bluuebunny/crossref_metadata_2025 huggingface dataset:
An Evaluation of Barriers and Facilitators for a Pressure Injury Prevention Link Nurse Role
Authors: Moir Chris , Taylor Peta , Seaton Philippa , Snell Helen
Published: July 2022

PURPOSE:

The purpose of this study was to identify barriers and facilitators for nurses in a pressure injury prevention (PIP) link nurse role.

DESIGN:

Mixed-methods study that used nominal group technique with focus groups, followed by online surveys.

SAMPLE AND SETTING:

The PIP link nurse project recruited 52 RNs; 32 completed the PIP educational program and participated in data collection. The sample was drawn from PIP link nurses, who were invited to participate in focus groups at the end of the project to identify perceived facilitators and barriers to their role. Focus groups were specific to work areas: aged care and community visiting, and hospital. Two were in an urban setting and one in a rural environment. Twenty-two PIP link nurses participated across 3 groups. To ensure comprehensive data from all involved in the project, online surveys were created using focus group priorities as the basis for questions to send to all PIP link nurses, their managers, and workplace colleagues.

METHODS:

Participants were invited to participate in focus groups to identify perceived facilitators and barriers to their role. These focus groups were organized around care settings: aged care, community visiting, and hospital. Using a nominal group technique focus group process, participants were asked to identify barriers and facilitators to their role. These were shared with the group until all answers were declared and understood. Voting on order of priority then took place, with majority voting leading to a prioritized list of facilitators and barriers for each group. Considering the similarities and differences across group priorities, researchers developed online surveys representing the main facilitators and barriers from the focus groups. Surveys were then distributed to all PIP link nurses, their managers, and colleagues. Survey data were collected and analyzed in REDCap and reported as percentages of agreement to the questions for each group of respondents.

RESULTS:

Focus group data indicated facilitating priorities included PIP link nurses' commitment to the role, the support they received from their managers and colleagues, and time release to complete the role. Barriers included lack of time—when other work pressures took priority, and PIP link nurses felt the focus on applying quality improvement theory was more challenging than they had anticipated. Surveys from all groups reiterated the importance of the support of the workplace team in facilitating the role, and the time pressures for the PIP link nurse were a barrier to the role.

CONCLUSION:

While the funding of such projects is advantageous, it should be carefully and generously considered how much time is required if the project is to succeed so that lack of time to complete the role does not become a barrier to successful completion.
Larval Therapy for Treatment of Chronic Wounds Colonized by Multi-resistant Pathogens in a Pediatric Patient
Authors: Pérez-Acevedo Gemma , Bosch-Alcaraz Alejandro , Torra-Bou Joan Enric
Published: July 2022

BACKGROUND:

Chronic wounds are susceptible to colonization with gram-positive and gram-negative bacteria that may be resistant to antimicrobial dressings and systemic antibiotics. In January 2004, the US Food and Drugs Administration approved use of medicinal larvae for use in humans and animals for resistant organisms. Despite use in adults, there is a paucity of evidence evaluating its efficacy and safety in the pediatric population.

CASE:

T was a 5-year-old boy with several chronic wounds infected with multidrug-resistant Pseudomonas aeruginosa. The wounds were originally treated with chemical debridement, dressings containing ionic silver, negative-pressure wound therapy (NPWT), and antibiotics without success. Consequently, a multidisciplinary team implemented maggot debridement therapy (MDT).

CONCLUSIONS:

After MDT, one wound completely epithelialized and the other wounds achieved a reduction in size with 70% epithelization. Therapy also led to a reduction in wound odor, exudate, and pain. The other wounds were closed after additional management with dressing containing nanocrystalline silver and NPWT.
‘Voice needs teeth to have bite’! Expanding community-led multisectoral action-learning to address alcohol and drug abuse in rural South Africa
Authors: D’Ambruoso Lucia , Mabetha Denny , Twine Rhian , van der Merwe Maria , Hove Jennifer , Goosen Gerhard , Sigudla Jerry , Witter Sophie
Published: July 2022

