bluuebunny/crossref_metadata_2025 huggingface dataset:
Quantitative PCR (qPCR) vs culture-dependent detection to assess honey contamination by Paenibacillus larvae
Authors: Crudele Simone , Ricchiuti Luciano , Ruberto Addolorato , Rossi Franca
Published: August 2019

The detection/quantification in honey of spores of the bacterial pathogen Paenibacillus larvae, the etiological agent of the American Foulbrood (AFB) infectious disease of honey bee, represents a useful diagnostic tool to identify apiaries at risk of infection and carry out focused prevention measures. Plate count is currently the recommended method used to analyze presence and number of spores for this pathogen. However, its validity needs to be re-assessed since P. larvae field strains have a low rate of germination in culture media.

Therefore, in this study, culture-dependent P. larvae detection/quantification was compared with quantitative PCR (qPCR) based analysis for 139 honey samples collected in 2017 and 2018 from as many apiaries in the Abruzzo region. According to qPCR based detection, 58.27% samples were positive for P. larvae, while only 33.8 % samples were positive by plate count.

Moreover, the levels of contamination with the two methods differed for most samples. Potential false positives were obtained by plate count for 12.9% samples that were negative with the qPCR test. On the other hand, 26.6% samples were culture negative but qPCR positive, suggesting that not all the field strains were able to develop in plate. This was confirmed by obtaining P. larvae growth from those samples after supplementing the medium with germination stimulants.

Results strongly suggested the necessity to improve culture methods or replace them with molecular detection/quantification for a more reliable AFB risk estimation.
Pathogenic impact of transcript isoform switching in 1209 cancer samples covering 27 cancer types using an isoform-specific interaction network
Authors: Kahraman Abdullah , Karakulak Tülay , Szklarczyk Damian , von Mering Christian
Published: August 2019

Under normal conditions, cells of almost all tissue types express the same predominant canonical transcript isoform at each gene locus. In cancer, however, splicing regulation is often disturbed, leading to cancer-specific switches in the most dominant transcripts (MDT). But what is the pathogenic impact of these switches and how are they driving oncogenesis? To address these questions, we have analyzed isoform-specific protein-protein interaction disruptions in 1209 cancer samples covering 27 different cancer types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) project of the International Cancer Genomics Consortium (ICGC). Our study revealed large variations in the number of cancer-specific MDT (cMDT) between cancer types. While carcinomas of the head and neck, or brain, had none or only a few cMDT, cancers of the female reproduction organs showed the highest number of cMDT. Interestingly, in contrast to the mutational load, the number of cMDT was tissue-specific, i.e. cancers arising from the same primary tissue had a similar number of cMDT. Some cMDT were found in 100% of all samples in a cancer type, making them candidates for diagnostic biomarkers. cMDT showed a tendency to fall at densely populated network regions where they disrupted protein interactions in the proximity of pathogenic cancer genes. A gene ontology enrichment analysis showed that these disruptions occurred mostly in enzyme signaling, protein translation, and RNA splicing pathways. Interestingly, no significant correlation between the number of cMDT and the number of coding or non-coding mutations could be identified. However, some transcript expressions correlated with mutations in non-coding splice-site and promoter regions of their genes. This work demonstrates for the first time the large extent of cancer-specific alterations in alternative splicing for 27 different cancer types. It highlights distinct and common patterns of cMDT and suggests novel pathogenic transcripts and markers that induce large network disruptions in cancers.
Sleep deprivation selectively down-regulates astrocytic 5-HT2B receptors and triggers depressive-like behaviors via stimulating P2X7 receptors
Authors: Xia Maosheng , Li Shuai , Liang Shanshan , Li Xiaowei , Li Zexiong , Verkhratsky Alexei , Guan Dawei , Li Baoman
Published: August 2019

Chronic loss of sleep damages health and disturbs quality of life. The long-lasting sleep deprivation (SD) as well as sleep abnormalities is a substantial risk factor for major depressive disorder (MDD), although the underlying mechanisms are not clear. In our previous studies, we report the activation of nucleotide-binding domain and leucine-rich repeat protein-3 (NLRP3) inflammasome induced by long-term SD is P2X7 receptors (P2X7R) dependent, and antidepressant fluoxetine could alleviate this neuroinflammasome via 5-HT2B receptors (5-HT2BR) in astrocytes. Here, we discovered that the chronic SD activates astroglial P2X7 receptors, which in turn selectively down-regulated expression of 5-HT2BR in astrocytes. Stimulation of P2X7R induced by SD suppressed the phosphorylation of AKT and FoxO3a selectively in astrocytes, but not in neurones. The over-expression of FoxO3a in astrocytes inhibited expression of 5-HT2BR. Down-regulation of 5-HT2BR instigated by SD suppressed activation of STAT3 and relieved the inhibition of Ca2+-dependent phospholipase A2 (cPLA2). This latter cascade promoted the release of arachidonic acid (AA) and prostaglandin E2 (PGE2). The depressive-like behaviours induced by SD were alleviated in P2X7R-KO mice. Our study reveals the mechanism underlying chronic SD-induced depressive-like behaviors and highlights that blocking P2X7 receptors or activating 5-HT2BR in astrocytes could play a key role for exploring the therapeutic strategies aimed at the depression evoked by sleep disorders.

