patients. Comparatively, patients with active disease had higher disability rates than those in remission (SMD [CI95] = 1.49[1.11, 1.88], I² = 94%, P<.01), while patients on biological treatment had lower disability rates than those receiving corticosteroid treatment (SMD [CI95] = −0.22[−0.36, −0.08], I² = 0%, P<.01). Disease activity and unemployment were found to be associated factors. The IBD-DI scored "good" for internal consistency, "fair" to "excellent" for intra-rater reliability and "excellent" for inter-rater reliability. Construct validity was "moderately strong" to "very strong" and structural validity was found to be mainly unidimensional. The IBD-DI had excellent responsiveness, while its interpretability was only useful on a group level.

Conclusions

This systematic review and meta-analysis found a significant association between disease activity, treatment received and disability; although significant heterogeneity was found. The IBD-DI is reliable and valid, but further studies are needed to measure its interpretability.

http://ift.tt/2g8jAfI

Beta-blockers in hospitalised patients with cirrhosis and ascites: mortality and factors determining discontinuation and reinitiation

Summary

Background

It has been suggested that beta-blockers may increase mortality in patients with cirrhosis and refractory ascites but the effect of beta-blockers discontinuation or reinitiation has not been examined.

Aims

To compare, in hospitalised patients with cirrhosis and ascites, the effect of BB on survival and to examine the effect/predictors of beta-blockers discontinuation and reinitiation.

Methods

Sub-analysis of NACSELD (North American consortium for the study of end-stage liver disease, database containing prospective data on hospitalised patients with cirrhosis) data from 7 centres enrolling >100 patients with ascites. Data on BB discontinuation and reinitiation were collected by chart review.

Results

Seven hundred and sixteen patients, 307 (43%) on beta-blockers at admission and 366 (51%) with refractory ascites, were followed to death or hospital discharge. Beta-blocker use was associated with a lower white blood cell count at admission. Beta-blocker use in hospitalised patients with ascites was not associated with a higher mortality, even in those with refractory ascites. No significant changes in mean arterial pressure (MAP) were observed between groups. Discontinuation of beta-blockers (49%) was driven by low MAP, infection and acute kidney injury at time of discontinuation but was not associated with a higher mortality. Beta-blocker reinitiation occurred in 40% prior to discharge and was mainly driven by an increase in MAP.

Conclusions

Beta-blocker use is safe in patients with cirrhosis and ascites (including those with refractory ascites) provided beta-blockers are discontinued in the presence of a low MAP and reinitiated once MAP reincreases. A potentially beneficial anti-inflammatory effect of beta-blockers is suggested.

http://ift.tt/2yBCzHg

Transcatheter embolization of a large mediastinal bronchial artery aneurysm with short neck

http://ift.tt/2y8eBQE

Review of appendicectomies over a decade in a tertiary hospital in New Zealand

Background

Acute appendicectomy is the most common emergency operation for patients with abdominal pain. In the last decade, computed tomography (CT) scans have increasingly been used to aid in the diagnosis in order to reduce the negative appendicectomy rate. The aim of this study was to evaluate our institution's negative appendicectomy rate and the use of pre-operative imaging.

Methods

A retrospective review was undertaken for all adult patients (>16 years), who underwent an appendicectomy on emergency basis in the years 2004, 2009 and 2014. Cases were identified from the hospital electronic theatre record system. Data were also obtained from the patients records and laboratory reports.

Results

A total of 874 patients were included, 227 in 2004, 308 in 2009 and 339 in 2014. The negative appendicectomy rate was 29.1% in 2004, 20.1% in 2009 and 19.5% in 2014 (P = 0.014). Negative appendicectomies were more common in women (P = <0.001), patients between the ages of 16–30 years (P = <0.001) and were associated with low inflammatory markers (median white cell count of 10.2, C-reactive protein of 8, P = <0.001). The use of CT scan prior to operation increased between 2009 and 2014 (34 (11.0%) versus 64 (18.9%), P = <0.001).

Conclusion

Though the number of appendicectomies being performed in our institution has increased over the last decade, the negative appendicectomy rate remains fairly static and the increased use of CT scans did not further decrease the proportion of negative appendicectomies between 2009 and 2014.

http://ift.tt/2wJwBzr

Natural history of endoscopically detected hiatus herniae at late follow-up

Background

Hiatus herniae are commonly seen at endoscopy. Many patients with a large hiatus hernia are endoscoped for symptoms associated with the hernia and many of these will progress to surgical treatment. However, little is known about the natural history of small to medium size hiatus herniae, and their risk of progressing to a larger hernia requiring surgery. This study aims to determine the need for subsequent surgery in these patients.

Methods

A retrospective audit of the endoscopy database at Flinders Medical Centre and the Repatriation General Hospital in Adelaide, South Australia for the 2-year period 2002–2003 was performed to identify all patients with a hiatus hernia. Patients under the age of 65 and with a sliding hiatus hernia <5 cm in length were selected for this study, and sent a questionnaire which determines the long-term (>10 years) outcome of these herniae.

Results

Small- to medium-sized hiatus herniae (<5 cm length) were found at 10% of endoscopies performed. In this group, 38% had reflux as the indication for endoscopy. 1.5% subsequently progressed to anti-reflux surgery or hiatus hernia repair. Thirty-nine percent reported being on proton pump inhibitors for symptom control. No patients required emergency surgical repair of their hiatus hernia.

Conclusion

While patients with small- to medium-sized sliding hiatus hernia commonly have symptomatic reflux, an acute problem requiring emergency surgery is unlikely over long-term follow-up.

http://ift.tt/2y8eB36

Issue Information

http://ift.tt/2ybO5rL

Spigelman Scoring System Underestimates the Risk of Ampullary and Duodenal Carcinoma in Patients With Familial Adenomatous Polyposis With Duodenal Polyposis

No abstract available

http://ift.tt/2gpMrZS

Residency Programs in Colon and Rectal Surgery

No abstract available

http://ift.tt/2yauOXG

The Author Replies

No abstract available

http://ift.tt/2gquzOx

Rectal Prolapse

No abstract available

http://ift.tt/2grxExL

Crohn’s Disease of the Pouch: A True Diagnosis or an Oversubscribed Diagnosis of Exclusion?

BACKGROUND: After IPAA, 8% of patients with ulcerative colitis are later diagnosed with Crohn's disease of the pouch, associated with an increased rate of pouch failure. No study has reported on how often the clinical diagnosis is correlated with histologic findings of Crohn's disease in the excised pouch. OBJECTIVE: The purpose of this study was to determine whether the clinical diagnosis is consistent with pathologic confirmation at pouch excision. SETTINGS: The study was conducted at a tertiary IBD referral center. PATIENTS: Patients with chronic ulcerative colitis who underwent pouch excision for presumed Crohn's disease of the pouch were included. MAIN OUTCOME MEASURES: Preoperative evaluation and pathologic variables at the time of pouch excision were measured. RESULTS: A total of 35 patients underwent pouch excision for Crohn's disease of the pouch based on a combination of clinical, radiographic, and endoscopic findings. Seven (20%) had surgical pathology consistent with Crohn's disease at pouch excision. There were no differences in those 7 patients and the remaining 28 in terms of diagnosis at colectomy, primary pouch symptoms, prepouch inflammation, ulceration, or granulomas at endoscopy. In the nonpathology-confirmed Crohn's disease, 40% (n = 11) had an anastomotic leak at time of IPAA versus 0% in the Crohn's disease group, and 86% (n = 24) had symptoms of pouch dysfunction within 5 months of ileostomy reversal versus 13 months in the Crohn's disease group. Of 28 without pathology-confirmed Crohn's disease, 100% (n = 28) were treated with antibiotics, 68% (n = 19) with steroids, 59% (n = 16) with immunomodulators, and 57% (n = 15) with biologic therapy for Crohn's disease of the pouch. LIMITATIONS: The study was limited by its single-center scope and lack of an established definition for Crohn's disease of the pouch. CONCLUSIONS: Pathologic confirmation of Crohn's disease was given to only one fifth of patients who underwent pouch excision for Crohn's disease of the pouch. Given the histologic variability in Crohn's disease, it may be unreasonable to expect histologic confirmation in every case; still, the diagnosis of Crohn's disease of the pouch may be overly ascribed, resulting in unnecessary immunosuppressive medications and exclusion from consideration for pouch reconstructive surgery. See Video Abstract at http://ift.tt/2ybghee .

http://ift.tt/2ybaSUl

Expert Commentary on Rectal Prolapse

No abstract available

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Surveillance of Duodenal Polyposis in Familial Adenomatous Polyposis: Should the Spigelman Score Be Modified?

BACKGROUND: Duodenal polyposis is a manifestation of adenomatous polyposis that predisposes to duodenal or ampullary adenocarcinoma. Duodenal polyposis is monitored by upper GI endoscopies and may require iterative resections and prophylactic radical surgical treatment when malignancy is threatening. OBJECTIVE: The purpose of this study was to evaluate severity scoring for surveillance and treatment in a large series of duodenal polyposis. DESIGN: From 1982 to 2014, every patient surveyed by upper GI endoscopies for duodenal polyposis was included. SETTINGS: The study was conducted at a single tertiary care center. PATIENTS: We performed 1912 upper GI endoscopies in 437 patients (median = 3; interquartile range, 2–6 endoscopies). MAIN OUTCOME MEASURES: Conservative treatment was performed in 103 patients (159 endoscopic and 17 surgical resections), whereas radical surgical treatment (Whipple procedure or duodenectomy) was required in 52 (median age, 47.5 y; range, 43.0–57.3 y) because of high-grade dysplasia or unresectable lesions. RESULTS: Genes involved were APC (n = 274; 62.7%) and MUTYH (n = 21; 4.8%). First upper GI endoscopies (median age, 32 y; range, 21–44 y) revealed duodenal polyposis in 190 (43.5%). Rates of low-grade dysplasia, high-grade dysplasia, and duodenal or ampulary adenocarcinoma at 5 years were 65% (range, 61.7%–66.9%), 12.1% (range, 10.3%–13.9%), and 2.4% (range, 1.5%–3.3%), whereas 10-year rates were 75.8% (range, 73.1%–78.5%), 20.8% (range, 18.2%–23.4%), and 5.4% (range, 3.8%–7.0%). The rate of ampullary abnormalities rose during surveillance from 18.3% at the first upper GI endoscopies to 47.4% at the fourth. Predictive factors for high-grade dysplasia were age at first upper GI endoscopy, type and age of colorectal surgery, Spigelman score, presence of an ampullary abnormality, and number of endoscopic treatments. In multivariate analysis, only age at first upper GI endoscopy and presence of an ampullary abnormality were independent predictive factors. Histologic analysis after radical surgical treatment showed high-grade dysplasia in 30 patients and duodenal or ampulary adenocarcinoma in 11 (4 patients had lymph node involvement). LIMITATIONS: The study was limited by its retrospective analysis of a prospective database. CONCLUSIONS: More than 20% of patients developed high-grade dysplasia with duodenal polyposis after 10 years. Iterative endoscopic resections allowed extended control, but surgery remained necessary in 12% of the patients and happened too late in many cases; 20% of those operated had developed duodenal or ampulary adenocarcinoma, whereas 8% exhibited malignancy with lymph node involvement. The trigger for prophylactic surgery required a more accurate predictive score leading to closer endoscopic surveillance. Modifying the Spigelman score by accounting for ampullary abnormalities should be considered as a means to increase compliance with closer endoscopic follow-up in high-risk patients. See Video Abstract at http://ift.tt/2ycFl4I .

http://ift.tt/2yclzGn

The Authors Reply

No abstract available

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Peritoneal Involvement Is More Common Than Nodal Involvement in Patients With High-Grade Appendix Tumors Who Are Undergoing Prophylactic Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy

BACKGROUND: Right hemicolectomy is routinely recommended in patients with histologic findings of high-grade appendix tumors after appendicectomy. Undetected peritoneal disease may be encountered at surgery. In high-grade appendix tumors with disease detected radiologically, complete cytoreduction may not be possible and outcomes poor. For these reasons, we adopted a policy of prophylactic cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. OBJECTIVE: The purpose of this study was to quantify the rates of peritoneal and nodal metastatic disease in patients with high-grade appendix tumors without obvious metastatic disease and to report the long-term outcomes of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in these patients. DESIGN: Data regarding peritoneal and nodal metastatic disease were extracted from surgical and histologic records. SETTINGS: The study was conducted at a high-volume tertiary referral center for peritoneal malignancy. PATIENTS: Patients referred with histologically high-grade appendix tumors at appendicectomy, without detectable metastatic spread, between January 1994 and September 2016 were included MAIN OUTCOME MEASURES: A total of 62 patients with high-grade pathology at appendicectomy, without clinical or radiological peritoneal disease, underwent complete cytoreduction with hyperthermic intraperitoneal chemotherapy. RESULTS: Thirty-five (57%) of 62 patients had peritoneal disease (median peritoneal cancer index 5 (range, 1–28)). Eleven (31%) of 35 had microscopic peritoneal disease. Overall, 23 (37%) of 62 had peritoneal disease beyond the confines of a standard right hemicolectomy. Nine (15%) of 62 had nodal involvement. Mean overall and disease-free survival were 110.9 (95% CI, 94.8–127.0 mo) and 102.1 months (95% CI, 84.3–119.9 mo), with 5-year overall and disease-free survival of 83.2% and 76.0%. LIMITATIONS: The retrospective nature limits the interpretation of these results. CONCLUSIONS: Complete cytoreduction was achieved in all of the patients, with excellent long-term survival. The incidence of peritoneal spread (57%) compared with nodal involvement (15%) supports cytoreductive surgery and hyperthermic intraperitoneal chemotherapy as definitive treatment rather than prophylaxis in patients with high-grade appendix tumors, even without radiologically detectable disease. High-grade appendix tumors benefit from early aggressive operative management to deal with potential peritoneal and nodal spread and should be considered for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. See Video Abstract at http://ift.tt/2ybVW8x .

http://ift.tt/2yauN64

Totally Laparoscopic Retroileal Transverse Colon to Rectal Anastomosis Following Extended Left Colectomy

No abstract available

http://ift.tt/2grmyZN

A New Prediction Model for Local Recurrence After Curative Rectal Cancer Surgery: Development and Validation as an Asian Collaborative Study

BACKGROUND: Local recurrence is one of the remaining problems in rectal and rectosigmoid cancer, and it is sometimes difficult to treat. OBJECTIVE: This study aimed to explore various factors that are highly related to local recurrence and to develop a new prediction model for local recurrence after curative resection. DESIGN: This is a retrospective cohort study SETTINGS: This study was conducted at 2 academic hospitals in Japan and Korea. PATIENTS: A total of 2237 patients with stage I to III rectal and rectosigmoid cancer who underwent a curative operation with a negative circumferential margin were selected. INTERVENTIONS: Surgical treatment was the intervention. MAIN OUTCOME MEASURES: Local recurrence was the primary outcome measure. RESULTS: A total of 1232 patients were selected, and rectosigmoid cancer with rare local recurrence (2/221) was excluded. A different set of 792 patients with rectal cancer were chosen for validation. Multivariate analysis showed the following factors as significant for local recurrence: poorly differentiated tumor (HR, 11.2; 95% CI, 4.5–28.0), tumor depth (HR, 5.0), lymph node metastasis (HR, 4.1), operative procedure (HR, 3.2), postoperative complications (HR, 2.9), tumor location (HR, 2.6), and CEA level (HR, 2.4); a new prediction score was created by using these factors. A poorly differentiated tumor was assigned 2 points, and all other factors were assigned 1 point each. Patients who scored more than 5 points (n = 21) were judged as "high risk," with a 2-year local recurrence rate of 66.5%. The new predictive model could also separate the patients into different risk groups in the validation set. The high-risk group had higher recurrence rates than medium- and low-risk groups (2-year local recurrence rate: 41%, 15%, and 2.1%). LIMITATIONS: This study was limited by its retrospective nature and potential for selection bias. CONCLUSIONS: Seven factors were shown to be significantly correlated with the local recurrence of rectal cancer, and the usefulness of this new prediction model was demonstrated. See Video Abstract at http://ift.tt/2ycybx5 .

http://ift.tt/2yaO2MO

Single-Incision Laparoscopic Colectomy with Complete Mesocolic Excision Versus Multiport Laparoscopic Colectomy for Colon Cancer

No abstract available

http://ift.tt/2gqufiN

A Distal Resection Margin of ≤1 mm and Rectal Cancer Recurrence After Sphincter-Preserving Surgery: The Role of a Positive Distal Margin in Rectal Cancer Surgery

BACKGROUND: There is little information about the prognostic value of a microscopically positive distal margin in patients who have rectal cancer. OBJECTIVE: We aimed to investigate the influence of a distal margin of ≤1 mm on oncologic outcomes after sphincter-preserving resection for rectal cancer. DESIGN: This is a retrospective cohort study. SETTINGS: The study was conducted at 2 hospitals. PATIENTS: A total of 6574 patients underwent anterior resection for rectal cancer from January 1999 to December 2014; 97 (1.5%) patients with a distal margin of ≤1 mm were included in this study. For comparative analyses, patients were matched with 194 patients with a negative distal margin (>1 mm) according to sex, age, BMI, ASA score, neoadjuvant treatment, tumor location, and stage. MAIN OUTCOME MEASURES: The oncologic outcomes of the 2 groups were compared. RESULTS: Perineural and lymphovascular invasion rates were significantly higher in patients with a positive distal margin (54.6% vs 28.9%; 67.0% vs 42.8%; both p

http://ift.tt/2gqueLL

A Collaborative Model for Accelerating the Discovery and Translation of Cancer Therapies

Preclinical studies using genetically engineered mouse models (GEMM) have the potential to expedite the development of effective new therapies; however, they are not routinely integrated into drug development pipelines. GEMMs may be particularly valuable for investigating treatments for less common cancers, which frequently lack alternative faithful models. Here, we describe a multicenter cooperative group that has successfully leveraged the expertise and resources from philanthropic foundations, academia, and industry to advance therapeutic discovery and translation using GEMMs as a preclinical platform. This effort, known as the Neurofibromatosis Preclinical Consortium (NFPC), was established to accelerate new treatments for tumors associated with neurofibromatosis type 1 (NF1). At its inception, there were no effective treatments for NF1 and few promising approaches on the horizon. Since 2008, participating laboratories have conducted 95 preclinical trials of 38 drugs or combinations through collaborations with 18 pharmaceutical companies. Importantly, these studies have identified 13 therapeutic targets, which have inspired 16 clinical trials. This review outlines the opportunities and challenges of building this type of consortium and highlights how it can accelerate clinical translation. We believe that this strategy of foundation–academic–industry partnering is generally applicable to many diseases and has the potential to markedly improve the success of therapeutic development. Cancer Res; 1–6. ©2017 AACR.

http://ift.tt/2g71EC9

Moonshot Acceleration Factor: Medical Imaging

Medical imaging is essential to screening, early diagnosis, and monitoring responses to cancer treatments and, when used with other diagnostics, provides guidance for clinicians in choosing the most effective patient management plan that maximizes survivorship and quality of life. At a gathering of agency officials, patient advocacy organizations, industry/professional stakeholder groups, and clinical/basic science academicians, recommendations were made on why and how one should build a "cancer knowledge network" that includes imaging. Steps to accelerate the translation and clinical adoption of cancer discoveries to meet the goals of the Cancer Moonshot include harnessing computational power and architectures, developing data sharing policies, and standardizing medical imaging and in vitro diagnostics. Cancer Res; 1–4. ©2017 AACR.

http://ift.tt/2hYCBlj

Sleeping Beauty insertional mutagenesis in mice identifies drivers of steatosis-associated hepatic tumor