There is limited operational understanding of multisectoral action in health inclusive of communities as active change agents. The objectives were to: (a) develop community-led action-learning, advancing multisectoral responses for local public health problems; and (b) derive transferrable learning. Participants representing communities, government departments and non-governmental organisations in a rural district in South Africa co-designed the process. Participants identified and problematised local health concerns, coproduced and collectively analysed data, developed and implemented local action, and reflected on and refined the process. Project data were analysed to understand how to expand community-led action across sectors. Community actors identified alcohol and other drug (AOD) abuse as a major problem locally, and generated evidence depicting a self-sustaining problem, destructive of communities and disproportionately affecting children and young people. Community and government actors then developed action plans to rebuild community control over AOD harms. Implementation underscored community commitment, but also revealed organisational challenges and highlighted the importance of coordination with government reforms. While the action plan was only partially achieved, new relationships and collective capabilities were built, and the process was recommended for integration into district health planning and review. We created spaces engaging otherwise disconnected stakeholders to build dialogue, evidence, and action. Engagement needed time, space, and a sensitive, inclusive approach. Regular engagement helped develop collaborative mindsets. Credible, actionable information supported engagement. Collectively reflecting on and adapting the process supported aligning to local systems priorities and enabled uptake. The process made gains raising community ‘voice’ and initiating dialogue with the authorities, giving the voice ‘teeth’. Achieving ‘bite’, however, requires longer-term engagement, formal and sustained connections to the system. Sustaining in highly fluid contexts and connecting to higher levels are likely to be challenging. Regular learning spaces can support development of collaborative mindsets in organisational contexts aligning community voice with state capacity to respond.
Deep convolution neural network for screening carotid calcification in dental panoramic radiographs
Authors: Amitay Moshe , Barnett-Itzhaki Zohar , Sudri Shiran , Drori Chana , Wase Tamar , Abu-El-Naaj Imad , Rieck Merton , Avni Yossi , Pogozelich Gil , Weiss Ervin , Mosseri Morris
Published: July 2022

Ischemic stroke, a leading global cause of death and disability, is caused by carotid arteries atherosclerosis. Such calcifications are classically detected by ultrasound screening. In recent years it was shown that these calcifications can also be inferred from routine panoramic dental radiographs. In this work, we focused on the panoramic dental radiographs taken from 500 patients, manually labelling each of the patients’ sides (each radiograph was treated as two sides), and which were used to develop an artificial intelligence (AI)-based algorithm to automatically detect carotid calcifications. The algorithm uses deep learning convolutional neural networks (CNN), with transfer learning (TL) approaches followed by eXtreme Gradient Boosting algorithm (XGBoost) that achieved true labels for each corner, and reaches a sensitivity (recall) of 0.82 and a specificity of 0.93 for individual artery, and a recall of 0.88 and specificity of 0.86 for individual patients. Applying and integrating the algorithm we developed in healthcare units and dental clinics has the potential of reducing stroke events and their mortality and morbidity consequences.

Author summary

Stroke is a leading global cause of death and disability. One major cause of stroke is carotid artery calcification (CAC). Traditional approaches for CAC detection are doppler ultrasound screening and angiography computerized tomography (CT), medical procedures that require financial expenses, are time consuming and discomforting to the patient. Of note, angiography CT involves the injection of contrast material and exposure to x-ray ionizing irradiation. In recent years researchers have shown that CAC can also be detected when analyzing routine panoramic dental radiographs, a non-invasive, cheap and easily accessible procedure. This study takes us one step further, in developing artificial intelligence (AI)-based algorithms trained to detect such calcifications in panoramic dental radiographs. The models developed are based on deep learning convolutional neural networks, transfer learning, and XGBoost algorithm, that enable an accurate automated detection of carotid calcifications, with a recall of 0.82 and a specificity of 0.93. Statistical approaches for assessing predictions per individual (i.e.: predicting the risk of calcification in at least one artery), were developed showing a recall of 0.88 and specificity of 0.86. Applying and integrating this approach in healthcare units may significantly contribute to identifying at-risk patients.
Feasibility and analysis considerations of continuous community-based cough monitoring in low- and middle-income settings
Authors: Huddart Sophie , Asege Lucy , Dang Hai , Deredinger Brigitta , Golla Marissa , Lerisha Lovelina , Christopher Devasahayam J. , Jaganath Devan , Theron Grant , Nhung Nguyen Viet , Andama Alfred , Yu Charles , Denkinger Claudia M. , Nahid Payam , Cattamanchi Adithya
Published: July 2022

Introduction

Cough is a hallmark symptom of multiple respiratory conditions. Technological advances have made it possible to monitor cough using smartphone applications continuously and objectively. However, these technologies have not yet been evaluated for their feasibility in real-world research conditions.