Main Points

Chronic SD selectively down-regulates expression of 5-HT2BR through activation of P2X7R in astrocytes. SD promotes the release of AA and PGE2 via the decreased 5-HT2BR, these factors induce depressive-like behaviors.
The putative Gαq-inhibiting pepducin P4Pal10 distinctly modulates function of the Gαi-coupled receptors FPR2 and FFA2R in neutrophils
Authors: Holdfeldt André , Lind Simon , Dahlgren Claes , Forsman Huamei
Published: August 2019

A novel mechanism of action was described, when a protease-activated receptor 4 (P4Pal10) derived lipopeptide (pepducin) was shown to inhibit signaling downstream of several unrelated Gαq-coupled receptors. We show that this putative Gαq-inhibiting pepducin lacks inhibitory effects on signaling downstream of the Gαq-coupled receptors for ATP (P2Y2R) and PAF (PAFR) expressed in human neutrophils. P4Pal10 inhibited however, signaling in neutrophils activated with agonists for the Gαi-coupled formyl peptide receptor 2 (FPR2) but not the closely related FPR1. In addition, the P4Pal10 pepducin was turned into an activating agonist in the presence of an allosteric modulator selective for free fatty acid receptor 2 (FFA2R). The results presented thus reveal Gαq-independent effects of P4Pal10 in modulating FPR2- and FFA2R-mediated neutrophil activation.
Hypusinated eIF5A is expressed in pancreas and spleen of individuals with type 1 and type 2 diabetes
Authors: Mastracci Teresa L. , Colvin Stephanie C. , Padgett Leah R. , Mirmira Raghavendra G.
Published: August 2019

Eukaryotic initiation factor 5A (EIF5A) is found in diabetes-susceptibility loci in mouse and human. eIF5A is the only protein known to contain hypusine (hydroxyputrescine lysine), a polyamine-derived amino acid formed post-translationally in a reaction catalyzed by deoxyhypusine synthase (DHPS). Previous studies showed pharmacologic blockade of DHPS in type 1 diabetic NOD mice and type 2 diabetic db/db mice improved glucose tolerance and preserved beta-cell mass, which suggests that hypusinated eIF5A (eIF5AHyp) may play a role in diabetes pathogenesis by direct action on the beta cells and/or altering the adaptive or innate immune responses. To translate these findings to human, we examined tissue from individuals with and without type 1 and type 2 diabetes to determine the expression of eIF5AHyp. We detected eIF5AHypin beta cells, exocrine cells and immune cells; however, there was also unexpected enrichment of eIF5AHypin pancreatic polypeptide-expressing PP cells. Interestingly, the presence of eIF5AHypco-expressing PP cells was not enhanced with disease. These data identify new aspects of eIF5A biology and highlight the need to examine human tissue to understand disease.
Chromosome-level genome reference ofVenturia effusa, causative agent of pecan scab
Authors: Winter David J. , Charlton Nikki D. , Krom Nick , Shiller Jason , Bock Clive H. , Cox Murray P. , Young Carolyn A.
Published: August 2019

Pecan scab, caused byVenturia effusa, is a devastating disease of pecan (Carya illinoinensis), which results in economic losses on susceptible cultivars throughout the southeastern U.S. To enhance our understanding of pathogenicity inV. effusa, we have generated a complete telomere-to-telomere genome reference ofV. effusaisolate FRT5LL7-Albino. By combining Illumina MiSeq and Oxford Nanopore MinION data, we assembled a 45.2 Mb genome represented by 20 chromosomes and containing 10,820 genes, of which 7,619 have at least one functional annotation. The likely causative mutation of the albino phenotype was identified as a single base insertion and a resulting frameshift in the gene encoding the polyketide synthaseALM1. This genome represents the first full chromosome level assembly of anyVenturiaspecies.
Predominance of deterministic microbial community dynamics in salterns exposed to different light intensities
Authors: Viver Tomeu , Orellana Luis H. , Díaz Sara , Urdiain Mercedes , Ramos‐Barbero María Dolores , González‐Pastor José E. , Oren Aharon , Hatt Janet K. , Amann Rudolf , Antón Josefa , Konstantinidis Konstantinos T. , Rosselló‐Móra Ramon
Published: August 2019

While the dynamics of microbial community assembly driven by environmental perturbations have been extensively studied, our understanding is far from complete, particularly for light‐induced perturbations. Extremely halophilic communities thriving in coastal solar salterns are mainly influenced by two environmental factors—salt concentrations and high sunlight irradiation. By experimentally manipulating light intensity through the application of shading, we showed that light acts as a deterministic factor that ultimately drives the establishment of recurrent microbial communities under near‐saturation salt concentrations. In particular, the stable and highly change‐resistant communities that established under high‐light intensities were dominated (>90% of metagenomic reads) by Haloquadratum spp. and Salinibacter spp. On the other hand, under 37‐fold lower light intensity, different, less stable and change‐resistant communities were established, mainly dominated by yet unclassified haloarchaea and relatively diverse photosynthetic microorganisms. These communities harboured, in general, much lower carotenoid pigment content than their high‐irradiation counterparts. Both assemblage types appeared to be highly resilient, re‐establishing when favourable conditions returned after perturbation (i.e. high‐irradiation for the former communities and low‐irradiation for the latter ones). Overall, our results revealed that stochastic processes were of limited significance to explain these patterns.
The most heat‐resistant conidia observed to date are formed by distinct strains of Paecilomyces variotii
Authors: van den Brule Tom , Punt Maarten , Teertstra Wieke , Houbraken Jos , Wösten Han , Dijksterhuis Jan
Published: August 2019

