bluuebunny/crossref_metadata_2025 huggingface dataset:
119 A Descriptive Epidemiological Study of Clinical Trials, Comparing Trials Targeted At Older People to Adults of All Ages
Authors: Renton J P , McAllister D
Published: March 2021

Introduction

Fewer clinical trials are carried out in older people. It is unclear how representative and applicable clinical trials carried out exclusively in older people are. We compared clinical trials recruiting older people exclusively “older trials” to those recruiting adults of all ages “all age trials”, using anti-hypertensives acting on the renin-angiotensin aldosterone system (RAAS drugs) as an exemplar.

Method

We searched the US clinical trials register 1, to identify all trials carried out exclusively in those aged over 60. From these we selected trials of RAAS drugs. These were matched in a 2:1 ratio to trials carried out in adults of all ages. Data regarding baseline characteristics, adverse events and eligibility criteria were collected from clinical trial reports and clinicaltrials.gov. Estimated associations were calculated for age, sex and adverse events. Eligibility criteria were described and ICD- 10 coded, as appropriate.

Results

71 clinical trials were carried out exclusively in older people.13 related to RAAS drugs. Participants in “Older trials” had higher mean age (73.1 and 55.9 respectively), mean difference 16.17 (CI 15.31–17.02). Older trials had fewer male participants. Participants in older trials had lower mean body mass index (BMI). A higher rate of participants in older trials experienced serious adverse events. (2.07, CI 1.55–2.75.) Few older trials had upper age limits (23.1% V 27% all age trials). All trials had exclusion criteria in multiple ICD blocks. Concurrent medications were a more common exclusion criterion in older trials (61.5% v 40.9%).

Conclusions

Clinical trials carried out exclusively in older people are representative in terms of age, serious adverse events and eligibility. Although there are multiple exclusion criteria for clinical trial participation in both groups, this is not prohibitive. This supports carrying out more trials exclusively in older people. References 1. NIH, US national library of medicine.ClinicalTrials.gov Available at https://clinicaltrials.gov/
129 “Pop-Up” Specialist End of Life Ward For COVID-19—The Nottingham Experience
Authors: Arnott R , Lewis A , Berbecila D , Deery J , Wells L , Poon M H
Published: March 2021

Background

Our hospital trust anticipated an increased need for palliation and end of life care (EoLC) in patients with Covid-19 who were not appropriate for escalation and mechanical ventilation.

Intervention

A dedicated ward was opened as part of the trust-wide Covid-19 admissions pathway, led by geriatricians with palliative care input and staffed by relocated nursing and auxiliary personnel. Retrospective data was collected for consecutive patients admitted to the ward between 3rd April and 26th May 2020 and qualitative data regarding staff experience using a questionnaire.

Result

Of the 168 patients (55% male) admitted, 31.5% came directly from Emergency Department, 17.3% from admission areas and the remainder from inpatient wards. Time spent on the ward ranged from 10 minutes to 17 days (median length of stay 43 hours). 75% had Clinical Frailty Scale score of 6 or more. 150 died with 75% naming Covid-19 as primary cause or contributing factor. Ward staff, who were not palliative care specialists, reported increased confidence in many aspects of palliation including assessing comfort, relieving symptoms, prescribing and administering anticipatory medications and in supporting and communicating with relatives. Staff apprehension about working on a Covid ward eased once the ward was established. Qualitative themes emerging from staff feedback included: professional competency, communication, prioritisation, team work, emotional response, care and consistency in a time of change.

Discussion

The pathway and referral system ensured that our ward cared for appropriate older patients living with frailty. The formation of a specialist unit over a short period of time created a series of logistical and management challenges. The emotional burden felt by staff was also prominent in feedback. These challenges were outweighed by the personal and professional development of staff coupled with the strong sense of teamwork, pride and enthusiasm felt in providing high quality care.
134 A Quality Improvement Project—Physiotherapy Caseload Management on the Older Person’s Unit
Authors: Snape C , Triteos N , Wood C A , Robert G , Jones J
Published: March 2021

Introduction

Complex health issues, co-morbidities and the number of patients living with frailty are critical concerns associated with the ageing population (Kojima et al, 2019). In this wider context, there is an emphasis on targeting resources efficaciously within the NHS. A consequence of capacity constraints, inpatient physiotherapy teams across the OPU at a large urban teaching hospital, prioritise their patient caseload, but lack evidence-based guidance on dosage and frequency of physiotherapy intervention, to inform the process. The aim of the quality improvement project was to design and deliver a staff education and training package to facilitate implementation of a newly-developed, evidence-based prioritisation resource.

Method

Plan-Do-Study-Act cycles and the Com-B model to influence behaviour changes were employed between October 2019 and March 2020. Stakeholders were engaged throughout the design process. Training to all 11 physiotherapists consisted of familiarisation with the resource through content discussion and “mock-use” training sessions to ensure intra/inter-rater-reliabilty. Physiotherapist staff knowledge and confidence of prioritisation was evaluated by questionnaire. Accuracy of use of the prioritisation tool was determined by comparison of staff prioritisation decision with expert opinion.

Results

From the 11 questionnaire responses, pre to post intervention physiotherapy knowledge of the prioritisation categories increased (43% to 100%), physiotherapist rated confidence using the prioritisation tool increased (mean score, 6.9 to 8.2/10) and accuracy of prioritisation of patients improved (mean 42.1% to 92.3%).

Conclusion

The education and training package developed to support implementation of the prioritisation tool resulted in improved staff knowledge and confidence of patient prioritisation and increased the accuracy of OPU physiotherapy targeting. This project has highlighted the importance of staff training in resource allocation to ensure that decisions regarding which patients receive physiotherapy intervention are efficacious. This has increased relevance in a department with a large number of rotational staff.
Comparison of Nuclear Grade, Necrosis, and Histologic Subtype Between Biopsy and Resection in Pleural Malignant Mesothelioma: An International Multi-Institutional Analysis
Authors: Schulte Jefree J , Chapel David B , Attanoos Richard , Brcic Luka , Burn Juliet , Butnor Kelly J , Chang Nina , Chen Heather , Dacic Sanja , De Perrot Marc , Fukuoka Junya , Galateau-Salle Francoise , Godschachner Theresa , Hiroshima Kenzo , Klebe Sonja , Krausz Thomas , Litzky Leslie , Marchevsky Alberto M , Mueller Jeffrey , Nabeshima Kazuki , Nicholson Andrew G , Pal Prodipto , Roden Anja C , Rorvig Sara , Santoni-Rugiu Eric , Tazelaar Henry , Tsao Ming-Sound , Walts Ann E , Weynand Birgit , Zaizen Yoshiaki , Zhang Yu Zhi , Husain Aliya N
Published: March 2021

Objectives

Numerous studies on malignant mesothelioma (MM) highlight the prognostic importance of histologic subtype, nuclear grade, and necrosis. This study compares these parameters in paired biopsy and resection specimens of pleural MM.

Methods

Histologic subtype, percentage of epithelioid morphology, nuclear grade, and the presence or absence of necrosis were compared in 429 paired biopsies and resection specimens of pleural MM from 19 institutions.

Results

Histologic subtype was concordant in 81% of cases (κ = 0.58). When compared with resection specimens, epithelioid morphology at biopsy had a positive predictive value (PPV) of 78.9% and a negative predictive value (NPV) of 93.5%; sarcomatoid morphology showed high PPV (92.9%) and NPV (99.3%), and biphasic morphology PPV was 89.7% and NPV was 79.7%. Agreement of the percentage of epithelioid morphology was fair (κ = 0.27). Nuclear grade and necrosis were concordant in 75% (κ = 0.59) and 81% (κ = 0.53) of cases, respectively. Nuclear grade showed moderate (κ = 0.53) and substantial (κ = 0.67) agreement from patients with and without neoadjuvant therapy, respectively, and necrosis showed moderate (κ = 0.47 and κ = 0.60) agreement, respectively, in the same subsets of paired specimens.

Conclusions

Paired biopsy-resection specimens from pleural MM show overall moderate agreement in pathologic parameters. These findings may help guide postbiopsy management and triage of patients with MM.
Broken, silent, and in hiding: tamed endogenous pararetroviruses escape elimination from the genome of sugar beet (Beta vulgaris)
Authors: Schmidt Nicola , Seibt Kathrin M , Weber Beatrice , Schwarzacher Trude , Schmidt Thomas , Heitkam Tony
Published: March 2021

Background and Aims

Endogenous pararetroviruses (EPRVs) are widespread components of plant genomes that originated from episomal DNA viruses of the Caulimoviridae family. Due to fragmentation and rearrangements, most EPRVs have lost their ability to replicate through reverse transcription and to initiate viral infection. Similar to the closely related retrotransposons, extant EPRVs were retained and often amplified in plant genomes for several million years. Here, we characterize the complete genomic EPRV fraction of the crop sugar beet (Beta vulgaris, Amaranthaceae) to understand how they shaped the beet genome and to suggest explanations for their absent virulence.

Methods

Using next- and third-generation sequencing data and genome assembly, we reconstructed full-length in silico representatives for the three host-specific EPRVs (beetEPRVs) in the B. vulgaris genome. Focusing on the endogenous caulimovirid beetEPRV3, we investigated its chromosomal localization, abundance and distribution by fluorescent in situ and Southern hybridization.

Key Results

Full-length beetEPRVs range between 7.5 and 10.7 kb in size, are heterogeneous in structure and sequence, and occupy about 0.3 % of the beet genome. Although all three beetEPRVs were assigned to the florendoviruses, they showed variably arranged protein-coding domains, different fragmentation, and preferences for diverse sequence contexts. We observed small RNAs that specifically target the individual beetEPRVs, indicating stringent epigenetic suppression. BeetEPRV3 sequences occur along all sugar beet chromosomes, preferentially in the vicinity of each other and are associated with heterochromatic, centromeric and intercalary satellite DNAs. BeetEPRV3 members also exist in genomes of related wild species, indicating an initial beetEPRV3 integration 13.4–7.2 million years ago.

Conclusions

Our study in beet illustrates the variability of EPRV structure and sequence in a single host genome. Evidence of sequence fragmentation and epigenetic silencing implies possible plant strategies to cope with long-term persistence of EPRVs, including amplification, fixation in the heterochromatin, and containment of EPRV virulence.
Direct evidence of cytosolic PNGase activity in Arabidopsis thaliana: in vitro assay system for plant cPNGase activity
Authors: Shirai Sahoko , Uemura Ryota , Maeda Megumi , Kajiura Hiroyuki , Misaki Ryo , Fujiyama Kazuhito , Kimura Yoshinobu
Published: March 2021

Cytosolic peptide:N-glycanase (cPNGase), which occurs ubiquitously in eukaryotic cells, is involved in the de-N-glycosylation of misfolded glycoproteins in the protein quality control system. In this study, we aimed to provide direct evidence of plant cPNGase activity against a denatured glycoprotein using a crude extract prepared from a mutant line of Arabidopsis thaliana lacking 2 acidic PNGase genes.
Song type and song type matching are important for joint territorial defense in a duetting songbird
Authors: Wheeldon Amie , Szymański Paweł , Surmacki Adrian , Osiejuk Tomasz S
Published: March 2021

Birds have a diverse acoustic communication system, with species-specific repertoires facilitating more complex behaviors in terms of both within- and between-pair communications. Certain song types are produced for specific functions, such as aggressive encounters. In addition, song matching behaviors, whereby neighboring individuals match song types, can be used in aggressive interactions as a sophisticated acoustic behavior. In this study, we examined the functions of song types, in a duet context, of male yellow-breasted boubous (Laniarius atroflavus), an Afromontane bush-shrike with a vocal sexual dimorphism. We aimed at assessing whether, structurally, certain song types elicited a heightened reaction than others and also whether song matching affected response behavior. A dual speaker playback procedure was performed for 18 pairs of boubous, each pair being exposed to duets with three different male song types. We found differences in response toward the different duet types but these differences resulted from the amount at which males matched different song types. Pairs responded stronger when a focal male matched the playback type, and matching was significantly more often found in cases where the rarest type of male song was used. We found no sex differences in terms of response strength to playback type. Our results indicate a two-level way of coding aggression toward intruding pairs. The yellow-breasted boubous utilize their repertoires, linking matching with structure in order to show aggression in terms of territory defense and sexual conflict. This study also confirms joint territorial defense as a main function of duets in this species.
The conspecific avoidance strategies of adult female-calf humpback whales
Authors: Indeck Katherine L , Noad Michael J , Dunlop Rebecca A
Published: March 2021

During migration, humpback whale (Megaptera novaeangliae) adult females and their calves use acoustic calling to help maintain contact. The signals produced by these pairs, however, may unintentionally attract nearby breeding males, which can result in interactions that have negative physical and physiological effects on the calf. Therefore, maternal females must choose the vocal and/or behavioral strategy that most effectively balances intra-pair communication with male avoidance. Here, we analyzed differences in adult female-calf vocal activity and movement behavior according to the presence of, and distance to, singing whales and other groups likely to contain males. The results of this study found that these pairs make only minimal changes to their vocal behavior in response to nearby males, suggesting that they have instead evolved calls that are naturally difficult to detect (i.e., produced at significantly lower rates and acoustic levels than other whale groups, resulting in a restricted active space). In addition, they maintain spatial separation from nearby groups by moving to shallower, inshore waters, increasing their proportion of time spent near the surface, and favoring a direct migratory course. This combination of cryptic strategies balances avoidance of unwanted conspecific interaction with the necessity of continued contact between maternal female humpback whales and their calves.
Modeling multifunctionality of genes with secondary gene co-expression networks in human brain provides novel disease insights
Authors: Sánchez Juan A , Gil-Martinez Ana L , Cisterna Alejandro , García-Ruíz Sonia , Gómez-Pascual Alicia , Reynolds Regina H , Nalls Mike , Hardy John , Ryten Mina , Botía Juan A
Published: March 2021

Motivation

Co-expression networks are a powerful gene expression analysis method to study how genes co-express together in clusters with functional coherence that usually resemble specific cell type behavior for the genes involved. They can be applied to bulk-tissue gene expression profiling and assign function, and usually cell type specificity, to a high percentage of the gene pool used to construct the network. One of the limitations of this method is that each gene is predicted to play a role in a specific set of coherent functions in a single cell type (i.e. at most we get a single  for each gene). We present here GMSCA (Gene Multifunctionality Secondary Co-expression Analysis), a software tool that exploits the co-expression paradigm to increase the number of functions and cell types ascribed to a gene in bulk-tissue co-expression networks.

Results

We applied GMSCA to 27 co-expression networks derived from bulk-tissue gene expression profiling of a variety of brain tissues. Neurons and glial cells (microglia, astrocytes and oligodendrocytes) were considered the main cell types. Applying this approach, we increase the overall number of predicted triplets  by 46.73%. Moreover, GMSCA predicts that the SNCA gene, traditionally associated to work mainly in neurons, also plays a relevant function in oligodendrocytes.

Availabilityand implementation

The tool is available at GitHub, https://github.com/drlaguna/GMSCA as open-source software.

Supplementary information

Supplementary data are available at Bioinformatics online.
Fast and sensitive taxonomic assignment to metagenomic contigs
Authors: Mirdita M , Steinegger M , Breitwieser F , Söding J , Levy Karin E
Published: March 2021

MMseqs2 taxonomy is a new tool to assign taxonomic labels to metagenomic contigs. It extracts all possible protein fragments from each contig, quickly retains those that can contribute to taxonomic annotation, assigns them with robust labels and determines the contig’s taxonomic identity by weighted voting. Its fragment extraction step is suitable for the analysis of all domains of life. MMseqs2 taxonomy is 2–18× faster than state-of-the-art tools and also contains new modules for creating and manipulating taxonomic reference databases as well as reporting and visualizing taxonomic assignments.

Availability and implementation

MMseqs2 taxonomy is part of the MMseqs2 free open-source software package available for Linux, macOS and Windows at https://mmseqs.com.

Supplementary information

Supplementary data are available at Bioinformatics online.
Highly variable sperm morphology in the masked finch (Poephila personata) and other estrildid finches
Authors: Mccarthy Elise , Mcdiarmid Callum S , Hurley Laura L , Rowe Melissah , Griffith Simon C
Published: March 2021

Spermatozoa exhibit remarkable levels of morphological diversification among and within species. Among the passerine birds, the zebra finch (Taeniopygia guttata) has become a model system for studies of sperm biology, yet studies of closely related Estrildidae finches remain scarce. Here, we examine sperm morphology in the masked finch (Poephila personata) and place the data into the broader context of passerine sperm morphology using data for an additional 189 species. The masked finch exhibited high levels of within- and among-male variation in total sperm length and in specific sperm components. Furthermore, among-male variance in sperm length was significantly greater in estrildid (N = 12) compared with non-estrildid species (N = 178). We suggest that the high variation in sperm morphology in the masked finch and other estrildid species is likely to be linked to low levels of sperm competition, hence relaxed or weak selection on sperm length, in the clade. Our findings highlight that the highly variable sperm of the masked finch and widely studied zebra finch are ‘typical’ for estrildid species and stress the relevance of studying groups of closely related species. Finally, we suggest that further studies of Estrildidae will enhance our understanding of sperm diversity and avian diversity more generally.
Genome-wide assessment elucidates connectivity and the evolutionary history of the highly dispersive marine invertebrate Littoraria flava (Littorinidae: Gastropoda)
Authors: Cortez Thainá , Amaral Rafael V , Sobral-Souza Thadeu , Andrade Sónia C S
Published: March 2021

An important goal of marine population genetics is to understand how spatial connectivity patterns are influenced by historical and evolutionary factors. In this study, we evaluate the demographic history and population structure of Littoraria flava, a highly dispersive marine gastropod in the Brazilian intertidal zone. To test the hypotheses that the species has (1) historically high levels of gene flow on a macrogeographical spatial scale and (2) a distribution in rocky shores that consists of subpopulations, we collected specimens along the Brazilian coastline and combined different sets of genetic markers (mitochondrial DNA, ITS-2 and single nucleotide polymorphisms) with niche-based modelling to predict its palaeodistribution. Low genetic structure was observed, as well as high gene flow over long distances. The demographic analyses suggest that L. flava has had periods of population bottlenecks followed by expansion. According to both palaeodistribution and coalescent simulations, these expansion events occurred during the Pleistocene interglacial cycles (21 kya) and the associated climatic changes were the probable drivers of the distribution of the species. This is the first phylogeographical study of a marine gastropod on the South American coast based on genomic markers associated with niche modelling.
Securitizing the Colour Revolution: Assessing the Political Role of Triads in Hong Kong’s Umbrella Movement
Authors: Lo T Wing , Kwok Sharon Ingrid , Garrett Daniel
Published: March 2021

In Hong Kong’s Umbrella Movement, the use of Chinese triads to attack protestors has attracted international attention, forcing the regime to constrain further acts of grand illegitimate violence. Research suggests that triads were used as ‘thugs-for-hire’ by the regime to achieve political ends. The present study aims to examine why the triads were hired and what their specific roles and motivations were. It concludes that triads acted as non-state securitization actors, agent provocateurs or extralegal protectors depending on several factors, such as financial incentives, being stakeholders in occupied sites, business interests in mainland China and individuals’ political ideology. It suggests that triads were used as vigilantes against the threats of Western-instigated Color Revolution and hybrid warfare targeting China.
Aromatic l-amino acid decarboxylase deficiency: a patient-derived neuronal model for precision therapies
Authors: Rossignoli Giada , Krämer Karolin , Lugarà Eleonora , Alrashidi Haya , Pope Simon , De La Fuente Barrigon Carmen , Barwick Katy , Bisello Giovanni , Ng Joanne , Counsell John , Lignani Gabriele , Heales Simon J R , Bertoldi Mariarita , Barral Serena , Kurian Manju A
Published: March 2021

Aromatic l-amino acid decarboxylase (AADC) deficiency is a complex inherited neurological disorder of monoamine synthesis which results in dopamine and serotonin deficiency. The majority of affected individuals have variable, though often severe cognitive and motor delay, with a complex movement disorder and high risk of premature mortality. For most, standard pharmacological treatment provides only limited clinical benefit. Promising gene therapy approaches are emerging, though may not be either suitable or easily accessible for all patients. To characterize the underlying disease pathophysiology and guide precision therapies, we generated a patient-derived midbrain dopaminergic neuronal model of AADC deficiency from induced pluripotent stem cells. The neuronal model recapitulates key disease features, including absent AADC enzyme activity and dysregulated dopamine metabolism. We observed developmental defects affecting synaptic maturation and neuronal electrical properties, which were improved by lentiviral gene therapy. Bioinformatic and biochemical analyses on recombinant AADC predicted that the activity of one variant could be improved by l-3,4-dihydroxyphenylalanine (l-DOPA) administration; this hypothesis was corroborated in the patient-derived neuronal model, where l-DOPA treatment leads to amelioration of dopamine metabolites. Our study has shown that patient-derived disease modelling provides further insight into the neurodevelopmental sequelae of AADC deficiency, as well as a robust platform to investigate and develop personalized therapeutic approaches.
Endogenous Oscillations Time-Constrain Linguistic Segmentation: Cycling the Garden Path
Authors: Henke Lena , Meyer Lars
Published: March 2021

Speech is transient. To comprehend entire sentences, segments consisting of multiple words need to be memorized for at least a while. However, it has been noted previously that we struggle to memorize segments longer than approximately 2.7 s. We hypothesized that electrophysiological processing cycles within the delta band (<4 Hz) underlie this time constraint. Participants’ EEG was recorded while they listened to temporarily ambiguous sentences. By manipulating the speech rate, we aimed at biasing participants’ interpretation: At a slow rate, segmentation after 2.7 s would trigger a correct interpretation. In contrast, at a fast rate, segmentation after 2.7 s would trigger a wrong interpretation and thus an error later in the sentence. In line with the suggested time constraint, the phase of the delta-band oscillation at the critical point in the sentence mirrored segmentation on the level of single trials, as indicated by the amplitude of the P600 event-related brain potential (ERP) later in the sentence. The correlation between upstream delta-band phase and downstream P600 amplitude implies that segmentation took place when an underlying neural oscillator had reached a specific angle within its cycle, determining comprehension. We conclude that delta-band oscillations set an endogenous time constraint on segmentation.
Influence of Obesity on Clinical Manifestations and Response to Therapy in Cutaneous Leishmaniasis Caused by Leishmania braziliensis
Authors: Lago Tainã , Carvalho Lucas P , Nascimento Mauricio , Guimarães Luiz H , Lago Jamile , Castellucci Léa , Carvalho Augusto M , Lago Alex , Carvalho Edgar M
Published: March 2021

Background

Cutaneous leishmaniasis (CL) caused by Leishmania braziliensis is characterized by a single ulcer or multiple cutaneous lesions with raised borders. Cure rates <60% are observed in response to meglumine antimoniate therapy. We investigated the impact of obesity on CL clinical presentation and therapeutic response.

Methods

A total of 90 age-matched patients with CL were included (30 obese, 30 overweight, and 30 with normal body mass index [BMI]). CL was diagnosed through documentation of L. braziliensis DNA by polymerase chain reaction or identification of amastigotes in biopsied skin-lesion samples. Serum cytokine levels were determined by chemiluminescence. Antimony therapy with Glucantime (Sanofi-Aventis; 20 mg/kg/day) was administered for 20 days.

Results

Obese CL patients may present hypertrophic ulcers rather than typical oval, ulcerated lesions. A direct correlation between BMI and healing time was noted. After 1 course of antimony, cure was achieved in 73% of patients with normal BMI, 37% of overweight subjects, yet just 18% of obese CL patients (P < .01). Obese CL cases additionally presented higher leptin levels than overweight patients or those with normal BMI (P < .05).

Conclusions

Obesity modifies the clinical presentation of CL and host immune response and is associated with greater failure to therapy.
Efficacy and Safety of Single Oral Dosing of Secnidazole for Trichomoniasis in Women: Results of a Phase 3, Randomized, Double-Blind, Placebo-Controlled, Delayed-Treatment Study
Authors: Muzny Christina A , Schwebke Jane R , Nyirjesy Paul , Kaufman Gregory , Mena Leandro A , Lazenby Gweneth B , Van Gerwen Olivia T , Graves Keonte J , Arbuckle Janeen , Carter Belvia A , McMahon Connette P , Eder Scott , Shaw Jackie , Pandey Brajesh , Chavoustie Steven E
Published: March 2021

Background

Trichomonas vaginalis is the most prevalent nonviral sexually transmitted infection. We evaluated the efficacy and safety of secnidazole vs placebo in women with trichomoniasis.

Methods

Women with trichomoniasis, confirmed by a positive T. vaginalis culture, were randomized to single-dose oral secnidazole 2 g or placebo. The primary endpoint was microbiological test of cure (TOC) by culture 6–12 days after dosing. At the TOC visit, participants were given the opposite treatment. They were followed for resolution of infection afterward and offered treatment at subsequent visits, if needed. Fifty patients per group (N = 100) provided approximately 95% power to detect a statistically significant difference between treatment groups.

Results

Between April 2019 and March 2020, 147 women enrolled at 10 sites in the United States. The modified intention-to-treat (mITT) population included 131 randomized patients (secnidazole, n = 64; placebo, n = 67). Cure rates were significantly higher in the secnidazole vs placebo group for the mITT population (92.2% [95% confidence interval {CI}: 82.7%–97.4%] vs 1.5% [95% CI: .0%–8.0%]) and for the per-protocol population (94.9% [95% CI: 85.9%–98.9%] vs 1.7% [95% CI: .0%–8.9%]). Cure rates were 100% (4/4) in women with human immunodeficiency virus (HIV) and 95.2% (20/21) in women with bacterial vaginosis (BV). Secnidazole was generally well tolerated. The most frequently reported treatment-emergent adverse events (TEAEs) were vulvovaginal candidiasis and nausea (each 2.7%). No serious TEAEs were observed.

Conclusions

A single oral 2 g dose of secnidazole was associated with significantly higher microbiological cure rates vs placebo, supporting a role for secnidazole in treating women with trichomoniasis, including those with HIV and/or BV.

Clinical Trials Registration

NCT03935217.
Clinical efficacy and safety of angiogenesis inhibitors: sex differences and current challenges
Authors: Cignarella Andrea , Fadini Gian Paolo , Bolego Chiara , Trevisi Lucia , Boscaro Carlotta , Sanga Viola , Seccia Teresa Maria , Rosato Antonio , Rossi Gian Paolo , Barton Matthias
Published: March 2021

Vasoactive molecules, such as vascular endothelial growth factor (VEGF) and endothelins, share cytokine-like activities and regulate endothelial cell (EC) growth, migration, and inflammation. Some endothelial mediators and their receptors are targets for currently approved angiogenesis inhibitors, drugs that are either monoclonal antibodies raised towards VEGF, or inhibitors of vascular receptor protein kinases and signalling pathways. Pharmacological interference with the protective functions of ECs results in a similar spectrum of adverse effects. Clinically, the most common side effects of VEGF signalling pathway inhibition include an increase in arterial pressure, left ventricular dysfunction facilitating the development of heart failure, thromboembolic events including pulmonary embolism and stroke, and myocardial infarction. Sex steroids, such as androgens, progestins, and oestrogens and their receptors (ERα, ERβ, GPER; PR-A, PR-B; AR) have been identified as important modifiers of angiogenesis, and sex differences have been reported for anti-angiogenic drugs. This review article discusses the current challenges clinicians are facing with regard to angiogenesis inhibitor therapy, including the need to consider sex differences affecting clinical efficacy and safety. We also propose areas for future research taking into account the role of sex hormone receptors and sex chromosomes. Development of new sex-specific drugs with improved target- and cell-type selectivity likely will open the way to personalized medicine in men and women requiring anti-angiogenic therapy to reduce adverse effects and to improve therapeutic efficacy.
A case report: biventricular takotsubo cardiomyopathy with sequential ventricular recovery due to pulmonary hypertension
Authors: Agarwal Megha , Kardos Attila
Published: March 2021

Background

Biventricular Takotsubo cardiomyopathy (BTC) is estimated to occur in 25–42% of those with Takotsubo cardiomyopathy (TC). Little is known about which subset of patients are predisposed to having concomitant right ventricular (RV) involvement, or the pattern of recovery in BTC.

Case summary

We describe a 69-year-old woman who presented with dyspnoea and was subsequently diagnosed with BTC. We propose that this was triggered by an exacerbation of chronic obstructive pulmonary disease on a background of multiple predisposing factors including recent bereavement, previous excessive alcohol use, status as a current smoker, and anxiety. During her admission, she required non-invasive ventilation and inotropic support to manage her type two respiratory failure and acute heart failure. Serial echocardiograms during the admission allowed us to capture and present the sequential recovery of ventricular systolic function, with the left ventricular (LV) recovery preceding the right ventricle.

Discussion

Our patient fulfils the International Takotsubo Diagnostic criteria of transient LV dysfunction, emotional and physical triggers, electrocardiogram abnormalities, raised troponin and brain natriuretic peptide and no occlusive coronary artery disease. We hypothesize that pulmonary hypertension-related strain on the right ventricle due to lung disease, may have led to the observed delay in the recovery of RV function, despite the full recovery of LV function.
Lending Cycles and Real Outcomes: Costs of Political Misalignment
Authors: Bircan Çağatay , Saka Orkun
Published: March 2021

We document a strong political cycle in bank credit and industry outcomes in Turkey. In line with theories of tactical redistribution, state-owned banks systematically adjust their lending around local elections compared with private banks in the same province based on electoral competition and political alignment of incumbent mayors. This effect only exists in corporate lending and creates credit constraints for firms in opposition areas, which suffer drops in assets, employment and sales but not firm entry. Financial resources and factors of production are misallocated as more efficient provinces and industries suffer the greatest constraints, reducing aggregate productivity.
Comparison of shunt types in the neonatal Norwood procedure for single ventricle
Authors: Ono Masamichi , Kido Takashi , Wallner Marie , Burri Melchior , Lemmer Julia , Ewert Peter , Strbad Martina , Cleuziou Julie , Hager Alfred , Hörer Jürgen
Published: March 2021

OBJECTIVES

The ideal shunt for pulmonary blood flow, modified Blalock–Taussig shunt (MBTS) or right ventricular–pulmonary artery conduit (RVPAC) is yet to be determined. This study aimed to evaluate outcomes after the Norwood procedure according to the type of shunt.

METHODS

A total of 322 neonates with hypoplastic left heart syndrome and related anomalies who underwent the Norwood procedure at our institution between 2001 and 2019 were divided into MBTS and RVPAC groups and the outcomes after the Norwood procedure were compared between the groups with respect to mortality after each staged procedure.

RESULTS

We identified 322 consequent patients who underwent neonatal Norwood procedure for hypoplastic left heart syndrome (271 patients, 84.2%) and its variant (51 patients, 15.8%). RVPAC was performed in 163 (50.6%) patients and MBTS was performed in 159 (49.4%). There were no differences in the rate of early death (11.0% vs 12.6%, P = 0.69) or late death (7.4% vs 6.9%, P = 0.87) between the 2 groups after the Norwood procedure, and no significant difference in the number of patients who reached bidirectional cavopulmonary shunt (77.9% vs 76.1%, P = 0.69), and there was no difference in mortality after bidirectional cavopulmonary shunt (12.3% vs 7.5%, P = 0.15) or Fontan completion rate (54.0% vs 52.2%, P = 0.42) between the 2 groups. Survival at 0.5, 1, 3 and 6 years after the Norwood procedure was 81.0%, 73.8%, 67.9% and 67.0% in patients with RVPAC and 77.1%, 73.3%, 69.1% and 67.9% in patients with MBTS. There was no significant difference in the survival between the 2 groups during the median follow-up of 2.6 (interquartile ranges: 0.3–8.4, maximal 18.8) years (P = 0.97).

CONCLUSIONS

In neonates undergoing the Norwood procedure, our available data of maximal 18.8 years follow-up showed no significant difference in early mortality, inter-stage attritions, or overall survival, between MBTS and RVPAC.
Estimating the effective sample size in association studies of quantitative traits
Authors: Ziyatdinov Andrey , Kim Jihye , Prokopenko Dmitry , Privé Florian , Laporte Fabien , Loh Po-Ru , Kraft Peter , Aschard Hugues
Published: March 2021

The effective sample size (ESS) is a metric used to summarize in a single term the amount of correlation in a sample. It is of particular interest when predicting the statistical power of genome-wide association studies (GWAS) based on linear mixed models. Here, we introduce an analytical form of the ESS for mixed-model GWAS of quantitative traits and relate it to empirical estimators recently proposed. Using our framework, we derived approximations of the ESS for analyses of related and unrelated samples and for both marginal genetic and gene-environment interaction tests. We conducted simulations to validate our approximations and to provide a quantitative perspective on the statistical power of various scenarios, including power loss due to family relatedness and power gains due to conditioning on the polygenic signal. Our analyses also demonstrate that the power of gene-environment interaction GWAS in related individuals strongly depends on the family structure and exposure distribution. Finally, we performed a series of mixed-model GWAS on data from the UK Biobank and confirmed the simulation results. We notably found that the expected power drop due to family relatedness in the UK Biobank is negligible.
XI. Opinion
Authors: Munday Roderick
Published: March 2021

This chapter discusses the law relating to the evidence of opinion. It first considers the rule on the evidence of opinion and explains its rationale, especially the nature of its relationship to the rules excluding hearsay. The chapter discusses two broad spheres of evidence of opinion: expert and non-expert. The first concerns matters calling for specialized skill or knowledge. In this sphere, the only questions are whether the subject of inquiry does raise issues calling for expertise, and whether the witness is a qualified expert. In the residuary non-expert sphere, evidence of opinion will be excluded if the subject is one with regard to which fact and inference can conveniently be kept separate. The chapter then illustrates the operation of the rule, together with the two areas of expert and non-expert opinion in which there are exceptions. Finally, this chapter deals with the reform of the rule.
XV. Documentary evidence
Authors: Munday Roderick
Published: March 2021

This chapter deals with documentary evidence. It first discusses the authentication of documents, by looking at proof under the new provisions of statements in documents generally; proof of business, and public, records; procedure under the Civil Procedure Rules; and some special considerations applying to public documents and to bankers' books. Next, the chapter turns to the proof of the execution of private documents. Here, the chapter considers the proof of handwriting and attestation, alongside the special provision permitting the use of electronic signatures. Finally, this chapter concerns whether, once a transaction has been embodied in a document, evidence may be given of terms other than those it mentions, and, second, the extent to which evidence may be given of the meaning of the terms used in the document.
Novel Genetic Variant Predicts Surgical Recurrence Risk in Crohn’s Disease Patients
Authors: Wang Ming-Hsi , Friton Jessica J , Raffals Laura E , Leighton Jonathan A , Pasha Shabana F , Picco Michael F , Monroe Kelly , Nix Billy D , Newberry Rodney D , Faubion William A
Published: March 2021

Background

We aimed to identify a model of clinical and genetic risk factors through hypothesis-free search across genome that can predict the surgical recurrence risk after the first abdominal surgery in CD patients.

Materials and Methods

Two independent inflammatory bowel disease (IBD) cohort studies were used to derive and validate the genetic risk profile. The study subjects were genotyped using Illumina Immunochip custom genotyping array. Surgical recurrence was defined as having the second or more abdominal bowel resections after the first abdominal surgery at the time of study enrollment; nonsurgical recurrence was defined as having no further abdominal resection after the first abdominal surgery.

Results

Among 372 CD patients who had at least 1 abdominal surgery at the study enrollment, 132 (35.5%) had subsequent surgical recurrence after their first abdominal surgery, and 240 (64.5%) required no subsequent abdominal surgery at the end of follow up. Among clinical factors, multivariable analysis showed that history of immunomodulatory use (odds ratio [OR], 3.96; P = 0.002) and early era of CD first surgery (OR, 1.12; P = 1.01E-04) remained significant. Genotypic association tests identified a genome-wide significant locus rs2060886 in TCF4 at chr18q21.2 associated with surgical recurrence risk (OR, dom, 4.10 [2.37–7.11]; P = 4.58E-08).

Conclusions

Novel genetic locus rs2060886 in TCF4 was associated with surgical recurrence risk at genome-wide significance level among CD patients after their first abdominal surgery. Early era of CD first intestinal surgery predicts higher surgical recurrence risk. These results suggest that genetic variants may help guide the CD management strategy in patients at the highest risk of repeated abdominal surgeries.
Metazoan diversity and seasonality through eDNA metabarcoding at a Mediterranean long-term ecological research site
Authors: Di Capua Iole , Piredda Roberta , Mazzocchi Maria Grazia , Zingone Adriana
Published: March 2021

Metabarcoding of environmental DNA has provided striking insights into marine microbial diversity. With this approach, we assessed the diversity of metazoan assemblages and their temporal variations at the Long-Term Ecological Research site MareChiara (LTER-MC) in the Gulf of Naples (Mediterranean Sea). The Illumina sequencing of the V4-18S rRNA fragment from 48 surface samples collected from 2011 to 2013 produced a total of 5 011 047 marine metazoan reads. The normalized dataset was generally dominated by copepods (60.3%), followed by annelids (34.7%) mostly represented by the invasive benthic polychaete Hydroides elegans. Non-copepod holoplankton was mainly represented by siphonophores, rotifers, and appendicularians, with occasional mass occurrences of jellyfish. The rest of meroplankton (mainly molluscs, annelids, and anthozoans) showed a high diversity, covering all 11 zooplankton phyla, from Porifera to Craniata. A high number of copepod genera were identified, with seasonal recurrence matching patterns observed in 30 years of studies in the Gulf of Naples. Despite limitations related to the molecular marker resolution and reference dataset, the study provided valuable insights into diversity and seasonal patterns of the whole metazoan assemblage, expanding the knowledge on rare or hardly identifiable taxa and confirming DNA metabarcoding as a powerful approach to be integrated at LTER sites.
Learning from safety incidents in high-reliability organizations: a systematic review of learning tools that could be adapted and used in healthcare
Authors: Serou Naresh , Sahota Lauren M , Husband Andy K , Forrest Simon P , Slight Robert D , Slight Sarah P
Published: March 2021

Objective

A high-reliability organization (HRO) is an organization that has sustained almost error-free performance, despite operating in hazardous conditions where the consequences of errors could be catastrophic. A number of tools and initiatives have been used within HROs to learn from safety incidents, some of which have the potential to be adapted and used in healthcare. We conducted a systematic review to identify any learning tools deemed to be effective that could be adapted and used by multidisciplinary teams in healthcare following a patient safety incident.

Methods

This review followed the Preferred Reporting Items for Systematic Reviews and MetaAnalyses for Protocols reporting guidelines and was registered with the PROSPERO (CRD42017071528). A search of databases was carried out in January 2021, from the date of their commencement. We conducted a search on electronic databases such as Web of Science, Science Direct, MEDLINE in Process Jan 1950-present, EMBASE Jan 1974-present, CINAHL 1982-present, PsycINFO 1967-present, Scopus and Google Scholar. We also searched the grey literature including reports from government agencies, relevant doctoral dissertations and conference proceedings. A customized data extraction form was used to capture pertinent information from included studies and Critical Appraisal Skills Programme tool to appraise on their quality.

Results

A total of 5921 articles were identified, with 964 duplicate articles removed and 4932 excluded at the title (4055), abstract (510) and full-text (367) stages. Twenty-five articles were included in the review. Learning tools identified included debriefing, simulation, crew resource management and reporting systems to disseminate safety messages. Debriefing involved deconstructing incidents using reflective questions, whilst simulation training involved asking staff to relive the event again by performing the task(s) in a role-play scenario. Crew resource management is a set of training procedures that focus on communication, leadership and decision-making. Sophisticated incident-reporting systems provide valuable information on hazards and were widely recommended as a way of disseminating key safety messages following safety incidents. These learning tools were found to have a positive impact on learning if conducted soon after the incident with efficient facilitation.

Conclusion

Healthcare organizations should find ways to adapt to the learning tools or initiatives used in HROs following safety incidents. It is challenging to recommend any specific one as all learning tools have shown considerable promise. However, the way these tools or initiatives are implemented is critical, and so further work is needed to explore how to successfully embed them into healthcare organizations so that everyone at every level of the organization embraces them.