bluuebunny/crossref_metadata_2025 huggingface dataset:
Acute pancreatitis in the older patient: Is a new risk score required?
Authors: Bath Michael F , Som Robin , Curley Daniel , Kerwat Rajab
Published: June 2020

Introduction

The average age of the surgical patient in the UK is increasing. Frailty and cognitive impairment have been shown to be important risk factors in elderly patients with surgical pathology. Limited work has previously assessed the outcomes of acute pancreatitis in the elderly population and the usefulness of current severity scoring methods. We aimed to assess the mortality rates in this cohort and identify any factors that may influence patient outcome.

Methods

All patients ≥ 80 years admitted with acute pancreatitis between 1 January 2014 and 31 May 2018 were retrospectively identified. Disease severity scores were measured by a modified Ranson score, and patients' co-morbidities were quantified with the Charlson Comorbidity Index. Primary endpoint was whether the patient was alive at discharge; multilevel logistic regression was used to identify any independent risk factors for patient outcomes.

Results

Eighty-seven patients were included, with an average age of 86 years. The most common aetiology was gallstones. Nine patients died during admission, and ITU admission was the only predictor of mortality (p = 0.027). Twenty-three patients had died by one year. Endoscopic retrograde cholangiopancreatography was more common in patients with gallstone disease who were alive at one year (p = 0.029).

Discussion

Risk severity and co-morbidity scores are not predictive of outcomes in elderly patients with acute pancreatitis. The use of endoscopic retrograde cholangiopancreatography should be considered in elderly patients with acute gallstone pancreatitis where suitable. Further work is needed to identify improved mortality prediction tools in the elderly with acute pancreatitis and optimal management strategies.
Targeting the gut–lung microbiota axis by means of a high-fibre diet and probiotics may have anti-inflammatory effects in COVID-19 infection
Authors: Conte Luana , Toraldo Domenico Maurizio
Published: June 2020

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 1 is a 2019 novel coronavirus, which only in the European area has led to more than 300,000 cases with at least 21,000 deaths. This manuscript aims to speculate that the manipulation of the microbial patterns through the use of probiotics and dietary fibers consumption may contribute to reduce inflammation and strengthen the immune system response in COVID-19 infection.

The reviews of this paper are available via the supplemental material section.
Eyelid Disease
Authors: Shaheen Tahir , Ahmed Mohammed Sohail , Mohyudin Mohammed Naeem
Published: June 2020

Eye symptoms are a common presentation in general practice. According to the RCGP, they account for 4 500 000 GP consultations and cost the UK economy £22 billion each year. Both patients and practitioners are understandably anxious about eye problems, as vision is a very delicate and vital sense. In this article we will discuss the most common eyelid disorders, the pathophysiology, signs and symptoms, and primary care management options. The plethora of overlapping symptoms and aetiologies of eyelid disorders often leads to blanket management plans in general practice and the underlying diagnosis can be mismanaged, leading to persisting problems.
General medicine at the frontline of acute care delivery: Comparison with family medicine hospitalist model implementation in Singapore
Authors: Lai Yi Feng , Leow Si Yun , Lee Sophia Yi-Fei , Xiong Jun , Lim Cher Wee , Ong Biauw Chi
Published: June 2020

Introduction

This mixed methods study seeks to assess the clinical outcomes and qualitative insights associated with the pragmatic implementation of a general medicine (GM) physician-led inpatient care model, first at Alexandra Hospital (AH) and then at Sengkang General Hospital (SKH), and to compare them with findings reported in an earlier implementation of the family medicine (FM) hospitalist model in Singapore.

Methods

Anonymous quantitative demographic and clinical data including length of stay, 30-day readmission rate, inpatient mortality rate and gross cost of hospitalisation bills were extracted from the hospital information system. Comparative analyses with the FM hospitalist model and usual care were made. Secondary qualitative data that were gathered focused on increased understanding of the proposed model, its perceived challenges and future opportunities for its implementation.

Results

The adapted GM care model implemented first at AH and then at SKH seemed to suggest that such a model run by physicians from various backgrounds was capable of producing similarly superior outcomes when compared with the FM hospitalist model piloted in 2011, which was juxtaposed with usual care. With regard to qualitative insights, three findings were reported: (a) perception of and mindset in relation to generalists, which illustrates the barriers to implementing GM; (b) education and training of generalists, which underlines the current lack of adequate supply of GM specialists; and (c) operational issues of care model implementation, which highlights the current mismatches between the prevailing healthcare philosophy and the requirements for successful implementation of the GM care model.

Conclusion

The success of a GM care model hinges on how it is operationalised. With clear protocols, definitions, and a high level of protocol compliance by healthcare team members, the intended outcomes show promise for replication at other interested sites.
Blood transfusion-transmissible malaria and its cost analysis in Hawassa regional blood bank, Southern Ethiopia
Authors: Tsehay Seblewongel , Hassen Fatuma , Hirigo Agete Tadewos , Abiy Zinegnaw , Desta Kassu
Published: June 2020

Background:

Blood transfusion is an intervention used to save life particularly for those patients who survive only with receiving blood. Establishing effective diagnostic test menus concerning the screening of transfusion-transmissible infections in the blood banks play a vital role to safeguard recipients from transfusion-transmissible infections.

Objective:

The aim of this study was to assess blood transfusion-transmissible malaria and its screening cost analysis in Hawassa regional blood bank, Hawassa, Sothern Ethiopia.

Methods:

An institutional-based cross-sectional study was conducted from April to May 2018 among 414 voluntary blood donors. Each participant’s blood sample was screened for most transfusion-transmissible infections using antigen/antibody tests, while rapid diagnostic test and microscopy were used for malaria screening and confirmation. In addition, the cost screening of transfusion-transmissible infections was calculated using activity-based costing method.

Results:

The overall seropositivity of transfusion-transmissible infections was 7.0% and the positivity rate of hepatitis B virus, syphilis, and Plasmodium falciparum was 5.6%, 1.0%, and 0.5%, respectively. The cost per test of each transfusion-transmissible infection was US$5.04 for human immunodeficiency virus, US$4.61 for hepatitis B virus, US$5.11 for hepatitis C virus, and US$4.75 for syphilis, while the cost per test of malaria rapid diagnostic test was US$4.74 and this is comparatively lower than the cost per test of other transfusion-transmissible infections except for hepatitis B virus. In addition, total cost of laboratory incurred for transfusion-transmissible infections screening is estimated to be US$213,634.5 per year, while it becomes US$265,537.5 if the malaria screening cost is added. This means 19.54% of the total cost of laboratory incurred per year or US$51,903.

Conclusion:

The positivity rate of malaria parasites among voluntary blood donors was 0.5%, and it might be increased if the study was conducted in high transmission seasons. A cost of malaria screening is comparatively lower than costs of other transfusion-transmissible infections except for hepatitis B virus. Therefore, the screening of malaria parasites should be considered as one of the test menus of transfusion-transmissible infections in blood banks, especially in malaria-endemic areas.
Sharing Knowledge and “Microbubbles”: Epistemic Communities and Insularity in US Political Journalism
Authors: Usher Nikki , Ng Yee Man Margaret
Published: June 2020

This article examines the peer-to-peer dynamics of Washington political journalists as Communities of Practice (CoPs) to better understand how journalists connect to and learn from each other and establish conventional knowledge. We employ inductive computational analysis that combines social network analysis of journalists’ Twitter interactions with a qualitative, thematic analysis of journalists’ work histories, organizational affiliations, and self-descriptions to identify nine major clusters of Beltway journalists. Among these are an elite/legacy community, a television producer community inclusive of Fox producers, and CNN, as its own self-referential community. Findings suggest Washington journalists may be operating in even smaller, more insular microbubbles than previously thought, raising additional concerns about vulnerability to groupthink and blind spots.
Hiding Traces of Status Seeking: Contradictory Tagging Strategies on Instagram
Authors: Fiers Floor
Published: June 2020

The prevailing presence of social media in the twenty-first century has changed processes of self-presentation. This study questions how Instagram users employ the platform’s tagging features to claim and seek status. Content analysis on a random sample of 787 posts carrying the hashtag “instagood” revealed that they utilize the tagging affordances to make their audience aware of their capital. In addition to displaying their capital through tags, however, users employ hashtags and account tags to increase their visibility on the platform. Interestingly, analysis shows the prevalence of attempts to conceal these obvious paratextual status-seeking strategies. Over half of the Instagram posts in the sample showed traces of the creators taking active steps to hide their use of like-hunter hashtags, through which users explicitly ask other Instagrammers for likes and follows. This finding builds upon Marwick’s concept of aspirational production: The perfecting of one’s online presentation does not only happen by producing a high-status image, but also by concealing the “inauthentic” nature of this production. Furthermore, the fact that traces of obvious status seeking can be found online implies that the lines between Goffman’s front- and backstage are blurred in the digital age.
Management of necrotising fasciitis within a burns centre: do outcomes differ?
Authors: Ward Joseph A , Gibson John A G , Nguyen Dai Q
Published: June 2020

Introduction:

Many similarities exist between the care of necrotising fasciitis (NF) and burn injury patients. Each group represents a small but complex cohort requiring multiple theatre trips, specialist reconstruction, meticulous wound care and multidisciplinary management. Over a six-year period, we sought to examine the clinical outcomes of NF patients managed within a burns centre against those managed by a plastic surgery service.

Methods:

A retrospective case-note review was performed for all identifiable patients referred to our institution’s designated burns centre or plastic surgery service between 2008–2014. Patient characteristics, length of stay, wound-related and clinical outcomes were extracted and descriptively presented with statistical analysis performed for survival and length of stay.

Results:

Twenty-nine patients were included in the study (burns centre [B]: 17 patients; plastic surgery service [P]: 12 patients). Median total length of stay (B: 37 vs. P: 50 days, P=0.38), local length of stay (27 vs. 19 days, P=0.29) and survival till discharge (94.4% vs. 100%, P=0.73) demonstrated no statistically significant difference.

Conclusion:

Caring for NF patients within a burns centre facilitated easier access to specialist reconstructive expertise and multidisciplinary care but did not lead to statistically significant differences in length of stay or survival. The management of NF within a burns centre facilitated provision of high-quality care to a highly challenging patient group.
Photodynamic therapy for keloids and hypertrophic scars: a review
Authors: Tosa Mamiko , Ogawa Rei
Published: June 2020

Purpose:

Keloid is a poorly understood disease that is unique to humans. Hypertrophic scars are similar to keloids and may transform into keloids over time. The standard treatments for these scars are limited by inconsistent efficacy and long treatment/follow-up times. Therefore, a new treatment that is effective for all abnormal scar cases is needed. One option may be photodynamic therapy (PDT). This review assesses the current evidence regarding the safety and efficacy of PDT for keloids and hypertrophic scars.

Methods:

PubMed, Medline and Web of Science were searched from 1900 onwards for the following terms: ‘keloid and photodynamic therapy (PDT)’; ‘hypertrophic scar and photodynamic therapy (PDT)’; and ‘scar and photodynamic therapy (PDT)’. Articles were included if they reported using topical PDT to treat keloids or hypertrophic scars, the patient(s) had one or more keloids and/or hypertrophic scars, and the effect of PDT on these abnormal scars was described.

Results:

In total, 538 articles were identified. Thirteen fulfilled all inclusion criteria. Eight were laboratory studies on keloid/hypertrophic scar explants, fibroblasts or tissue-engineered skin models and five were clinical studies/case reports. The clinical results of PDT on keloids and hypertrophic scars are encouraging.

Conclusion:

PDT appears to play a promising role in keloid and hypertrophic scar therapy but additional clinical studies, particularly randomised clinical trials, are needed.
The Effect of Listening Strategy Instruction on Second Language Listening Anxiety and Self-Efficacy of Iranian EFL Learners
Authors: Fathi Jalil , Derakhshan Ali , Torabi Saeede
Published: June 2020

The aim of the present study was to evaluate the effectiveness of listening strategy instruction on second language (L2) listening comprehension ability, listening anxiety, and listening self-efficacy of Iranian English as a foreign language (EFL) learners. To this end, a sample of 52 English major learners of two intact classes from a university in Iran was employed as the participants of the study. The intact groups were randomly assigned to an experimental group and a control group. The experimental group ( N = 27) received the listening strategy instruction based on the framework proposed by Yeldham and Gruba, whereas the participants in the control group ( N = 25) were instructed traditionally without receiving any strategy instruction. To collect the required data, the listening section of the International English Language Testing System (IELTS), Foreign Language Listening Anxiety Scale (FLLAS), and Second Language Listening Self-Efficacy Questionnaire (SLLSQ) were administered to assess the listening comprehension, listening anxiety, and listening self-efficacy of the learners before and after the intervention. The findings of the study indicated that listening strategy instruction significantly improved learners’ listening comprehension ability and reduced learners’ L2 listening anxiety. However, it was revealed that listening strategy intervention failed to significantly improve L2 listening self-efficacy of the learners. In light of the gained results, the implications of this study are discussed with respect to L2 teachers, learners, and curriculum developers.
Push and Pull Factors Influencing the Winter Sport Tourists in China: The Case of Leisure Skiers
Authors: Wang Xinghua , Zhang James J. , Song Guandong , Wan Xia
Published: June 2020

The purpose of this study was to examine the push (i.e., socio-motivation) and pull (i.e., ski resort attribute preference) factors influencing the level of participation of leisure skiing in China. Leisure skiers ( N = 300) from a major ski resort in China participated in this study. Based on a comprehensive review of the literature and a test of content validity, a survey questionnaire was formulated to measure push and pull variables, demographic information, and ski resort participation frequency. Conducting multiple regression analyses to discover the relationship between push factors and skiing frequency, the escape factor was found to be influencing the skiing frequency most significantly ( p < .05). Four pull factors including sceneries, condition of slopes and snow, training course feature, and cost showed different demand when the demographic backgrounds of participants were taken into consideration (i.e., gender, age, skiing frequency). Discussions are centered on the theoretical and managerial implications on procedures of pushing and pulling consumers to ski resorts at large and increasing skiing participation in China.
Facial Soft Tissue Augmentation With Bellafill: A Review of 4 Years of Clinical Experience in 212 Patients
Authors: Solomon Philip , Ng Chew Lip , Kerzner Jaimie , Rival Richard
Published: June 2020

Introduction:

Bellafill (Suneva Medical Inc) is a semipermanent injectable soft tissue filler composed of smooth and uniform polymethylmetacrylate (PMMA) microspheres suspended in a bovine collagen gel. It is a third generation PMMA filler, with more uniform shapes and sizes of the PMMA microspheres, which has been purported to decrease the incidence of granuloma formation.

Methods:

We performed a retrospective review of our clinical experience from 2014 to 2017 with Bellafill as a soft tissue injectable filler in the following clinical scenarios: deep nasolabial folds, depressed facial acne scars, malar volume loss, temporal wasting, tear trough deformity, chin augmentation, angle of jaw augmentation, and lip augmentation. The primary outcome is the rate of adverse events, and the secondary outcome is subjective patient satisfaction.

Results:

From 2014 to 2017, 842 syringes of Bellafill were administered to 212 patients, for a total of 417 procedures. Of the 417 procedures, 96 (23.0%) were for acne scars, 82 (19.7%) malar volume restorations, 65 (15.6%) nasolabial fold augmentations, 45 (10.8%) chin augmentations, 42 (10.1%) tear trough volume restorations, 28 (6.7%) temple volume restorations, 25 (6.0%) rhinoplasty touch-ups for small areas of nasal depression, 22 (5.3%) lip augmentations, and 12 (2.9%) jaw angle augmentations were performed. A range of 1 to 12 syringes were injected into each patient, over 1 to 3 sessions; 6 cases of adverse events occurred (1.4%). There were 4 cases of solitary nodules in the injection site, 1 case of lower eyelid oedema which persisted for 3 months and 1 case of lower lip oedema which resolved within hours. Patient satisfaction rates ranged from 83.3% for angle of jaw augmentation to 99.0% for improvement of acne scars.

Conclusion:

Bellafill is a safe and effective option for a semipermanent soft tissue filler, with high patient satisfaction and a good safety profile.
Reaction of Stock Price to Frauds’ Announcements: Evidence from Indian Banking Sector
Authors: Sharma Dhanraj , Verma Ruchita
Published: June 2020

This paper is an attempt to investigate the reaction of stock price of Indian banks with respect to announcements of frauds. The Event Study Methodology is used to examine the impact of frauds’ announcements to stock price of banks which experienced fraud. The fraud cases which exceed ₹1,000 crores are considered for the period from January 2014 to December 2018. The results indicate that the fraud announcements do affect the stock price of banks which experienced fraud. In majority of cases of frauds under consideration, the study found significant abnormal loss which further supported by the results of abnormal volume ratio. The highest abnormal loss is found in the stock price of Punjab National Bank (8.74 per cent) which involves the scam committed by the Nirav Modi. Due to increased frauds in the banking sector, the confidence of the investors adversely affects which may further lead to consequences on concerned banks. In this direction, the results of the study have importance for the policy makers and regulators for analysing the behaviour of stock price with respect to the announcements of frauds in the Indian banking sector.
Book review: Malvika Maheshwari, Art Attacks: Violence and Offense-taking in India
Authors: Liang Lawrence
Published: June 2020

Malvika Maheshwari, Art Attacks: Violence and Offense-taking in India. Oxford University Press. 2019. 372 pages. ₹995.
First Case of Nocardia pseudobrasiliensis Causing Primary Cutaneous Nocardiosis in an Immunocompetent Patient
Authors: Makadia Shraddhadevi , Patel Ishan , Soosaipillai Ivan , Tarasiuk-Rusek Aneta
Published: June 2020

Nocardia brasiliensis is the most common cause of cutaneous nocardiosis. Nocardia pseudobrasiliensis is an emerging species responsible for invasive and disseminated disease in immunocompromised patients. We describe a case of a 67-year-old immunocompetent patient without significant past medical history diagnosed with primary cutaneous nocardiosis with N pseudobrasiliensis as the causative organism. In our opinion, we report the first case of primary cutaneous nocardiosis in an immunocompetent patient with N pseudobrasiliensis being the causative agent.
Return to Sport After Anterior Cruciate Ligament Injury: Panther Symposium ACL Injury Return to Sport Consensus Group
Authors: Meredith Sean J. , Rauer Thomas , Chmielewski Terese L. , Fink Christian , Diermeier Theresa , Rothrauff Benjamin B. , Svantesson Eleonor , Hamrin Senorski Eric , Hewett Timothy E. , Sherman Seth L. , Lesniak Bryson P. ,   the Panther Symposium ACL Injury Return to Sport Consensus Group, Bizzini Mario , Chen Shiyi , Cohen Moises , Villa Stefano Della , Engebretsen Lars , Feng Hua , Ferretti Mario , Fu Freddie H. , Imhoff Andreas B. , Kaeding Christopher C. , Karlsson Jon , Kuroda Ryosuke , Lynch Andrew D. , Menetrey Jacques , Musahl Volker , Navarro Ronald A. , Rabuck Stephen J. , Siebold Rainer , Snyder-Mackler Lynn , Spalding Tim , van Eck Carola , Vyas Dharmesh , Webster Kate , Wilk Kevin
Published: June 2020

Background:

A precise and consistent definition of return to sport (RTS) after anterior cruciate ligament (ACL) injury is lacking, and there is controversy surrounding the process of returning patients to sport and their previous activity level.

Purpose:

The aim of the Panther Symposium ACL Injury Return to Sport Consensus Group was to provide a clear definition of RTS after ACL injury and a description of the RTS continuum as well as provide clinical guidance on RTS testing and decision-making.

Study Design:

Consensus statement.

Methods:

An international, multidisciplinary group of ACL experts convened as part of a consensus meeting. Consensus statements were developed using a modified Delphi method. Literature review was performed to report the supporting evidence.

Results:

Key points include that RTS is characterized by achievement of the preinjury level of sport and involves a criteria-based progression from return to participation to RTS and, ultimately, return to performance. Purely time-based RTS decision-making should be abandoned. Progression occurs along an RTS continuum, with decision-making by a multidisciplinary group that incorporates objective physical examination data and validated and peer-reviewed RTS tests, which should involve functional assessment as well as psychological readiness. Consideration should be given to biological healing, contextual factors, and concomitant injuries.

Conclusion:

The resultant consensus statements and scientific rationale aim to inform the reader of the complex process of RTS after ACL injury that occurs along a dynamic continuum. Research is needed to determine the ideal RTS test battery, the best implementation of psychological readiness testing, and methods for the biological assessment of healing and recovery.
The language corridor revisited: Vernacular scripts and migration pathways
Authors: David Holm
Published: June 2020

Over two decades ago, Jerold Edmondson and Li Jinfang conducted linguistic fieldwork in the China–Vietnam borderlands, and posited the existence of a migration corridor running between Guizhou province and the northern provinces of Vietnam, passing through the eastern part of Yunnan. This hypothesis was based on linguistic evidence, so they called it the language corridor, and looked at the correspondences between the speech of isolated communities in northern Vietnam and speech varieties in Guizhou, Guangxi and Yunnan. Historic migrations of populations, large and small, bring with them other traces of their original homelands. In the case of the Tai-speaking peoples of the China–Vietnam area, the evidence includes local varieties of vernacular character scripts based on Chinese. This article will present new information based on survey evidence, and propose a new enhancement of established methods in historical anthropology and historical linguistics.
Mechanical properties of coconut trunk particle/polyester composite based on alkali treatment
Authors: Hoang Van-Tho , Pham Thanh-Nhut , Yum Young-Jin
Published: June 2020

Coir is a well-known natural fiber extracted from the husk of a coconut tree. In polymer composite materials, the ultimate performance of coir has been shown using surface modification methods. Among them, sodium hydroxide (NaOH) is a comparative and efficient solution used for surface treatment of lignocellulosic fiber. In contrast to coir, coconut timber, a hardwood that dominates the weight of the coconut tree, has not been appropriately considered for use in polymer composites. Therefore, in this article, coconut trunk particle/unsaturated polyester resin composites were experimentally investigated. As a pioneering study, a large range of NaOH concentrations from 2 wt% to 10 wt% (with an interval of 2 wt%) was utilized to treat the surface of the filler. Finally, 4 wt% alkali solution was found as the best content for surface modification based on the mechanical properties of the composite, including those determined by tensile, flexural, and impact test results.
Controversies in the diagnosis of polycystic ovary syndrome
Authors: Rao Preetham , Bhide Priya
Published: June 2020

Polycystic ovary syndrome is a common endocrinological condition which is found to be prevalent in 5–10% of women of reproductive age. Historically, a combination of anovulation and androgen excess was considered a hallmark in the diagnosis of polycystic ovary syndrome. Addition of ultrasound features of polycystic ovary syndrome has improved the detection of variation in the polycystic ovary syndrome phenotype. Despite the widespread use of consensus diagnostic criteria, there remain several unresolved controversies in the diagnosis of polycystic ovary syndrome. Difficulty arises in methods of assessment and types of androgens to be measured to detect biochemical hyperandrogenism, setting a cut-off value for the diagnosis of clinical hyperandrogenism, setting an ultrasound threshold of antral follicle count to diagnose polycystic ovaries and also diagnosing this condition in adolescence where there is no clear definition for ‘irregular cycles’. This article looks at various controversies in the diagnosis of polycystic ovary syndrome.
Interleukin-18 and cytotoxic impairment are independent and synergistic causes of murine virus-induced hyperinflammation
Authors: Tsoukas Paul , Rapp Emily , Van Der Kraak Lauren , Weiss Eric S. , Dang Vinh , Schneider Corinne , Klein Edwin , Picarsic Jennifer , Salcedo Rosalba , Stewart C. Andrew , Canna Scott W.
Published: June 2020

Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are life-threatening hyperinflammatory syndromes typically associated with underlying hematologic and rheumatic diseases, respectively. Familial HLH is associated with genetic cytotoxic impairment and thereby to excessive antigen presentation. Extreme elevation of serum interleukin-18 (IL-18) has been observed specifically in patients with MAS, making it a promising therapeutic target, but how IL-18 promotes hyperinflammation remains unknown. In an adjuvant-induced MAS model, excess IL-18 promoted immunopathology, whereas perforin deficiency had no effect. To determine the effects of excess IL-18 on virus-induced immunopathology, we infected Il18-transgenic (Il18tg) mice with lymphocytic choriomeningitis virus (LCMV; strain Armstrong). LCMV infection is self-limited in wild-type mice, but Prf1−/− mice develop prolonged viremia and fatal HLH. LCMV-infected Il18-transgenic (Il18tg) mice developed cachexia and hyperinflammation comparable to Prf1−/− mice, albeit with minimal mortality. Like Prf1−/− mice, immunopathology was largely rescued by CD8 depletion or interferon-γ (IFNg) blockade. Unlike Prf1−/− mice, they showed normal target cell killing and normal clearance of viral RNA and antigens. Rather than impairing cytotoxicity, excess IL-18 acted on T lymphocytes to amplify their inflammatory responses. Surprisingly, combined perforin deficiency and transgenic IL-18 production caused spontaneous hyperinflammation specifically characterized by CD8 T-cell expansion and improved by IFNg blockade. Even Il18tg;Prf1-haplosufficient mice demonstrated hyperinflammatory features. Thus, excess IL-18 promotes hyperinflammation via an autoinflammatory mechanism distinct from, and synergistic with, cytotoxic impairment. These data establish IL-18 as a potent, independent, and modifiable driver of life-threatening innate and adaptive hyperinflammation and support the rationale for an IL-18–driven subclass of hyperinflammation.
Procoagulant activities of skeletal and cardiac muscle myosin depend on contaminating phospholipid
Authors: Novakovic Valerie A. , Gilbert Gary E.
Published: June 2020

Recent reports indicate that suspended skeletal and cardiac myosin, such as might be released during injury, can act as procoagulants by providing membrane-like support for factors Xa and Va in the prothrombinase complex. Further, skeletal myosin provides membrane-like support for activated protein C. This raises the question of whether purified muscle myosins retain procoagulant phospholipid through purification. We found that lactadherin, a phosphatidyl-l-serine–binding protein, blocked >99% of prothrombinase activity supported by rabbit skeletal and by bovine cardiac myosin. Similarly, annexin A5 and phospholipase A2 blocked >95% of myosin-supported activity, confirming that contaminating phospholipid is required to support myosin-related prothrombinase activity. We asked whether contaminating phospholipid in myosin preparations may also contain tissue factor (TF). Skeletal myosin supported factor VIIa cleavage of factor X equivalent to contamination by ∼1:100 000 TF/myosin, whereas cardiac myosin had TF-like activity >10-fold higher. TF pathway inhibitor inhibited the TF-like activity similar to control TF. These results indicate that purified skeletal muscle and cardiac myosins support the prothrombinase complex indirectly through contaminating phospholipid and also support factor X activation through TF-like activity. Our findings suggest a previously unstudied affinity of skeletal and cardiac myosin for phospholipid membranes.
CD38 deletion of human primary NK cells eliminates daratumumab-induced fratricide and boosts their effector activity
Authors: Naeimi Kararoudi Meisam , Nagai Yuya , Elmas Ezgi , de Souza Fernandes Pereira Marcelo , Ali Syed Abbas , Imus Philip Hollingsworth , Wethington Darren , Borrello Ivan Marques , Lee Dean Anthony , Ghiaur Gabriel
Published: June 2020

Multiple myeloma (MM) is a plasma cell neoplasm that commonly expresses CD38. Daratumumab (DARA), a human monoclonal antibody targeting CD38, has significantly improved the outcome of patients with relapsed or refractory MM, but the response is transient in most cases. Putative mechanisms of suboptimal efficacy of DARA include downregulation of CD38 expression and overexpression of complement inhibitory proteins on MM target cells as well as DARA-induced depletion of CD38high natural killer (NK) cells resulting in crippled antibody-dependent cellular cytotoxicity (ADCC). Here, we tested whether maintaining NK cell function during DARA therapy could maximize DARA-mediated ADCC against MM cells and deepen the response. We used the CRISPR/Cas9 system to delete CD38 (CD38KO) in ex vivo expanded peripheral blood NK cells. These CD38KO NK cells were completely resistant to DARA-induced fratricide, showed superior persistence in immune-deficient mice pretreated with DARA, and enhanced ADCC activity against CD38-expressing MM cell lines and primary MM cells. In addition, transcriptomic and cellular metabolic analysis demonstrated that CD38KO NK cells have unique metabolic reprogramming with higher mitochondrial respiratory capacity. Finally, we evaluated the impact of exposure to all-trans retinoic acid (ATRA) on wild-type NK and CD38KO NK cell function and highlighted potential benefits and drawbacks of combining ATRA with DARA in patients with MM. Taken together, these findings provide proof of concept that adoptive immunotherapy using ex vivo expanded CD38KO NK cells has the potential to boost DARA activity in MM.
Activation of the receptor tyrosine kinase RET improves long-term hematopoietic stem cell outgrowth and potency
Authors: Grey W. , Chauhan R. , Piganeau M. , Huerga Encabo H. , Garcia-Albornoz M. , McDonald N. Q. , Bonnet D.
Published: June 2020

Expansion of human hematopoietic stem cells (HSCs) is a rapidly advancing field showing great promise for clinical applications. Recent evidence has implicated the nervous system and glial family ligands (GFLs) as potential drivers of hematopoietic survival and self-renewal in the bone marrow niche; how to apply this process to HSC maintenance and expansion has yet to be explored. We show a role for the GFL receptor, RET, at the cell surface of HSCs in mediating sustained cellular growth, resistance to stress, and improved cell survival throughout in vitro expansion. HSCs treated with the key RET ligand/coreceptor complex, glial-derived neurotrophic factor and its coreceptor, exhibit improved progenitor function at primary transplantation and improved long-term HSC function at secondary transplantation. Finally, we show that RET drives a multifaceted intracellular signaling pathway, including key signaling intermediates protein kinase B, extracellular signal-regulated kinase 1/2, NF-κB, and p53, responsible for a wide range of cellular and genetic responses that improve cell growth and survival under culture conditions.
Extended clinical and immunological phenotype and transplant outcome in CD27 and CD70 deficiency
Authors: Ghosh Sujal , Köstel Bal Sevgi , Edwards Emily S. J. , Pillay Bethany , Jiménez Heredia Raúl , Erol Cipe Funda , Rao Geetha , Salzer Elisabeth , Zoghi Samaneh , Abolhassani Hassan , Momen Tooba , Gostick Emma , Price David A. , Zhang Yu , Oler Andrew J. , Gonzaga-Jauregui Claudia , Erman Baran , Metin Ayse , Ilhan Inci , Haskologlu Sule , Islamoglu Candan , Baskin Kubra , Ceylaner Serdar , Yilmaz Ebru , Unal Ekrem , Karakukcu Musa , Berghuis Dagmar , Cole Theresa , Gupta Aditya K. , Hauck Fabian , Kogler Hubert , Hoepelman Andy I. M. , Baris Safa , Karakoc-Aydiner Elif , Ozen Ahmet , Kager Leo , Holzinger Dirk , Paulussen Michael , Krüger Renate , Meisel Roland , Oommen Prasad T. , Morris Emma , Neven Benedicte , Worth Austen , van Montfrans Joris , Fraaij Pieter L. A. , Choo Sharon , Dogu Figen , Davies E. Graham , Burns Siobhan , Dückers Gregor , Becker Ruy Perez , von Bernuth Horst , Latour Sylvain , Faraci Maura , Gattorno Marco , Su Helen C. , Pan-Hammarström Qiang , Hammarström Lennart , Lenardo Michael J. , Ma Cindy S. , Niehues Tim , Aghamohammadi Asghar , Rezaei Nima , Ikinciogullari Aydan , Tangye Stuart G. , Lankester Arjan C. , Boztug Kaan
Published: June 2020

Biallelic mutations in the genes encoding CD27 or its ligand CD70 underlie inborn errors of immunity (IEIs) characterized predominantly by Epstein-Barr virus (EBV)-associated immune dysregulation, such as chronic viremia, severe infectious mononucleosis, hemophagocytic lymphohistiocytosis (HLH), lymphoproliferation, and malignancy. A comprehensive understanding of the natural history, immune characteristics, and transplant outcomes has remained elusive. Here, in a multi-institutional global collaboration, we collected the clinical information of 49 patients from 29 families (CD27, n = 33; CD70, n = 16), including 24 previously unreported individuals and identified a total of 16 distinct mutations in CD27, and 8 in CD70, respectively. The majority of patients (90%) were EBV+ at diagnosis, but only ∼30% presented with infectious mononucleosis. Lymphoproliferation and lymphoma were the main clinical manifestations (70% and 43%, respectively), and 9 of the CD27-deficient patients developed HLH. Twenty-one patients (43%) developed autoinflammatory features including uveitis, arthritis, and periodic fever. Detailed immunological characterization revealed aberrant generation of memory B and T cells, including a paucity of EBV-specific T cells, and impaired effector function of CD8+ T cells, thereby providing mechanistic insight into cellular defects underpinning the clinical features of disrupted CD27/CD70 signaling. Nineteen patients underwent allogeneic hematopoietic stem cell transplantation (HSCT) prior to adulthood predominantly because of lymphoma, with 95% survival without disease recurrence. Our data highlight the marked predisposition to lymphoma of both CD27- and CD70-deficient patients. The excellent outcome after HSCT supports the timely implementation of this treatment modality particularly in patients presenting with malignant transformation to lymphoma.
Association between lithium in tap water and suicide mortality rates in Miyazaki Prefecture
Authors: Kozaka Naomi , Takeuchi Shouhei , Ishii Nobuyoshi , Terao Takeshi , Kuroda Yoshiki
Published: June 2020

Background

Most studies have reported that suicide mortality rates are negatively associated with lithium levels in tap water; however, a few studies showed either no association or a positive association. Thus, the association between suicide mortality and lithium levels in tap water remains controversial. To clarify the association, our study evaluated the association between lithium levels in tap water and suicide mortality rates in Miyazaki Prefecture of Japan, after adjusting for confounding factors.

Methods

We measured lithium levels in tap water across the 26 municipalities of Miyazaki Prefecture in Japan. We examined the standardized mortality ratio (SMR) for suicide in each municipality and used the data as the average suicide SMRs over 5 years (2009–2013). Weighted least-squares regression analysis, adjusted for the size of each municipality’s population, was used to investigate the association between lithium levels in tap water and suicide SMRs. In addition to a crude model, in an adjusted model, potential confounding factors (proportion of elderly people, proportion of one-person households, annual marriage rate, annual mean income, unemployment rate, the density of medical doctors per 100,000 people, annual total rainfall, and proportion of people with a college education or higher) were added as covariates.

Results

We showed that male and female suicide SMRs were not associated with lithium levels in tap water in Miyazaki Prefecture. After adjusting for confounders, male suicide SMRs were significantly and positively associated with the proportion of elderly people in the population and annual total rainfall, and female suicide SMRs were associated with the proportion of elderly people in the population.

Conclusions

No association between lithium levels in tap water and suicide mortality rates was found in Miyazaki Prefecture.
Intergenerational transmission of economic success in Austria with a focus on migration and gender
Authors: Reiter Daniel , Palz Mario Thomas , Kreimer Margareta
Published: June 2020

In this paper, we analyse the intergenerational transmission of economic success in Austria using the European Union Statistics on Income and Living Conditions 2011 dataset (EU-SILC 2011). Starting point of the investigation is a two-step estimation procedure, where we detect a significant positve intergenerational association between the economic situation of the parental household and educational attainments as well as gross hourly wages of their male and female descendants independently. Furthermore, we shed some light on the intergenerational social mobility black box by explaining the direct effect of the income situation of the parental generation on attainable wages of the child generation within the transmission system. It turns out that this effect is significantly underestimated when applying ordinary least squares regressions only, where the perceived socioeconomic status is taken exogenous. Finally, we apply instrumental variable quantile regressions to demonstrate that the direct intergenerational economic association between parents and their descendants is strongest for top earners. Alongside this proceeding, we introduce an alternative way to think about the impact of a bundle of additional intergenerational transmission channels like cognitive ability, noncognitive personal traits, and aspects of physical appearance on an empirical level. Overall, the findings of the paper, where special attention is paid to migrants, offer a better understanding on the intergenerational transmission of economic success mechanism and to what extent this process influences income persistence between generations.
Simulating ComBat: how batch correction can lead to the systematic introduction of false positive results in DNA methylation microarray studies
Authors: Zindler Tristan , Frieling Helge , Neyazi Alexandra , Bleich Stefan , Friedel Eva
Published: June 2020

Background

Systematic technical effects—also called batch effects—are a considerable challenge when analyzing DNA methylation (DNAm) microarray data, because they can lead to false results when confounded with the variable of interest. Methods to correct these batch effects are error-prone, as previous findings have shown.

Results

Here, we demonstrate how using the R function ComBat to correct simulated Infinium HumanMethylation450 BeadChip (450 K) and Infinium MethylationEPIC BeadChip Kit (EPIC) DNAm data can lead to a large number of false positive results under certain conditions. We further provide a detailed assessment of the consequences for the highly relevant problem of p-value inflation with subsequent false positive findings after application of the frequently used ComBat method. Using ComBat to correct for batch effects in randomly generated samples produced alarming numbers of false discovery rate (FDR) and Bonferroni-corrected (BF) false positive results in unbalanced as well as in balanced sample distributions in terms of the relation between the outcome of interest variable and the technical position of the sample during the probe measurement. Both sample size and number of batch factors (e.g. number of chips) were systematically simulated to assess the probability of false positive findings. The effect of sample size was simulated using n = 48 up to n = 768 randomly generated samples. Increasing the number of corrected factors led to an exponential increase in the number of false positive signals. Increasing the number of samples reduced, but did not completely prevent, this effect.

Conclusions

Using the approach described, we demonstrate, that using ComBat for batch correction in DNAm data can lead to false positive results under certain conditions and sample distributions. Our results are thus contrary to previous publications, considering a balanced sample distribution as unproblematic when using ComBat. We do not claim completeness in terms of reporting all technical conditions and possible solutions of the occurring problems as we approach the problem from a clinician’s perspective and not from that of a computer scientist. With our approach of simulating data, we provide readers with a simple method to assess the probability of false positive findings in DNAm microarray data analysis pipelines.
A structural UGDH variant associated with standard Munchkin cats
Authors: Struck Ann-Kathrin , Braun Marina , Detering Kim Aline , Dziallas Peter , Neßler Jasmin , Fehr Michael , Metzger Julia , Distl Ottmar
Published: June 2020

Background

Munchkin cats were founded on a naturally occurring mutation segregating into long-legged and short-legged types. Short-legged cats showed disproportionate dwarfism (chondrodysplasia) in which all four legs are short and are referred as standard Munchkin cats. Long-legged animals are referred as non-standard Munchkin cats. A previous study using genome-wide single nucleotide polymorphisms (SNPs) for genome-wide association analysis identified a significantly associated region at 168–184 Mb on feline chromosome (FCA) B1.

Results

In this study, we validated the critical region on FCA B1 using a case-control study with 89 cats and 14 FCA B1-SNPs. A structural variant within UGDH (NC_018726.2:g.173294289_173297592delins108, Felis catus 8.0, equivalent to NC_018726.3:g.174882895_174886198delins108, Felis catus 9.0) on FCA B1 was perfectly associated with the phenotype of short-legged standard Munchkin cats.

Conclusion

This UGDH structural variant very likely causes the chondrodysplastic (standard) phenotype in Munchkin cats. The lack of homozygous mutant phenotypes and reduced litter sizes in standard Munchkin cats suggest an autosomal recessive lethal trait in the homozygote state. We propose an autosomal dominant mode of inheritance for the chondrodysplastic condition in Munchkin cats.