bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical performance of immediately placed and immediately loaded single implants in the esthetic zone: A systematic review and meta‐analysis
Authors: Wittneben Julia‐Gabriela , Molinero‐Mourelle Pedro , Hamilton Adam , Alnasser Muhsen , Obermaier Barbara , Morton Dean , Gallucci German O. , Wismeijer Daniel
Published: September 2023

Objectives

The aim of this study was to assess the following PIO question: In adult patients treated with an indication for single tooth extraction in the maxillary esthetic zone (15–25), what is the influence of an immediate implant placement and immediate loading protocol on the clinical performance (primary aim) and esthetic outcomes (secondary aim) focusing on investigations published after 2010.

Material and Methods

An electronic search in Medline (PubMed), the Cochrane Central Register of Controlled Trials, and EMBASE databases up to April 2022 was performed to identify clinical studies investigating the outcome of single implants subjected to immediate placement with immediate restoration/loading (Type 1A).

Results

Sixty‐three studies (10 randomized controlled trials, 28 prospective and 25 retrospective cohort studies) were included with a follow‐up ranging from 12 to 96 months. One thousand nine hundred sixty‐one implants reported survival rates of 99.2 (98.6–99.5) % at 1 year, 97.5 (95.9–98.4) % after 3 years, and 95.8 (93.3–97.4) % after 5 years; 1064 immediately loaded restorations presented survival rates of 98.9 (97.8–99.5) % after 1 year, 96.8 (93.6–98.4) % after 2 years, and 94.8 (89.6–97.4) % after 5 years. Comparing baseline to 12‐month data using the Hedges' g effect size (95% CI), papilla height presented an overall effect size of −0.71 (−1.25, −0.1) mm, midfacial recession change of −0.15 (−0.66, 0.36) mm, and a 0.82 (0.37, 1.28) gain in PES.

Conclusions

Immediate implant placement and immediate loading can be considered a predictable and safe treatment option for single maxillary anterior restorations with adequate survival rates and favorable esthetics outcomes for up to 5 years.
Treatment priorities and arrival time of traumatic dental injuries—An 8‐year retrospective study
Authors: Šimunović Luka , Špiljak Bruno , Vranić Lara , Negovetić Vranić Dubravka
Published: September 2023

Background/Aim

Most of the previous studies in the available literature discussed the time of arrival in general to the healthcare system, while a minority studied the relationship between the type of trauma and arrival. The aim of this retrospective study is to assess the arrival time of traumatic dental injuries (TDIs) depending on the urgency of treatment according to Andreasen.

Materials and Methods

This 8‐year retrospective study was carried out at the Department of Pediatric Dentistry at the University Dental Clinic in Zagreb, Croatia. Andreasen's classification was used to define the kind of TDI as well as to divide them by the need for urgent treatment or treatment priorities in three groups: acute, subacute, and delayed.

Results

The sample consisted of 1040 children (59% male and 41% female) with a median age of 7. Each year, the age group most affected by TDIs was 6–12 years old. While there is a general increase in the prevalence of TDIs overall, there is a decline in TDIs among children aged 6–12 and an increase among preschoolers and adolescents (below 6 and above 12 years old). Throughout the years, 52.73% red/acute and 41.16% yellow/subacute TDIs were not treated on time due to delayed arrival. More patients from Zagreb come in the first 24 h, while more patients from outside Zagreb come to the clinic a month or more after their injuries. Patients which suffered TDI accompanied with soft‐tissue injury arrived sooner.

Conclusions

It is necessary to introduce monitoring and education of patients under the age of 6 and over 12, as well as their parents/caregivers. New programs should be implemented and new referent centers that specialize in treating TDIs outside of Zagreb should be established.
Solving the unsolved genetic epilepsies: Current and future perspectives
Authors: Johannesen Katrine M. , Tümer Zeynep , Weckhuysen Sarah , Barakat Tahsin Stefan , Bayat Allan
Published: September 2023

Many patients with epilepsy undergo exome or genome sequencing as part of a diagnostic workup; however, many remain genetically unsolved. There are various factors that account for negative results in exome/genome sequencing for patients with epilepsy: (1) the underlying cause is not genetic; (2) there is a complex polygenic explanation; (3) the illness is monogenic but the causative gene remains to be linked to a human disorder; (4) family segregation with reduced penetrance; (5) somatic mosaicism or the complexity of, for example, a structural rearrangement; or (6) limited knowledge or diagnostic tools that hinder the proper classification of a variant, resulting in its designation as a variant of unknown significance. The objective of this review is to outline some of the diagnostic options that lie beyond the exome/genome, and that might become clinically relevant within the foreseeable future. These options include: (1) re‐analysis of older exome/genome data as knowledge increases or symptoms change; (2) looking for somatic mosaicism or long‐read sequencing to detect low‐complexity repeat variants or specific structural variants missed by traditional exome/genome sequencing; (3) exploration of the non‐coding genome including disruption of topologically associated domains, long range non‐coding RNA, or other regulatory elements; and finally (4) transcriptomics, DNA methylation signatures, and metabolomics as complementary diagnostic methods that may be used in the assessment of variants of unknown significance. Some of these tools are currently not integrated into standard diagnostic workup. However, it is reasonable to expect that they will become increasingly available and improve current diagnostic capabilities, thereby enabling precision diagnosis in patients who are currently undiagnosed.
Investor attention and stock price efficiency: Evidence from quasi‐natural experiments in China
Authors: Li Zhibing , Liu Jie , Liu Xiaoyu , Wu Chonglin
Published: September 2023

We examine whether increasing investor attention affects stock price efficiency. To identify the causal effect, we employ daily repeated quasi‐natural experiments in China where investor attention difference is purely driven by price rounding effect without information regarding stock fundamentals. Stocks tend to draw significant more attention and show higher price efficiency after being exposed to the Winner List. We also find supporting evidence for two nonexclusive channels through which investor attention enhance stock price efficiency: increasing stock liquidity and stronger net inflows from large orders. The positive relationship between investor attention and price efficiency is more pronounced among stocks with lower institutional shareholdings, stocks without overseas or Big Four audit firms, and stocks without B‐ or H‐shares. Our findings further shed light on the significant impact of saliency on the capital market.
Divergence time estimates for the hypoxia‐inducible factor‐1 alpha (HIF1α) reveal an ancient emergence of animals in low‐oxygen environments
Authors: Belato Flavia A. , Mello Beatriz , Coates Christopher J. , Halanych Kenneth M. , Brown Federico D. , Morandini André C. , de Moraes Leme Juliana , Trindade Ricardo I. F. , Costa‐Paiva Elisa Maria
Published: September 2023

Unveiling the tempo and mode of animal evolution is necessary to understand the links between environmental changes and biological innovation. Although the earliest unambiguous metazoan fossils date to the late Ediacaran period, molecular clock estimates agree that the last common ancestor (LCA) of all extant animals emerged ~850 Ma, in the Tonian period, before the oldest evidence for widespread ocean oxygenation at ~635–560 Ma in the Ediacaran period. Metazoans are aerobic organisms, that is, they are dependent on oxygen to survive. In low‐oxygen conditions, most animals have an evolutionarily conserved pathway for maintaining oxygen homeostasis that triggers physiological changes in gene expression via the hypoxia‐inducible factor (HIFa). However, here we confirm the absence of the characteristic HIFa protein domain responsible for the oxygen sensing of HIFa in sponges and ctenophores, indicating the LCA of metazoans lacked the functional protein domain as well, and so could have maintained their transcription levels unaltered under the very low‐oxygen concentrations of their environments. Using Bayesian relaxed molecular clock dating, we inferred that the ancestral gene lineage responsible for HIFa arose in the Mesoproterozoic Era, ~1273 Ma (Credibility Interval 957–1621 Ma), consistent with the idea that important genetic machinery associated with animals evolved much earlier than the LCA of animals. Our data suggest at least two duplication events in the evolutionary history of HIFa, which generated three vertebrate paralogs, products of the two successive whole‐genome duplications that occurred in the vertebrate LCA. Overall, our results support the hypothesis of a pre‐Tonian emergence of metazoans under low‐oxygen conditions, and an increase in oxygen response elements during animal evolution.
Improvement of physicochemical properties and flavour of pickled radish through the use of a direct‐vat set starter consisting of Lactiplantibacillus plantarum and Leuconostoc mesenteroides
Authors: Xiong Jie , Wang Ya‐Ying , Yousaf Muhammad , Liu Dong‐Mei
Published: September 2023

The fermented vegetable is a long‐history food, and the addition of probiotics in recent years has pushed it in a novel direction. This study explored the impact of a direct‐vat set (DVS) starter, comprising Lactiplantibacillus plantarum MC14 and Leuconostoc mesenteroides, on pickled radish (PR). The addition of DVS triggered a rapid reduction in pH and titratable acidity, leading to lowered nitrite levels and increased viable count. Textural analysis showed that DVS increased the springiness and chewiness of PR by about 55.07% and 25.73%, respectively. Organic acid analysis unveiled eight compounds. The addition of probiotics did not significantly affect the antioxidant properties but was able to significantly enhance the XO inhibitory activity of PR. DVS decreased undesirable flavour compounds such as isothiocyanates and sulphides, while elevating esters, aldehydes and acids. Our results suggested that DVS is a promising starter culture that can enhance the texture and flavour of fermented vegetables.
Evaluating training effectiveness in India: Exploring the relationship between training components, metacognition and learning outcomes
Authors: Bhat Zahid Hussain
Published: September 2023

This study aims to examine the key training factors that significantly impact the learning outcomes of trainees. A comprehensive framework is proposed to investigate the interrelationships among various training components, trainer performance, training usefulness, and their effects on metacognition and learning. Empirical testing of the model is conducted using the partial least squares structural equation modelling approach, analyzing data collected from 322 public servants in North India. The findings reveal that almost all the focal factors comprising a training programme, such as the usefulness of training, trainer performance and metacognition, positively influence trainees' learning. While training agencies should consider all components of the training programme, the perceived usefulness, trainer performance and trainees' metacognition are particularly influential factors in facilitating learning. Training components and trainer performance predict the usefulness of training. This study integrates all focal factors of a training programme into a comprehensive framework using employee data, explaining a significant portion (45%–64%) of the variance in trainees' learning. These findings emphasize the importance of addressing these focal factors thoughtfully when designing and implementing effective training programmes.
Corporate Philanthropy and Innovation: The Case of the Pharmaceutical Industry
Authors: Bereskin Frederick L. , Hsu Po‐Hsuan
Published: September 2023

For decades now, pharmaceutical companies have engaged in corporate social responsibility (CSR) initiatives to strengthen their reputations, brand names, marketing, and public relations. But evidence from the authors’ recent study suggests that one particularly effective form of corporate philanthropy has been direct contributions to universities and other non‐profit research organizations, many of which have led to relationships that have developed into highly productive research partnerships. Such direct industry support for academic institutions and other research partners has ranged from unrestricted gifts to fee‐for‐service, and has taken the form of joint ventures and new research institutions as well as research contests and other types of collaborations.

Moreover, such corporate giving should be viewed as an important, and highly productive, part of these companies’ innovation strategies. In support of this argument, the authors report that direct contributions by big pharma result in a greater quantity and quality of innovations—as measured by new patents—than the research that results from other forms of corporate philanthropy, notably grants made to and administered by the companies’ own foundations. Such direct contributions are also associated with patents that are more likely to broaden the corporate scope beyond the firms’ traditional areas of expertise, and that tend to have greater success in obtaining FDA drug approvals, than the patents resulting from R&D conducted by corporate‐sponsored foundations.
Proactive Leverage Increases and The Value of Financial Flexibility
Authors: Denis David J. , McKeon Stephen B.
Published: September 2023

Traditional tradeoff models of corporate capital structure, although still featured prominently in finance textbooks and widely accepted by practitioners, have been criticized by financial economists for doing a poor job of explaining observed debt ratios. Moreover, the observed ratios are far less stable than what would be predicted by the standard tradeoff models.

In a study published several years ago in the Review of Financial Studies, the authors of this article aimed to shed more light on the underlying forces governing capital structure decisions by analyzing a set of major changes in capital structure in which companies initiated large increases in leverage through substantial new borrowings. They then attempted to explain why these companies chose to increase leverage and how their capital structures changed during the years after the large debt issues.

As summarized in this article, the authors' findings indicate, first of all, that the large debt financings were used primarily to fund major corporate investments—and not, for example, to make large distributions to shareholders. And the changes in leverage ratios that came after the debt offerings were driven far more by the evolution of the companies' realized cash flows and their investment opportunities than by deliberate or decisive attempts to rebalance their capital structures toward a stationary target. In fact, many of the companies chose to take on even more debt when faced with cash‐flow deficits, despite operating with leverage that was already well above any reasonable estimate of their estimated target leverage. At the same time, companies that generated financial surpluses used them to reduce debt, even when their leverage had fallen well below their estimated targets.

Taken as a whole, the findings of the authors' study support the idea that unused debt capacity represents an important source of financial flexibility, and that preserving such flexibility—and making use of it when valuable investment opportunities materialize—may well be the critical missing link in connecting capital structure theory with observed corporate behavior.
A Qualitative Analysis of Experiences of Medical Students Serving as Abortion Doulas
Authors: Pearlman Shapiro Marit Anne , Crystal‐Ornelas Lara , Lunde Britt
Published: September 2023

Introduction

Innovative strategies are needed in clinical education to teach empathetic behavior and communication skills. This study aimed to investigate preclinical medical students’ experiences volunteering as abortion doulas and to understand the impact of their participation on their professional training.

Methods

In this qualitative study, the authors conducted semistructured interviews with medical students who had volunteered as abortion doulas in March to July 2016. The interviews described motivations for participating, experiences volunteering as a doula, approach to caring for patients, and acquisition of communication skills and knowledge of abortion. The authors analyzed interview transcripts using a conventional content analysis approach, and themes were identified.

Results

The authors performed 22 interviews. For most participants, this was their first exposure to an abortion procedure or patient care in any capacity. Participants identified acquisition of skills including patient advocacy, communication, and empathy that they were later able to apply throughout their clinical clerkships. This opportunity improved well‐being and solidified their decision to apply for residencies in reproductive health fields.

Discussion

After volunteering as abortion doulas, medical students were able to develop communication skills, empathy, and patient advocacy applicable to other areas of patient care. Preclinical students, potentially in other health care professions training, participating in patient care as doulas have the potential to further personal development, professionalism, and activism.
Financial debts and subjective well‐being of young adults: An adaption of the stress process model
Authors: Fan Lu , Ryu Soomin
Published: September 2023

Using a stress process theoretical framework, this article examines the relationship between financial debts and the subjective well‐being of young adults and the role of social and personal resources in the mechanism. The analyses include 2348 young adults from the 2017 Transition into Adulthood Supplement study of Panel Study of Income Dynamics, using the structural equation modeling method. We found that when faced with student loans as a stress exposure, young adults' social resources (financial support and social participation) and personal psychological resources (self‐esteem) may act in different ways explaining life satisfaction and subjective well‐being. Having student loans increased the likelihood of receiving financial support from family and social activity participation, while also boosting one's self‐esteem. However, financial support as a social resource was negatively associated with young adults' life satisfaction and subjective well‐being, whereas self‐esteem as a personal resource was positively associated with life satisfaction and subjective well‐being. Our study suggests that exploring the underlying mechanism of the association between debts and subjective well‐being is necessary and crucial because the mediating roles of social and personal resources were important in determining young adults' subjective well‐being. Further research should explore this topic, as recent young adults are more exposed to debt burdens than preceding cohorts.
The role of differentiated dysplasia in the prediction of malignant transformation of oral leukoplakia
Authors: Wils Leon J. , Poell Jos B. , Peferoen Laura A. N. , Evren Ilkay , Brouns Elisabeth R. , de Visscher Jan G. A. M. , van der Meij Erik H. , Brakenhoff Ruud H. , Bloemena Elisabeth
Published: September 2023

Objective

Oral leukoplakia is the most common oral potentially malignant disorder. Malignant transformation of oral leukoplakia occurs at an annual rate of 1%–7%. WHO‐defined classic epithelial dysplasia is an important predictor of malignant transformation of oral leukoplakia, but we have previously shown in a proof of concept study that prediction improves by incorporation of an architectural pattern of dysplasia, also coined as differentiated dysplasia. We aimed to analyze this finding in a larger cohort of patients.

Method

For this retrospective study 176 oral leukoplakia patients were included. Biopsies for all patients were assessed for the presence of dysplasia and analyzed for cytokeratin 13 and 17 expression. Moreover, the inter‐observer agreement for the diagnosis of differentiated dysplasia was determined.

Results

In total, 33 of 176 patients developed oral squamous cell carcinoma during follow‐up. Presence of classic epithelial dysplasia increased cancer risk two‐fold (HR = 2.18, p = 0.026). Lesions without classic epithelial dysplasia could be further risk‐stratified by the presence of differentiated dysplasia (HR = 7.36, p < 0.001). Combined classic epithelial and differentiated dysplasia imparted a seven‐fold increased risk of malignant transformation (7.34, p = 0.001). Inter‐observer agreement for the diagnosis of dysplasia, including differentiated dysplasia, was moderate (κ = 0.56, p < 0.001).

Discussion

This study emphasizes the importance of the recognition of the architectural pattern of differentiated dysplasia as a separate entity for risk prediction of malignant transformation of oral leukoplakia. Presence of any pattern of dysplasia results in accurate prediction of malignant transformation risk of oral leukoplakia.
Arf6 is required for endocytosis and filamentous actin assembly during angiogenesis in vitro
Authors: Francis Caitlin R. , Bell Makenzie L. , Skripnichuk Marina M. , Kushner Erich J.
Published: September 2023

Objective

Endocytosis is a process vital to angiogenesis and vascular homeostasis. In pathologies where supraphysiological growth factor signaling underlies disease etiology, such as in diabetic retinopathy and solid tumors, strategies to limit chronic growth factor signaling by way of blunting endocytic processes have been shown to have tremendous clinical value. ADP ribosylation factor 6 (Arf6) is a small GTPase that promotes the assembly of actin necessary for clathrin‐mediated and clathrin‐independent endocytosis. In its absence, growth factor signaling is greatly diminished, which has been shown to ameliorate pathological signaling input in diseased vasculature. However, it is less clear if there are bystander effects related to loss of Arf6 on angiogenic behaviors. Our goal was to provide an analysis of Arf6's function in angiogenic endothelium, focusing on its role in actin and endocytosis as well as sprouting morphogenesis.

Methods

Primary endothelial cells were cultured in both 2D and 3D environments. Here, endothelial cells were fixed and stained for various proteins or transfected with fluorescently‐tagged constructs for live‐cell imaging.

Results

We found that Arf6 localized to both filamentous actin and sites of endocytosis in two‐dimensional culture. Loss of Arf6 distorted both apicobasal polarity and reduced the total cellular filamentous actin content, which may be the primary driver underlying gross sprouting dysmorphogenesis in its absence.

Conclusions

Our findings highlight that endothelial Arf6 is a potent mediator of both actin regulation and endocytosis and is required for proper sprout formation.
Tracing the Signature Dynamics of Language Teacher Immunity: A Retrodictive Qualitative Modeling Study
Authors: HIVER PHIL
Published: September 2023

This article describes a validation study using Retrodictive Qualitative Modeling, a framework for conducting research from a dynamic and situated perspective, to establish an empirical foundation for a new phenomenological construct—language teacher immunity. Focus groups (N = 44) conducted with second language (L2) practitioners and teacher educators and a cluster analysis of questionnaire data with a larger sample (N = 293) of K–12 language teachers were used to identify and corroborate typical archetypes across the spectrum of language teacher immunity outcomes. Serial in‐depth interviews were then conducted with representative respondents from each archetype (N = 18) to trace developmental trajectories and investigate how these profiles manifested phenomenologically in teachers’ motivated thought and instructional practices. Results indicate that teacher immunity is associated with practitioners’ psychological, emotional, and cognitive functioning in the social setting of the L2 classroom. These findings contribute to the field's understanding of how language teachers sustain their adaptivity, openness to change, psychological well‐being, and their sense of purpose and investment in students’ learning. Thus, teacher immunity has the potential to bridge individual and situative concerns in second language teacher education and the psychology of language teaching and learning.
Standing up for supervenience
Authors: Streumer Bart
Published: September 2023

There is a well‐known argument against irreducibly normative properties that appeals to the following claim about supervenience: for all possible worlds W and W*, if the instantiation of descriptive properties in W and W* is exactly the same, then the instantiation of normative properties in W and W* is also exactly the same. This claim used to be uncontroversial, but recently several philosophers have challenged it. Do these challenges undermine this argument? I argue that they do not, since the negation of this claim about supervenience has consequences that are much more implausible than the negations of key premises in these challenges.
Fair and efficient vaccine allocation: A generalized Gini index approach
Authors: Gutjahr Walter J.
Published: September 2023

The paper proposes an optimization model for the allocation of vaccines to a heterogeneous population composed of several subpopulations with different sizes and epidemiological disease transmission parameters. As the objective, an aggregated function combining a standard utilitarian efficiency criterion with a Gini index–related penalty term is considered. Contrary to previous work, we adopt an outcome equity view: The inequity measure is not based on vaccination fractions or other input factors, but on the fractions of individuals escaping infection, as predicted by an susceptible‐infectious‐removed (SIR) model. An adjusted pro rata (APR) policy of vaccine allocation minimizing inequity in this outcome view is introduced, and a numerical procedure for its determination is presented. The concepts are developed both for the case of segregated subpopulations and for that of interactions between the subpopulations. Interestingly, in a large number of instances, the optimal solution under the aggregated objective function turns out to be identical to APR. Whether APR is locally or even globally optimal in a concrete case depends on the relation of an inequity aversion parameter to certain threshold values. While the local optimality threshold can be determined by linear programming, the determination of the global optimality threshold, as the vaccine allocation problem itself, is a problem of nonconvex optimization. We suggest an exact optimization approach for smaller instances, and propose algorithms building on particle swarm optimization for threshold determination and allocation optimization at larger instances. Extensions to alternative outcome measures such as the number of fatalities are presented as well. In addition to the investigation of randomly generated instances, two test cases from the literature are revisited in the context of the present work. Moreover, a new case study based on data from the COVID‐19 outbreak in Austria in 2020 is introduced and analyzed.
HLA‐haplotype redundancy and rareness in Canadian Blood Services' Stem Cell Registry and Cord Blood Bank: Novel metrics for optimizing utility
Authors: Bailey Adrian J. M. , Blake John , Ganz Kathy , Seftel Matthew D. , Allan David S.
Published: September 2023

Background

The utility of unrelated donor registries that support allogeneic hematopoietic cell transplantation could be optimized through greater understanding of redundancy and rareness of HLA phenotypes.

Methods

HLA phenotype rareness was determined using known HLA haplotype frequencies. Donor redundancy was determined through pairwise comparison of donor HLA profiles within an inventory.

Results

Among 61,730 registrants in the Canadian Blood Services (CBS) Stem Cell Registry (SCR) with high resolution HLA typing at 5 loci, 6.6% of HLA phenotypes were redundant with variation across ethnic groups (8.3% of Caucasian phenotypes; 8% of Native American/First Nations, 4.4% of Asia‐Pacific Islanders (API), 2.1% of Hispanic, 0.7% of African‐American (AFA), and 4.5% of other ethnicities). A total of 18.5% of registrants had redundant HLA phenotypes with variation across ethnic groups. All 3716 cord blood units in the CBS's cord blood bank (CBB) had high resolution HLA typing at 5 loci and 202 units were redundant (5.4%) comprising 78 HLA phenotypes, with varying rareness. Repeated HLA phenotypes were from Caucasian donors (77%), multiple ethnicity (13%), API (9%), and AFA (1%). Registrants and CBUs with AFA ethnicity had the rarest phenotypes while Caucasian ethnicity was associated with the most common HLA phenotypes.

Conclusions

Redundancy was greater in the SCR compared to the CBB and was most common with CAU ethnicity. Recruiting non‐Caucasian registrants and continued cord blood banking should reduce redundancy. A sub‐inventory of redundant donors and cord blood units could support new uses for donor‐supported cellular therapies that do not require HLA matching.
Exploring avibactam and relebactam inhibition of
Klebsiella pneumoniae
carbapenemase D179N variant: role of the Ω loop-held deacylation water
Authors: Alsenani T. A. , Viviani S. L. , Papp-Wallace K. M. , Bonomo R. A. , van den Akker F.
Published: September 2023

Klebsiella pneumoniae
carbapenemase-2 (KPC-2) presents a clinical threat as this β-lactamase confers resistance to carbapenems. Recent variants of KPC-2 in clinical isolates contribute to concerning resistance phenotypes.
Klebsiella pneumoniae
expressing KPC-2 D179Y acquired resistance to the ceftazidime/avibactam combination affecting both the β-lactam and the β-lactamase inhibitor yet has lowered minimum inhibitory concentrations for all other β-lactams tested. Furthermore,
Klebsiella pneumoniae
expressing the KPC-2 D179N variant also manifested resistance to ceftazidime/avibactam yet retained its ability to confer resistance to carbapenems although significantly reduced. This structural study focuses on the inhibition of KPC-2 D179N by avibactam and relebactam and expands our previous analysis that examined ceftazidime resistance conferred by D179N and D179Y variants. Crystal structures of KPC-2 D179N soaked with avibactam and co-crystallized with relebactam were determined. The complex with avibactam reveals avibactam making several hydrogen bonds, including with the deacylation water held in place by Ω loop. These results could explain why the KPC-2 D179Y variant, which has a disordered Ω loop, has a decreased affinity for avibactam. The relebactam KPC-2 D179N complex revealed a new orientation of the diazabicyclooctane (DBO) intermediate with the scaffold piperidine ring rotated ~150° from the standard DBO orientation. The density shows relebactam to be desulfated and present as an imine-hydrolysis intermediate not previously observed. The tetrahedral imine moiety of relebactam interacts with the deacylation water. The rotated relebactam orientation and deacylation water interaction could potentially contribute to KPC-mediated DBO fragmentation. These results elucidate important differences that could aid in the design of novel β-lactamase inhibitors.
Oh my gut! Is the microbial origin of neurodegenerative diseases real?
Authors: Walker Alyssa , Czyz Daniel M.
Published: September 2023

There is no cure or effective treatment for neurodegenerative protein conformational diseases (PCDs), such as Alzheimer’s or Parkinson’s diseases, mainly because the etiology of these diseases remains elusive. Recent data suggest that unique changes in the gut microbial composition are associated with these ailments; however, our current understanding of the bacterial role in the pathogenesis of PCDs is hindered by the complexity of the microbial communities associated with specific microbiomes, such as the gut, oral, or vaginal microbiota. The composition of these specific microbiomes is regarded as a unique fingerprint affected by factors such as infections, diet, lifestyle, and antibiotics. All of these factors also affect the severity of neurodegenerative diseases. The majority of studies that reveal microbial contribution are correlational, and various models, including worm, fly, and mouse, are being utilized to decipher the role of individual microbes that may affect disease onset and progression. Recent evidence from across model organisms and humans shows a positive correlation between the presence of gram-negative enteropathogenic bacteria and the pathogenesis of PCDs. While these correlational studies do not provide a mechanistic explanation, they do reveal contributing bacterial species and provide an important basis for further investigation. One of the lurking concerns related to the microbial contribution to PCDs is the increasing prevalence of antibiotic resistance and poor antibiotic stewardship, which ultimately select for proteotoxic bacteria, especially the gram-negative species that are known for intrinsic resistance. In this review, we summarize what is known about individual microbial contribution to PCDs and the potential impact of increasing antimicrobial resistance.
Transfusion-transmitted
Babesia
spp.: a changing landscape of epidemiology, regulation, and risk mitigation
Authors: Drews Steven J. , Kjemtrup Anne M. , Krause Peter J. , Lambert Grayson , Leiby David A. , Lewin Antoine , O'Brien Sheila F. , Renaud Christian , Tonnetti Laura , Bloch Evan M.
Published: September 2023

Babesia
spp. are tick-borne parasites with a global distribution and diversity of vertebrate hosts. Over the next several decades, climate change is expected to impact humans, vectors, and vertebrate hosts and change the epidemiology of
Babesia
. Although humans are dead-end hosts for tick-transmitted
Babesia
, human-to-human transmission of
Babesia
spp. from transfusion of red blood cells and whole blood-derived platelet concentrates has been reported. In most patients, transfusion-transmitted
Babesia
(TTB) results in a moderate-to-severe illness. Currently, in North America, most cases of TTB have been described in the United States. TTB cases outside North America are rare, but case numbers may change over time with increased recognition of babesiosis and as the epidemiology of
Babesia
is impacted by climate change. Therefore, TTB is a concern of microbiologists working in blood operator settings, as well as in clinical settings where transfusion occurs. Microbiologists play an important role in deploying blood donor screening assays in
Babesia
endemic regions, identifying changing risks for
Babesia
in non-endemic areas, investigating recipients of blood products for TTB, and drafting TTB policies and guidelines. In this review, we provide an overview of the clinical presentation and epidemiology of TTB. We identify approaches and technologies to reduce the risk of collecting blood products from
Babesia
-infected donors and describe how investigations of TTB are undertaken. We also describe how microbiologists in
Babesia
non-endemic regions can assess for changing risks of TTB and decide when to focus on laboratory-test-based approaches or pathogen reduction to reduce TTB risk.
Capsid–host interactions for HIV-1 ingress
Authors: Jang Sooin , Engelman Alan N.
Published: September 2023

The HIV-1 capsid, composed of approximately 1,200 copies of the capsid protein, encases genomic RNA alongside viral nucleocapsid, reverse transcriptase, and integrase proteins. After cell entry, the capsid interacts with a myriad of host factors to traverse the cell cytoplasm, pass through the nuclear pore complex (NPC), and then traffic to chromosomal sites for viral DNA integration. Integration may very well require the dissolution of the capsid, but where and when this uncoating event occurs remains hotly debated. Based on size constraints, a long-prevailing view was that uncoating preceded nuclear transport, but recent research has indicated that the capsid may remain largely intact during nuclear import, with perhaps some structural remodeling required for NPC traversal. Completion of reverse transcription in the nucleus may further aid capsid uncoating. One canonical type of host factor, typified by CPSF6, leverages a Phe-Gly (FG) motif to bind capsid. Recent research has shown these peptides reside amid prion-like domains (PrLDs), which are stretches of protein sequence devoid of charged residues. Intermolecular PrLD interactions along the exterior of the capsid shell impart avid host factor binding for productive HIV-1 infection. Herein we overview capsid–host interactions implicated in HIV-1 ingress and discuss important research questions moving forward. Highlighting clinical relevance, the long-acting ultrapotent inhibitor lenacapavir, which engages the same capsid binding pocket as FG host factors, was recently approved to treat people living with HIV.
Safety and tolerability of tedizolid as oral treatment for bone and joint infections
Authors: Miller Loren G. , Flores Evelyn A. , Launer Bryn , Lee Pamela , Kalkat Praneet , Derrah Kelli , Agrawal Shalini , Schwartz Matthew , Steele Grant , Kim Tae , Kuvhenguhwa Maita S.
Published: September 2023

Bone and joint infections (BJIs) are common infections increasingly managed with oral therapy. However, there are limited safe oral options for many Gram-positive pathogens. In animal studies and short-term human use, tedizolid lacks the hematologic and neurologic toxicity of the other available oxazolidinone, linezolid. However, there are limited prospective safety data. We conducted an open-label, non-comparative trial of oral tedizolid for BJI treatment. Primary outcomes were safety and cure rate. Eligible patients had a BJI caused by documented or suspected Gram-positive pathogen, required 4–12 weeks of therapy, and did not have myelosuppression or peripheral/optic neuropathy. Subjects underwent weekly evaluation for cytopenias and neuropathy. We enrolled 44 subjects; five were lost to follow-up. Two subjects did not complete planned treatment because of rash (
n
= 1) and urgent surgery (
n
= 1). Of 37 patients with evaluable outcomes, 17 (46%) had hardware-associated infection, 13 (35%) had osteomyelitis, 5 (14%) had prosthetic joint infection, and 2 (5%) had other BJIs. Median (mean, range) treatment duration was 12 (10.1, 4–12) weeks. There were no cases of cytopenias or peripheral or optic neuropathy. Treatment cure occurred in 13 (35%); 19 (51%) required antibiotic continuation after 12 weeks of tedizolid related to retained hardware at the BJI site, and failure occurred in four (11%), two unlikely, one possibly, and one probably due to tedizolid. We found that oral tedizolid was well tolerated for prolonged BJI treatment without significant toxicity. Clinical failure rate was similar to that of other published BJI investigations. (This study has been registered at Clinicaltrials.gov under identifier NCT03009045.)

IMPORTANCE

Bone and joint infections are common infections with limited effective and safe oral options for Gram-positive infections. The largest prospective clinical trial of tedizolid therapy for bone and joint infections enrolled 44 patients and tested each in person weekly with detailed safety monitoring including tests for leukopenia, anemia, thrombocytopenia, peripheral neuropathy, and optic neuropathy for up to 12 weeks. Findings demonstrated tedizolid was generally well tolerated and there were no incident cases of cytopenias or neuropathy. Cure rates were similar to that in other bone and joint infection studies. In summary, oral tedizolid appears to be a well-tolerated oral option for Gram-positive bone and joint infections.
Supplemental Material: Ice-rafted dropstones at midlatitudes in the Cretaceous of continental Iberia
Authors: Rodríguez-López Juan Pedro , Liesa Carlos L. , al. et
Published: September 2023

(I) Supplementary text (geological setting, sedimentology and morphometric analysis of dropstones, FESEM analysis of quartz grains, and methods); (II) supplementary Figures. S1–S7; and (III) supplementary Table S1.  
Clinical outcomes ofStaphylococcus capitisisolation from neonates, England, 2015–2021: a retrospective case–control study
Authors: Yuan Jin-Min , Nugent Christopher , Wilson Allegra , Verlander Neville Q , Alexander Eliza , Fleming Paul , Modi Neena , Oughham Kayleigh , Ratnaraja Natasha , Wan Yu , Thorn Louise , Felgate Heather , Webber Mark A , Ogundipe Enitan , Brown Colin S , Paranthaman Karthik , Demirjian Alicia
Published: September 2023

Objective

Staphylococcus capitis, a coagulase-negative staphylococci (CoNS) species, has been increasingly detected from UK sterile site samples and has caused neonatal unit outbreaks worldwide. We compared survival to discharge and 30-day mortality for the detection ofS. capitisversus other CoNS species.

Methods

In this retrospective case–control study, we included hospitalised infants with any CoNS species detected from a normally sterile body site up to 90 days of age. We linked English laboratory reports from the Second Generation Surveillance System database, mortality data from the Personal Demographics Service, and neonatal unit admissions from the National Neonatal Research Database. In primary analysis, multivariable logistic regression was used, with two co-primary outcomes: survival to discharge and death within 30 days of positive specimen date. Sensitivity analyses using multiply imputed datasets followed.

Results

We identified 16 636 CoNS episodes relating to 13 745 infants. CoNS episodes were highest among infants born extremely preterm (22–27 weeks) and with extremely low birth weight (400–999 g). In primary analysis, there were no differences in survival to discharge (p=0.71) or 30-day mortality (p=0.77) between CoNS species. In sensitivity analyses, there were no differences in outcomes between infection with four of the most common CoNS species (Staphylococcus epidermidis, S. capitis,Staphylococcus haemolyticusandStaphylococcus warneri) but the remaining CoNS species were at higher risk of adverse outcomes when treated in aggregate.

Conclusion

Infants withS. capitisdetected from sterile site samples did not experience significant differences in either survival to discharge or 30-day mortality compared with infants with detection of other common CoNS species.
Systematic comparison of Mendelian randomisation studies and randomised controlled trials using electronic databases
Authors: Sobczyk Maria K , Zheng Jie , Davey Smith George , Gaunt Tom R
Published: September 2023

Objective

To scope the potential for (semi)-automated triangulation of Mendelian randomisation (MR) and randomised controlled trials (RCTs) evidence since the two methods have distinct assumptions that make comparisons between their results invaluable.

Methods

We mined ClinicalTrials.Gov, PubMed and EpigraphDB databases and carried out a series of 26 manual literature comparisons among 54 MR and 77 RCT publications.

Results

We found that only 13% of completed RCTs identified in ClinicalTrials.Gov submitted their results to the database. Similarly low coverage was revealed for Semantic Medline (SemMedDB) semantic triples derived from MR and RCT publications –36% and 12%, respectively. Among intervention types that can be mimicked by MR, only trials of pharmaceutical interventions could be automatically matched to MR results due to insufficient annotation with Medical Subject Headings ontology. A manual survey of the literature highlighted the potential for triangulation across a number of exposure/outcome pairs if these challenges can be addressed.

Conclusions

We conclude that careful triangulation of MR with RCT evidence should involve consideration of similarity of phenotypes across study designs, intervention intensity and duration, study population demography and health status, comparator group, intervention goal and quality of evidence.
Impact of COVID-19 on health service utilisation in sub-Saharan Africa: protocol for a scoping review
Authors: Tannor Elliot Koranteng , Quentin Wilm , Busse Reinhard , Opoku Daniel , Amuasi John
Published: September 2023

Introduction

The COVID-19 pandemic has exposed weaknesses in health systems of many countries, including those in sub-Saharan Africa. Despite comparatively low rates of COVID-19 admissions and deaths in sub-Saharan Africa, the pandemic still had a significant impact by disrupting health service utilisation (HSU). The aim of this scoping review is to synthesise the available evidence on HSU in sub-Saharan Africa during the COVID-19 pandemic, especially focusing on (1) changes in HSU compared with the prepandemic period, (2) changes in HSU among particular patient groups studied and (3) identifying factors determining changes in HSU as a result of the COVID-19 pandemic.

Method and analysis

The scoping review will be guided by the methodological framework for conducting scoping reviews developed by Arskey and O’Malley. We will identify relevant studies on HSU in sub-Saharan Africa during the COVID-19 pandemic using PubMed (MEDLINE), Embase, Scopus and Web of Science databases from 1 December, 2019 to 31 March 2023. We will search grey literature, government and organisational websites for reports and conference proceedings. Included studies will be restricted to those reported in English or French. Two reviewers will independently screen articles at the title and abstract stage for inclusion into full text screening. We will provide a general descriptive overview, tabular summaries and content analysis for the extracted data.

Ethics and dissemination

Ethical approval is not required for the conduct of the scoping review. We will disseminate our findings via open access peer-reviewed journals and scientific presentations. Our scoping review findings will help to determine the feasibility of a subsequent systematic review (and meta-analysis) on HSU during the COVID-19 pandemic.
Inequalities in children’s mental health before and during the COVID-19 pandemic: findings from the UK Household Longitudinal Study
Authors: Miall Naomi , Pearce Anna , Moore Jamie C , Benzeval Michaela , Green Michael J
Published: September 2023

Background

There are concerns that child mental health inequalities may have widened during the COVID-19 pandemic. We investigated whether child mental health inequalities changed in 2020/2021 compared with prepandemic.

Methods

We analysed 16 361 observations from 9272 children in the population representative UK Household Longitudinal Study. Child mental health was measured using the Strengths and Difficulties Questionnaire (SDQ) at ages 5 and 8 years in annual surveys 2011–2019, and at ages 5–11 years in July 2020, September 2020 and March 2021. Inequalities in cross-sectional SDQ scores among 5 and 8 year olds, before and during the pandemic, were modelled using linear regression. Additionally, interactions between time (before/during pandemic) and: sex, ethnicity, family structure, parental education, employment, household income and area deprivation on mental health were explored.

Results

A trend towards poorer mental health between 2011 and 2019 continued during the pandemic (b=0.12, 95% CI 0.08 to 0.17). Children with coupled, highly educated, employed parents and higher household income experienced greater mental health declines during the pandemic than less advantaged groups, leading to narrowed inequalities. For example, the mean difference in child SDQ scores for unemployed compared with employed parents was 2.35 prepandemic (1.72 to 2.98) and 0.02 during the pandemic (−1.10 to 1.13). Worse scores related to male sex and area deprivation were maintained. White children experienced worse mental health than other ethnicities, and greater declines during the pandemic.

Conclusion

Mental health among UK 5 and 8 year olds deteriorated during the pandemic, although several inequalities narrowed. Interventions are needed to improve child mental health while ensuring inequalities do not widen.