Methods

We conducted 14-day continuous cough monitoring of presumptive TB patients enrolled as outpatients in a multi-center prospective tuberculosis diagnostics trial in Uganda, South Africa, Vietnam, the Philippines and India. Participants were given a smartphone with the Hyfe Research application installed, a carrier sling, and training on how to use both the phone and the cough application. We evaluated how often and how long participants recorded, and when coughs were detected. We also compared multiple cough frequency metrics for their performance in detecting changes in cough frequency.

Results

Of 693 participants who consented to continuous cough monitoring for 14 days, 568 (82.0%) completed at least one recording session successfully. Among these 568 participants, 421 (74.1%) recorded on at least 10 of the 14 days in the recording period for a median of 23.9 hours per day. We detected coughs in a diurnal pattern with a median of 1 cough per hour detected between 6am and 2pm local time and a median of 0 coughs for all other hours. We found median coughs per hour to be the cough frequency metric most robust to outlier values while still detecting changes in cough frequency during the recording period. Implementation challenges include the visibility of cough monitoring devices, nighttime recording and concurrent charging of devices.

Conclusions

Continuous cough monitoring using a smartphone application is feasible in low- and middle-income country settings.
Antigenic landscape analysis of individuals vaccinated with a universal influenza virus vaccine candidate reveals induction of cross-subtype immunity
Authors: Meade Philip , Strohmeier Shirin , Bermúdez-González Maria Carolina , García-Sastre Adolfo , Palese Peter , Simon Viviana , Krammer Florian
Published: July 2022

Current influenza virus vaccines have to be closely matched to circulating strains to provide good protection and antigenic drift and emerging pandemic influenza virus strains present a difficult challenge for them. Universal influenza virus vaccines, including chimeric hemagglutinin (cHA)-based constructs that target the conserved stalk domain of hemagglutinin, are in clinical development. Due to the conservation of the stalk domain, antibodies directed to it show broad binding profiles, usually within group 1 and group 2 influenza A or influenza B virus phylogenies. However, determining the binding breadth of these antibodies with commonly used immunological methods can be challenging. Here, we analyzed serum samples from a phase I clinical trial (CVIA057, NCT03300050) using an influenza virus protein microarray (IVPM). The IVPM technology allowed us to assess immune responses not only to a large number of group 1 hemagglutinins but also group 2 and influenza B hemagglutinins. In CVIA057, different vaccine modalities including a live attenuated influenza virus vaccine and inactivated influenza virus vaccines with or without adjuvant, all in the context of cHA constructs, were tested. We found that vaccination with adjuvanted, inactivated vaccines induced a very broad antibody response covering group 1 hemagglutinins, with limited induction of antibodies to group 2 hemagglutinins. Our data show that cHA constructs do indeed induce very broad immune responses and that the IVPM technology is a useful tool to measure this breadth that broadly protective or universal influenza virus vaccines aim to induce.

Importance

The development of a universal influenza virus vaccine that protects against seasonal drifted, zoonotic or emerging pandemic influenza viruses would be an extremely useful public health tool. Here we test a technology designed to measure the breadth of antibody responses induced by this new class of vaccines.
The role of SARS-CoV-2 genomic surveillance and innovative analytical platforms for informing public health preparedness in Bengaluru, India
Authors: Harsha Pulleri Kandi , Pattabiraman Chitra , George Anson Kunjumon , J Madhusudhan , Mardikar Saumitra , Nazaar Mudasir , Adimoolam Srivathsan , A Divya Priya , Pitale Jayee , Nagarajan Mahesh , Sridharan Srikant , Kannan Yasodha , Janakiraman Anand , Veeramachaneni Vamsi , Hariharan Ramesh , Rao Vishal US , Shariff Mohammed , Chandra Thrilok , Sudhakar K. , Dev Randeep , Vasanthapuram Ravi , Chandru Vijay
Published: July 2022

A comprehensive SARS-CoV-2 genomic surveillance programme that integrates logistics, laboratory work, bioinformatics, analytics, and timely reporting was deployed through a public-private partnership in the city of Bengaluru, Karnataka in India. As a result, 12461 samples have been sequenced and reported to the Karnataka State public health officials as time-sensitive, decision support during the last one year and uploaded in global public databases in a timely manner. This programme has developed an analytics platform for studying SARS-CoV-2 sequences and their epidemiological context. Continuous sequencing effort enabled timely detection of emergence of Omicron variant in India and the subsequent spread of the same and its sub-lineages with more logistic growth (BA.10, BA.12 and BA.5) in Bengaluru. Our data also helped to provide timely information on variants to determine which of the Variants of Concern tracked globally, were observed in Bengaluru, ensuring targeted efforts and reducing unwarranted fear. This effort highlights the importance of, and the urgent need to, increase genomic surveillance to support the states with limited sequencing and bioinformatics capacity. We describe the development and deployment of this end-to-end solution for genomic surveillance of SARS-CoV-2 in the city of Bengaluru.
Timing of blood draws among hospitalized patients: An evaluation of the electronic health records from a large health care system
Authors: Caraballo César , Mahajan Shiwani , Huang Chenxi , Aneja Sanjay , Murugiah Karthik , Mortazavi Bobak J. , Lu Yuan , Khera Rohan , Krumholz Harlan M.
Published: July 2022

Importance

Early morning blood draws disrupt patients’ sleep and adversely affect patient experience.

Objective

To describe the trends in non-urgent early morning blood draws in a large health care system.

Design

This cross-sectional study analyzed trends in non-urgent early morning (04:00–06:59) blood draws using the electronic medical records of patients hospitalized between November 2016 and October 2019.

Setting

The study was done at Yale New Haven Health System, which is Connecticut’s largest health care system consisting of 5 hospitals.

Participants

We included all blood draw events for hospitalized adult patients (≥18 years at the time of admission).

Main outcome and measures

We assessed the timing of non-urgent (excluding blood draws performed in the emergency department, critical care units, step-down units, and during the first 24 hours of admission) blood draws among hospitalized patients and determined if the trends of early morning (04:00–06:59) blood draws varied by patient characteristics or over the study duration.

Results

Of the 5,676,802 blood draw events included, 38.9% occurred between 04:00–06:59 with only modest differences across age, race and ethnicity, and gender subgroups. The proportion of early morning blood draws increased over the study period from 36.9% to 41.4% (P<0.001). Of the early morning samples, those collected between 04:00–04:59 decreased from 25.6% to 18.5%, those collected between 05:00–05:59 increased from 39.6% to 45.5%, and those collected between 06:00–06:59 increased from 34.6% to 36.0% (P<0.001, each).

Conclusions and relevance

The proportion of non-urgent early morning blood draws was persistently high over 3 years. There is a need to redesign hospital care to reduce sleep interruptions from non-urgent interventions.

KEY POINTS

Question

What are the trends in non-urgent early morning (04:00–06:59) blood draws among non-critically ill hospitalized patients across a large health care system?

Findings

This cross-sectional study showed that 38.9% of all blood draws occurred between 04:00–06:59, with only modest differences across age, race and ethnicity, and gender subgroups. The proportion of early morning blood draws increased over the study period from 36.9% to 41.4% (P<0.001).

Meaning

The proportion of non-urgent early morning blood draws remains persistently high, suggesting a need to redesign hospital care to reduce sleep interruptions from non-urgent interventions.
Retaining dermatology patients in primary care using dialogues with secondary care: A service evaluation
Authors: Brainard Julii , Crawford Amy , Wright Beth , Everden Paul
Published: July 2022

Background

Wait list sizes for specialist secondary care have soared in recent years. Dermatology is a good candidate service for retaining patients in primary care and avoiding unnecessary waits to see a specialist. A dermatology dialogue service between primary and secondary care (DDPS) was developed in Norfolk and Waveney, eastern England. The service involved primary care referrers uploading patient images of skin complaints for review by and dialogue with secondary specialists to see if the patient could be retained in primary care, or should be referred to secondary care routinely, urgently or on the two week wait cancer pathway.

Objectives

To evaluate service performance with respect to specific targets including reduction in secondary care wait list growth in the period March 2021-March 2022 inclusive.

Methods

Service activity was summarized with respect to speed of resolution, case counts and dispositions. Clinician and patient satisfaction were canvased with structured questionnaires. Actual new referral counts were compared to projections based on historical data. Wait list growth was compared to other specialisms and other areas. Wait times to receive first treatment at start and end of monitoring period were monitored.

Results

Over 3600 patients were enrolled in the DDPS system. Over 98% of cases were reported by the dermatologists within 36 hours. Clinician and patient satisfaction were high. Frequently asked questions and conditions were highlighted by dermatologists to design and deliver an educational event for primary care clinicians that was well received. Wait list growth to see dermatology in the commissioning area was smaller for dermatology than other large specialisms, and mostly smaller growth than dermatology wait lists commissioned by other NHS commissioners. Negative impact on the urgent priority (cancer pathway) wait list could not be observed.

Conclusions

The DDPS was satisfactory to clinicians and patients and coincided with smaller dermatology wait list growth than might otherwise have been expected.
Continuous Bayesian Variant Interpretation Accounts for Incomplete Penetrance among Mendelian Cardiac Channelopathies
Authors: O’Neill Matthew J. , Sala Luca , Denjoy Isabelle , Wada Yuko , Kozek Krystian , Crotti Lia , Dagradi Federica , Kotta Maria-Christina , Spazzolini Carla , Leenhardt Antoine , Salem Joe-Elie , Kashiwa Asami , Ohno Seiko , Tao Ran , Roden Dan M. , Horie Minoru , Extramiana Fabrice , Schwartz Peter J. , Kroncke Brett M.
Published: July 2022

Background

The congenital Long QT Syndrome (LQTS) and Brugada Syndrome (BrS) are Mendelian autosomal dominant diseases which frequently precipitate fatal cardiac arrhythmias. Incomplete penetrance is a barrier to clinical management of heterozygotes harboring variants in the major implicated disease genes KCNQ1, KCNH2, and SCN5A. We apply and evaluate a Bayesian penetrance estimation strategy that accounts for this phenomenon and evaluate penetrance distributions and rationalize their structural underpinnings across four genotype-phenotype pairs.

Methods

We generated Bayesian penetrance estimation models for KCNQ1-LQT1 and SCN5A-LQT3 using variant-specific features and clinical data from the literature, international arrhythmia genetic centers, and population controls. We analyzed the distribution of posterior penetrance estimates across four-genotype phenotype relationships and compared continuous estimates to ClinVar annotations. Posterior estimates were mapped onto protein structure.

Results

Bayesian models of KCNQ1-LQT1 and SCN5A-LQT3 are well-calibrated to clinical observations. Variant-informed penetrance estimates of KCNQ1-LQT1 and SCN5A-LQT3 are empirically equivalent to 10 and 5 heterozygote clinical phenotypes, respectively. Posterior penetrance estimates were bimodal for KCNQ1-LQT1 and KCNH2-LQT2, with a higher fraction of missense variants with high penetrance among KCNQ1 variants. SCN5A-LQT3 and SCN5A-BrS had comparatively more variants with predicted low penetrance. There was a wide distribution of variant penetrance estimates among similar categories of ClinVar annotations. Structural mapping revealed heterogeneity among ‘hot spot’ regions and featured high penetrance estimates for KCNQ1 variants in contact with calmodulin and the S6 domain.

Conclusions

Bayesian penetrance estimates provide a continuous framework for variant interpretation, provide higher resolution within ‘hot spot’ domains, and facilitate prospective clinical management of variant heterozygotes.
Gene-by-gene screen of the unknown proteins encoded onP. falciparumchromosome 3
Authors: Kimmel Jessica , Schmitt Marius , Sinner Alexej , Jansen Pascal , Mainye Sheila , Ramón-Zamorano Gala , Toenhake Christa Geeke , Wichers Jan Stephan , Cronshagen Jakob , Sabitzki Ricarda , Mesén-Ramírez Paolo , Behrens Hannah Michaela , Bártfai Richárd , Spielmann Tobias
Published: July 2022

Taxa-specific proteins are key determinants defining the biology of all organisms and represent prime drug targets in pathogens. However, lacking comparability with proteins in other lineages makes them particularly difficult to study. In malaria parasites this is exacerbated by technical limitations. Here, we analysed the cellular location, essentiality, function and, in selected cases, interactome of all unknown non-secretory proteins encoded on an entireP. falciparumchromosome. The nucleus was the most common localisation, indicating it is a hotspot of parasite-specific biology. More in-depth functional studies with four proteins revealed essential roles in DNA replication and mitosis. The novel mitosis proteins defined a possible orphan complex and a highly diverged complex needed for the spindle-kinetochore connection. Structure-function comparisons indicated that the taxa-specific proteins evolved by different mechanisms. This work demonstrates the feasibility of gene-by-gene screens to elucidate the biology of malaria parasites and reveal critical parasite-specific processes of interest as drug targets.
Building pyramids against the evolutionary emergence of pathogens
Authors: Gandon Sylvain , Guillemet Martin , Gatchitch François , Nicot Antoine , Renaud Ariane C. , Tremblay Denise M. , Moineau Sylvain
Published: July 2022

Mutations allowing pathogens to escape host immunity promote the spread of infectious diseases in heterogeneous host populations and can lead to major epidemics. Understanding the conditions favoring these evolutionary emergences is key for the development of durable control strategies against pathogens. Here we compare the durability of three different control strategies: (i) a mixing strategy where the host population results from the mix of two single-resistant genotypes, (ii) a pyramiding strategy where host resistance is due to a single double-resistant genotype, (iii) a combining strategy where host resistance is due to a mix between a single-resistant genotype and a double-resistant genotype. First, we use evolutionary epidemiology theory to clarify the interplay between demographic stochasticity and evolutionary dynamics to show that the pyramiding strategy always yields lower probability of evolutionary emergence. Second, we confirm experimentally these predictions using virulent bacteriophages introduced in bacterial populations where we can manipulate the diversity and the depth of CRISPR immunity. Our work shows that pyramiding multiple defenses into the same individual host and avoiding mixing with single-defense strategies is a robust way to protect individuals and populations against pathogen evolutionary emergence. These results have practical implications for the optimal deployment of host resistance in agriculture and biotechnology but also for the optimal use of vaccination against human pathogens.
The Na+/K+ pump dominates control of glycolysis in hippocampal dentate granule cells
Authors: Meyer Dylan J. , Díaz-García Carlos Manlio , Nathwani Nidhi , Rahman Mahia , Yellen Gary
Published: July 2022

Cellular ATP that is consumed to perform energetically expensive tasks must be replenished by new ATP through the activation of metabolism. Neuronal stimulation, an energetically demanding process, transiently activates aerobic glycolysis, but the precise mechanism underlying this glycolysis activation has not been determined. We previously showed that neuronal glycolysis is correlated with Ca2+ influx, but is not activated by feedforward Ca2+ signaling (Díaz-García, Meyer, et al., 2021). Since ATP-powered Na+ and Ca2+ pumping activities are increased following stimulation to restore ion gradients and are estimated to consume most neuronal ATP, we aimed to determine if they are coupled to neuronal glycolysis activation. By using two-photon imaging of fluorescent biosensors and dyes in dentate granule cell somas of acute mouse hippocampal slices, we observed that production of cytoplasmic NADH, a byproduct of glycolysis, is strongly coupled to changes in intracellular Na+, while intracellular Ca2+ could only increase NADH production if both forward Na+/Ca2+ exchange and Na+/K+ pump activity were intact. Additionally, antidromic stimulation-induced intracellular [Na+] increases were reduced >50% by blocking Ca2+ entry. These results indicate that neuronal glycolysis activation is predominantly a response to an increase in activity of the Na+/K+ pump, which is strongly potentiated by Na+ influx through the Na+/Ca2+ exchanger during extrusion of Ca2+ following stimulation.
Human malaria parasite cold shock protein plays an essential role in asexual and sexual stage development and presents an excellent druggable target
Authors: Behl Ankita , Saini Monika , De Leon Fernando , Kumari Geeta , Kumar Vikash , Shoaib Rumaisha , Singh Harshita , Garg Swati , Arenz Christoph , Singh Shailja
Published: July 2022

Cold shock proteins are well characterized in bacteria, plants and humans, however there is no information on their existence and role in malaria parasite. Here, we have delineated the function of a novel cold shock protein of Plasmodium falciparum (Pf) which we have annotated ‘PfCoSP’. Our results show that recombinant PfCoSP has both DNA and RNA binding activity, and also interacts with alpha and beta tubulin of Pf. PfCoSP binds with RNA and alpha tubulin simultaneously to form a complex. Expression of PfCoSP was found during asexual blood stages and gametocyte stages of malaria parasite. PfCoSP expression up-regulates many folds upon cold treatment, suggesting its role during hypothermic cold shock. Interestingly, PfCoSP showed binding with human cold shock protein LIN28A inhibitor ‘LI71’ that also inhibits PfCSP -alpha/beta tubulin interactions. LI71 showed antimalarial activity against asexual blood stage and gametocyte stage suggesting its multi-stage, transmission-blocking potential. We propose that PfCoSP may form a workbench for translation during cold stress via its interactions with target mRNAs and the cytoskeleton protein tubulin.
How to deal with toxic amino acids: the bipartite AzlCD complex exports histidine in Bacillus subtilis
Authors: Meißner Janek , Schramm Thorben , Hoßbach Ben , Stark Katharina , Link Hannes , Stülke Jörg
Published: July 2022

In the Gram-positive model bacterium Bacillus subtilis, the presence of the amino acid glutamate triggers potassium uptake due to the glutamate-mediated activation of the potassium channel KtrCD. As a result, the intracellular accumulation of glutamate is toxic in strains lacking the second messenger cyclic di-AMP since these cells are unable to limit potassium uptake. We observed that the presence of histidine, which is degraded to glutamate, is also toxic for a B. subtilis strain that lacks all three c-di-AMP synthesizing enzymes. However, suppressor mutants emerged, and whole genome sequencing revealed mutations in the azlB gene encoding the repressor of the azl operon. This operon encodes an exporter and an importer for branched-chain amino acids. The suppressor mutations result in overexpression of the azl operon. Deletion of the azlCD genes encoding the branched-chain amino acid exporter restored the toxicity of histidine indicating that this exporter is required for histidine export and resistance to otherwise toxic levels of the amino acid. The higher abundance of the amino acid exporter AzlCD increased the extracellular concentration of histidine, thus confirming the new function of AzlCD as a histidine exporter. Unexpectedly, AzlB-mediated repression of the operon remains active even in the presence of amino acids suggesting that expression of the azl operon requires mutational inactivation of AzlB.

IMPORTANCE

Amino acids are building blocks for protein biosynthesis in each living cell. However, due to their reactivity as well as the similarity between several amino amino acids, they may also be involved in harmful reactions or in non-cognate interactions and thus be toxic. Bacillus subtilis can deal with otherwise toxic histidine by overexpressing a bipartite amino acid exporter AzlCD. Although encoded in an operon that also contains a gene for an amino acid importer, the corresponding genes are not expressed, irrespective of the availability or not of amino acids in the medium. This suggests that the azl operon is a last resort to deal with histidine stress that can be expressed due to mutational inactivation of the cognate repressor, AzlB.
Comparative Effect of Metformin versus Sulfonylureas with Dementia and Parkinson's Disease Risk in US patients over 50 with Type 2 Diabetes Mellitus
Authors: Newby Danielle , Linden Andrew , Fernandes Marco , Winchester Laura , Molero Yasmina , Sproviero William , Ghose Upamanyu , Li Qingqin , Launer Lenore J , van dujn Cornelia , Nevado-holgado Alejo
Published: July 2022

Introduction: Type 2 diabetes is a risk factor for dementia and Parkinson's disease (PD). Drug treatments for diabetes, such as metformin, could be used as potential novel treatments for these neurological conditions. Using medical records from the USA (OPTUM) we aimed to assess the association of metformin with all cause dementia, dementia subtypes, and PD compared to sulfonylureas.
Research Design and Methods: A new user comparator study design was conducted in patients >50 years old with diabetes who were new users of metformin or sulfonylureas between 2006-2018. Primary outcomes were all cause dementia and PD. Secondary outcomes were Alzheimer's disease (AD), vascular dementia (VD), and mild cognitive impairment (MCI). Cox proportional hazard models with inverse probability of treatment weighting (IPTW) were used to estimate the hazard ratios (HR). Sub analyses included stratification by age, race, renal function, and glycemic control.
Results: We identified 96,140 and 16,451 new users of metformin and sulfonylureas, respectively. Mean age was 66.4 +/- 8.2 years (48% male, 83% Caucasian). Over the 5-year follow-up, 3,207 patients developed all cause dementia (2,256 [2.3%] metformin, 951 [5.8%] sulfonylurea users) and 760 patients developed PD (625 [0.7%] metformin, 135 [0.8%] sulfonylurea users). After IPTW, HRs for all cause dementia and PD were 0.80 (95%CI 0.73-0.88) and 1.00 (95%CI 0.79-1.27). HRs for AD, VD and MCI were 0.81 (0.70-0.94), 0.79 (0.63-0.99) and 0.91 (0.79-1.04). Stronger associations were observed in patients who were younger (<75 years old), Caucasian, and with moderate renal function.
Conclusions: Metformin users compared with sulfonylureas users were associated with a lower risk of all cause dementia, AD and VD but not with PD or MCI. Age and renal function modified risk reduction. Our findings support the hypothesis that metformin provides more neuroprotection for dementia than sulfonylureas but not for PD, but further work is required to assess causality.
Incorporating alternative Polygenic Risk Scores into the BOADICEA breast cancer risk prediction model
Authors: Mavaddat N , Ficorella L , Carver T , Lee A , Cunningham AP , Lush M , Dennis J , Tischkowitz M , Downes K , Donglei H , Hahnen E , Schmutzler R , Stockley T , Downs G , Zhang T , Chiarelli AM , Bojesen S , Cong L , Chung WK , Pardo M , Feliubadaló L , Balmana J , Simard J , Antoniou AC , Easton DF
Published: July 2022

Background

The multifactorial risk prediction model BOADICEA enables identification of women at higher or lower risk of developing breast cancer. BOADICEA models genetic susceptibility in terms of the effects of rare variants in breast cancer susceptibility genes and a polygenic component, decomposed into an unmeasured and a measured component - the polygenic risk score (PRS). The current version was developed using a 313 SNP PRS. Here, we evaluated approaches to incorporating this PRS and alternative PRS in BOADICEA.

Methods

The mean, standard deviation (SD), and proportion of the overall polygenic component explained by the PRS (α2) need to be estimated. α was estimated using logistic regression, where the age-specific log-relative risk is constrained to be a function of the age-dependent polygenic relative risk in BOADICEA; and using a retrospective likelihood (RL) approach that models, in addition, the unmeasured polygenic component.

Results

Parameters were computed for 11 PRS, including 6 variations of the 313 SNP PRS used in clinical trials and implementation studies. The logistic regression approach underestimates α, as compared with the RL estimates. The RL α estimates were very close to those obtained by assuming proportionality to the odds ratio per 1 SD, with the constant of proportionality estimated using the 313 SNP PRS. Small variations in the SNPs included in the PRS can lead to large differences in the mean.

Conclusions

BOADICEA can be readily adapted to different PRS in a manner that maintains consistency of the model.

Impact

The methods described enable comprehensive breast cancer risk assessment.
Post-COVID Phenotypic Manifestations are Associated with New-Onset Psychiatric Disease: Findings from the NIH N3C and RECOVER Studies
Authors: Coleman Ben , Casiraghi Elena , Callahan Tiffany J , Blau Hannah , Chan Lauren , Laraway Bryan , Clark Kevin B. , Re’em Yochai , Gersing Ken R. , Wilkins Ken , Harris Nomi L. , Valentini Giorgio , Haendel Melissa A , Reese Justin , Robinson Peter N ,   the RECOVER Consortium
Published: July 2022

Acute COVID-19 infection can be followed by diverse clinical manifestations referred to as Post Acute Sequelae of SARS-CoV2 Infection (PASC). Studies have shown an increased risk of being diagnosed with new-onset psychiatric disease following a diagnosis of acute COVID-19. However, it was unclear whether non-psychiatric PASC-associated manifestations (PASC-AMs) are associated with an increased risk of new-onset psychiatric disease following COVID-19.

A retrospective EHR cohort study of 1,603,767 individuals with acute COVID-19 was performed to evaluate whether non-psychiatric PASC-AMs are associated with new-onset psychiatric disease. