bluuebunny/crossref_metadata_2025 huggingface dataset:
Does military veteran status and deployment history impact officer involved shootings? A case–control study
Authors: Reingle Gonzalez Jennifer M , Bishopp Stephen A , Jetelina Katelyn K , Paddock Ellen , Gabriel Kelley Pettee , Cannell M Brad
Published: August 2018

Background

Despite veterans’ preference hiring policies by law enforcement agencies, no studies have examined the nature or effects of military service or deployments on health outcomes. This study will examine the effect of military veteran status and deployment history on law enforcement officer (LEO)-involved shootings.

Methods

Ten years of data were extracted from Dallas Police Department records. LEOs who were involved in a shooting in the past 10 years were frequency matched on sex to LEOs never involved in a shooting. Military discharge records were examined to quantify veteran status and deployment(s). Multivariable logistic regression was used to estimate the effect of veteran status and deployment history on officer-involved shooting involvement.

Results

Records were abstracted for 516 officers. In the adjusted models, veteran LEOs who were not deployed were significantly more likely to be involved in a shooting than non-veteran officers. Veterans with a deployment history were 2.9 times more likely to be in a shooting than non-veteran officers.

Conclusions

Military veteran status, regardless of deployment history, is associated with increased odds of shootings among LEOs. Future studies should identify mechanisms that explain this relationship, and whether officers who experienced firsthand combat exposure experience greater odds of shooting involvement.
Narrative review of affinities and differences between the social determinants of oral and general health in Canada: establishing a common agenda
Authors: Raphael Dennis
Published: August 2018

Background

This article overviews Canadian work on the social determinants of oral and general health noting their affinities and differences.

Methods

A literature search identified Canadian journal articles addressing the social determinants of oral health and/or oral health inequalities. Analysis identified affinities and differences with six themes in the general social determinants of health literature.

Results

While most Canadian social determinants activity focuses on physical and mental health there is a growing literature on oral health—literature reviews, empirical studies and policy analyses—with many affinities to the broader literature. In addition, since Canada provides physical and mental health services on a universal basis, but does not do so for dental care, there is a special concern with the reasons behind, and the health effects—oral, physical and mental—of the absence of publicly financed dental care.

Conclusions

The affinities between the social determinants of oral health and the broader social determinants of health literature suggests the value of establishing a common research and action agenda. This would involve collaborative research into common social determinants of oral and general health and combined policy advocacy efforts to improve Canadians’ living and working conditions as means of achieving health for all.
Complications in Pediatric Regional Anesthesia
Authors: Walker Benjamin J. , Long Justin B. , Sathyamoorthy Madhankumar , Birstler Jennifer , Wolf Christine , Bosenberg Adrian T. , Flack Sean H. , Krane Elliot J. , Sethna Navil F. , Suresh Santhanam , Taenzer Andreas H. , Polaner David M. ,   on behalf of the Pediatric Regional Anesthesia Network Investigators
Published: August 2018

Editor’s Perspective

What We Already Know about This Topic

What This Article Tells Us That Is New

Background

Complications in pediatric regional anesthesia are rare, so a large sample size is necessary to quantify risk. The Pediatric Regional Anesthesia Network contains data on more than 100,000 blocks administered at more than 20 children’s hospitals. This study analyzed the risk of major complications associated with regional anesthesia in children.

Methods

This is a prospective, observational study of routine clinical practice. Data were collected on every regional block placed by an anesthesiologist at participating institutions and were uploaded to a secure database. The data were audited at multiple points for accuracy.

Results

There were no permanent neurologic deficits reported (95% CI, 0 to 0.4:10,000). The risk of transient neurologic deficit was 2.4:10,000 (95% CI, 1.6 to 3.6:10,000) and was not different between peripheral and neuraxial blocks. The risk of severe local anesthetic systemic toxicity was 0.76:10,000 (95% CI, 0.3 to 1.6:10,000); the majority of cases occurred in infants. There was one epidural abscess reported (0.76:10,000, 95% CI, 0 to 4.8:10,000). The incidence of cutaneous infections was 0.5% (53:10,000, 95% CI, 43 to 64:10,000). There were no hematomas associated with neuraxial catheters (95% CI, 0 to 3.5:10,000), but one epidural hematoma occurred with a paravertebral catheter. No additional risk was observed with placing blocks under general anesthesia. The most common adverse events were benign catheter-related failures (4%).

Conclusions

The data from this study demonstrate a level of safety in pediatric regional anesthesia that is comparable to adult practice and confirms the safety of placing blocks under general anesthesia in children.
Why Money Alone Can’t (Always) “Nudge” Physicians: The Role of Behavioral Economics in the Design of Physician Incentives
Authors: Lubarsky David A. , French Michael T. , Gitlow Howard S. , Rosen Lisa F. , Ullmann Steven G.
Published: August 2018

Behavioral economics seeks to define how humans respond to incentives, how to maximize desired behavioral change, and how to avoid perverse negative impacts on work effort. Relatively new in their application to physician behavior, behavioral economic principles have primarily been used to construct optimized financial incentives. This review introduces and evaluates the essential components of building successful financial incentive programs for physicians, adhering to the principles of behavioral economics. Referencing conceptual publications, observational studies, and the relatively sparse controlled studies, the authors offer physician leaders, healthcare administrators, and practicing anesthesiologists the issues to consider when designing physician incentive programs to maximize effectiveness and minimize unintended consequences.
Background Speech Disrupts Working Memory Span in 5-Year-Old Children
Authors: Grieco-Calub Tina M. , Collins Maya-Simone , Snyder Hillary E. , Ward Kristina M.
Published: August 2018

Objectives:

The present study tested the effects of background speech and nonspeech noise on 5-year-old children’s working memory span.

Design:

Five-year-old typically developing children (range = 58.6 to 67.6 months; n = 94) completed a modified version of the Missing Scan Task, a missing-item working memory task, in quiet and in the presence of two types of background noise: male two-talker speech and speech-shaped noise. The two types of background noise had similar spectral composition and overall intensity characteristics but differed in whether they contained verbal content. In Experiments 1 and 2, children’s memory span (i.e., the largest set size of items children successfully recalled) was subjected to analyses of variance designed to look for an effect of listening condition (within-subjects factor: quiet, background noise) and an effect of background noise type (between-subjects factor: two-talker speech, speech-shaped noise).

Results:

In Experiment 1, children’s memory span declined in the presence of two-talker speech but not in the presence of speech-shaped noise. This result was replicated in Experiment 2 after accounting for a potential effect of proactive interference due to repeated administration of the Missing Scan Task.

Conclusions:

Background speech, but not speech-shaped noise, disrupted working memory span in 5-year-old children. These results support the idea that background speech engages domain-general cognitive processes used during the recall of known objects in a way that speech-shaped noise does not.
Clinical characteristics and preliminary morphological observation of 47 cases of primary anorectal malignant melanomas
Authors: Liu Guang , Wang Yan , Fei Fei , Wang Xinlu , Li Chunyuan , Liu Kai , Du Jiaxing , Cao Yuan , Zhang Shiwu
Published: August 2018

The clinical data and paraffin-embedded samples of 47 cases of primary anorectal malignant melanomas (ARMMs) detected from 2004 to 2017 were collected to investigate the clinicopathological characteristics. The ARMMs were grouped according to tumour size, appearance of melanin granules in the plasma of the tumour cell, linearly patterned programmed cell necrosis (LPPCN) in tumour tissue and lymph node metastasis. On the basis of size, these tumours were divided into two groups: group I (volume of tumour >20 cm3, or minimal diameter >1 cm and volume of tumour <20 cm3, but >10 cm3) and group II (volume of tumour <20 cm3and minimal diameter <1 cm). The number of polyploid giant cancer cells (PGCCs) detected and vasculogenic mimicry (VM) observed were compared across the different groups. Immunohistochemical double-staining was used to confirm the differentiation of melanoma cells into fibroblasts and endothelial cells. The results of our study showed that PGCCs and VMs exist in ARMMs. The number of PGCCs was significantly higher in group I than in group II, in tumours with LPPCN than in tumours without LPPCN and in tumours with lymph node metastasis than in tumours without metastasis. VM channel formation was significantly higher in amelanotic ARMMs than in melanotic ARMMS. Furthermore, PGCCs and their generated erythroid cells can form VMs to supply the oxygen and nutrition to the tumour. Some tumour cells were positive for both, fibronectin or CD34, and HMB45. These results showed that the number of PGCCs and VMs were related to the development and progression of ARMMs.
Impact of Pathways Triple P on Pediatric Health-Related Quality of Life in Maltreated Children
Authors: Lanier Paul , Dunnigan Allison , Kohl Patricia L.
Published: August 2018

Objective:

Child maltreatment is an adverse childhood experience associated with reductions in child well-being. This study examines whether an evidence-based parenting intervention delivered to families served by the child welfare system (CWS) affects pediatric health-related quality of life (HRQoL).

Method:

This study is a randomized controlled trial of Pathways Triple P (PTP) delivered to families with open child welfare cases for child physical abuse or neglect (N = 119). Children were 5 to 11 years old and remained in the home after the investigation. The primary outcome measure for this study was the Pediatric Quality of Life Inventory (PedsQL) 4.0, which measures HRQoL across 4 subdomains: physical functioning, emotional functioning, social functioning, and school functioning. Child- and parent-reported PedsQL 4.0 was assessed at baseline and post-test after the 14-week intervention.

Results:

Controlling for other factors, children in families randomly assigned to the PTP condition had a significant improvement in overall HRQoL after the intervention compared with families receiving usual services (βchild-report = 6.08, SE = 2.77, p = 0.03; βparent-report = 3.83, SE = 1.88, p = 0.04). Subdomain effect sizes differed when considering children's self-report or parents' proxy report. Children's self-report yielded the largest improvement in emotional functioning, whereas social functioning had the largest gain based on parents' proxy report.

Conclusion:

The PTP parenting intervention was associated with higher pediatric HRQoL as reported by both the child and parent. This intervention holds promise to improve child well-being when implemented in the CWS.
Diabetes Status and Susceptibility to the Effects of PM2.5 Exposure on Cardiovascular Mortality in a National Canadian Cohort
Authors: Pinault Lauren , Brauer Michael , Crouse Daniel L. , Weichenthal Scott , Erickson Anders , van Donkelaar Aaron , Martin Randall V. , Charbonneau Shannon , Hystad Perry , Brook Jeffrey R. , Tjepkema Michael , Christidis Tanya , Ménard Richard , Robichaud Alain , Burnett Richard T.
Published: August 2018

Background:

Diabetes is infrequently coded as the primary cause of death but may contribute to cardiovascular disease (CVD) mortality in response to fine particulate matter (PM2.5) exposure. We analyzed all contributing causes of death to examine susceptibility of diabetics to CVD mortality from long-term exposure.

Methods:

We linked a subset of the 2001 Canadian Census Health and Environment Cohort (CanCHEC) with 10 years of follow-up to all causes of death listed on death certificates. We used survival models to examine the association between CVD deaths (n = 123,500) and exposure to PM2.5among deaths that co-occurred with diabetes (n = 20,600) on the death certificate. More detailed information on behavioral covariates and diabetes status at baseline available in the Canadian Community Health Survey (CCHS)-mortality cohort (n = 12,400 CVD deaths, with 2,800 diabetes deaths) complemented the CanCHEC analysis.

Results:

Among CanCHEC subjects, comention of diabetes on the death certificate increased the magnitude of association between CVD mortality and PM2.5(HR = 1.51 [1.39–1.65] per 10 μg/m3) versus all CVD deaths (HR = 1.25 [1.21–1.29]) or CVD deaths without diabetes (HR = 1.20 [1.16–1.25]). Among CCHS subjects, diabetics who used insulin or medication (included as proxies for severity) had higher HR estimates for CVD deaths from PM2.5(HR = 1.51 [1.08–2.12]) relative to the CVD death estimate for all respondents (HR = 1.31 [1.16–1.47]).

Conclusions:

Mention of diabetes on the death certificate resulted in higher magnitude associations between PM2.5and CVD mortality, specifically among those who manage their diabetes with insulin or medication. Analyses restricted to the primary cause of death likely underestimate the role of diabetes in air pollution–related mortality. See video abstract at, http://links.lww.com/EDE/B408.
Parental Smoking and Risk of Childhood-onset Type 1 Diabetes
Authors: Magnus Maria C. , Tapia German , Olsen Sjurdur F. , Granstrom Charlotta , Mårild Karl , Ueland Per M. , Midttun Øivind , Svensson Jannet , Johannesen Jesper , Skrivarhaug Torild , Joner Geir , Njølstad Pål R. , Størdal Ketil , Stene Lars C.
Published: August 2018

Background:

A few prospective studies suggest an association between maternal smoking during pregnancy and lower risk of type 1 diabetes. However, the role of unmeasured confounding and misclassification remains unclear.

Methods:

We comprehensively evaluated whether maternal smoking in pregnancy predicts lower risk of childhood-onset type 1 diabetes in two Scandinavian pregnancy cohorts (185,076 children; 689 cases) and a Norwegian register-based cohort (434,627 children; 692 cases). We measured cord blood cotinine as an objective marker of nicotine exposure during late pregnancy in 154 cases and 476 controls. We also examined paternal smoking during pregnancy, in addition to environmental tobacco smoke exposure the first 6 months of life, to clarify the role of characteristics of smokers in general.

Results:

In the pregnancy cohorts, maternal smoking beyond gestational week 12 was inversely associated with type 1 diabetes, pooled adjusted hazard ratio (aHR) 0.66 (95% CI = 0.51, 0.85). Similarly, in the Norwegian register-based cohort, children of mothers who still smoked at the end of pregnancy had lower risk of type 1 diabetes, aHR 0.65 (95% CI = 0.47, 0.89). Cord blood cotinine ≥30 nmol/L was also associated with reduced risk of type 1 diabetes, adjusted odds ratio 0.42 (95% CI = 0.17, 1.0). We observed no associations of paternal smoking during pregnancy, or environmental tobacco smoke exposure, with childhood-onset type 1 diabetes.

Conclusion:

Maternal sustained smoking during pregnancy is associated with lower risk of type 1 diabetes in children. This sheds new light on the potential intrauterine environmental origins of the disease.
Epithelial–Myoepithelial Carcinoma Presenting as a Pseudo Veno-Lymphatic Malformation
Authors: Li Emily , Distefano Alberto , Sinard John , Wong Amanda , Pointdujour-Lim Renelle
Published: August 2018

A 41-year-old woman presented with several days of right eye pain and blurred vision. Examination and radiologic workup were consistent with a veno-lymphatic malformation, including demonstration of cystic fluid–fluid levels on imaging. Histopathology supported the presence of cystic spaces but revealed the final diagnosis of lacrimal epithelial–myoepithelial carcinoma, a rare neoplasm typically associated with the salivary gland. This represents the first reported case of lacrimal epithelial–myoepithelial carcinoma presenting with pain and evidence of intralesional cysts on radiographic and histopathologic evaluation. Better characterization will enable recognition, complete surgical excision, and potential adjuvant radiation therapy.
Fibroblast growth factor–transforming growth factor beta dialogues, endothelial cell to mesenchymal transition, and atherosclerosis
Authors: Chen Pei-Yu , Simons Michael
Published: August 2018

Purpose of review

Despite much effort, atherosclerosis remains an important public health problem, leading to substantial morbidity and mortality worldwide. The purpose of this review is to provide an understanding of the role of endothelial cell fate change in atherosclerosis process.

Recent findings

Recent studies indicate that a process known as endothelial-to-mesenchymal transition (EndMT) may play an important role in atherosclerosis development. Transforming growth factor beta (TGFβ) has been shown to be an important driver of the endothelial cell phenotype transition.

The current review deals with the current state of knowledge regarding EndMT's role in atherosclerosis and its regulation by fibroblast growth factor (FGF)–TGFβ cross-talk. A better understanding of FGF–TGFβ signaling in the regulation of endothelial cell phenotypes is key to the development of novel therapeutic agents.
Point-of-Care Ultrasound Diagnosis of Retinoblastoma in the Emergency Department
Authors: Giacalone Martina , Mastrangelo Greta , Parri Niccolò
Published: August 2018

An 18-month-old girl presented to the emergency department with the chief complaint of squinting. The right eye demonstrated esotropia, heterochromia, and anisocoria. Ocular point-of-care ultrasound facilitated the rapid diagnosis of retinoblastoma, which was confirmed by computed tomography scan and orbital magnetic resonance imaging.
Lyme Arthritis
Authors: Long Katharine Christina , Cohn Keri Anne
Published: August 2018

Lyme disease is the most common vector-borne illness in North America, with the majority of cases occurring in the Northeast and upper Midwest. Lyme arthritis is the most prevalent manifestation of late-stage Lyme disease. Lyme arthritis typically presents as a monoarthritis or oligoarthritis in large joints such as the knee. Accompanying positive 2-tier Lyme serologies or polymerase chain reaction from synovial fluid/tissue is considered diagnostic for patients from an endemic area. The mainstay of initial treatment is a prolonged course of oral antibiotics.
Ultrasound-Guided Interventions in Lateral Epicondylitis
Authors: Shergill Ravi , Choudur Hema Nalini
Published: August 2018

Lateral epicondylitis is a painful condition related to the myotendinous origin of the extensor muscles at the lateral epicondyle of the humerus. Primary treatment typically involves the use of rest, non-steroidal anti-inflammatory drugs (NSAIDs), and physiotherapy. However, in refractory cases where conventional therapy is ineffective, ultrasound-guided injection therapies have become a growing form of treatment. These include needle tenotomy, autologous whole blood injection (AWB), platelet-rich plasma (PRP) injection and steroid injection. The consensus regarding the efficacy of individual approaches of ultrasound-guided treatment is unclear in the literature, and is explored further in this review.

When evaluating these injection therapies individually, there are multiple case series describing the efficacy of each intervention in refractory lateral epicondylitis. A systematic review of needle tenotomy demonstrates an improvement in pain symptoms for patients with this condition, but all studies were poorly designed with no placebo or control group. Additionally, for PRP therapy, a systematic review performed in 2013 demonstrated a statistically significant improvement in pain and functionality for refractory lateral epicondylitis. However, these studies were similarly associated with a high risk of bias. Autologous whole blood injection has been evaluated through well-designed studies to show statistically significant reductions in pain with this intervention. But very few studies in total have been completed using AWB for lateral epicondylitis, and therefore no clear conclusions can be drawn at this time. Finally, corticosteroid use overall is unsupported in the evidence both in the short and long term, especially given that this condition is not an inflammatory pathology.
Considerations for Temporomandibular Joint Procurement in Vascularized Composite Allotransplantation
Authors: Khavanin Nima , Davidson Edward H. , Smith Ryan M. , Macmillan Alexandra , Byrne Patrick , Dorafshar Amir H.
Published: August 2018

Methods for harvest of the temporomandibular joint (TMJ) for transplantation may involve several anatomic levels. The authors aim to assess the feasibility and identify challenges with 2 such methods, resuspending the donor condyles from the recipient glenoid fossae and en bloc harvest of the joint and surrounding temporal bone with plate-fixation to the recipient skull base. Two mock face transplantations were carried out using 4 fresh cadavers. Computed tomography imaging was obtained before and after the procedures to assess the technical success of each method. Both techniques were technically successful, allowing for full passive jaw range of motion following graft transfer and appropriate condyle positioning as assessed by computed tomography. En bloc TMJ harvest allowed for transfer of the entire joint without violating its capsule or altering its biomechanics. The authors found this technique better able to avoid issues with size mismatch between the donor mandible and recipient skull base width. When no such mismatch exists, graft harvest at the level of the mandibular condyle is technically easier and less time consuming. Although both methods of TMJ harvest are technically feasible with acceptable immediate postoperative jaw position and range of motion, the en bloc technique allows for more natural jaw function with less risk of postoperative joint immobility by preserving the joint capsule and its ligamentous support.
Surgical Correction of Proptosis in Craniofacial Benign Bone Lesions Involving the Orbit
Authors: Chi Tzu-Yang , Yu Zheyuan , Xu Liang , Duan Huichuan , Shim Yoong Hoon , Cao Dejun
Published: August 2018

Craniofacial bone lesions involving the orbit are often associated with symptoms, including proptosis, orbital dystopia, and overall facial asymmetry. Fibrous dysplasia and osteoma are the 2 most commonly observed bone tumors in the craniofacial area. Nine patients with either craniofacial fibrous dysplasia or osteoma and an unacceptable aesthetic appearance were treated from January 2015 to July 2016. All patients underwent preoperative craniofacial 3-dimensional computed tomographic (CT) scanning, and standard photographs were obtained. Proptosis measurements were performed on CT images using an annotation ruler provided by the imaging system both pre- and postoperatively. All patients were treated surgically, and a coronal incision was used. Outcomes were assessed by CT scans, and photographs were obtained during routine follow-ups at 1 week, 3 to 6 months, and 1 year after surgery. The Likert scale was used to investigate patients’ postoperative satisfaction rate. Favorable outcomes were achieved in all patients. The mean difference between eyeball proptosis was reduced from 3.6 mm before surgery to 1.6, 0.6, and 0.3 mm after the surgery at 1 week, 3 to 6 months, and 1 year, respectively. No complications, such as facial and/or optic nerve injury, recurrence, and malignant degeneration, were noted. This study demonstrated that surgical treatment of craniofacial bone lesions involving the orbit achieved acceptable results shortly after the surgery, and more prominently, starting from 3 to 6 months.
3-Factor Versus 4-Factor PCC in Coagulopathy of Trauma: Four is Better Than Three
Authors: Zeeshan Muhammad , Hamidi Mohammad , Kulvatunyou Narong , Jehan Faisal , O’Keeffe Terence , Khan Muhammad , Rashdan Lana , Tang Andrew , Zakaria El-Rasheid , Joseph Bellal
Published: August 2018

Introduction:

Coagulopathy of trauma (COT) is common and highly lethal. Prothrombin complex concentrate (PCC) has been advocated for correction of COT. However, the difference in efficacy between three-factor PCC (3-PCC) versus four-factor PCC (4-PCC) remains unclear. The aim of our study was to compare efficacy of 3-PCC versus 4-PCC in COT.

Methods:

Five-year (2013–2017) review of coagulopathic trauma patients at our Level-I trauma center who received 3- or 4-PCC. Patients were divided into two groups (4-PCC and 3-PCC) and matched in 1:1 ratio using propensity-score-matching for demographics, injury parameters, admission vitals, and hematological parameters. Primary outcomes were time to correction of international normalized ratio (INR), blood products transfusion, thromboembolic complications, and mortality. Secondary outcomes were hospital-length of stay (LOS), intensive care unit (ICU)-LOS, cost of therapy, and total hospital cost.

Results:

Six hundred fifty-seven patients met inclusion criteria of whom 250 patients (4-PCC:125; 3-PCC:125) were matched. The mean age was 50 ± 19.4 y, 64% were male, and median-injury severity score was 24[15–33]. 4-PCC was associated with accelerated correction of INR (365 vs. 428 min, P 
= 0.01), decrease in red blood cells (7 units vs. 10 units, P 
= 0.04) and FFP (6 units vs. 8 units, P 
= 0.03) transfused. There was no difference in platelet transfusion, thromboembolic complications, mortality, hospital, and ICU-LOS. 4-PCC was associated with higher cost of PCC therapy, and lower cost of transfusion. There was no difference regarding the total hospital cost between the two groups.

Conclusion:

Compared with 3-factor PCC, the use of 4-factor PCC is associated with a rapid reversal of INR and reduction in transfusion requirement without increasing the overall hospital cost or the risk of thromboembolic events. 4-PCC may be preferred as an adjunct for the resuscitation of coagulopathic trauma patients.
Novel Benefits of Remote Ischemic Preconditioning Through VEGF-dependent Protection From Resection-induced Liver Failure in the Mouse
Authors: Kambakamba Patryk , Linecker Michael , Schneider Marcel , Kron Philipp , Limani Perparim , Tschuor Christoph , Ungethüm Udo , Humar Bostjan , Clavien Pierre-Alain
Published: August 2018

Objective:

To investigate the impact of remote ischemic preconditioning (RIPC) on liver regeneration after major hepatectomy.

Summary Background Data:

RIPC is a strategy applied at remote sites to mitigate ischemic injury. Unlike other preconditioning approaches, RIPC spares target organs as it acts via systemic VEGF elevations. In the liver, however, VEGF is an important driver of regeneration following resection. Therefore, RIPC may have pro-regenerative effects.

Methods:

RIPC was applied to C57BL/6 mice through intermittent clamping of the femoral vessels prior to standard 68%-hepatectomy or extended 86%-hepatectomy, with the latter causing liver failure and impaired survival. Liver regeneration was assessed through weight gain, proliferative markers (Ki67, pH3, mitoses), cell cycle-associated molecules, and survival. The role of the VEGF-ID1-WNT2 signaling axis was assessed through WIF1 (a WNT antagonist) and recombinant WNT2 injected prior to hepatectomy.

Results:

RIPC did not affect regeneration after 68%-hepatectomy, but improved liver weight gain and hepatocyte mitoses after 86%-hepatectomy. Importantly, RIPC raised survival from 40% to 80% after 86%-hepatectomy, indicating the promotion of functional recovery. Mechanistically, the RIPC-induced elevations in VEGF were accompanied by increases in the endothelial transcription factor Id1, its target WNT2, and its hepatocellular effector β-catenin. WIF1 injection prior to 86%-hepatectomy abrogated the RIPC benefits, while recombinant WNT2 had pro-regenerative effects akin to RIPC.

Conclusion:

RIPC improves the regenerative capacity of marginal liver remnants in a VEGF-dependent way. If confirmed in patients, RIPC may become the preconditioning strategy of choice in the setting of extended liver resections.
Circulating Free Methylated Tumor DNA Markers for Sensitive Assessment of Tumor Burden and Early Response Monitoring in Patients Receiving Systemic Chemotherapy for Colorectal Cancer Liver Metastasis
Authors: Bhangu Jagdeep Singh , Beer Andrea , Mittlböck Martina , Tamandl Dietmar , Pulverer Walter , Schönthaler Silvia , Taghizadeh Hossein , Stremitzer Stefan , Kaczirek Klaus , Gruenberger Thomas , Gnant Michael , Bergmann Michael , Mannhalter Christine , Weinhäusel Andreas , Oehler Rudolf , Bachleitner-Hofmann Thomas
Published: August 2018

Background:

Neoadjuvant chemotherapy (neoCTx) followed by hepatic resection is the treatment of choice for patients with colorectal cancer liver metastasis (CLM). Treatment response is generally assessed using radiologic imaging after several cycles of chemotherapy. However, earlier assessment of response would be desirable since nonresponders could be switched early to an alternative chemotherapy regimen. Recent evidence suggests that circulating free methylated tumor DNA is a highly sensitive biomarker and may more accurately reflect tumor burden and treatment response than conventional markers for CRC.

Patients and Methods:

Thirty-four patients with CLM who received neoCTx prior to intended hepatic resection were included in this prospective nonrandomized study. Peripheral blood plasma was collected at baseline and before each cycle of neoCTx and was then analyzed for aberrant methylation of 48 CRC-associated genes. Methylation marker levels were correlated with baseline tumor volume and treatment response and compared with the standard tumor markers CEA and CA 19-9.

Results:

The methylation markers SEPT9, DCC, BOLL, and SFRP2 were present in all patients at baseline and displayed a stronger correlation with tumor volume than CEA and CA 19-9. Serial measurement of these methylation markers allowed for discrimination between operated and nonoperated patients already after 1 cycle of neoCTx with high sensitivity and specificity. The early dynamic changes of SEPT9 and DCC also seemed to correlate with pathohistological response.

Conclusion:

Our data suggest that serial measurements of CRC-associated methylation markers could be a particularly valuable tool for early response assessment in patients receiving neoCTx for CLM.
A Phase II Clinical Trial of Molecular Profiled Neoadjuvant Therapy for Localized Pancreatic Ductal Adenocarcinoma
Authors: Tsai Susan , Christians Kathleen K. , George Ben , Ritch Paul S. , Dua Kulwinder , Khan Abdul , Mackinnon A. Craig , Tolat Parag , Ahmad Syed A. , Hall William A. , Erickson Beth A. , Evans Douglas B.
Published: August 2018

Objectives:

One facet of precision medicine is the use of tumor molecular profiling to guide chemotherapeutic selection. We conducted the first prospective clinical trial of molecular profiling to guide neoadjuvant therapy in patients with operable pancreatic ductal adenocarcinoma (PDAC). We hypothesized that more effective systemic therapy would prevent disease progression during neoadjuvant therapy and, therefore, allow more patients to undergo surgery.

Methods:

In patients with resectable and borderline resectable (BLR) PDAC, molecular profiling consisted of immunocytochemical staining of pretreatment endoscopic ultrasound-guided fine needle aspiration tumor biopsies using 6 biomarkers. Neoadjuvant systemic therapy was selected based on the molecular profiling results. The primary endpoint was the completion of all intended neoadjuvant therapy and surgery.

Results:

The trial enrolled 130 patients; 61 (47%) resectable and 69 (53%) BLR. Molecular profiling was reported within a median of 5 business days (IQR: 3). Of the 130 patient samples, 95 (73%) had adequate cellularity for molecular profiling and 92 (71%) patients received molecular profile-directed therapy. Of the 92 patients who had predictive profiling, 74 (80%) received fluoropyrimidine-based therapy and 18 (20%) received gemcitabine-based therapies. Of the 130 patients, 107 (82%) completed all intended neoadjuvant therapy and surgery; 56 (92%) of the 61 with resectable PDAC and 51 (74%) of 69 with BLR PDAC.

Conclusions:

We report the first prospective clinical trial that utilized molecular profiling to select neoadjuvant therapy in patients with operable PDAC. Such high resectability rates have not been observed in prior neoadjuvant trials, suggesting that molecular profiling may improve the efficacy of chemotherapy in these patients.
Minimally Invasive Versus Open Distal Pancreatectomy (LEOPARD)
Authors: de Rooij Thijs , van Hilst Jony , van Santvoort Hjalmar , Boerma Djamila , van den Boezem Peter , Daams Freek , van Dam Ronald , Dejong Cees , van Duyn Eino , Dijkgraaf Marcel , van Eijck Casper , Festen Sebastiaan , Gerhards Michael , Groot Koerkamp Bas , de Hingh Ignace , Kazemier Geert , Klaase Joost , de Kleine Ruben , van Laarhoven Cornelis , Luyer Misha , Patijn Gijs , Steenvoorde Pascal , Suker Mustafa , Abu Hilal Moh’d , Busch Olivier , Besselink Marc
Published: August 2018

Objective:

This trial followed a structured nationwide training program in minimally invasive distal pancreatectomy (MIDP), according to the IDEAL framework for surgical innovation, and aimed to compare time to functional recovery after minimally invasive and open distal pancreatectomy (ODP).

Background:

MIDP is increasingly used and may enhance postoperative recovery as compared with ODP, but randomized studies are lacking.

Methods:

A multicenter patient-blinded randomized controlled superiority trial was performed in 14 centers between April 2015 and March 2017. Adult patients with left-sided pancreatic tumors confined to the pancreas without vascular involvement were randomly assigned (1:1) to undergo MIDP or ODP. Patients were blinded for type of surgery using a large abdominal dressing. The primary endpoint was time to functional recovery. Analysis was by intention to treat. This trial was registered with the Netherlands Trial Register (NTR5689).

Results:

Time to functional recovery was 4 days [interquartile range (IQR) 3–6) in 51 patients after MIDP versus 6 days (IQR 5–8) in 57 patients after ODP (P < 0.001). The conversion rate of MIDP was 8%. Operative blood loss was less after MIDP (150 vs 400 mL; P < 0.001), whereas operative time was longer (217 vs 179 minutes; P = 0.005). The Clavien–Dindo grade ≥III complication rate was 25% versus 38% (P = 0.21). Delayed gastric emptying grade B/C was seen less often after MIDP (6% vs 20%; P = 0.04). Postoperative pancreatic fistulas grade B/C were seen in 39% after MIDP versus 23% after ODP (P = 0.07), without difference in percutaneous catheter drainage (22% vs 20%; P = 0.77). Quality of life (day 3–30) was better after MIDP as compared with ODP, and overall costs were non-significantly less after MIDP. No 90-day mortality was seen after MIDP versus 2% (n = 1) after ODP.

Conclusions:

In patients with left-sided pancreatic tumors confined to the pancreas, MIDP reduces time to functional recovery compared with ODP. Although the overall rate of complications was not reduced, MIDP was associated with less delayed gastric emptying and better quality of life without increasing costs.
Characterization of capsule genes in non-pathogenic Neisseria species
Authors: Clemence Marianne Elizabeth Alexandra , Maiden Martin Christopher James , Harrison Odile Barbara
Published: August 2018

The genus Neisseria comprises a diverse group of commensal bacteria, which typically colonize the mucosal surfaces of humans and other animals. Neisseria meningitidis, the meningococcus, is notable for its potential to cause invasive meningococcal disease (IMD) in humans; however, IMD is comparatively rare, and meningococci normally colonize the nasopharynx asymptomatically. Possession of a polysaccharide capsule has been shown to be a prerequisite for disease in almost all IMD cases, and was previously considered unique to N. meningitidis, and potentially acquired by horizontal genetic transfer (HGT). Nevertheless, the capsule must also have some role in asymptomatic colonization and/or transmission, consistent with the existence of six non-disease-associated meningococcal capsule serogroups. In this study, full complements of putative capsule genes were identified in non-pathogenic Neisseria species, including Neisseria subflava and Neisseria elongata. These species contained genes for capsule transport and translocation homologous to those of N. meningitidis, as well as novel putative capsule synthesis genes. Phylogenetic analyses were consistent with the proposal that these genes were acquired by the meningococcus through HGT. In contrast with previous evolutionary models, however, the most parsimonious explanation of these data was that capsule transport genes had been lost in the common ancestor of the meningococcus, gonococcus, and their close relatives, and then reacquired by some meningococci. The most likely donor of the meningococcal transport genes was another Neisseria species.
Corrigendum to: T cell apoptosis at the maternal-fetal interface in early human pregnancy, involvement of galectin-1.- A correction with an important twist
Authors: Kopcow Hernan
Published: August 2018

We previously published a paper reporting the apoptotic nature of first trimester human decidual T cells (Kopcow et al 2008). New experiments and data re-analysis produced confirmatory, negative and contradictory results. We had previously shown by TUNEL and sub diploid DNA content analysis (SD) that ex-vivo decidual T cells, isolated either as CD3+ cells or as CD4+/8+ cells, are apoptotic and that the level of apoptosis differs significantly from peripheral blood T cells isolated in a similar way. Data re-examination including data points previously unintentionally ignored results in indetermination in the dataset structure with contradictory statistical significance results between TUNEL and SD and the two isolation approaches. Furthermore, data disaggregation and granular examination reveals discrepant TUNEL and SD readings within individual samples. We have previously shown that decidual CD3+ lymphocytes stain brighter with AnnexinV -Fitc than peripheral blood T cells and other decidual lympohocyte populations. Independent repetitions with modified and alternative isolation protocols using different flow cytometry equipment in the hands of another researcher failed to reproduce those results, while side by side repetition under the published conditions as well as under the alternative isolation protocol reproduced the published pattern when samples were ran in the same equipment used for the publication. A reflection on these results proposes to understand the scientific paper as one among other possible constructed narratives.
Cancer cell lipid class homeostasis is altered under nutrient-deprivation but stable under hypoxia
Authors: Lisec Jan , Jaeger Carsten , Zaidi Nousheen
Published: August 2018

Under oxygen/nutrient deprivation cancer cells modify the balance between fatty acid (FA) synthesis and uptake, which alters the levels of individual triglyceride or phospholipid sub-species. These modifications may affect survival and drug-uptake in cancer cells. Here, we aimed to attain a more holistic overview of the lipidomic profiles of cancer cells under stress and assess the changes in major lipid-classes. First, expressions of markers of FA synthesis/uptake in cancer cells were assessed and found to be differentially regulated under metabolic stress. Next, we performed a broad lipidomics assay, comprising 244 lipids from six major classes, which allowed us to investigate robust stress induced changes in median levels of different lipid classes -additionally stratified by fatty acid side chain saturation status. The lipidomic profiles of cancer cells were predominantly affected by nutrient-deprivation. Neutral lipid compositions were markedly modified under serum-deprivation and, strikingly, the cellular level of triglyceride subspecies decreased with increasing number of double bonds in their fatty acyl chains. In contrast, cancer cells maintained lipid class homeostasis under hypoxic stress. We conclude that although the levels of individual lipid moieties alter under hypoxia, the robust averages of broader lipid class remain unchanged.
Static Kinks or Flexible Hinges: Conformational Distributions of Bent DNA Bound to Integration Host Factor Mapped by Fluorescence Lifetime Measurements
Authors: Connolly Mitchell , Arra Aline , Zvoda Viktoriya , Steinbach Peter J. , Rice Phoebe A. , Ansari Anjum
Published: August 2018

Gene regulation depends on proteins that bind to specific DNA sites. Such specific recognition often involves severe DNA deformations including sharp kinks. It has been unclear how rigid or flexible these protein-induced kinks are. Here, we investigated the dynamic nature of DNA in complex with integration host factor (IHF), a nucleoid-associated architectural protein known to bend one of its cognate sites (35 base pair H’) into a U-turn by kinking DNA at two sites. We utilized fluorescence lifetime based FRET spectroscopy to map the distribution of bent conformations in various IHF-DNA complexes. Our results reveal a surprisingly dynamic specific complex: while 80% of the IHF-H’ population exhibited FRET efficiency consistent with the crystal structure, 20% exhibited FRET efficiency indicative of unbent or partially bent DNA. This conformational flexibility is modulated by sequence variations in the cognate site. In another site (H1) that lacks an A-tract of H’ on one side of the binding site, the population in the fully U-bent conformation decreased to 36%, as did the extent of bending. A similar decrease in the U-bent population was observed with a single base mutation in H’ in a consensus region on the other side. Taken together, these results provide important insights into the finely tuned interactions between IHF and its cognate sites that keep the DNA bent (or not), and yield quantitative data on the dynamic equilibrium between different DNA conformations (kinked or not kinked) that depend sensitively on DNA sequence and deformability. Notably, the difference in dynamics between IHF-H’ and IHF-H1 reflects the different roles of these complexes in their natural context, in the phage lambda “intasome” (the complex that integrates phage lambda into theE. colichromosome).
Macrophage-induced rifampin tolerance across Mycobacterium tuberculosis lineages is Rv1258c-dependent
Authors: Adams Kristin N. , Verma Amit Kumar , Gopalaswamy Radha , Adikesavalu Harresh , Singhal Dinesh Kumar , Tripathy Srikanth , Ranganathan Uma Devi , Sherman David R. , Urdahl Kevin B. , Ramakrishnan Lalita , Hernandez Rafael E.
Published: August 2018

The Mycobacterium tuberculosis (Mtb) Lineage 4 strains CDC1551 and H37Rv develop tolerance to multiple antibiotics upon macrophage residence. Genetic mutation of the efflux pump Rv1258c in CDC1551 abolishes rifampin tolerance but not isoniazid tolerance. Here we show that clinical isolates from the other predominant Mtb lineages developed macrophage-induced isoniazid tolerance. Furthermore, all lineages developed rifampin tolerance except Lineage 2 Beijing strains, which are natural Rv1258c mutants. Thus macrophage-induced antibiotic tolerance is featured across the majority of Mtb lineages. Our findings further link Rv1258c to rifampin tolerance among clinical isolates.
The genetics of the mood disorder spectrum: genome-wide association analyses of over 185,000 cases and 439,000 controls
Authors: Coleman Jonathan R. I. , Gaspar Héléna A. , Bryois Julien ,   Bipolar Disorder Working Group of the Psychiatric Genomics Consortium,   Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Breen Gerome
Published: August 2018

Background

Mood disorders (including major depressive disorder and bipolar disorder) affect 10-20% of the population. They range from brief, mild episodes to severe, incapacitating conditions that markedly impact lives. Despite their diagnostic distinction, multiple approaches have shown considerable sharing of risk factors across the mood disorders.

Methods

To clarify their shared molecular genetic basis, and to highlight disorder-specific associations, we meta-analysed data from the latest Psychiatric Genomics Consortium (PGC) genome-wide association studies of major depression (including data from 23andMe) and bipolar disorder, and an additional major depressive disorder cohort from UK Biobank (total: 185,285 cases, 439,741 controls; non-overlapping N = 609,424).

Results

Seventy-three loci reached genome-wide significance in the meta-analysis, including 15 that are novel for mood disorders. More genome-wide significant loci from the PGC analysis of major depression than bipolar disorder reached genome-wide significance. Genetic correlations revealed that type 2 bipolar disorder correlates strongly with recurrent and single episode major depressive disorder. Systems biology analyses highlight both similarities and differences between the mood disorders, particularly in the mouse brain cell types implicated by the expression patterns of associated genes. The mood disorders also differ in their genetic correlation with educational attainment – positive in bipolar disorder but negative in major depressive disorder.

Conclusions

The mood disorders share several genetic associations, and can be combined effectively to increase variant discovery. However, we demonstrate several differences between these disorders. Analysing subtypes of major depressive disorder and bipolar disorder provides evidence for a genetic mood disorders spectrum.
Ending AIDS: trends in the incidence of HIV in eastern and southern Africa
Authors: Williams Brian G. , Granich Reuben
Published: August 2018

While great progress has been made in the control and management of the HIV epidemic there is still much to be done. Using trends in the rate of new HIV infections in eastern and southern Africa we assess the current state of the epidemic and evaluate the future prospects for controlling it. If we let an incidence of 1 per 1,000 people represent a control threshold then this has been reached, or will probably be reached by 2020, in eastern Africa and is reachable by 2020 in those southern African countries that do not have particularly strong social and economic ties to South Africa if they continue to scale up their treatment programmes. In South Africa and its immediate neighbours Lesotho, Mozambique and Swaziland, the prospects are less certain. These countries are unlikely to reach the control threshold by 2020 but with sufficient political will and commitment to ‘treatment for all’ could do so by 2030.

There are two important caveats. First, reaching the control threshold still leaves 35 thousand new infections a year. As the lessons of polio remind us, finding the last few, hard to reach cases will demand more focussed strategies. Second, ending AIDS will not end HIV and about 35 million people will have to be kept on ART for the next 30 to 40 years unless and until a cure is discovered. Even if we assume a modest cost of, say, US$100 per person per year for ART treatment and support, this corresponds to a continuing financial commitment of US$3.5 Bn per year although this is substantially less than the approximately US$ 40 Bn per year currently committed to HIV and AIDS.