Hepatic steatosis is a strong risk factor for the development of hepatocellular carcinoma (HCC), yet little is known about the molecular pathology associated with this factor. In this study, we performed a forward genetic screen using Sleeping Beauty (SB) transposon insertional mutagenesis in mice treated to induce hepatic steatosis, and compared the results to human HCC data. In humans, we determined that steatosis increased the proportion of female HCC patients, a pattern also reflected in mice. Our genetic screen identified 203 candidate steatosis-associated HCC genes, many of which are altered in human HCC and are members of established HCC-driving signaling pathways. The protein kinase A/cyclic AMP signaling pathway was altered frequently in mouse and human steatosis-associated HCC. We found that activated PKA expression drove steatosis-specific liver tumorigenesis in a mouse model. Another candidate HCC driver, the N-acetyltransferase NAT10, which we found to be overexpressed in human steatosis-associated HCC and associated with decreased survival in human HCC, also drove liver tumorigenesis in a steatotic mouse model. This study identifies genes and pathways promoting HCC that may represent novel targets for prevention and treatment in the context of hepatic steatosis, an area of rapidly growing clinical significance.

http://ift.tt/2g6e25k

PACE4 Undergoes an Oncogenic Alternative Splicing Switch in Cancer

Inhibition of PACE4, a proprotein convertase that is overexpressed in prostate cancer, has been shown to block cancer progression in an androgen-independent manner. However, the basis for its overexpression and how its growth inhibitory effects are mitigated and uncertain. Here we report that PACE4 pre-mRNA undergoes DNA methylation-sensitive alternative splicing of its terminal exon 3' untranslated region, generating an oncogenic, C-terminally modified isoform (PACE4-altCT). We found this isoform to be strongly expressed in prostate cancer cells, where it displayed an enhanced auto-activating process and a distinct intracellular routing that prevented its extracellular secretion. Together these events led to a dramatic increase in processing of the pro-growth differentiation factor pro-GDF15 as the first PACE4 substrate to be identified in prostate cancer. We detected robust expression of PACE4-altCT in other cancer types, suggesting that an oncogenic switch for this pro-enzyme may offer a therapeutic target not only in advanced prostate cancer but perhaps also more broadly in human cancer. 

http://ift.tt/2i056yW

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

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

http://ift.tt/2g7t76L

Firearm-Related Injury and Death — A U.S. Health Care Crisis in Need of Health Care Professionals

What would happen if on one day more than 50 people died and over 10 times that many were harmed by an infectious disease in the United States? Likely, our nation's esteemed and highly capable public health infrastructure would gear up to care for those harmed and study the problem. There would be…

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The alternative sigma factors SigE and SigB are involved in tolerance and persistence to antitubercular drugs [PublishAheadOfPrint]

Emergence and spread of drug resistant Mycobacterium tuberculosis strains threatens our ability the possibility to treat this disease in the future. Even if two new antitubercular drugs were recently introduced, there is still the need to design new molecules whose mechanism of action could reduce treatment length. We showed that two alternative sigma factors of M. tuberculosis (SigE and SigB) have a major role in determining the level of basal resistance to several drugs and the amount of persisters surviving long drug treatment. We also demonstrate that ethambutol, a bacteriostatic drug is highly bactericidal for M. tuberculosis mutants missing either SigE or SigB. We suggest that developing molecules able to interfere with their activity could not only reduce M. tuberculosis virulence in vivo, but also boost the effect of other drugs by increasing its sensitivity and reducing the number of persisters able to escape killing.

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Amikacin pharmacokinetics to optimize dosing in neonates with perinatal asphyxia treated with hypothermia [PublishAheadOfPrint]

Aminoglycosides pharmacokinetics (PK) is expected to change in neonates with perinatal asphyxia treated with therapeutic hypothermia (PATH). Several amikacin dosing guidelines have been proposed to treat neonates with (suspected) septicemia, however, none provide adjustments in the case of PATH. Therefore, we aimed to quantify the differences in amikacin PK between neonates with and without PATH to propose suitable dosing recommendations.

Based on amikacin therapeutic drug monitoring data collected retrospectively from neonates with PATH, combined with a published dataset, we assessed the impact of PATH on amikacin PK using population modelling. Monte Carlo and stochastic simulations were performed to establish amikacin exposures in neonates with PATH after dosing according to the current guidelines and according to proposed model-derived dosing guidelines.

Amikacin clearance was decreased by 40.6% in neonates with PATH, with no changes in volume of distribution. Simulations showed that, increasing the dosing interval with 12 hours results in a decrease in percentage of neonates reaching toxic trough levels (> 5 mg/L) from 40—76% to 14—25%, while still reaching efficacy targets, compared to current dosing regimens.

Based on this study, a 12-hour increase in amikacin dosing interval in neonates with PATH is proposed to correct for the reduced clearance, yielding safe and effective exposures. As amikacin is renally excreted, further studies into other renally excreted drugs may be required as their clearance may also be impaired.

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The effects of maraviroc versus efavirenz in combination with zidovudine/lamivudine on the CD4/CD8 ratio in treatment-naïve HIV-infected individuals. [PublishAheadOfPrint]

A low CD4/CD8 ratio during treated HIV infection reflects heightened immune activation and predicts mortality. The effect of different ART regimens on CD4/CD8 ratio recovery remains unclear. We performed a post hoc analysis of the MERIT study, a randomized, double-blind, trial of maraviroc versus efavirenz, in combination with zidovudine-lamivudine, in treatment-naive HIV-infected individuals. We found higher rates of CD4/CD8 ratio normalization with efavirenz, which was driven by greater CD8+ T-cell decline.

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Molecular characterization of carbapenemase-producing Pseudomonas aeruginosa of Czech origin: evidence for clonal spread of extensively resistant ST357 expressing IMP-7 metallo-{beta}-lactamase [PublishAheadOfPrint]

The objective of this study was to perform molecular surveillance for assessing the spread of carbapenemase-producing P. aeruginosa in Czech hospitals. One-hundred thirty-six carbapenemase-producing isolates were recovered from 22 hospitals, located throughout the country. ST357 dominated (n=120) among carbapenemase producers. One-hundred seventeen isolates produced IMP-type (IMP-7 [n=116] and IMP-1 [n=1]) metallo-β-lactamases (MβLs), fifteen produced the VIM-2 MβL, while the remaining isolates expressed the GES-5 enzyme. The bla_IMP-like genes were located in three main integron types, with In-p110-like being the most prevalent (n=115). The two other IMP-encoding integrons (In1392 and In1393) have not been described previously. bla_VIM-2-carrying integrons included In59-like, In56, and a novel element (In1391). bla_GES-5 was carried by In717. Sequencing data showed that In-p110-like was associated with a Tn4380-like transposon inserted in genomic island LESGI-3, in P. aeruginosa chromosome. The other integrons were also integrated into P. aeruginosa chromosome. These findings indicated the clonal spread of ST357 P. aeruginosa, carrying the IMP-7-encoding integron In-p110, in Czech hospitals. Additionally, the sporadic emergence of P. aeruginosa producing different carbapenemase types, associated with divergent or novel integrons, punctuated the ongoing evolution of these bacteria.

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Morphological sectors, impacting on antifungal susceptibility testing and virulence studies [PublishAheadOfPrint]

Morphological heterogeneity of Aspergillus terreus cultures was observed during continued cultivation of AMB-resistant isolates on drug-free medium. Outgrowth leads to the emergence of multiple sectors that might result from increased growth rates at drug-free conditions. We evaluated the differences in AmB susceptibility and virulence between sector subcultures (ATSec), AmB-resistant strains (ATR), and AmB-susceptible strains (ATS). By comparing AmB resistant A. terreus strains (ATR) and A. terreus sector cultures (ATSec) a highly significant reduction of AmB MICs in ATSec was observed (ATR: MIC: 2-32μg/ml, ATSec 0.12-5 μg/ml). Furthermore Galleria mellonella survival studies revealed an enhanced virulence of ATSec, which was comparable with AmB-sensitive Aspergillus terreus strains (ATS) (median survival rate for ATS: 72 h, ATSec G1: 84 h, and ATR: 144 h).

Our findings clearly demonstrate that spontaneous culture degeneration occurs in A. terreus and most importantly crucially impacts drug efficacy and virulence.

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In vitro activity of Pexiganan and 10 comparator antimicrobials against 502 anaerobic isolates recovered from skin and skin-structure infections (SSSI). [PublishAheadOfPrint]

Pexiganan, a cationic peptide, exhibited a broad range of anti-anaerobic antimicrobial activity. MIC₉₀s were as follows: B. fragilis, 16 μg/ml; other Bacteroides fragilis group spp., 4 μg/ml; Prevotella and Fusobacterium spp., 32 μg/ml; and Porphyromonas spp., 64 μg/ml; P. acnes, 4 μg/ml; E. lenta and P. anaerobius, 32 μg/ml; other Gram-positive rods and cocci, 4 μg/ml; Clostridium perfringens, 128 μg/ml; and other clostridia, 256 μg/ml. Pexiganan cream shows potential as adjunctive therapy for SSSIs involving anaerobes.

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Antibiotics Promote Escherichia coli-Pseudomonas aeruginosa Conjugation through Inhibiting Quorum Sensing [PublishAheadOfPrint]

The effect of antibiotics on horizontal gene transfer is controversial and the underlying mechanism remains poorly understood. Here, using E. coli SM10 which carries a chromosomally integrated RP4 plasmid as donor strain, we investigated the effect of antibiotics on conjugational transfer of a mobilizable gentamicin (Gm) resistance plasmid. The results showed that exposure to gentamicin that may restrict the survival of recipient cells significantly enhanced SM10-P. aeruginosa (PAO1) conjugation, which was attenuated by deficiency of lasI/rhlI, genes associated with generation of the quorum sensing signals N-acyl homoserine lactones (AHLs) in PAO1, or deletion of the AHLs receptor SdiA in SM10. Subsequent mechanism investigations revealed that treatment with Gm repressed the mRNA expression of lasI and rhlI in PAO1 and upregulated traI expression in SM10. Moreover, PAO1 treated with other QS-inhibitory antibiotics such as azithromycin or chloramphenicol also showed conjugation-promoting ability. On the other hand, when using non-AHLs- producing E. coli strain EC600 as recipient cells, the promoting effect of Gm on conjugation could not be observed. These data suggest that AHLs-SdiA contributes to the effectiveness of antibiotics on plasmid conjugation. Collectively, our findings highlight the HGT-promoting effect of antibiotics and suggest quorum sensing as a promising target for controlling antibiotic resistance dissemination. These findings have implications for assessing the risks of antibiotic use and developing advisable antibiotic treatment protocols.

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Emergence of various NDM-type metallo-{beta}-lactamase-producing Escherichia coli clinical isolates in Nepal [PublishAheadOfPrint]

Of 250 clinical isolates of Escherichia coli obtained in Nepal, 38 were carbapenem-resistant with MICs ≥4 μg/ml to imipenem or meropenem. All 38 isolates harbored bla_NDMs: bla_NDM-1, bla_NDM-3, bla_NDM-4, bla_NDM-5, bla_NDM-7, bla_NDM-12 and bla_NDM-13. Most of these isolates also harbored the 16S rRNA methylase gene(s) armA, rmtB and/or rmtC.

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Evaluation of PK/PD model-based optimized combination regimens against multidrug-resistant Pseudomonas aeruginosa in a murine thigh infection model using humanized dosing schemes [PublishAheadOfPrint]

We previously optimized imipenem and tobramycin combination regimens against a double-resistant clinical P. aeruginosa isolate using in vitro infection models, mechanism-based PK/PD modeling (MBM) and Monte Carlo simulations. The current study aimed to evaluate these regimens in a neutropenic murine thigh infection model and to characterize the time-course of bacterial killing and regrowth via MBM. We studied monotherapies and combinations of imipenem with tobramycin in vivo against the double-resistant clinical P. aeruginosa isolate using humanized dosing schemes. Viable count profiles of total and resistant populations were quantified over 24h. Tobramycin monotherapy (7 mg/kg q24h as 0.5h infusions) was ineffective. Imipenem monotherapies (continuous infusion of 4 or 5 g/day with 1 g loading dose) yielded 2.47 and 2.57 log₁₀ CFU/thigh killing at 6h. At 24h, imipenem 4 g/day led to regrowth up to the initial inoculum (4.79±0.26 log₁₀ CFU/thigh), whereas imipenem 5 g/day displayed 1.75 log₁₀ killing versus the initial inoculum. The combinations (i.e. imipenem 4 or 5 g/day plus tobramycin) provided a clear benefit with bacterial killing of ≥2.51 and ≥1.50 log₁₀ CFU/thigh compared to the respective most active monotherapy at 24h. No colonies were detected on 3xMIC agar plates for combinations, whereas increased resistance (at 3xMIC) emerged for monotherapies (except imipenem 5 g/day). MBM suggested tobramycin considerably enhanced the imipenem target site concentration up to 2.6-fold. The combination regimens, rationally optimized via a translational modeling approach, demonstrated substantially enhanced bacterial killing and suppression of regrowth in vivo against a double-resistant isolate, and are therefore promising for future clinical evaluation.

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Inhibition of fosfomycin resistance protein FosA by phosphonoformate (foscarnet) in multidrug-resistant Gram-negative pathogens [PublishAheadOfPrint]

FosA proteins confer fosfomycin resistance in Gram-negative pathogens via glutathione-mediated modification of the antibiotic. In this study, we assessed whether inhibition of FosA by sodium phosphonoformate (PPF; foscarnet), a clinically approved antiviral agent, would reverse fosfomycin resistance in representative Gram-negative pathogens. The inhibitory activity of PPF against purified recombinant FosA from Escherichia coli (FosA3), Klebsiella pneumoniae (FosA^KP), Enterobacter cloacae (FosA^EC) and Pseudomonas aeruginosa (FosA^PA) was determined by steady-state kinetics. The antibacterial activity of PPF against FosA was evaluated by susceptibility testing and time-kill assays in clinical strains of these species. PPF increased the Michaelis constant K_m for fosfomycin in a dose dependent manner without impacting the maximum rate of the reaction (V_max) for all four FosA enzymes tested, denoting a competitive mechanism of inhibition. Inhibitory constants (K_i) were 22.6, 35.8, 24.4 and 56.3 μM for FosA^KP, FosA^EC, FosA^PA and FosA3, respectively. Addition of clinically achievable concentrations of PPF (~667 μM) reduced the MICs of fosfomycin by ≥4-fold among 52% of K. pneumoniae, E. cloacae and P. aeruginosa clinical strains tested and lead to a bacteriostatic or bactericidal effect in time-kill assays among representative strains. PPF inhibits FosA activity across Gram-negative species, and can potentiate fosfomycin activity against the majority of strains with chromosomally encoded fosA. These data suggest that PPF may be repurposed as an adjuvant for fosfomycin to treat infections caused by some of FosA-producing, multidrug-resistant Gram-negative pathogens.

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Choosing optimal antifungal agents to prevent fungal infections in non-neutropenic critically ill patients: trial sequential analysis, network meta-analysis, and pharmacoeconomic analysis [PublishAheadOfPrint]

The use of antifungal interventions in critically ill patients prior to invasive fungal infection (IFI) being microbiologically confirmed as well as the preferred drug are still controversial. A systematic literature search was performed to identify randomized controlled trials (RCTs) that have compared untargeted antifungal treatments applied to non-neutropenic critically ill patients. The primary outcomes were all-cause mortality and proven IFI rates. A random-effects model was used with trial sequential analyses (TSA), a network meta-analysis (NMA) was conducted to obtain indirect evidence, and a cost-effectiveness analysis using a decision-analytic model was completed from the patient perspective over a lifetime horizon. In total, 19 RCTs involving 2556 patients (7 interventions) were included. Untargeted antifungal treatment did not significantly decrease all-cause mortality (odds ratio [OR]=0.89, 95% confidence interval [CI]=0.70--1.14), but it did reduce the incidence of proven IFI (OR=0.45, 95%CI=0.29--0.71) relative to placebo/no intervention. The TSA showed that there was sufficient evidence supporting these findings. In the NMA, the only significant difference found for both primary outcomes was between fluconazole and placebo/no intervention in preventing proven IFI (OR=0.35, 95%CI=0.19--0.65). The incremental cost-effectiveness ratios per life-years saved for fluconazole, caspofungin, and micafungin relative to placebo/no intervention were US$ 889, US$ 9994 and US$ 10351, respectively. Untargeted antifungal treatment significantly reduced proven IFI rates in non-neutropenic critically ill patients but with no mortality benefits relative to placebo/no intervention. Fluconazole remains an only effective for IFI prevention and well-tolerated antifungals that is significantly cheaper than echinocandins.

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A dynamic stress model explains the delayed drug effect in artemisinin treatment of Plasmodium falciparum [PublishAheadOfPrint]

Artemisinin resistance constitutes a major threat to the continued success of control programs for malaria, particularly in light of developing resistance to partner drugs. Improving our understanding of how artemisinin-based drugs act and how resistance manifests is essential for the optimisation of dosing regimens and the development of strategies to prolong the lifespan of current first-line treatment options. Recent short drug-pulse in vitro experiments have shown that the parasite killing rate depends not only on drug concentration but also the exposure time, challenging the standard pharmacokinetic-pharmacodynamic(PK-PD) paradigm in which the killing rate depends only on drug concentration. Here we introduce a "dynamic stress" model of parasite killing and show through application to 3D7 laboratory strain viability data that the inclusion of a time-dependent parasite stress response dramatically improves the model's explanatory power compared to a traditional PK-PD model. Our model demonstrates that the previously reported hypersensitivity of early ring stage parasites of the 3D7 strain to dihydroartemisinin compared to other parasite stages is primarily due to a faster development of stress, rather than a higher maximum achievable killing rate. We also perform in vivo simulations using the dynamic stress model and demonstrate that the complex temporal features of artemisinin action observed in vitro have a significant impact on predictions for in vivo parasite clearance. Given the important role that PK-PD models play in the design of clinical trials for the evaluation of alternative drug dosing regimens, our novel model will contribute to the further development and improvement of antimalarial therapies.

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Long-Term Sleep Duration as a Risk Factor for Breast Cancer: Evidence from a Systematic Review and Dose-Response Meta-Analysis

Sleep patterns have been associated with the development of cancers, although the association between sleep duration and breast cancer remains controversial. The purpose of our study was to explore the relationship between sleep duration and breast cancer risk. The PubMed and Web of Science databases were searched, and restricted cubic splines were used to explore the dose-response relationship. Data from 415,865 participants were derived from 10 studies. A J-shaped nonlinear trend was found between sleep duration and breast cancer incidence ( = 0.012); compared with the reference hours (6 h or 7 h), with increasing sleep hours, the risk of breast cancer increased ( = 0.028). Moreover, a nonlinear relationship was found between sleep duration and estrogen receptor-positive breast cancer ( = 0.013); the risk of estrogen receptor-positive breast cancer increased with increasing sleep hours compared to the reference hours ( = 0.024). However, no nonlinear relationship was found between sleep duration and estrogen receptor-negative breast cancer; the risk of estrogen receptor-negative breast cancer was 1.035 for every additional sleep hour. Compared to women with the reference number of sleep hours, women with a longer sleep duration might have a significantly increased risk of breast cancer, especially estrogen receptor-positive breast cancer.

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The PDZ-Binding Motif of HPV16-E6 Oncoprotein Modulates the Keratinization and Stemness Transcriptional Profile In Vivo

Objective. The aim of this work was to compare the early gene expression profiles in the skin of HPV16-E6 transgenic mice regulated by the E6 PDZ-binding motif. Materials and Methods. The global transcriptional profiles in dorsal skin biopsies from K14E6 and K14E6Δ146-151 transgenic mice were compared using microarrays. Relevant genes obtained from the most differentially expressed processes were further examined by RT-qPCR, in situ RT-PCR, Western blot, or immunofluorescence. Results. The transcriptomic landscape of K14E6 versus K14E6Δ146-151 shows that the most affected expression profiles were those related to keratinocyte differentiation, stem cell maintenance, and keratinization. Additionally, downregulation of epidermal stemness markers such as K15 and CD34, as well as the upregulation of cytokeratin 6b, appeared to be dependent on the E6 PDZ-binding motif. Finally, wound healing, a physiological process linked to stemness, is impaired in the K14E6 mice compared to K14E6Δ146-151. Conclusion. The E6 PDZ-binding motif appears to affect stemness and keratinization during early stages of skin carcinogenesis. As E6 plays a significant role in HPV-induced skin carcinogenesis, the K14E6 versus K14E6Δ146-151 transcriptional profile provides a source of valuable data to uncover novel E6 functions in the skin.

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Risk Factors of Allergic Disease: A Study with a Large Data Set

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Nationwide Quality of Hospice Care: Findings from the Centers for Medicare & Medicaid Services (CMS) Hospice Quality Reporting Program (HQRP)

With increasing use of the Medicare hospice benefit, policymakers recognize the need for quality measurement to assure that terminally ill patients receive high quality care and have the information they need when selecting a hospice. Towards these goals, CMS has been collecting standardized patient-level quality data via the Hospice Item Set (HIS) since July 1, 2014.

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Cardiac pathologic findings in three unusual cases of sudden cardiac death related to anorexiant drugs

Amphetamine congeners can be prescribed as anorexiant drugs, despite their potential side effects, including cardiac toxicity. However, the morphologic features of cardiac damage related to protracted use of these compounds are unknown. We provide a detailed description of cardiac autopsy findings in three cases of sudden death associated with protracted use of high-doses of phendimetrazine and/or phenylpropanolamine or bupropion prescribed as anorexiants, in association with other compounds. The main cardiac findings were similar in all three cases: i) mild–moderate hypertrophy of the left ventricle and/or the septum; ii) myocardial non-ischemic scarring (mid-mural and/or sub-epicardial) appearing as discrete foci or with a band/like morphology; iii) mild–moderate intramural small vessel disease, in absence of significant epicardial coronary artery stenosis; iv) acute/recent inflammatory lesions consistent with toxic myocarditis.

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Management of a Circumferential Duodenal Polyp

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EUS-guided pancreatic pseudoaneurysm therapy: better to be lucky than good

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Massive esophageal hemorrhage

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Can a Negative High-Sensitivity Troponin Result Rapidly Rule Out Acute Myocardial Infarction?

Eleven studies were included, with a total of 9,241 patients. Overall acute myocardial infarction prevalence was 15.4%. Of the total included patient population, 30.6% were classified as being at low risk for acute myocardial infarction by a single negative hs-cTnT result and a nonischemic ECG result. Of these patients, 14 (0.5%) received a diagnosis of acute myocardial infarction. In 7 of these cases, the time between symptom onset and blood sampling was less than 3 hours. The pooled performance estimates for the primary and secondary outcomes of acute myocardial infarction and major adverse cardiac events are presented in the Table.

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What Measures Improve Reduction of Intussusception in Pediatric Patients?

Investigators included 6 randomized controlled trials with 822 patients for analysis. The addition of glucagon to liquid enema versus liquid enema alone did not improve the rate of successful reduction of intussusception.1,2 Studies comparing these 2 interventions did not report on numbers of children with bowel perforations or recurrent intussusception. Air or liquid enema with dexamethasone intramuscularly versus air or liquid enema alone resulted in no benefit in regard to successful reduction or incidence of bowel perforation, although it did result in decreased risk of recurrent intussusception (risk ratio 0.14; 95% confidence interval [CI] 0.03 to 0.60), with a number needed to treat for an additional beneficial outcome (NNTB) of 13.

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SEP-1: A Sepsis Measure in Need of Resuscitation?

SEE RELATED ARTICLE, P. ■■■.

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Assessing Bleeding Risk in Patients With Intentional Overdoses of Novel Antiplatelet and Anticoagulant Medications

In recent years, the use of novel anticoagulants and antiplatelet agents has become widespread. Little is known about the toxicity and bleeding risk of these agents after acute overdose. The primary objective of this study is to evaluate the relative risk of all bleeding and major bleeding in patients with acute overdose of novel antiplatelet and anticoagulant medications.

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Estimated depth of apatite and collagen degradation in human dentine by sequential exposure to sodium hypochlorite and EDTA: a quantitative FTIR study

Abstract

Aim

To characterise chemical degradation of the principal constituents of dentine after exposure to NaOCl and EDTA using Infrared Spectroscopy (ATR-FTIR).

Methodology

Ground dentine particles, from extracted permanent human molars, were passed through sieves of 38 to1000 μm to provide six size ranges. Portions (250 mg) of each size range were reacted with 5mL of 2.5% NaOCl for 2-10 minutes; or 17% EDTA for 5-1440 minutes. Powders larger than 75μm were also sequentially exposed to NaOCl/EDTA/NaOCl each for 10 minutes. All experiments were repeated 5 times. Reacted and unreacted powders were washed and dried. Particles larger than 75μm were then reground. FTIR spectra of unground and reground reacted particles enabled assessment of particle surface versus bulk chemistry, respectively, plus estimation of reaction depth. Changes in the ratio of the 1640 cm⁻¹ collagen: 1010 cm⁻¹ phosphate peak height or its inverse were obtained. These were used to estimate surface and bulk fraction reacted and thus depth to which collagen or phosphate were reduced following immersion in NaOCl or EDTA, respectively. The data was analysed descriptively.

Results

Surface collagen fraction declined by ~40% within 2 minutes of NaOCl exposure, and plateaued at ~60% between 6–10 minutes. Bulk spectra showed average depth of collagen loss at 10 minutes was 16±13 μm. Ten minute EDTA exposure caused ~60% loss of surface phosphate. Average depth of phosphate loss was 19±12 μm and 89±43 μm after 10 and 1440 minutes EDTA immersion, respectively. Sequential NaOCl/EDTA immersion, yielded a 62±28 μm thick phosphate-depleted surface. Sequential NaOCl/EDTA/NaOCl treatment resulted in approximately 85 μm of collagen loss.

Conclusions

Data revealed the sequential depletion of collagen by NaOCl and apatite by EDTA in dentine, simultaneously exposing the other moeity. Alternate exposure to NaOCl and EDTA therefore enhances the depth of erosion.

This article is protected by copyright. All rights reserved.

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AJH Peer Review 2016

The review process is a fundamental aspect of the publication of scientific literature. Reviewers are second only to authors in the contribution to scientific knowledge, and their expertise, fairness, and rigor ensure that what we publish in the American Journal of Hypertension will advance our understanding of the science of hypertension. We are thankful to all our reviewers who commit their busy time to ensuring the quality of the manuscripts that are published in the Journal, their efforts are highly appreciated.

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Corrigendum

Normal Range of Human Dietary Sodium Intake: A Perspective Based on 24-Hour Urinary Sodium Excretion Worldwide Am J Hypertens (2013) 26 (10): 1218–1223. doi: 10.1093/ajh/hpt139

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Abstract from the Chinese Journal of Hypertension

Effects of Exercise Training on Glucose and Lipid Metabolism in Rats With Metabolic Syndrome

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Abstract from the Chinese Journal of Hypertension

Analysis of the Antihypertensive Drug Usage and Effectiveness in 3 Counties With Different Altitudes in Tibet Autonomous Region in China

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Erratum

Glomerular hyperfiltration in obese African American hypertensive patients is associated with elevated urinary mitochondrial-DNA by Eirin et al. (Am J Hypertens; 2017:30 (11)). doi:10.1093/ajh/hpx103

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Effect of Exercise on Arterial Stiffness: Is There a Ceiling Effect?

Abstract

BACKGROUND

Whether arterial stiffness (AS) can be improved by regular exercise in healthy individuals remains equivocal according to cross-sectional and longitudinal studies assessing arterial properties at discrete time points. The purpose of the present study was to pinpoint the time course of training-induced adaptations in central AS.

METHODS

Aorta characteristic impedance (Z_c) and carotid distensibility (CD) were determined with ultrasonography prior to (week 0) and across 8 weeks (weeks 2, 4, and 8) of supervised endurance training (ET) (3 × 60 minutes cycle ergometry sessions per week), in 9 previously untrained healthy normotensive adults (27 ± 4 years) with no history of cardiovascular disease. Exercise capacity was assessed by maximal oxygen consumption (VO_2max) elicited by incremental ergometry.

RESULTS

VO_2max increased throughout the ET intervention (+12% from week 0 to week 8, P < 0.001, P for linear trend <0.001). Systolic blood pressure rose with ET (+7% from week 0 to week 8, P = 0.019, P for linear trend <0.001). Aorta Z_c augmented from week 0 to week 8 of ET in all individuals (+38%, P = 0.003, P for linear trend = 0.002). CD did not significantly differ among time points (P = 0.196) although a linear decreasing trend was detected (P = 0.016).

CONCLUSIONS

Central AS augments during a conventional ET intervention that effectively enhances aerobic exercise capacity in young individuals. This suggests that normal, healthy elastic arteries are not amendable to improvement unless impairment is present.

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Response to: The Cause of the Arteriolar Injury in Malignant Hypertension

We are grateful to Quinn M.J.¹ for the interest in our review article and comments on possible mechanisms contributing to the pathophysiology of malignant hypertension. We agree that pathogenesis of malignant hypertension remains obscure. Similar to essential hypertension, it is likely that development of malignant hypertension has more than one mechanism involved and this is supported by the fact that over the decades of research no unique etiology of malignant hypertension has been identified.

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Hypertension and Atrial Fibrillation: Balancing Stroke and Bleeding Risks

Hypertension (HTN) is the commonest cardiovascular comorbidity related to atrial fibrillation (AF), with 49–90% of AF patients included in clinical trials having a previous history of HTN. Elevated blood pressure (BP) has been one of the strongest predictors of the development of AF and HTN per se increases the risk of AF by 2-fold.¹ The intimate association between HTN and AF has led to the proposal that AF is yet another manifestation of hypertensive target organ damage.¹

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Masked Uncontrolled Hypertension in the Elderly: A Dangerous Affair

Blood pressure (BP) values and thresholds are dependent on the setting in which BP is measured. When patients are categorized according to office and ambulatory or home BP, different combinations may result, with different prognostic significance. There is little doubt that patients with uncontrolled hypertension in the office and out-of-office have a worse prognosis than patients with controlled hypertension. Studies mainly performed in the general population, involving untreated or treated subjects, indicate that the incidence of cardiovascular events is not significantly different between individuals with white-coat hypertension and true normotension, whereas the outcome is worse in those with masked hypertension.^1–3 Thus, each BP elevation carries an increase in risk which adds to that of other BP elevations, in a sort of "continuum" from normotension to sustained hypertension, passing through white-coat hypertension and masked hypertension. Such risk may vary in treated vs. untreated patients and in younger vs. older hypertensives.^4,5 It is thus important to identify patients with masked hypertension or white-coat hypertension because failure to do so may result in significant misdiagnosis and mismanagement of hypertension, with increase in patients' cardiovascular risk.

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The Etiology of Arteriolar Injury in Malignant Hypertension

Drs Shantsila and Lip set out the clinical and histological features of malignant hypertension, and, describe its increasing incidence.¹ Serendipitous observations in the uterine circulation offer an explanation for the histologic changes in visceral arteriolar walls including both uterus and kidney in preeclampsia and nonpregnant hypertension.²

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Hypertension and Cardiovascular Risk Profile in a Middle-Income Setting: The HELISUR Study

Abstract

BACKGROUND

Hypertension is the leading risk factor responsible for premature death worldwide, but its burden has shifted to low- and middle-income countries. Therefore, we studied hypertension and cardiovascular risk in the population of Suriname, a middle-income country with a predominantly urban population of African and Asian ancestry.

METHODS

A random sample of 1,800 noninstitutionalized men and women aged 18–70 years was selected to be interviewed at home and examined at the local hospital for cardiovascular risk factors, asymptomatic organ damage, and cardiovascular disease.

RESULTS

The 1,157 participants examined (37% men) were mainly of self-defined Asian (43%) or African (39%) ancestry, mean age 43 years (SD 14). The majority of the population (71%) had hypertension or prehypertension, respectively, 40% and 31%. Furthermore, 72% was obese or overweight, while 63% had diabetes or prediabetes. Only 1% of the adult population had an optimal cardiovascular risk profile. Hypertension awareness, treatment, and control were respectively 68%, 56%, and 20%. In line with this, 22% of the adult population had asymptomatic organ damage, including increased arterial stiffness, left ventricular hypertrophy, microalbuminuria, or asymptomatic chronic kidney disease.

CONCLUSIONS

In this first extensive cardiovascular assessment in the general population of this middle-income Caribbean country, high prevalence of hypertension with inadequate levels of treatment and control was predominant. The findings emphasize the need for collaborative effort from national and international bodies to prioritize the implementation of affordable and sustainable public health programs that combat the escalating hypertension and cardiovascular risk factor burden.

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Prognosis of Masked and White Coat Uncontrolled Hypertension Detected by Ambulatory Blood Pressure Monitoring in Elderly Treated Hypertensive Patients

Abstract

BACKGROUND

Prognosis of masked and white coat uncontrolled hypertension (MUCH and WCUCH, respectively) detected by ambulatory blood pressure (BP) monitoring is incompletely clear in elderly treated hypertensive patients. We evaluated prognosis of MUCH and WCUCH identified by ambulatory BP monitoring in this setting.

METHODS

The occurrence of a composite endpoint was evaluated in 1,191 elderly treated hypertensive patients. Controlled hypertension (CH) was defined as clinic BP <140/90 mm Hg and 24-hour BP <130/80 mm Hg, MUCH as clinic BP <140/90 mm Hg and 24-hour BP ≥130 and/or ≥80 mm Hg, WCUCH as clinic BP ≥140 and/or ≥90 mm Hg and 24-hour BP <130/80 mm Hg and sustained uncontrolled hypertension (SUCH) as clinic BP ≥140 and/or ≥90 mm Hg and 24-hour BP ≥130 and/or ≥80 mm Hg.

RESULTS

MUCH was identified in 142 patients (12% of all the population, 34% of those with normal clinic BP) and WCUCH in 230 patients (19% of all the population, 30% of those with high clinic BP). During the follow-up (9.1 ± 4.9 years, range 0.4–20 years), 392 events occurred. After adjustment for various covariates, patients with MUCH (hazard ratio (HR) 1.60, 95% confidence interval (CI) 1.12–2.29, P = 0.01) and SUCH (HR 1.81, 95% CI, 1.35–2.42, P < 0.001) had significantly higher cardiovascular risk than those with CH, whereas those with WCUCH (HR 1.09, 95% CI, 0.74–1.60, P = 0.66) had not significantly higher risk.

CONCLUSIONS

In elderly treated hypertensive patients evaluated by ambulatory BP monitoring, compared to individuals with CH, those with MUCH have significantly higher risk and those with WCUCH have slightly and not significantly higher risk.

http://ift.tt/2ybPrSJ

Office and Home Blood Pressures as Determinants of Electrocardiographic Left Ventricular Hypertrophy Among Black Nigerians Compared With White Flemish

Abstract

BACKGROUND

The association of electrocardiographic left ventricular hypertrophy (ECG-LVH) with blood pressure (BP) in Blacks living in sub-Saharan Africa remains poorly documented.

METHODS

In 225 Black Nigerians and 729 White Flemish, we analyzed QRS voltages and voltage-duration products and 12 criteria diagnostic of ECG-LVH in relation to office BP (mean of 5 consecutive readings) and home BP (duplicate morning and evening readings averaged over 1 week).

RESULTS

In multivariable analyses, QRS voltage and voltage-duration indexes were generally higher in Blacks than Whites. By using any of 12 criteria, ECG-LVH was more prevalent among Black than White men (54.4% vs. 36.0%) with no ethnic difference among women (17.1%). Precordial voltages and voltage-duration products increased with office and home systolic BP (SBP), and increases were up to 3-fold steeper in Blacks. In Blacks vs. Whites, increases in the Sokolow–Lyon voltage associated with a 10-mm Hg higher SBP were 0.18 mV (95% confidence interval [CI], 0.09–0.26) vs. 0.06 mV (0.02–0.09) and 0.17 mV (0.07–0.28) vs. 0.11 mV (CI, 0.07–0.15) for office and home BP, respectively, with a significant ethnic gradient (P < 0.05). The risk of ECG-LVH increased more with office and home BP in Blacks than Whites.

CONCLUSIONS

Associations of ECG voltages and voltage-duration products and risk of ECG-LVH with BP are steeper in Black Nigerians compared with a White reference population. In resource-poor settings of sub-Saharan Africa, the ECG in combination with office and home BP is an essential instrument in risk stratification across the entire BP range.

http://ift.tt/2fVDvKQ

Steady State vs. Pulsatile Blood Pressure Component and Regional Cerebral Perfusion

Abstract

BACKGROUND

Arterial blood pressure (BP) can be divided into steady state component that is determined by mean arterial pressure and pulsatile component that is explored by pulse pressure (PP). We determined relationships between BP components and regional cerebral perfusion.

METHODS

A total of 52 apparently healthy and cognitively normal adults aged 40–60 years were studied. Regional cerebral perfusion was measured using functional magnetic resonance imaging (MRI) arterial spin labeling technique in 10 a priori regions of interest.

RESULTS

There were 5 regions with cerebral perfusion values significantly associated with either pulsatile BP component (i.e., hippocampus, posterior insula, and central white matter) or both steady and pulsatile components (i.e., anterior white matter, and occipitoparietal area). After controlling for body mass index, education, age, and sex, associations between pulsatile BP components and regional cerebral perfusion remained significant in 2 regions (i.e., hippocampus and anterior white matter). Multiple linear regression analyses revealed that brachial systolic pressure (β = −0.35, P = 0.03) and PP (β = −0.36, P = 0.02) explained 11 and 12% of the variability in hippocampus perfusion, independent of the entered covariates.

CONCLUSIONS

The present preliminary study indicated that pulsatile component of BP was more strongly related to regional cerebral perfusion in areas susceptible to cerebrovascular diseases than steady state component.

http://ift.tt/2ycgg9G

Underlying Mechanism for Reduced Left Ventricular Mass by Physical Activity in Obese and Hypertensive Subjects

To the Editor: We read with great interest the article by Dr Kamimura et al.¹ dealing with the relationship between physical activity (PA) and left ventricular (LV) mass in obese and hypertensive African Americans. The results of their study demonstrated that, after adjusting for confounding factors, higher PA index was independently associated with lower cardiac LV mass index. In addition, higher PA index was associated with lower LV mass more in obese or hypertensive participants compared with nonobese or nonhypertensive participants. The authors have proposed that higher PA index might be associated with reduced LV hypertrophy in obese and hypertensive African Americans, suggesting that PA could prevent LV hypertrophy and potentially reduce the risk of heart failure.

http://ift.tt/2fXlNqp

Longitudinal Changes in Mean and Pulse Pressure, and All-Cause Mortality: Data From 71,629 Untreated Normotensive Individuals

Abstract

BACKGROUND

Blood pressure (BP) includes a steady (mean arterial pressure, MAP) and a pulsatile component that independently predict mortality. The association between longitudinal changes in central (c) pulse pressure (PP), brachial (b) PP, MAP, and incident mortality has never been investigated in this context.

METHODS

Brachial MAP and PP were measured at 2 routine checkups (1^st visit 1992; mean interval, 5.8 ± 2.4 years) in 71,629 individuals, age 16–95 years, none on antihypertensive drugs. cPP was estimated with a validated algorithm. Each change (visit 2-1) in bPP, cPP, and MAP, expressed in mm Hg/year, was categorized as: increase, decrease, or no-change, with the latter representing the control-group. Follow-up data (6.9 ± 3.3 years) on all-cause mortality (2,033 deaths) were documented.

RESULTS

All-cause mortality Cox regression models adjusted for confounders showed that compared to the subgroup with steady BP at both visits, the subgroup with: (i) increased bPP or cPP had an approximately 200% increase in relative risk (RR); (ii) decreased cPP and bPP had a 15% reduction in RR; (iii) increased MAP had a 68% increase in RR; (iv) decreased MAP had a 7% increase in RR of mortality. Interaction analysis stratified by gender showed that annual increases in PP, but not MAP, were greater in younger than older men and lower in younger than older women. Age cutoff value was 55 years.

CONCLUSIONS

MAP and PP have distinct characteristics affecting all-cause mortality. PP integrates the effects of age and gender on all-cause mortality more notably than MAP, thus impacting significantly on cardiovascular risk.

http://ift.tt/2ybHflq

Factors Associated With Home Blood Pressure Monitoring Among US Adults: National Health and Nutrition Examination Survey, 2011–2014

Abstract

BACKGROUND

Home blood pressure monitoring (HBPM) has a substantial role in hypertension management and control.

METHODS

Cross-sectional data for noninstitutionalized US adults 18 years and older (10,958) from the National Health and Nutrition Examination Survey (NHANES), years 2011–2014, were used to examine factors related to HBPM.

RESULTS

In 2011–2014, estimated 9.5% of US adults engaged in weekly HBPM, 7.2% engaged in monthly HBPM, 8.0% engaged in HBPM less than once a month, and 75.3% didn't engage any HBPM. The frequency of HBPM increased with age, body mass index, and the number of health care visits (all, P < 0.05). Also, race/ethnicity (Non-Hispanic Blacks and non-Hispanic Asians), health insurance, diagnosed with diabetes, told by a health care provider to engage in HBPM, and diagnosed as hypertensive, were all associated with more frequent HBPM (P < 0.05). Adjusting for covariates, hypertensives who were aware of, treated for, and controlled engaged in more frequent HBPM compared to their respective references: unaware (odds ratio [OR] = 2.00, 95% confidence interval [CI] = 1.53–2.63), untreated (OR = 1.99, 95% CI = 1.52–2.60), and uncontrolled (OR = 1.42, 95% CI = 1.13–1.82). Hypertensive adults (aware/unaware, treated/untreated, or controlled/uncontrolled), who received providers' recommendations to perform HBPM, were more likely to do so compared to those who did not receive recommendations (OR = 8.04, 95% CI = 6.56–9.86; OR = 7.98, 95% CI = 6.54–9.72; OR = 8.75, 95% CI = 7.18–10.67, respectively).

CONCLUSIONS

Seventeen percent of US adults engaged in monthly or more frequent HBPM and health care providers' recommendations to engage in HBPM have a significant impact on the frequency of HBPM.

http://ift.tt/2fVDqa0

Glomerular Hyperfiltration in Obese African American Hypertensive Patients Is Associated With Elevated Urinary Mitochondrial-DNA Copy Number

Abstract

BACKGROUND

Glomerular hyperfiltration may contribute to the high incidence of renal disease in Obese African Americans essential hypertensive (ObAAEH) patients, but the precise mechanisms responsible for renal injury have not been elucidated. Mitochondria are important determinants of renal injury in hypertension, and increased levels of mitochondrial DNA (mtDNA) in the urine may indicate renal mitochondrial injury. We hypothesized that urine mtDNA copy numbers would be higher in ObAAEH compared to Caucasian essential hypertensive (CEH) patients.

METHODS

We prospectively measured systemic, renal vein (RV), inferior vena cava (IVC), and urinary copy number of the mtDNA genes COX3 and ND1 by quantitative-PCR in CEH and ObAAEH patients during constant sodium intake and antihypertensive regimens, and compared them with healthy volunteers (HV) (n = 23 each).

RESULTS

Blood pressure was similarly elevated in CEH and ObAAEH, while glomerular filtration rate (GFR) was higher and age lower in ObAAEH. Urinary (but not plasma) COX3 and ND1 were higher in CEH compared to HV, and further elevated in ObAAEH patients. COX3 and ND1 renal gradients (RV–IVC) were higher in ObAAEH vs. CEH, and their urinary levels directly correlated with GFR. In multivariate analysis, GFR remained the only predictor of elevated urinary COX3 and ND1 levels.

CONCLUSIONS

Urinary fragments of the mitochondrial genome are elevated in ObAAEH patients and correlate with glomerular hyperfiltration. A positive gradient across the kidney in ObAAEH suggests selective renal release. These results are consistent with mitochondrial injury that may aggravate renal damage and accelerate hypertension-related morbidity/mortality rates in ObAAEH.

http://ift.tt/2yc9JM6

Sauna Bathing and Incident Hypertension: A Prospective Cohort Study

Abstract

BACKGROUND

Sauna bathing is associated with reduced cardiovascular risk, but the mechanisms underlying this beneficial effect are not entirely understood. We aimed to assess the relationship between sauna bathing and risk of incident hypertension.

METHODS

Frequency of sauna bathing was ascertained using questionnaires in the Kuopio Ischemic Heart Disease Study, a prospective cohort study conducted in Eastern Finland that comprised a population-based sample of 1,621 men aged 42 to 60 years without hypertension at baseline. The incidence of hypertension was defined as a physician diagnosis of hypertension, systolic blood pressure (SBP) >140 mm Hg, diastolic blood pressure >90 mm Hg, or use of antihypertensive medication.

RESULTS

During a median follow-up of 24.7 years, 251 incident cases (15.5%) were recorded. In Cox regression analysis adjusted for baseline age, smoking, body mass index, and SBP; compared to participants reporting 1 sauna session per week, the hazard ratio for incident hypertension in participants reporting 2 to 3 sessions and 4 to 7 sessions was 0.76 (95% confidence interval: 0.57–1.02) and 0.54 (0.32–0.91), respectively. The corresponding hazard ratios were similar after further adjustment for glucose, creatinine, alcohol consumption, heart rate, family history of hypertension, socioeconomic status, and cardiorespiratory fitness: 0.83 (95% confidence interval: 0.59–1.18) and 0.53 (0.28–0.98), respectively.

CONCLUSIONS

Regular sauna bathing is associated with reduced risk of hypertension, which may be a mechanism underlying the decreased cardiovascular risk associated with sauna use. Further epidemiological and experimental studies could help elucidate the effects of sauna bathing on cardiovascular function.

http://ift.tt/2fVDnek

Relationship of Hypertension and Systolic Blood Pressure With the Risk of Stroke or Bleeding in Patients With Atrial Fibrillation: The Fushimi AF Registry

Abstract

BACKGROUND

Hypertension is considered a major risk factor of stroke and systemic embolism (SE) as well as bleeding in patients with atrial fibrillation (AF). The purpose of this study was to investigate the relationship of hypertension and systolic blood pressure (SBP) with the risk of stroke/SE or bleeding in AF patients.

METHODS

The Fushimi AF Registry, a community-based prospective survey, was designed to enroll all of the AF patients in Fushimi-ku, Kyoto. Fushimi-ku is densely populated with a total population of 283,000. Follow-up data were available for 3,713 patients (follow-up rate 90.0%) as of August 2015, and the median follow-up period was 1,035 days.

RESULTS

We compared the clinical backgrounds at baseline, and follow-up outcomes of AF patients between those with hypertension (HTN; n = 2,304, 62.1% of total) and those without (non-HTN; n = 1,409). History of hypertension was neither associated with the incidence of stroke/SE, ischemic stroke, hemorrhagic stroke nor major bleeding. However, when we divided the HTN group by baseline SBP ≥150 mm Hg (HTN-high blood pressure [HBP]: n = 305, 13.3% of HTN group) or <150 mm Hg (HTN-low blood pressure [LBP]: n = 1,983), HTN-HBP group was significantly associated with a higher incidence of both stroke/SE (hazard ratio [HR]: 1.74, 95% confidence interval [CI]: 1.08–2.72) and major bleeding (HR: 2.01, 95% CI: 1.21–3.23) compared with the non-HTN group. In contrast, HTN-LBP group was not associated with the risk of stroke/SE or major bleeding, compared with the non-HTN group.

CONCLUSION

The incidences of stroke/SE and bleeding were higher in AF and hypertension patients with elevated SBP.UMIN Clinical Trials Registry: UMIN000005834

http://ift.tt/2yc51Oj

Resilience and Recovery of Dehalococcoides mccartyi Following Low pH Exposure

Abstract

Bioremediation treatment (e.g. biostimulation) can decrease groundwater pH with consequences for Dehalococcoides mccartyi (Dhc) reductive dechlorination activity. To explore the pH resilience of Dhc, the Dhc-containing consortium BDI was exposed to pH 5.5 for up to 40 days. Following 8- and 16-day exposure periods to pH 5.5, dechlorination activity and growth recovered when returned to pH 7.2; however, the ability of the culture to dechlorinate VC to ethene was impaired (i.e. decreased rate of VC transformation). Dhc cells exposed to pH 5.5 for 40 days did not recover the ethene-producing phenotype upon transfer to pH 7.2 even after 200 days of incubation. When returned to pH 7.2 conditions after an 8-, a 16- and a 40-day low pH exposure, tceA and vcrA genes showed distinct fold increases, suggesting Dhc strain-specific responses to low pH exposure. Furthermore, an independent survey of Dhc biomarker genes in groundwater samples revealed the average abundances of Dhc 16S rRNA, tceA and vcrA genes in pH 4.5–6 groundwater were significantly lower (p-value < 0.05) than in pH 6–8.3 groundwater. Overall, the results of the laboratory study and the assessment of field data demonstrate that sustained Dhc activity should not be expected in low pH groundwater, and the duration of low pH exposure affects the ability of Dhc to recover activity at circumneutral pH.

http://ift.tt/2y8AfnI

Due Diligence in the Open-Access Explosion Era: Choosing a Reputable Journal for Publication

open accesspredatory journalspredatory publisherscharacteristics of ethical and unethical publishing practicesdue diligence activities for selecting reputable journals

http://ift.tt/2xtlZsX

Behavioral Changes in Children after Emergency Department Procedural Sedation

Abstract

Objective

The purpose of this study was to determine the proportion of children undergoing procedural sedation for fracture reduction in the emergency department (ED) observed to experience negative post-discharge behaviors. Predictors of negative behaviors were evaluated, including anxiety.

Methods

This was a prospective cohort study of children receiving intravenous ketamine sedation for ED fracture reduction. The child's anxiety prior to sedation was measured with the Modified Yale Preoperative Anxiety Scale. Negative behavioral changes were measured with the Post-Hospitalization Behavior Questionnaire 1-2 weeks after discharge. Descriptive statistics and odds ratios were calculated. Chi square test was used for comparisons between groups. Multivariable logistic regression models evaluated predictors of negative behavioral change after discharge.

Results

97 patients were enrolled, 82 (85%) completed follow-up. Overall, 33 (40%) children were observed to be highly anxious pre-sedation and 18 (22%) had significant negative behavior changes after ED discharge. Independent predictors for negative behaviors were high anxiety (OR=9.0, 95% CI 2.3-35.7) and non-white race (OR= 6.5, 95% CI 1.7-25.0).

Conclusion

For children undergoing procedural sedation in the ED, two in five children have high pre-procedure anxiety and almost one in four have significant negative behaviors 1-2 weeks after discharge. Highly anxious and non-white children have increased risk of negative behavioral changes which have not been previously recognized in the ED setting.

This article is protected by copyright. All rights reserved.

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New Application of an Atmospheric Pressure Plasma Jet as a Neuro-protective Agent Against Glucose Deprivation-induced Injury of SH-SY5Y Cells

A protocol for the neuroprotective application of low-dose atmospheric pressure plasma treatment on glucose deprivation-induced SH-SY5Y injuries.

http://ift.tt/2gqdO6a

A Chronic Cardiac Ischemia Model in Swine Using an Ameroid Constrictor

The purpose of this protocol is to demonstrate the placement of a delayed constricting device (an ameroid constrictor) around a coronary artery in a swine model. This device creates an ischemic area of the heart that is useful for studying new diagnostic imaging techniques and new methods of treatment.

http://ift.tt/2y4U0ix

Genetic Diversity and Worldwide Distribution of the Deltavirus Genus: a Study of 2,152 Clinical Strains

ABSTRACT

Hepatitis delta virus (HDV) is responsible for the most severe form of acute and chronic viral hepatitis. We previously proposed that the Deltavirus genus is composed of 8 major clades. However, few sequences were available to confirm this classification. Moreover, little is known about the structural and functional consequences of HDV variability. One practical consequence is the failure of most quantification assays to properly detect or quantify plasmatic HDV RNA. Between 2001 and 2014, 2,152 HDV strains were prospectively collected and genotyped in our reference laboratory by means of nucleotide sequencing and extensive phylogenetic analyses of a 400-nucleotide region of the genome (R0) from nucleotide 889 to 1289 encompassing the 3' end of the delta protein-coding gene. In addition, the full-length genome sequence was generated for 116 strains selected from the different clusters, allowing for in-depth characterization of the HDV genotypes and subgenotypes. This study clearly confirms that HDV genus is composed of eight genotypes (HDV-1 to -8) defined by an inter-genotype similarity >85% or >80%, according to the partial or full-length genome sequence, respectively. Furthermore, genotypes can be segregated into 2 to 4 subgenotypes, characterized by an inter-subgenotype similarity >90% (>84% for HDV-1) over the whole genome sequence. Systematic analysis of genome and protein sequences revealed highly conserved functional nucleotide and amino acid motifs and positions across all (sub)genotypes, indicating strong conservatory constraints on the structure and function of the genome and the protein. Conclusion: this study provides new insights into genetic diversity of HDV, provides a clear view of their geographical localization and allows speculating the hypothesis as to the worldwide spread of the virus, very likely from an initial African origin. This article is protected by copyright. All rights reserved.

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Proton pump inhibitor use associated with changes in gut microbiota composition

We read with great interest the recent publications in Gut by Imhann et al and Jackson et al, which assessed the impact of proton pump inhibitor (PPI) use on gut microbiota diversity and composition in humans.1 2 PPIs are one of the most commonly used drug classes worldwide. Once initiated, they are often used chronically without clear therapeutic intent.3 PPIs alter GI pH4 and delay gastric emptying rate,5 which could directly affect gut microbiota and survival of enteric pathogens. Using three independent cohorts (211 PPI users and 1604 non-users), Imhann et al1 reported a significant decrease in alpha diversity and changes in 20% of bacterial taxa in PPI users compared with non-users. Among 1827 healthy twins, Jackson et al2 also found a significant decrease in alpha diversity and alteration of bacterial composition in PPI users. Notably, both...

http://ift.tt/2z9qMN3

A genetic roadmap of pancreatic cancer: still evolving

A diagnosis of pancreatic ductal adenocarcinoma (PDA) is often fatal. PDA is widely recognised as one of the 'incurable cancers' because therapies against this tumour type are generally ineffective. The fatal nature of this tumour is due to its aggressive clinical course. Pancreatic cancer commonly presents at the metastatic stage; even in cases where tumours are localised to the pancreas at diagnosis, metastatic seeds have often been invariably been spawned off, frustrating surgical attempts to cure the cancer. The key principles of pancreatic cancer mutational development were outlined nearly two decades ago using the genetics of precursor lesions to position the various stages of tumour progression. Since then, there has been a cavalcade of new data. How these recent studies impact the classical perceptions of pancreatic cancer development is a work in progress. Given that significant improvements in patient outcomes are not in sight for this disease, it is likely that broadening the current perspectives and acquiring deeper biological insights into the morphogenetic route of tumour development will be needed to foster new strategies for more effective cancer control.

http://ift.tt/2yb4zzK

A Performance-testing Platform for a Conduction Micropump with an FR-4 Copper-clad Electrode Plate

This paper presents a protocol for the fabrication of a conduction micropump using symmetric planar electrodes on flame-retardant glass-reinforced epoxy (FR-4) copper-clad laminate (CCL) to test the influence of chamber dimensions on the performance of a conduction micropump.

http://ift.tt/2xsTbRa

Empirical, Metagenomic, and Computational Techniques Illuminate the Mechanisms by which Fungicides Compromise Bee Health

Microbial consortia within bumble bee hives enrich and preserve pollen for bee larvae. Using next generation sequencing, along with laboratory and field-based experiments, this manuscript describes protocols used to test the hypothesis that fungicide residues alter the pollen microbiome, and colony demographics, ultimately leading to colony loss.

http://ift.tt/2xsTaN6

Axillary tumour burden in women with a fine-needle aspiration/core biopsy-proven positive node on ultrasonography compared to women with a positive sentinel node

Background

The sensitivity of axillary ultrasonography (AUS) has increased in recent years, enabling detection of even low-volume axillary nodal metastases. The aim here was to evaluate the axillary tumour burden in women with a fine-needle aspiration/core biopsy-proven positive node on AUS and in those with a positive sentinel node biopsy (SNB).

Methods

This retrospective cohort study included all patients with early breast cancer who had AUS and axillary lymph node dissection (ALND) between 2011 and 2014.

Results

A total of 332 patients who had ALND were eligible for the study, 191 (57·5 per cent) in the AUS-positive group and 141 (42·5 per cent) in the SNB-positive group. Patients in the AUS-positive group were older at diagnosis (P = 0·018), more likely to have larger tumours (P = 0·002), higher tumour grade (P = 0·005), positive human epidermal growth factor 2 status (P = 0·015), and negative oestrogen receptor status (P < 0·001). The AUS-positive group also had a larger number of lymph nodes with macrometastases (P < 0·001) and were more likely to have extranodal invasion (P < 0·001). In the AUS-positive group, 40·3 per cent of patients (77 of 191) had only one or two nodes with macrometastases identified at histology after ALND. Tumour size no larger than 20 mm, invasive ductal or lobular histology and breast-conserving surgery were associated with the presence of two or fewer macrometastases at ALND. Only tumour size and tumour histology remained significant in multiple logistic regression analysis.

Conclusion

Patients with AUS-detected metastases had a higher axillary tumour burden than those with SNB-detected metastases. Around 40 per cent of patients with AUS-detected nodal disease had one or two nodes with macrometastases and were thus overtreated by ALND.

http://ift.tt/2hZpwbt

Continuous versus interrupted suture technique in microvascular anastomosis in rats

Abstract Purpose: To compare the continuous and interrupted suture technique on femoral artery on rats after vessel repair and 14 days after. Methods: Twenty rats were operated randomly divided into two group matched according to the suture technique used: interrupted or continuous. We performed a femoral anastomosis on the right femoral artery. We analyzed weight, arterial caliber, anastomosis time and patency after vessel repair and 14 days after. Results: There was no significant difference between groups in the weight (p=0.64), diameter of the femoral artery (p=0.95) and patency (p=1.00). The time spent in the anastomosis was 451 seconds in the continuous group and 718 seconds in the interrupted group, presenting significant difference (p<0.01). Conclusion: The continuous suture technique shows a similar patency rates than interrupted technique, however with a shorter time to perform the anastomosis.

http://ift.tt/2kzACER

End-to-side versus end-to-end neurorrhaphy at the peroneal nerve in rats

Abstract Purpose: To evaluate three different kinds of neurorrhaphy of the peroneal nerve. Methods: Eigthy rats were divided into 5 groups. Control: nerve had no intervention. End-to-end (EE): nerve was cut and elongated with a nerve graft with two end-to-end neurorrhaphies. End-to-side (ES): nerve was cut and sutured to the graft with at the lateral side of the nerve. Side-to-end (SE): the nerve was cut and sutured to the graft with end-to-end neurorrhaphy. Denervated: nerve was cut and both endings were buried into the muscle. The evaluation was done by walking track analysis, electrophysiology, body mass, cranial tibial muscle mass, nerve and muscle fibers morphometry. Results: The EE, ES and SE have the same potential of reinnervation. Conclusion: There is no functional or histological difference between these different types of neurorrhaphy.

http://ift.tt/2wHR2g7

Ultrastructural analysis and residual DNA evaluation of rabbit vein scaffold

Abstract Purpose: To investigate the ultrastructural characteristics and analysis of residual DNA in scaffold models, produced with decellularized vena cava in an experimental model with rabbits. Methods: Three groups were created for ultrastructural and residual DNA analysis: group 1 - control, consisting of samples of vena cava in natura; group 2 - SD, consisting of vein fragments submitted to 2% sodium deoxycholate decellularization by shaking (160rpm - Shaker News Brunswick Scientific®) for 1 hour at controlled temperature shaker at 37°C; group 3 - SDS, consisting of vein fragments submitted to 1% sodium dodecyl sulfate decellularization under the same previous condition, for 2 hours. Results: The ultrastructural matrix of the blood vessel maintained its vintegrity after either decellularization models. The results of the two quantification methods demonstrated a significant decrease in the DNA content of the decellularized vena cava samples as compared to the control samples and, differed statistically from each other, p <0.05. Conclusion: The 2% DS protocol for vein decellularization, in this experimental model, was considered the best protocol because it presented less amount of residual DNA without causing substantial destruction of the extracellular matrix.

http://ift.tt/2kBlqqX