bluuebunny/crossref_metadata_2025 huggingface dataset:
Fitness Barriers Limit Reversion of a Proofreading-Deficient Coronavirus
Authors: Graepel Kevin W. , Agostini Maria L. , Lu Xiaotao , Sexton Nicole R. , Denison Mark R.
Published: July 2019

Coronaviruses encode an exoribonuclease (ExoN) that is important for viral replication, fitness, and virulence, yet coronaviruses with a defective ExoN (ExoN-AA) have not reverted under diverse experimental conditions. In this study, we identify multiple impediments to MHV-ExoN-AA reversion. We show that ExoN-AA reversion is possible but evolutionarily unfavorable. Instead, compensatory mutations outside ExoN-AA motif I are more accessible and beneficial than partial reversion. We also show that coevolution between replicase proteins over long-term passage partially compensates for ExoN-AA motif I but renders the virus inhospitable to a reverted ExoN. Our results reveal the evolutionary basis for the genetic stability of ExoN-inactivating mutations, illuminate complex functional and evolutionary relationships between coronavirus replicase proteins, and identify potential mechanisms for stabilization of ExoN-AA coronavirus mutants.
Frog Virus 3 Genomes Reveal Prevalent Recombination between Ranavirus Lineages and Their Origins in Canada
Authors: Vilaça Sibelle T. , Bienentreu Joe-Felix , Brunetti Craig R. , Lesbarrères David , Murray Dennis L. , Kyle Christopher J.
Published: July 2019

Amphibian populations are declining worldwide, and these declines have been linked to a number of anthropogenic factors, including disease. Among the pathogens associated with amphibian mortality, ranaviruses have caused massive die-offs across continents. In North America, frog virus 3 (FV3) is a widespread ranavirus that can infect wild and captive amphibians. In this study, we sequenced full FV3 genomes isolated from frogs in Canada. We report widespread recombination between FV3 and common midwife toad virus (CMTV). Phylogenies indicate a recent origin for FV3 in Canada, possibly as a result of international amphibian trade.
The Vaccinia Virus (VACV) B1 and Cellular VRK2 Kinases Promote VACV Replication Factory Formation through Phosphorylation-Dependent Inhibition of VACV B12
Authors: Rico Amber B. , Wang Zhigang , Olson Annabel T. , Linville Alexandria C. , Bullard Brianna L. , Weaver Eric A. , Jones Clinton , Wiebe Matthew S.
Published: July 2019

Constraints placed on viral genome size require that these pathogens must employ sophisticated, yet parsimonious mechanisms to effectively integrate with host cell signaling pathways. Poxviruses are no exception and employ several methods to balance these goals, including encoding single proteins that impact multiple downstream pathways. This study focuses on the vaccinia virus B1 protein kinase, an enzyme that promotes virus replication at multiple phases of the viral lifecycle. Herein, we demonstrate that in addition to its previously characterized functions, B1 inhibits vaccinia virus B12 protein via a phosphorylation-dependent mechanism and that this function of B1 can be complemented by the cellular B1 homolog VRK2. Combined with previous data implicating functional overlap between B1 and an additional cellular B1 homolog, VRK1, these data provide evidence of how poxviruses can be multifaceted in their mimicry of cellular proteins through the consolidation of functions of both VRK1 and VRK2 within the viral B1 protein kinase.
Human Immunodeficiency Virus C.1086 Envelope gp140 Protein Boosts following DNA/Modified Vaccinia Virus Ankara Vaccination Fail To Enhance Heterologous Anti-V1V2 Antibody Response and Protection against Clade C Simian-Human Immunodeficiency Virus Challenge
Authors: Styles Tiffany M. , Gangadhara Sailaja , Reddy Pradeep B. J. , Hicks Sakeenah , LaBranche Celia C. , Montefiori David C. , Derdeyn Cynthia A. , Kozlowski Pamela A. , Velu Vijayakumar , Amara Rama Rao
Published: July 2019

HIV, the virus that causes AIDS, is responsible for millions of infections and deaths annually. Despite intense research for the past 25 years, there remains no safe and effective vaccine available. The significance of this work is in identifying the pros and cons of adding a protein boost to an already well-established DNA/MVA HIV vaccine that is currently being tested in the clinic. Characterizing the effects of the protein boost can allow researchers going forward to design vaccines that generate responses that will be more effective against HIV. Our results in rhesus macaques show that boosting with a specific HIV envelope protein does not significantly boost antibody responses that were identified as immune correlates of protection in a moderately successful RV144 HIV vaccine trial in humans and highlight the need for the development of improved HIV envelope immunogens.
Rectal Swabs from Critically Ill Patients Provide Discordant Representations of the Gut Microbiome Compared to Stool Samples
Authors: Fair Katherine , Dunlap Daniel G. , Fitch Adam , Bogdanovich Tatiana , Methé Barbara , Morris Alison , McVerry Bryan J. , Kitsios Georgios D.
Published: July 2019

Rectal swabs have been proposed as potential alternatives to stool samples for gut microbiome profiling in outpatients or healthy adults, but their reliability in assessment of critically ill patients has not been defined. Because stool sampling is not practical and often not feasible in the intensive care unit, we performed a detailed comparison of gut microbial sequencing profiles between rectal swabs and stool samples in a longitudinal cohort of critically ill patients. We identified systematic differences in gut microbial profiles between rectal swabs and stool samples and demonstrated that the timing of the rectal swab sampling had a significant impact on sequencing results. Our methodological findings should provide valuable information for the design and interpretation of future investigations of the role of the gut microbiome in critical illness.
(p)ppGpp and CodY Promote Enterococcus faecalis Virulence in a Murine Model of Catheter-Associated Urinary Tract Infection
Authors: Colomer-Winter C. , Flores-Mireles A. L. , Kundra S. , Hultgren S. J. , Lemos J. A.
Published: July 2019