Fungi colonize habitats by means of spores. These cells are stress‐resistant compared with growing fungal cells. Fungal conidia, asexual spores, formed by cosmopolitan fungal genera like Penicillium, Aspergillus and Peacilomyces are dispersed by air. They are present in places where food products are stored and as a result, they cause food spoilage. Here, we determined the heterogeneity of heat resistance of conidia between and within strains of Paecilomyces variotii, a spoiler of foods such as margarine, fruit juices, canned fruits and non‐carbonized sodas. Out of 108 strains, 31 isolates showed a conidial survival >10% after a 10‐min‐heat treatment at 59°C. Three strains with different conidial heat resistance were selected for further phenotyping. Conidia of DTO 212‐C5 and DTO 032‐I3 showed 0.3% and 2.6% survival in the screening respectively, while survival of DTO 217‐A2 conidia was >10%. The decimal reduction times of these strains at 60°C (D60 value) were 3.7 ± 0.08, 5.5 ± 0.35 and 22.9 ± 2.00 min respectively. Further in‐depth analysis revealed that the three strains showed differences in morphology, spore size distributions, compatible solute compositions and growth under salt stress. Conidia of DTO 217‐A2 are the most heat‐resistant reported so far. The ecological consequences of this heterogeneity of resistance, including food spoilage, are discussed.
Essential roles of interstitial cells in testicular development and function
Authors: Heinrich A. , DeFalco T.
Published: August 2019

Background

Testicular architecture and sperm production are supported by a complex network of communication between various cell types. These signals ensure fertility by: regulating spermatogonial stem/progenitor cells; promoting steroidogenesis; and driving male‐specific differentiation of the gonad. Sertoli cells have long been assumed to be the major cellular player in testis organogenesis and spermatogenesis. However, cells in the interstitial compartment, such as Leydig, vascular, immune, and peritubular cells, also play prominent roles in the testis but are less well understood.

Objectives

Here, we aim to outline our current knowledge of the cellular and molecular mechanisms by which interstitial cell types contribute to spermatogenesis and testicular development, and how these diverse constituents of the testis play essential roles in ensuring male sexual differentiation and fertility.

Methods

We surveyed scientific literature and summarized findings in the field that address how interstitial cells interact with other interstitial cell populations and seminiferous tubules (i.e., Sertoli and germ cells) to support spermatogenesis, male‐specific differentiation, and testicular function. These studies focused on 4 major cell types: Leydig cells, vascular cells, immune cells, and peritubular cells.

Results and Discussion

A growing number of studies have demonstrated that interstitial cells play a wide range of functions in the fetal and adult testis. Leydig cells, through secretion of hormones and growth factors, are responsible for steroidogenesis and progression of spermatogenesis. Vascular, immune, and peritubular cells, apart from their traditionally acknowledged physiological roles, have a broader importance than previously appreciated and are emerging as essential players in stem/progenitor cell biology.

Conclusion

Interstitial cells take part in complex signaling interactions with both interstitial and tubular cell populations, which are required for several biological processes, such as steroidogenesis, Sertoli cell function, spermatogenesis, and immune regulation. These various processes are essential for testicular function and demonstrate how interstitial cells are indispensable for male fertility.
Acupuncture alleviates acid‐ and purine‐induced pain in rodents
Authors: Zhang Ying , Huang Lumei , Kozlov Sergey A. , Rubini Patrizia , Tang Yong , Illes Peter
Published: August 2019

Background and Purpose

We set out to investigate the effects of electroacupuncture (EAP) and moxibustion on pain states mediated by a range of acid‐ and ATP‐sensitive nociceptors in acute and inflammatory rodent pain models.

Experimental Approach

We injected PBS (pH 6.0 or 4.0) or α,β‐methylene ATP into the paw of rats or mice to cause thermal hypersensitivity, which was quantified by the paw withdrawal latency (PWL). Inflammatory pain was induced by the injection of complete Freund's adjuvant (CFA) into the rat paw.

Key Results

EAP and moxibustion counteracted the decrease of PWL mediated by acid‐sensing ion channel 3 (ASIC3) and transient receptor potential vanilloid 1 (TRPV1) channels in response to pH 6.0 PBS, but not that mediated by TRPV1 channels only, initiated by the injection of pH 4.0 PBS. Similarly, EAP and moxibustion prevented the purinergically induced pain which was caused by stimulation of P2X3 (P2X2/3) and P2X7 receptors. The effect of CFA was also relieved by EAP and moxibustion.

Conclusions and Implications

During acute thermal pain and CFA‐induced inflammatory pain, ASIC3/TRPV1 channels and P2X3/P2X7 receptors are activated by protons and exogenous α,β‐methylene ATP or endogenously released ATP respectively. Low‐threshold acute acidic pain mediated by the activation of ASIC3/TRPV1 channels was reversed by EAP/moxibustion, while high‐threshold acidic pain that is mediated exclusively by the activation of TRPV1 channels was not. ASIC3 and P2X3 receptors appear to interact with each other in responding to both protons and ATP, by forming an ASIC3/P2X3 “cognate receptor”, sensitive to EAP/moxibustion.
Molecular and clinical analysis of Chinese patients with anaplastic lymphoma kinase (ALK)‐rearranged non‐small cell lung cancer
Authors: Zhou Xiaoyun , Shou Jiawei , Sheng Jin , Xu Chunwei , Ren Shengxiang , Cai Xiuyu , Chu Qian , Wang Wenxian , Zhen Qinhong , Zhou Yuefen , Li Wenfeng , Pan Hong , Li Hongsen , Sun Tao , Cheng Huanqing , Wang Huina , Lou Feng , Rao Chuangzhou , Cao Shanbo , Pan Hongming , Fang Yong
Published: August 2019

Anaplastic lymphoma kinase (ALK) fusions have been recognized as a therapeutic target in non‐small cell lung cancer (NSCLC). However, molecular signatures and clinical characteristics of the Chinese population with ALK‐rearranged NSCLC are not well elucidated. In the present study, we carried out targeted next‐generation sequencing on tissue and plasma ctDNA samples in 1688 patients with NSCLC. Overall, ALK fusions were detected in 70 patients (4.1%), and the frequencies of ALK fusions detected in tissue and plasma samples were 5.1% and 3.3%, respectively. Additionally, the prevalence of breakpoint locations for EML4‐ALK fusions in ctDNA was significantly correlated with that in tumor tissues (R2 = .91, P = .045). According to age, the incidence rates of ALK fusions among young (age <45 years), middle‐aged (between 45 and 70 years) and elderly (>70 years) patients were significantly different (P < .001). In 70 ALK‐rearranged cases, coexistence of epidermal growth factor receptor (EGFR) alterations and ALK fusions was detected in 12 cases (17.1%) and EGFR mutations tended to coexist with non‐EML4‐ALK rearrangements. Notably, novel ALK fusion partners, including TRIM66, SWAP70, WNK3, ERC1, TCF12 and FBN1 were identified in the present study. Among EML4‐ALK fusion variants, patients with variant V1 were younger than patients with variant V3 (P = .023), and TP53 mutations were more frequently concurrent with variant V3 compared with variant V1 (P = .009). In conclusion, these findings provide new insights into the molecular‐clinical profiles of patients with ALK‐rearranged NSCLC that may improve the treatment strategy of this population.
Effect of isoxazole derivatives of tetrahydrofuran neolignans on intracellular amastigotes of Leishmania (Leishmania) amazonensis: A structure–activity relationship comparative study with triazole‐neolignan‐based compounds
Authors: das Neves Amarith R. , Trefzger Ozildéia S. , Barbosa Natália V. , Honorato Antonio M. , Carvalho Diego B. , Moslaves Iluska S. , Kadri Mônica C. T. , Yoshida Nidia C. , Kato Massuo J. , Arruda Carla C. P. , Baroni Adriano C. M.
Published: August 2019

Isoxazole analogues derived from the neolignans veraguensin, grandisin, and machilin G were previously synthesized with different substitution patterns through the bioisosterism strategy. These compounds were tested on intracellular amastigotes of Leishmania (Leishmania) amazonensis; the derivatives proved to be active against intracellular amastigotes, with IC50 values ranging from 0.4 to 25 μM. The most active analogues were 4′, 14′, 15′, and 18′, with IC50 values of 0.9, 0.4, 0.7, and 1.4 μM, respectively, showing high selectivity indexes (SI = 277.0; 625.0; 178.5 and 357.1). Overall, the isoxazole analogues did not induce nitric oxide (NO) production by infected cells; there was no evidence that NO influences the antileishmanial mechanism of action, except for compound 4′. Trimethoxy groups as substituents seemed to be critical for antileishmanial activity. The SAR study demonstrated that the isoxazole compounds were more active than 1,2,3‐triazole compounds with the same substitution pattterns, demonstrating the importance of the bioisosterism strategy in drug design.
Estimation of minimally important differences and responder definitions for EORTC QLQ‐MY20 scores in multiple myeloma patients
Authors: Sully Kate , Trigg Andrew , Bonner Nicola , Moreno‐Koehler Alejandro , Trennery Claire , Shah Nina , Yucel Emre , Panjabi Sumeet , Cocks Kim
Published: August 2019

Objectives

Thresholds for the minimally important difference (MID) or responder definition (RD) in health‐related quality‐of‐life (HRQoL) scores are required to interpret the impact of an intervention or change in the trajectory of the condition which is meaningful to patients. This study aimed to establish MID and RD for the European Organisation for Research and Treatment of Cancer Quality of Life Multiple Myeloma questionnaire (EORTC QLQ‐MY20).

Methods

A novel mixed‐methods approach was applied by utilizing both existing clinical trial data and prospective patient interviews. Anchor‐based, distribution‐based, and qualitative‐based estimates of meaningful change were triangulated to form recommended RDs for each scale of the EORTC QLQ‐MY20. Anchor‐based MIDs were summarized using weighted correlation.

Results

Recommended MIDs were as follows: Disease Symptoms (DS 10 points), Side Effects of Treatment (SE 10 points), Body Image (BI 13 points), and Future Perspective (FP 9 points). Recommended RDs were as follows: DS (16 improvement; 11 worsening), SE (6 improvement; 9 worsening), BI (33 improvement; 33 worsening), and FP (11 improvement; 11 worsening).

Conclusions

The study generated estimates of the MID and RD for each scale of the EORTC QLQ‐MY20. Published estimates will enable investigators and clinicians to adopt these as standard for interpretation and for hypothesis testing. Consequently, analyses from trials of different interventions can be more comparable.
Efficacy and safety of a new resilient hyaluronic acid dermal filler, in the correction of moderate‐to‐severe nasolabial folds: A 64‐week, prospective, multicenter, controlled, randomized, double‐blind and within‐subject study
Authors: Kaufman‐Janette Joely , Taylor Susan C. , Cox Sue Ellen , Weinkle Susan H. , Smith Stacy , Kinney Brian M.
Published: August 2019

Background

Injectables that behave similarly to native tissue and preserve facial expressiveness represent a new frontier in aesthetic medicine. A range of fillers made of high molecular weight hyaluronic acid (HA) chains with low crosslinking have been specifically developed to complement facial dynamics.

Aims

The efficacy and safety of one of these resilient HA fillers, and its noninferiority to an effective comparator available in the US, were tested in the treatment of dynamic wrinkles.

Methods

A 15‐month, prospective, multicenter, controlled, randomized, double‐blind, within‐subject (split‐face) clinical trial was conducted on 140 subjects with moderate‐to‐severe nasolabial folds (NLF). Study endpoints included improvement on a proprietary Wrinkle Severity Rating Scale (WSRS) and Global Aesthetic Improvement Scale, according to Blind Live Evaluators (BLE), subjects, and treating investigators (TI). Subject perception was evaluated with FACE‐Q and satisfaction scales.

Results

The per‐protocol population included 88 subjects (92% women) of all Fitzpatrick phototypes, with a mean age of 57 years. WSRS improvement was significantly greater with the resilient HA than its comparator over 15 months, including at week 24 (primary endpoint), as rated by BLE and TI. Results demonstrated the noninferiority of the resilient HA filler to its comparator. Aesthetic improvement and subject satisfaction were durably high, with an overall trend toward higher scores for the resilient HA filler. Both treatments were safe and well tolerated.

Conclusion

The resilient HA filler made of long chains lightly crosslinked is at least equivalent to a well‐established comparator for the correction of NLF in subjects of diverse skin phototypes.
Behavioural, physiological and molecular changes in alloparental caregivers may be responsible for selection response for female reproductive investment in honey bees
Authors: Wu Fan , Ma Chuan , Han Bin , Meng Lifeng , Hu Han , Fang Yu , Feng Mao , Zhang Xufeng , Rueppell Olav , Li Jianke
Published: August 2019

Reproductive investment is a central life history variable that influences all aspects of life. Hormones coordinate reproduction in multicellular organisms, but the mechanisms controlling the collective reproductive investment of social insects are largely unexplored. One important aspect of honey bee (Apis mellifera) reproductive investment consists of raising female‐destined larvae into new queens by alloparental care of nurse bees in form of royal jelly provisioning. Artificial selection for commercial royal jelly production over 40 years has increased this reproductive investment by an order of magnitude. In a cross‐fostering experiment, we establish that this shift in social phenotype is caused by nurse bees. We find no evidence for changes in larval signalling. Instead, the antennae of the nurse bees of the selected stock are more responsive to brood pheromones than control bees. Correspondingly, the selected royal jelly bee nurses are more attracted to brood pheromones than unselected control nurses. Comparative proteomics of the antennae from the selected and unselected stocks indicate putative molecular mechanisms, primarily changes in chemosensation and energy metabolism. We report expression differences of several candidate genes that correlate with the differences in reproductive investment. The functional relevance of these genes is supported by demonstrating that the corresponding proteins can competitively bind one previously described and one newly discovered brood pheromone. Thus, we suggest several chemosensory genes, most prominently OBP16 and CSP4, as candidate mechanisms controlling queen rearing, a key reproductive investment, in honey bees. These findings reveal novel aspects of pheromonal communication in honey bees and explain how sensory changes affect communication and lead to a drastic shift in colony‐level resource allocation to sexual reproduction. Thus, pheromonal and hormonal communication may play similar roles for reproductive investment in superorganisms and multicellular organisms, respectively.
Technical Note: Optimal Salesforce Compensation with Supply–Demand Mismatch Costs
Authors: Xiao Binqing , Xiao Wenqiang
Published: August 2019

In this study, we characterize the optimal compensation scheme for a firm that sells a single product with a limited stocking quantity through a sales agent. Our focus is on understanding how the supply–demand mismatch costs affect the firm’s optimal compensation scheme. There are two main findings. First, under the deterministic demand response, the classical optimality result of the convex increasing compensation scheme breaks with the consideration of supply–demand mismatch costs. Instead, the optimal compensation is S‐shaped under certain conditions. Second, under the stochastic demand response, the classical optimality result of the menu of linear compensation schemes fails to hold with the consideration of supply–demand mismatch costs. Instead, the optimal compensation schemes consist of a menu of linear compensation coupled with a penalty of the agent’s forecast error.
Post‐phenomenology and space: A geography of comprehension, form and power
Authors: Ash James
Published: August 2019

Post‐phenomenological geographies have critiqued the idea that the world appears for humans alone. In turn, these geographies have begun to develop concepts to investigate the way entities appear to one another in ways that exceed or confound human sense, while recognising that these entities can only be investigated through human modes of access. Addressing the absence of explicit spatial theorisation in this literature, the paper develops a post‐phenomenological account of space. Building on relational and phenomenological geographies and expanding the work of Tristan Garcia, the paper analyses space in terms of the comprehension and form of entities. In doing so, it defines space as a dual process of differentiation and distanciation that produces different modes of nearness and farness that are specific to the intercomprehension of particular entities. Through this analysis the paper offers an account of power as tied to the spatiality of entities, where power is defined as the inequality of comprehensions between entities and how these inequalities are designed to provoke and encourage particular forms of engagement.
Towards understanding global patterns of antimicrobial use and resistance in neonatal sepsis: insights from the NeoAMR network
Authors: Li Grace , Bielicki Julia Anna , Ahmed A S M Nawshad Uddin , Islam Mohammad Shahidul , Berezin Eitan Naaman , Gallacci Clery B , Guinsburg Ruth , da Silva Figueiredo Carlos Eduardo , Santarone Vieira Rosilene , Silva Andre Ricardo , Teixeira Cristiane , Turner Paul , Nhan Ladin , Orrego Jaime , Pérez Paola Marsela , Qi Lifeng , Papaevangelou Vassiliki , Triantafyllidou Pinelope , Iosifidis Elias , Roilides Emmanuel , Sarafidis Kosmas , Jinka Dasaratha Ramaiah , Nayakanti Raghuprakash Reddy , Kumar Praveen , Gautam Vikas , Prakash Vinayagam , Seeralar Arasar , Murki Srinivas , Kandraju Hemasree , Singh Sanjeev , Kumar Anil , Lewis Leslie , Pukayastha Jayashree , Nangia Sushma , K N Yogesha , Chaurasia Suman , Chellani Harish , Obaro Stephen , Dramowski Angela , Bekker Adrie , Whitelaw Andrew , Thomas Reenu , Velaphi Sithembiso Christopher , Ballot Daynia Elizabeth , Nana Trusha , Reubenson Gary , Fredericks Joy , Anugulruengkitt Suvaporn , Sirisub Anongnart , Wong Pimol , Lochindarat Sorasak , Boonkasidecha Suppawat , Preedisripipat Kanchana , Cressey Tim R , Paopongsawan Pongsatorn , Lumbiganon Pagakrong , Pongpanut Dounghatai , Sukrakanchana Pra-ornsuda , Musoke Philippa , Olson Linus , Larsson Mattias , Heath Paul T , Sharland Michael
Published: August 2019

Objective

To gain an understanding of the variation in available resources and clinical practices between neonatal units (NNUs) in the low-income and middle-income country (LMIC) setting to inform the design of an observational study on the burden of unit-level antimicrobial resistance (AMR).

Design

A web-based survey using a REDCap database was circulated to NNUs participating in the Neonatal AMR research network. The survey included questions about NNU funding structure, size, admission rates, access to supportive therapies, empirical antimicrobial guidelines and period prevalence of neonatal blood culture isolates and their resistance patterns.

Setting

39 NNUs from 12 countries.

Patients

Any neonate admitted to one of the participating NNUs.

Interventions

This was an observational cohort study.

Results

The number of live births per unit ranged from 513 to 27 700 over the 12-month study period, with the number of neonatal cots ranging from 12 to 110. The proportion of preterm admissions <32 weeks ranged from 0% to 19%, and the majority of units (26/39, 66%) use Essential Medicines List ‘Access’ antimicrobials as their first-line treatment in neonatal sepsis. Cephalosporin resistance rates in Gram-negative isolates ranged from 26% to 84%, and carbapenem resistance rates ranged from 0% to 81%. Glycopeptide resistance rates among Gram-positive isolates ranged from 0% to 45%.

Conclusion

AMR is already a significant issue in NNUs worldwide. The apparent burden of AMR in a given NNU in the LMIC setting can be influenced by a range of factors which will vary substantially between NNUs. These variations must be considered when designing interventions to improve neonatal mortality globally.
A 3-year follow-up study of a new corneal inlay: clinical results and outcomes
Authors: Beer Sandra Maria Canelas , Werner Liliana , Nakano Eliane Mayumi , Santos Rodrigo T , Hirai Flavio , Nitschke Enrico J , Francesconi Benicio Claudia , Campos Mauro S Q
Published: August 2019

Purpose

Here, we report the results of a 3-year follow-up analysis of the outcomes of the Flexivue Microlens corneal inlay.

Patients

Non-dominant eyes (n=31) of emmetropic presbyopic patients (spherical equivalent: −0.5 to 1.00 dioptre).

Methods

A Flexivue Microlens corneal inlay was implanted after the creation of a 300 μm deep stromal pocket using a femtosecond laser. Patients were followed up according to a clinical protocol involving refraction, anterior segment imaging analysis (Oculyser), optical quality analysis (OPD-Scan), monocular binocular uncorrected and corrected visual acuity tests, contrast sensitivity measurements (photopic and mesopic), satisfaction questionnaire results and adverse event reporting.

Results

Thirty patients were examined at the 3-year follow-up in this ongoing study. The mean uncorrected near visual acuity improved to Jaeger 1 in 76.9% of eyes treated with the inlays (vs 87.1% at the 1-year follow-up). All eyes improved four lines in all visits, except for four patients for whom the inlay was explanted. Patients reported that their near vision was good or excellent in 73.3% of cases (vs 90.3% in the first year). The UDVA remained stable over time. Three patients were explanted due to blurred vision for near-point and far-point distances. One patient developed a superficial corneal ulcer after 20 months. Two patients underwent cataract removal. Four patients underwent inlay exchange to increase near power correction.

Conclusions

The Presbia Flexivue Microlens provided presbyopia treatment by improving near vision. Manageable complications may occur over the long term.

Clinical trial registration number

U1111-1185-5684 and 0310451200000550.
Relationship between gay app use and HIV testing among men who have sex with men in Shenzhen, China: a serial cross-sectional study
Authors: Wei Lan , Chen Lin , Zhang Haibo , Yang Zhengrong , Liu Shaochu , Tan Wei , Xie Wei , Liu Liegang , Zhao Jin , Cheng Jinquan
Published: August 2019

Objectives

To investigate the relationship between gay app use and HIV testing among men who have sex with men (MSM).

Design

Serial cross-sectional study.

Setting

A newly well-developed city in China.

Participants

4935 MSM were recruited through offline sampling methods from 2015 to 2017.

Primary and secondary outcomes

The primary outcome is the difference in HIV testing between app and non-app users.

Results

2872 (58.2%) and 2159 (43.7%) participated MSM had been tested for HIV within lifetime and the past year, respectively. Compared with non-app-using MSM, app-using MSM had a significantly higher prevalence of HIV testing within lifetime (adjusted OR (AOR): 1.48, 95% CI 1.27 to 1.72) and the past year (AOR: 1.36, 95% CI 1.18 to 1.57). App-using MSM were more likely to take an HIV test at the Centers for Disease Control and Prevention (AOR: 1.48, 95% CI 1.24 to 1.76) and community-based organisations (AOR: 1.71, 95% CI 1.44 to 2.03), but less often at gay venues (AOR: 0.49, 95% CI 0.37 to 0.63). Meanwhile, app-using MSM were more likely to take self-testing (AOR: 1.61, 95% CI 1.21 to 2.14). Predictors of HIV testing in the past year were: having an education level of college or higher (AOR: 1.29, 95% CI 1.01 to 1.65), being self-identified as a homosexual (AOR: 1.23, 95% CI 1.02 to 1.46), being recruited through clinic-based sampling (AOR: 1.30, 95% CI 1.06 to 1.60), using gay app (AOR: 1.49, 95% CI 1.21 to 1.83), engaging in group sex (AOR: 1.64, 95% CI 1.23 to 2.19), having received HIV-related service (AOR: 5.49, 95% CI 4.57 to 6.60), having a high level of HIV-related knowledge (AOR: 1.33, 95% CI 1.10 to 1.61) and high-risk perception (AOR: 2.95, 95% CI 1.40 to 6.23).

Conclusions

Gay app use was significantly associated with increased HIV testing among MSM hard to reach by traditional outreach. Therefore, it is imperative to expand HIV testing among non-app-using MSM. Continued efforts, innovative strategies and increased resource are highly needed to realise the first ‘90’ target.
Media Coverage of the Benefits and Harms of Testing the Healthy: a protocol for a descriptive study
Authors: O'Keeffe Mary , Barratt Alexandra , Maher Christopher , Zadro Joshua , Fabbri Alice , Jones Mark , Moynihan Ray
Published: August 2019

Introduction

Much testing in medicine is aimed at healthy people to facilitate the early detection of health conditions. However, there is growing evidence that early detection is a double-edged sword that may cause harm in the form of overdiagnosis. The media can be seen as a major generator of consumer demand for health services. Previous research shows that media coverage tends to overstate the benefits and downplay the harms of medical interventions for the sick, and often fails to cover relevant conflicts of interest of those promoting those interventions. However, little is known about how the benefits and harms of testing the healthy are covered by media. This study will examine the media coverage of the benefits and harms of testing the healthy, and coverage of potential conflicts of interest of those promoting the testing.

Methods and analysis

We will examine five tests: 3D mammography for the early detection of breast cancer; blood liquid biopsy for the early detection of cancer; blood biomarker tests for the early detection of dementia; artificial intelligence technology for the early detection of dementia; and the Apple Watch Series 4 electrocardiogram sensor for the early detection of atrial fibrillation. We will identify media coverage using Google News and the LexisNexis and ProQuest electronic databases. Sets of two independent reviewers will conduct story screening and coding. We will include English language media stories referring to any of the five tests from January 2016 to May 2019. We will include media stories if they refer to any benefits or harms of the test for our conditions of interest. Data will be analysed using categorical data analysis and multinomial logistic regression.

Ethics and dissemination

No ethical approval is required for this study. Results will be presented at relevant scientific conferences and in peer-reviewed literature.
Access delays to essential surgical care using the Three Delays Framework and Bellwether procedures at Timor Leste’s national referral hospital
Authors: Bagguley Dominic , Fordyce Andrew , Guterres Jose , Soares Alito , Valadares Edgar , Guest Glenn Douglas , Watters David
Published: August 2019

Objectives

Our objectives were to characterise the nature and extent of delay times to essential surgical care in a developing nation by measuring the actual stages of delay for patients receiving Bellwether procedures.

Setting

The study was conducted at Timor Leste’s national referral hospital in Dili, the country’s capital.

Participants

All patients requiring a Bellwether procedure over a 2-month period were included in the study. Participants whose procedure was undertaken more than 24 hours from initial hospital presentation were excluded.

Primary and secondary outcome measures

Data pertaining to the patient journey from onset of symptoms to emergency procedure was collected by interview of patients, their treating surgeons or anaesthetists and the medical records. Timelines were then calculated against the Three Delays Framework.

Results

Fifty-six patients were entered into the study. Their mean delay from symptom onset to entering the anaesthesia bay for a procedure was 32.3 hours (+/-11.6). The second delay (4.1+/-2.5 hours) was significantly less than the first (20.9+/-11.5 hours; p<0.005) and third delays (7.2+/-1.2 hours; p<0.05). Additionally, patients with acute abdominal pain (of which 18/20 ultimately had open appendicectomy and two emergency laparotomies) had a delay time of 53.3 hours (+/-21.3), significantly more than that for emergency caesarean (22.9+/-18.6 hours; p<0.05) or management of an open long-bone fracture (15.5+/-5.56 hours; p<0.05).

Conclusions

Substantial delays were observed for all three stages and each Bellwether procedure. This study methodology could be used to measure access and the three delays to emergency surgical care in low/middle-income countries, although the actual reasons for delay may vary between regions and countries and would require a qualitative study.
A mixed-methods study of challenges experienced by clinical teams in measuring improvement
Authors: Woodcock Thomas , Liberati Elisa G , Dixon-Woods Mary
Published: August 2019

Objective

Measurement is an indispensable element of most quality improvement (QI) projects, but it is undertaken to variable standards. We aimed to characterise challenges faced by clinical teams in undertaking measurement in the context of a safety QI programme that encouraged local selection of measures.

Methods

Drawing on an independent evaluation of a multisite improvement programme (Safer Clinical Systems), we combined a qualitative study of participating teams’ experiences and perceptions of measurement with expert review of measurement plans and analysis of data collected for the programme. Multidisciplinary teams of frontline clinicians at nine UK NHS sites took part across the two phases of the programme between 2011 and 2016.

Results

Developing and implementing a measurement plan against which to assess their improvement goals was an arduous task for participating sites. The operational definitions of the measures that they selected were often imprecise or missed important details. Some measures used by the teams were not logically linked to the improvement actions they implemented. Regardless of the specific type of data used (routinely collected or selected ex novo), the burdensome nature of data collection was underestimated. Problems also emerged in identifying and using suitable analytical approaches.

Conclusion

Measurement is a highly technical task requiring a degree of expertise. Simply leveraging individual clinicians’ motivation is unlikely to defeat the persistent difficulties experienced by clinical teams when attempting to measure their improvement efforts. We suggest that more structural initiatives and broader capability-building programmes should be pursued by the professional community. Improving access to, and ability to use repositories of validated measures, and increasing transparency in reporting measurement attempts, is likely to be helpful.
The relationships between rugby union and health: a scoping review protocol
Authors: Griffin Steffan Arthur , Panagodage Perera Nirmala Kanthi , Murray Andrew , Hartley Catherine , Brooks John H M , Kemp Simon P T , Stokes Keith A
Published: August 2019

Introduction

Rugby union is played by over eight million people across the world and is considered a form of moderate-to-vigorous physical activity. Consequently, playing rugby may confer health benefits; however, to date, the principal focus of research has been on associated injuries and potential detrimental long-term health sequelae. This protocol outlines the methods behind studying any potential associations between rugby union and both physical and mental health.

Methods and analysis

Best practice methodological frameworks (Arksey and O'Malley, Levacet aland the Joanna Briggs Institute) and previously published scoping review protocols in sport informs the methodology of this protocol. This protocol enables us to map the key concepts and evidence available, summarise and share existing research ﬁndings, and identify research gaps in the current literature. A three-step search strategy will identify reviews, original research, and published and grey literature. An initial search will identify suitable search terms, followed by a search using keyword and index terms. Two reviewers will independently screen identiﬁed studies for final inclusion.

Dissemination

When publishing the scoping review, we will map key concepts and evidence both numerically and thematically, as well as identify key research priorities for further studies. The review will subsequently be disseminated to stakeholder groups, practitioners and policymakers through a variety of peer-reviewed and non-peer-reviewed publications, conferences and via multimedia platforms.
Flow diversion treatment for acutely ruptured aneurysms
Authors: ten Brinck Michelle F M , Jäger Maike , de Vries Joost , Grotenhuis J André , Aquarius René , Mørkve Svein H , Rautio Riitta , Numminen Jussi , Raj Rahul , Wakhloo Ajay K , Puri Ajit S , Taschner Christian A , Boogaarts Hieronymus D
Published: August 2019

Background and purpose

Flow diverters are sometimes used in the setting of acutely ruptured aneurysms. However, thromboembolic and hemorrhagic complications are feared and evidence regarding safety is limited. Therefore, in this multicenter study we evaluated complications, clinical, and angiographic outcomes of patients treated with a flow diverter for acutely ruptured aneurysms.

Methods

We conducted a retrospective observational study of 44 consecutive patients who underwent flow diverter treatment within 15 days after rupture of an intracranial aneurysm at six centers. The primary end point was good clinical outcome, defined as modified Rankin Scale score (mRS) 0–2. Secondary endpoints were procedure-related complications and complete aneurysm occlusion at follow-up.

Results

At follow-up (median 3.4 months) 20 patients (45%) had a good clinical outcome. In 20 patients (45%), 25 procedure-related complications occurred. These resulted in permanent neurologic deficits in 12 patients (27%). In 5 patients (11%) aneurysm re-rupture occurred. Eight patients died resulting in an all-cause mortality rate of 18%. Procedure-related complications were associated with a poor clinical outcome (mRS 3–6; OR 5.1(95% CI 1.0 to 24.9), p=0.04). Large aneurysms were prone to re-rupture with rebleed rates of 60% (3/5) vs 5% (2/39) (p=0.01) for aneurysms with a size ≥20 mm and <20 mm, respectively. Follow-up angiography in 29 patients (median 9.7 months) showed complete aneurysm occlusion in 27 (93%).

Conclusion

Flow diverter treatment of ruptured intracranial aneurysms was associated with high rates of procedure-related complications including aneurysm re-ruptures. Complications were associated with poor clinical outcome. In patients with available angiographic follow-up, a high occlusion rate was observed.
Evolutionary Models of Preference Formation
Authors: Alger Ingela , Weibull Jörgen W.
Published: August 2019

The literature on the evolution of preferences of individuals in strategic interactions is vast and diverse. We organize the discussion around the following question: Supposing that material outcomes drive evolutionary success, under what circumstances does evolution promote Homo economicus, defined as material self-interest, and when does it instead lead to other preferences? The literature suggests that Homo economicus is favored by evolution only when individuals’ preferences are their private information and the population is large and well-mixed, so that individuals with rare mutant preferences almost never get to interact with each other. If rare mutants instead interact more often (say, due to local dispersion), then evolution instead favors a certain generalization of Homo economicus including a Kantian concern. If individuals interact under complete information about preferences, then evolution destabilizes Homo economicus in virtually all games.