Catheter-associated urinary tract infections (CAUTIs) are one of the most frequent types of infection found in the hospital setting that can develop into serious and potentially fatal bloodstream infections. One of the infectious agents that frequently causes complicated CAUTI is the bacterium
Enterococcus faecalis
, a leading cause of hospital-acquired infections that are often difficult to treat due to the exceptional multidrug resistance of some isolates. Understanding the mechanisms by which
E. faecalis
causes CAUTI will aid in the discovery of new druggable targets to treat these infections. In this study, we report the importance of two nutrient-sensing bacterial regulators, named (p)ppGpp and CodY, for the ability of
E. faecalis
to infect the catheterized bladder of mice.
Treatment of Virulent Mycobacterium tuberculosis and HIV Coinfected Macrophages with Gallium Nanoparticles Inhibits Pathogen Growth and Modulates Macrophage Cytokine Production
Authors: Choi Seoung-ryoung , Britigan Bradley E. , Narayanasamy Prabagaran
Published: July 2019

GaNP interrupts iron-mediated enzymatic reactions, leading to growth inhibition of virulent HIV-M. tuberculosiscoinfection in macrophages, and also modulates release of cytokines that may contribute to HIV-TB pathogenesis. Macrophage-targeting GaNP are a promising therapeutic approach to provide sustained antimicrobial activity against HIV-M. tuberculosiscoinfection.
Freezing of gait and postural instability: the unpredictable response to levodopa in Parkinson’s disease
Authors: Moreira Fradique , Rebelo Gomes Inês , Januário Cristina
Published: July 2019

Freezing of gait (FOG) and postural instability are challenging motor symptoms that present a serious therapeutic dilemma in Parkinson’s disease. Appropriate distinction between FOG subtypes may be difficult during routine clinical visits, as shown in the case we present. The patient was examined in three different states in relation to levodopa (L-DOPA) and apomorphine subcutaneous (sc) tests with video documentation: (1) ‘overnight-off’, after 12 hours without medication; (2)‘on’, 60 min after intake of regular levodopa dose (200 mg) and 20 min after 2 mg of apomorphine sc; and (3) ‘supra-on’, after 350 mg of L-DOPA and 3 mg of apomorphine sc. The patient clearly showed a dose-dependent paradoxical response to L-DOPA treatment with the emergence of severe FOG and postural instability. The tendency to develop these axial symptoms was less pronounced with apomorphine at doses that achieved similar improvements of other Parkinsonian features.
Not all colonic growths are malignant
Authors: Iype Geethu Rachel , Kalipatnapu Sasank , Masih Dipti , Varghese Gigi
Published: July 2019

We present the case of a 34-year-old woman who was diagnosed to have adenocarcinoma of the caecum based on the clinical, radiological, histopathological and intraoperative findings. However, postoperative histopathology showed only features of xanthogranulomatous inflammation without any evidence of malignancy. This benign chronic inflammatory condition could present as a histological surprise. It is important for both surgeons and pathologists alike to be aware of this.
Pure yolk sac tumour, post-pubertal type, arising from cryptorchid testes
Authors: Janugade Hemant , Monteiro Jeffrey , Gouda Shekhar
Published: July 2019

Yolk sac tumour (YST), the most common germ cell tumour (GCT) in infants and children, accounts for 80% of GCTs in this age group.1It is observed in only 2.4% of adult patients in their pure form since up to 42% of mixed GCTs have some component of the yolk sac.2We present a 46-year-old cryptorchid man who presented with complaints of abdominal lump, pain and altered bowel habits since 1 month. CT scan of the abdomen revealed a mass arising from the pelvic cavity with feeders predominantly from the left gonadal vessel. Mass was excised via exploratory laparotomy and sent for histological examination. Microscopic examination was suggestive of pure YST. Immunohistochemistry stained positive for cytokeratin, placental-like alkaline phosphatase, Glypican 3 and alpha fetoprotein. The patient succumbed prior to commencing chemotherapy. Pure YSTs of post-pubertal origins are extremely rare and are more aggressive than their prepubertal counterparts.
Magnetic resonance features of sinonasal melanotic mucosal melanoma
Authors: Nardi Cosimo , Vignoli Chiara , Vannucchi Margherita , Pietragalla Michele
Published: July 2019

A 67-year-old man presented to ear, nose and throat department complaining of nasal congestion and recurrent epistaxis for 5 months. Nasal endoscopy revealed a pigmented polyp obstructing the right nasal cavity. MRI with contrast agent showed a right nasal cavity polypoid mass with hyper signal intensity (SI) both in non-enhanced T1-w and diffusion imaging, marked hypo SI in T2-w sequences and avidly contrast enhancement characterised by rapid wash-in without significant wash-out on dynamic perfusion imaging. Histological specimen showed epithelioid and spindle cells with focal intense pigmentations and immunohistochemical features compatible with primary melanotic sinonasal mucosal melanoma (SNM). As melanotic SNM shows MRI pathognomonic high non-enhanced T1-w SI, this case underlines the crucial role of MRI not only in assessing the local tumour extension/recurrence but also in increasing the diagnostic confidence of detecting melanotic SNM. Thus, MRI should be always performed in case of clinical–endoscopic suspicion of SNM.
Endometriosis of the appendix causing small bowel obstruction in a virgin abdomen
Authors: Choi Joseph Do Woong , Yunaev Michael
Published: July 2019

A 29-year-old, otherwise well, nulligravid woman presented to the emergency department with 1-day history of generalised abdominal pain and vomiting. She had similar symptoms 6 months prior following recent menstruations, which resolved conservatively. She had no prior history of abdominal surgery or endometriosis. CT scan demonstrated distal small bowel obstruction. A congenital band adhesion was suspected, and she underwent prompt surgical intervention. During laparoscopy, a thickened appendix was adhered to a segment of distal ileum. There was blood in the pelvis. Laparoscopic adhesiolysis and appendicectomy were performed. Histopathology demonstrated multiple foci of endometriosis of the appendix with endometrial glands surrounded by endometrial stroma. Oestrogen receptor and CD10 immunostains highlighted the endometriotic foci. The patient made a good recovery and was referred to a gynaecologist for further management.
Longitudinal evaluation of a countywide alternative to the Quality and Outcomes Framework in UK General Practice aimed at improving Person Centred Coordinated Care
Authors: Close James , Fosh Ben , Wheat Hannah , Horrell Jane , Lee William , Byng Richard , Bainbridge Michael , Blackwell Richard , Witts Louise , Hall Louise , Lloyd Helen
Published: July 2019

Objectives

To evaluate a county-wide deincentivisation of the Quality and Outcomes Framework (QOF) payment scheme for UK General Practice (GP).

Setting

In 2014, National Health Service England signalled a move towards devolution of QOF to Clinical Commissioning Groups. Fifty-five GPs in Somerset established the Somerset Practice Quality Scheme (SPQS)—a deincentivisation of QOF—with the goal of redirecting resources towards Person Centred Coordinated Care (P3C), especially for those with long-term conditions (LTCs). We evaluated the impact on processes and outcomes of care from April 2016 to March 2017.

Participants and design

The evaluation used data from 55 SPQS practices and 17 regional control practices for three survey instruments. We collected patient experiences (‘P3C-EQ’; 2363 returns from patients with 1+LTC; 36% response rate), staff experiences (‘P3C-practitioner’; 127 professionals) and organisational data (‘P3C-OCT’; 36 of 55 practices at two time points, 65% response rate; 17 control practices). Hospital Episode Statistics emergency admission data were analysed for 2014–2017 for ambulatory-sensitive conditions across Somerset using interrupted time series.

Results

Patient and practitioner experiences were similar in SPQS versus control practices. However, discretion from QOF incentives resulted in time savings in the majority of practices, and SPQS practice data showed a significant increase in P3C oriented organisational processes, with a moderate effect size (Wilcoxon signed rank test; p=0.01; r=0.42). Analysis of transformation plans and organisational data suggested stronger federation-level agreements and informal networks, increased multidisciplinary working, reallocation of resources for other healthcare professionals and changes to the structure and timings of GP appointments. No disbenefits were detected in admission data.

Conclusion

The SPQS scheme leveraged time savings and reduced administrative burden via discretionary removal of QOF incentives, enabling practices to engage actively in a number of schemes aimed at improving care for people with LTCs. We found no differences in the experiences of patients or healthcare professionals between SPQS and control practices.
Comparing regional neonatal mortality rates: the influence of registration of births as live born for birth weight <500 g in Taiwan
Authors: Wang Liang-Yi , Chang Yu-Shan , Liang Fu-Wen , Lin Yung-Chieh , Lin Yuh-Jyh , Lu Tsung-Hsueh , Lin Chyi-Her
Published: July 2019

Objective

To investigate regional variation in the registration of births (still+live) as live born for birth weight <500 g and the impact on the city/county ranking of neonatal mortality rate (NMR) in Taiwan.

Design

Population-based cross-sectional ecological study.

Setting

20 cities/counties in Taiwan.

Participants

Registered births for birth weight <500 g and neonatal deaths in 2015–2016.

Main outcome measures

City/county percentage of births <500 g registered as live born and ranking of city/county NMR (deaths per 1000 live births) including and excluding live births <500 g.

Results

The percentage of births <500 g registered as live born ranged from 0% in Keelung City (0/26) and Penghu County (0/4) to 20% in Taipei City (112/558), 24% in Hsinchu County (5/21) and 28% in Hualien County (9/32). The change in city/county ranking of NMR from including to excluding live births <500 g was most prominent in Taipei City (from the 15th to the 1st) followed by Kaohsiung City (from the 18th to the 14th).

Conclusions

The city/county NMR in Taiwan is influenced by variation in the registration of live born for births with uncertain viability. We recommend presenting city/county NMR using both criteria (with or without minimum threshold of gestation period or birth weight) for better interpretation of the findings of comparisons of city/county NMR.
Occupational hazard in an immunosuppressed patient
Authors: Finkel Jemima , Smith Philip J , Potts Jonathan , Yu Dominic , Hearn Pasco , Trembling Paul M , Cropley Ian , Jalan Rajiv , Marshall Aileen
Published: July 2019

A 60-year-old male liver transplant recipient presented to his local hospital with left-sided partial seizures following a few days of generalised headache. He had undergone transplantation for primary sclerosing cholangitis 4 years earlier and maintained on tacrolimus monotherapy immunosuppression. He had no other comorbidities of note and worked as an arable farmer. At last follow-up, he had been well with preserved graft function and afternoon trough tacrolimus levels of 2–4 ng/mL. Over the preceding 4 weeks, he had been investigated locally for weight loss and a productive cough, where CT of the chest showed calcified mediastinal and hilar lymphadenopathy. Bronchoscopy samples were negative for acid-fast bacilli and he had been empirically treated for assumed community acquired pneumonia. Initial seizure management was with intravenous diazepam and phenytoin. On transfer to our centre, he was noted to be dysarthric with persisting 4/5 left upper limb weakness and nystagmus to all extremes of gaze. Blood tests were significant for mild anaemia (haemoglobin 90 g/L) and elevated C reactive protein (134 mg/L). The peripheral white cell count was 6.6×109/L. Biochemical liver graft function was normal and the 8am trough tacrolimus level was low at 2 ng/mL.

CT head revealed bilateral ring enhancing cerebral lesions with surrounding vasogenic oedema but no mass effect. On MRI these exhibited restricted diffusion and marked perilesional oedema, suggestive of infection. Cerebrospinal fluid (CSF) analysis was as follows: white cell count <1/mm3, protein 0.57 g/L (normal range <45 g/L) and glucose 3 mmol/L (paired plasma glucose 4.8 mmol/L). Testing for virological causes via PCR, toxoplasma serology and blood and CSF cultures, including for tuberculosis, were all negative. Whole body positron emission tomography-CT demonstrated uptake in numerous peritoneal and intramuscular lesions as well as right-sided cervical lymphadenopathy, which was sampled with fine needle aspiration. Microscopy revealed a filamentous, beading and branching Gram-positive bacillus that was partially acid-fast, subsequently speciated asNocardia farcinica.
Acute versus chronic myocardial injury and long-term outcomes
Authors: Kadesjö Erik , Roos Andreas , Siddiqui Anwar , Desta Liyew , Lundbäck Magnus , Holzmann Martin J
Published: July 2019

Objective

There is a paucity of data regarding prognosis in patients with acute versus chronic myocardial injury for long-term outcomes. We hypothesised that patients with chronic myocardial injury have a similar long-term prognosis as patients with acute myocardial injury.

Methods

In an observational cohort study of 22 589 patients who had high-sensitivity cardiac troponin T (hs-cTnT) measured in the emergency department during 2011–2014, we identified all patients with level >14 ng/L and categorised them as acute myocardial injury, type 1 myocardial infarction (T1MI), type 2 myocardial infarction (T2MI) or chronic myocardial injury through adjudication. We estimated adjusted HRs with 95% CIs for the primary outcome all-cause mortality and secondary outcomes MI, and heart failure in patients with acute myocardial injury, T1MI and T2MI compared with chronic myocardial injury.

Results

In total, 3853 patients were included. During 3.9 (±2) years of follow-up, 48%, 24%, 44% and 49% of patients with acute myocardial injury, T1MI, T2MI and chronic myocardial injury died, respectively. Patients with acute myocardial injury had higher adjusted risks of death (1.21, 95% CI 1.08 to 1.36) and heart failure (1.24, 95% CI 1.07 to 1.43), but a similar risk for myocardial infarction (MI) compared with the reference group. Patients with T1MI had a lower adjusted risk of death (0.86, 95% CI 0.74 to 1.00) and higher risk of MI (2.09, 95% CI 1.62 to 2.68), but a similar risk of heart failure. Patients with T2MI had a higher adjusted risk of death (1.46, 95% CI 1.18 to 1.80) and heart failure (1.30, 95% CI 1.00 to 1.69) compared with patients with chronic myocardial injury.

Conclusions

Absolute long-term risks for death are similar, and adjusted risks are slightly higher, among patients with acute myocardial injury and T2MI, respectively, compared with chronic myocardial injury. The lowest risk of long-term mortality was found in patients with T1MI. Both acute and chronic myocardial injury are associated with very high risks of adverse outcomes.
Convalescent troponin and cardiovascular death following acute coronary syndrome
Authors: Adamson Philip D , McAllister David , Pilbrow Anna , Pickering John William , Poppe Katrina , Shah Anoop , Whalley Gillian , Ellis Chris , Mills Nicholas L , Newby David E , Pemberton Chris , Troughton Richard W , Doughty Rob N , Richards A Mark
Published: July 2019

Objectives

High-sensitivity cardiac troponin testing is used in the diagnosis of acute coronary syndromes but its role during convalescence is unknown. We investigated the long-term prognostic significance of serial convalescent high-sensitivity cardiac troponin concentrations following acute coronary syndrome.

Methods

In a prospective multicentre observational cohort study of 2140 patients with acute coronary syndrome, cardiac troponin I concentrations were measured in 1776 patients at 4 and 12 months following the index event. Patients were stratified into three groups according to the troponin concentration at 4 months using the 99th centile (women>16 ng/L, men>34 ng/L) and median concentration of those within the reference range. The primary outcome was cardiovascular death.

Results

Troponin concentrations at 4 months were measurable in 99.0% (1759/1776) of patients (67±12 years, 72% male), and were ≤5 ng/L (median) and >99th centile in 44.8% (795) and 9.3% (166), respectively. There were 202 (11.4%) cardiovascular deaths after a median of 4.8 years. After adjusting for the Global Registry of Acute Coronary Events score, troponin remained an independent predictor of cardiovascular death (HR 1.4, 95% CI 1.3 to 1.5 per doubling) with the highest risk observed in those with increasing concentrations at 12 months. Patients with 4-month troponin concentrations >99th centile were at increased risk of cardiovascular death compared with those ≤5 ng/L (29.5% (49/166) vs 4.3% (34/795); adjusted HR 4.9, 95% CI 3.8 to 23.7).

Conclusions

Convalescent cardiac troponin concentrations predict long-term cardiovascular death following acute coronary syndrome. Recognising this risk by monitoring troponin may improve targeting of therapeutic interventions.

Trial registration number

ACTRN12605000431628;Results.
Sex disparities in the management of coronary heart disease in general practices in Australia
Authors: Lee Crystal Man Ying , Mnatzaganian George , Woodward Mark , Chow Clara K , Sitas Freddy , Robinson Suzanne , Huxley Rachel R
Published: July 2019

Objectives

To determine whether sex differences exist in the management of patients with a history of coronary heart disease (CHD) in primary care.

Methods

General practice records of patients aged ≥18 years with a history of CHD in a large general practice dataset in Australia, MedicineInsight, were analysed. Sex-specific, age-standardised proportions of patients prescribed with recommended medications; assessed for cardiovascular risk factors; and achieved treatment targets according to the General Practice Management Plan were reported.

Results

Records of 130 926 patients (47% women) from 438 sites were available from 2014 to 2018. Women were less likely to be prescribed with recommended medications (prescribed ≥3 medications: women 44%, men 61%; p<0.001). Younger patients, especially women aged <45 years, were substantially underprescribed (aged <45 years prescribed ≥3 medications: women 2%, men 8%; p<0.001). Lower proportions of women were assessed for cardiovascular risk factors (blood test for lipids: women 70%–76%, men 77%–81%; p<0.001). Body size was not commonly assessed (body mass index: women 59%, men 62%; p<0.001; waist: women 23%, men 25%; p<0.001). Higher proportions of women than men achieved targets for most risk factors (achieved ≥4 targets in patients assessed for all risk factors: women 82%, men 76%).

Conclusion

Gaps in preventative management including prescription of indicated medications and risk factor monitoring have been reported from the late 1990s and this large-scale general practice data analysis indicate they still persist. Moreover, the gap is larger in women compared to men. We need new ways to address these gaps and the sex inequity.
Usefulness of high-resolution three-dimensional proton density-weighted turbo spin-echo MRI in distinguishing a junctional dilatation from an intracranial aneurysm of the posterior communicating artery: a pilot study
Authors: Kim Sunghan , Chung Joonho , Cha Jihoon , Kim Byung Moon , Kim Dong Joon , Kim Yong Bae , Lee Jae Whan , Huh Seung Kon , Park Keun Young
Published: July 2019

Background

Discriminating a junctional dilatation from a true saccular aneurysm is clinically important.

Purpose

To evaluate the usefulness of high-resolution three-dimensional proton density-weighted turbo spin-echo magnetic resonance imaging (PD MRI) in distinguishing a junctional dilatation from an aneurysm of the posterior communicating artery (PcomA).

Methods

Eighty-two consecutive patients with 83 PcomA lesions, which were evaluated by time-of-flight (TOF) MR angiography (MRA), PD MRI, and digital subtraction angiography (DSA), were enrolled. These radiologic data were retrospectively and independently reviewed by two neurosurgeons, and each diagnosis based on TOF MRA, PD MRI, and DSA was compared. The diagnostic efficacy (interobserver agreement, intermodality agreement, and diagnostic performance) of PD MRI was compared with that of TOF MRA.

Results

PD MRI showed higher AC1 (Gwet’s agreement coefficient, PD MRI: 0.8942, 95% CI 0.8204 to 0.968; TOF MRA: 0.7185, 95% CI 0.5753 to 0.8617) and prevalence-adjusted bias-adjusted kappa coefficient (PABAK) (PD MRI: 0.8554, TOF MRA: 0.5904) than TOF MRA for interobserver agreement. For intermodality agreement, PD MRI also showed higher AC1 (PD MRI: 0.9069, 95% CI 0.8374 to 0.9764; TOF MRA: 0.7983, 95% CI 0.6969 to 0.8996) and PABAK (PD MRI: 0.8735, TOF MRA: 0.7289) than TOF MRA. The diagnostic performance of PD MRI was statistically superior to that of TOF MRA in sensitivity, specificity, positive predictive value, and negative predictive value.

Conclusions

PD MRI could provide excellent diagnostic accuracy and better information in distinguishing a junctional dilatation from a true saccular aneurysm of the PcomA compared with TOF MRA.
Using G-FAST to recognize emergent large vessel occlusion: a training program for a prehospital bypass strategy
Authors: Chiu Yu-Chen , Tang Sung-Chun , Sun Jen-Tang , Tsai Li-Kai , Hsieh Ming-Ju , Lee Chung-Wei , Jeng Jiann-Shing , Lee Yu-Ching , Chien Yu-Chun , Wang Yao-Cheng , Chiang Wen-Chu , Ma Matthew Huei-Ming
Published: July 2019

Introduction

The shorter the time between the onset of symptoms and reperfusion using endovascular thrombectomy, the better the functional outcome of patients. A training program was designed for emergency medical technicians (EMTs) to learn the gaze-face-arm-speech-time test (G-FAST) score for initiating a prehospital bypass strategy in an urban city. This study aimed to evaluate the effect of the training program on EMTs.

Methods

All EMTs in the city were invited to join the training program. The program consisted of a 30 min lecture and a 20 min video which demonstrated the G-FAST evaluation. The participants underwent tests before and after the program. The tests included (1) a questionnaire of knowledge, attitudes, confidence, and behaviors towards stroke care; and (2) watching 10 different scenarios in a video and answering questions, including eight sub-questions of G-FAST parameters, and choosing a suitable receiving hospital.

Results

In total, 1058 EMTs completed the training program. After the program, significant improvement was noted in knowledge, attitudes, and confidence, as well as scenario judgement. The performance of the EMTs in evaluating G-FAST criteria in comatose patients was relatively poor in the pre-test and improved significantly after the training course. Although the participants answered the G-FAST items correctly, they tended to overtriage the patients and refer them to higher-level hospitals.

Conclusions

A short training program can improve the ability to identify stroke patients and choose a suitable receiving hospital. A future training program could put further emphasis on how to evaluate comatose patients and choose a suitable receiving hospital.
Pruritus and myoclonus following five consecutive doses of morphine administered through an epidural catheter in a dog
Authors: Dancker Christian , MacFarlane Paul , Love Emma J
Published: July 2019

A 2‐year, 10‐month‐old male entire whippet had an epidural catheter placed to provide postoperative analgesia following lateral thoracotomy. He received 0.1 mg/kg preservative free morphine every 12 hours via the epidural catheter. After the fifth dose, the dog showed sudden signs of pruritus and myoclonus and became severely distressed, and the epidural catheter was removed. Despite initial treatment with sedatives (dexmedetomidine and propofol), antihistamines (chlorphenamine) and the opioid antagonist naloxone, the pruritus did not completely resolve. Ten hours after the onset of clinical signs, having received additional sedation (dexmedetomidine) and supportive treatment, the dog returned to normal behaviour and the pruritus stopped. The dog subsequently recovered uneventfully. Pruritus and myoclonus following epidural administration of morphine can be difficult to manage and may appear after several doses have been administered.
Hydrochronology of a proposed deep geological repository for low- and intermediate-level nuclear waste in southern Ontario from U–Pb dating of secondary minerals: response to Silurian and Cretaceous events
Authors: Davis D.W. , Sutcliffe C.N. , Thibodeau A.M. , Spalding J. , Schneider D. , Cruden A. , Adams J. , Parmenter A. , Jensen M. , Zajacz Z.
Published: July 2019

A record of fluid flow has been documented within a Paleozoic carbonate platform sequence by U–Pb dating of calcite in veins and vugs from rock core sampled through a shallowly dipping sequence of sedimentary rocks beneath the Bruce nuclear site, Ontario, Canada. Secondary calcite from >650 m deep Ordovician carbonate rocks yields a Silurian age of 434 ± 5 Ma possibly related to infiltration of seawater from overlying evaporitic basins as well as hydrothermal solutions that infiltrated from below. In contrast, near-surface Devonian rocks mostly give vein infill ages over the range of 80–100 Ma with evidence for younger infill down to 50 Ma. Vein calcite samples previously dated from surface outcrops of Ordovician carbonate exposed up to 500 km to the east yielded similar U–Pb ages. Coincidence of near-surface vein calcite ages indicates widespread vein emplacement synchronous with a change in direction of motion of the North American plate as well as possible erosional unroofing following passage of the region over the Great Meteor hotspot approximately 125 Myr ago. Deeper carbonate formations have remained apparently impermeable to post-Paleozoic disturbance despite these perturbations.
Oral ethinylestradiol–levonorgestrel normalizes fructose-induced hepatic lipid accumulation and glycogen depletion in female rats
Authors: Olaniyi Kehinde Samuel , Olatunji Lawrence Aderemi
Published: July 2019

The present study investigated the effects of oral ethinylestradiol–levonorgestrel (EEL) on hepatic lipid and glycogen contents during high fructose (HF) intake, and determined whether pyruvate dehydrogenase kinase-4 (PDK-4) and glucose-6-phosphate dehydrogenase (G6PD) activity were involved in HF and (or) EEL-induced hepatic dysmetabolism. Female Wistar rats weighing 140–160 g were divided into groups. The control, EEL, HF, and EEL+HF groups received water (vehicle, p.o.), 1.0 μg ethinylestradiol plus 5.0 μg levonorgestrel (p.o.), fructose (10% w/v), and EEL plus HF, respectively, on a daily basis for 8 weeks. Results revealed that treatment with EEL or HF led to insulin resistance, hyperinsulinemia, increased hepatic uric acid production and triglyceride content, reduced glycogen content, and reduced production of plasma or hepatic glutathione- and G6PD-dependent antioxidants. HF but not EEL also increased fasting glucose and hepatic PDK-4. Nonetheless, these alterations were attenuated by EEL in HF-treated rats. Our results demonstrate that hepatic lipid accumulation and glycogen depletion induced by HF is accompanied by increased PDK-4 and defective G6PD activity. The findings also suggest that EEL would attenuate hepatic lipid accumulation and glycogen depletion by suppression of PDK-4 and enhancement of a G6PD-dependent antioxidant barrier.
Characterization of ℓ1 minimizer in one-bit compressed sensing
Authors: Bi Ning , Tan Jun
Published: July 2019

The conception of one-bit compressive sensing (one-bit CS) was first introduced in 2008 by Boufounos and Baraniuk [1-Bit compressive sensing, in Proc. Conf. on Information Science and Systems (CISS, Princeton, NJ, 2008)]. Since then, many efficient algorithms have been developed for dealing with the one-bit CS problem. However, few theoretical results are available on one-bit CS. In this paper, we focus on one-bit CS theory with its relaxation model [Formula: see text] and present a necessary and sufficient condition such that the signal [Formula: see text] is the unique [Formula: see text] minimizer in noiseless one-bit CS (Theorem 3). Moreover, by using the improved separation theorem of convex sets (Theorem 6), we completely characterize the [Formula: see text] minimizer in one-bit CS (Theorem 2). Finally, as an application of Theorem 2, the [Formula: see text] minimizer for the considered model can, in general, be a non-sparse vector.
Comparison of stresses in 3D v. 2D geomechanical modelling of salt structures in the Tarfaya Basin, West African coast
Authors: Hooghvorst Jean Joseph , Harrold Toby W. D. , Nikolinakou Maria A. , Fernandez Oscar , Marcuello Alejandro
Published: July 2019

We predict stresses and strains in the Tarfaya salt basin on the West African coast using a 3D static geomechanical model and compare the results against a simplified 2D plane-strain model. Both models are based on present-day basin geometries, are drained, and use a poroelastic description for the sediments and visco-plastic description for salt. We focus on a salt diapir, where an exploratory well has been drilled crossing a major fault. The 3D model shows a significant horizontal stress reduction in sediments at the top of the diapir, validated with measured data later obtained from the well. The 2D model predicts comparable stress reduction in sediments at the crest of the diapir. However, it shows a broader area affected by the stress reduction, overestimating its magnitude by as much as 1.5 MPa. Both models predict a similar pattern of differential displacement in sediments along both sides of the major fault, above the diapir. These displacements are the main cause of horizontal stress reduction detected at the crest of the diapir. Sensitivity analysis in both models shows that the elastic parameters of the sediments have a minimal effect on the stress–strain behaviour. In addition, the 2D sensitivity analysis concludes that the main factors controlling stress and strain changes are the geometry of the salt and the difference in rock properties between encasing sediments and salt. Overall, our study demonstrates that carefully built 2D models at the exploration stage can provide stress information and useful insights comparable to those from more complex 3D geometries.

Thematic collection:
This article is part of the Mechanics of salt systems: state of the field in numerical methods collection available at:
https://www.lyellcollection.org/cc/mechanics-of-salt-systems
A Mutation in Histone H2B Represents a New Class of Oncogenic Driver
Authors: Bennett Richard L. , Bele Aditya , Small Eliza C. , Will Christine M. , Nabet Behnam , Oyer Jon A. , Huang Xiaoxiao , Ghosh Rajarshi P. , Grzybowski Adrian T. , Yu Tao , Zhang Qiao , Riva Alberto , Lele Tanmay P. , Schatz George C. , Kelleher Neil L. , Ruthenburg Alexander J. , Liphardt Jan , Licht Jonathan D.
Published: July 2019

By examination of the cancer genomics database, we identified a new set of mutations in core histones that frequently recur in cancer patient samples and are predicted to disrupt nucleosome stability. In support of this idea, we characterized a glutamate to lysine mutation of histone H2B at amino acid 76 (H2B-E76K), found particularly in bladder and head and neck cancers, that disrupts the interaction between H2B and H4. Although H2B-E76K forms dimers with H2A, it does not form stable histone octamers with H3 and H4 in vitro, and when reconstituted with DNA forms unstable nucleosomes with increased sensitivity to nuclease. Expression of the equivalent H2B mutant in yeast restricted growth at high temperature and led to defective nucleosome-mediated gene repression. Significantly, H2B-E76K expression in the normal mammary epithelial cell line MCF10A increased cellular proliferation, cooperated with mutant PIK3CA to promote colony formation, and caused a significant drift in gene expression and fundamental changes in chromatin accessibility, particularly at gene regulatory elements. Taken together, these data demonstrate that mutations in the globular domains of core histones may give rise to an oncogenic program due to nucleosome dysfunction and deregulation of gene expression.

Significance:

Mutations in the core histones frequently occur in cancer and represent a new mechanism of epigenetic dysfunction that involves destabilization of the nucleosome, deregulation of chromatin accessibility, and alteration of gene expression to drive cellular transformation.

See related commentary by Sarthy and Henikoff, p. 1346.

This article is highlighted in the In This Issue feature, p. 1325
Engineered Adoptive T-cell Therapy Prolongs Survival in a Preclinical Model of Advanced-Stage Ovarian Cancer
Authors: Anderson Kristin G. , Voillet Valentin , Bates Breanna M. , Chiu Edison Y. , Burnett Madison G. , Garcia Nicolas M. , Oda Shannon K. , Morse Christopher B. , Stromnes Ingunn M. , Drescher Charles W. , Gottardo Raphael , Greenberg Philip D.
Published: July 2019

Adoptive T-cell therapy using high-affinity T-cell receptors (TCR) to target tumor antigens has potential for improving outcomes in high-grade serous ovarian cancer (HGSOC) patients. Ovarian tumors develop a hostile, multicomponent tumor microenvironment containing suppressive cells, inhibitory ligands, and soluble factors that facilitate evasion of antitumor immune responses. Developing and validating an immunocompetent mouse model of metastatic ovarian cancer that shares antigenic and immunosuppressive qualities of human disease would facilitate establishing effective T-cell therapies. We used deep transcriptome profiling and IHC analysis of human HGSOC tumors and disseminated mouse ID8VEGF tumors to compare immunologic features. We then evaluated the ability of CD8 T cells engineered to express a high-affinity TCR specific for mesothelin, an ovarian cancer antigen, to infiltrate advanced ID8VEGF murine ovarian tumors and control tumor growth. Human CD8 T cells engineered to target mesothelin were also evaluated for ability to kill HLA-A2+ HGSOC lines. IHC and gene-expression profiling revealed striking similarities between tumors of both species, including processing/presentation of a leading candidate target antigen, suppressive immune cell infiltration, and expression of molecules that inhibit T-cell function. Engineered T cells targeting mesothelin infiltrated mouse tumors but became progressively dysfunctional and failed to persist. Treatment with repeated doses of T cells maintained functional activity, significantly prolonging survival of mice harboring late-stage disease at treatment onset. Human CD8 T cells engineered to target mesothelin were tumoricidal for three HGSOC lines. Treatment with engineered T cells may have clinical applicability in patients with advanced-stage HGSOC.
The Relation between Hemogram Parameters and Survival in Extensive-Stage Small Cell Lung Cancer
Authors: Sakin Abdullah , Sahin Suleyman , Yasar Nurgul , Demir Cumhur , Arici Serdar , Geredeli Caglayan , Cihan Sener
Published: July 2019

Purpose: To determine whether hemogram parameters have prognostic effects on survival in patients with extensive-stage small cell lung cancer (ED-SCLC). Methods: This retrospective analysis included 113ED-SCLC patients, who were followed in an oncology clinic. The data regarding the baseline patient demographic characteristics, complete blood count (white blood cell, red blood cell, hemoglobin, hematocrit, mean platelet volume, platelet, total neutrophil, total lymphocyte, total monocyte, neutrophil-to-lymphocyte ratio [NLR], platelet-to-lymphocyte ratio [PLR], and monocyte-to-lymphocyte ratio [MLR]), and survival were analyzed. According to the ROC curve drawn for overall survival (OS) analysis, the cutoff values were determined as follows: NLR ≥3, with 71.4% sensitivity and 63.6% specificity; PLR ≥0.150, with 68.1% sensitivity and 52.4% specificity; and MLR ≥0.367, with 64.4% sensitivity and 71.4% specificity. Results: Of the 113 patients with ED-SCLC, 92 (81.4%) were men and 21 (18.6%) were women. The median age was 65 years (range, 35–81 years). NLR was <3 in 40 (65.4%) patients. Patients with NLR <3 had significantly higher OS than those with NLR ≥3 (15 vs. 5 months, respectively, p < 0.001). Patients with PLR <150 had significantly higher median OS than those with PLR ≥150 (14 vs. 6 months, respectively, p = 0.014). The median OS was significantly greater in patients with MLR <0.367 compared to that in patients with MLR ≥0.367 (11 vs. 6 months, respectively, p = 0.016). In multivariate analysis, NLR was the only factor associated with OS (HR = 2.26, 95% Cl 1.24–4.10). Conclusion: NLR was determined as an independent negative prognostic factor for OS in ED-SCLC patients at diagnosis, thus may help determine disease prognosis as a useful prognostic marker.
Inguinal Metastasis from Basal Cell Carcinoma of the Vulva
Authors: Dalton Anna Katrina , Wan King Man , Gomes Deborah , Wyatt Jenny Ma , Oehler Martin K.
Published: July 2019

Vulval basal cell carcinomas (BCC) are an important differential diagnosis of painful, itchy vulval lesions, which can occur at all ages but commonly affect women in their senium. BCC tend to grow locally in an invasive and destructive pattern and seldom metastasize. Here we describe the rare case of inguinal metastasis in a 70-year-old woman with vulval BCC who was treated with radical hemivulvectomy, bilateral inguinal node sampling and adjuvant external beam radiotherapy. We discuss the clinical management of vulval BCC and provide an overview of the previously reported cases in the literature.
Accelerating the Depletion of Circulating Anti-Phospholipase A2 Receptor Antibodies in Patients with Severe Membranous Nephropathy: Preliminary Findings with Double Filtration Plasmapheresis and Ofatumumab
Authors: Podestà Manuel Alfredo , Gennarini Alessia , Portalupi Valentina , Rota Stefano , Alessio Maria Grazia , Remuzzi Giuseppe , Ruggenenti Piero
Published: July 2019

Patients with membranous nephropathy (MN) and persistent nephrotic syndrome (NS) are at increased risk of ­progression to end-stage renal disease. The discovery of ­autoantibodies against the podocyte-expressed M-type phospholipase A2 receptor (PLA2R) provided a clear pathophysiological rationale for interventions targeting the B-cell lineage to prevent antibody production and subepithelial immune-complex deposition. The anti-CD20 monoclonal antibodies, rituximab and ofatumumab, are safe and achieve remission of NS in approximately two-thirds of patients with MN. In patients with PLA2R-related MN, remission can be predicted by anti-PLA2R antibody depletion, and faster depletion is associated with earlier reduction of proteinuria and improved nephroprotection. Selective apheresis methods, such as double-filtration plasmapheresis (DFPP), may accelerate the clearance of autoreactive antibodies and at the same time avoid the side effects of plasma-exchange. In this preliminary, explorative, proof-of-concept study, we observed that in patients with PLA2R-related MN, NS and high antibody levels, ofatumumab-induced B-cell depletion followed by DFPP accelerated anti-PLA2R depletion compared to anti-CD20 monotherapy. This therapeutic regimen was safe and well tolerated. These observations may provide the background for controlled trials aimed at formally testing whether the addition of DFPP to anti-CD20 therapy could offer a novel therapeutic option, especially for patients with more severe MN.
The Genetic Relevance of Human Induced Pluripotent Stem Cell-Derived Microglia to Alzheimer’s Disease and Major Neuropsychiatric Disorders
Authors: Butler III Robert R. , Kozlova Alena , Zhang Hanwen , Zhang Siwei , Streit Michael , Sanders Alan R. , Laudanski Krzysztof , Pang Zhiping P. , Gejman Pablo V. , Duan Jubao
Published: July 2019

Microglia are the primary innate immune cell type in the brain that have been implicated in the pathogenesis of several neurodegenerative and neuropsychiatric disorders, most notably Alzheimer’s disease (AD) and schizophrenia. Microglia generated from human induced pluripotent stem cells (hiPSCs) represent a promising in vitro cellular model for studying the neuroimmune interactions involved in these disorders. Among several methods of generating ­hiPSC-derived microglia (iMG) – varying in duration and resultant purity – a recent protocol by Brownjohn et al. [Stem Cell Reports. 2018 Apr;10(4):1294–307] is particularly simple and efficient. However, the replicability of this method, transcriptomic similarity of these iMG to primary adult microglia, and their genetic relevance to disease (i.e., enrichment of disease risk loci in genes preferentially expressed in these cells) remains unclear. Using two hiPSC lines, we demonstrated that Brownjohn’s protocol can rapidly generate iMG that morphologically and functionally resembled microglia. The iMG cells we generated were found to be transcriptionally similar to previously reported iMG, as well as fetal and adult microglia. Furthermore, by using cell type-specific gene expression to partition disease heritability, we showed that iMG cells are genetically relevant to AD but found no significant enrichments of risk loci of Parkinson’s disease, schizophrenia, major depressive disorder, bipolar disorder, autism spectrum disorder, or body mass index. Across a range of neuronal and immune cell types, we found only iMG, primary microglia, and microglia-like cell types exhibited a significant enrichment for AD heritability. Our results thus support the use of iMG as a human cellular model for understanding AD biology and underlying genetic factors, as well as for developing and efficiently screening new therapeutics.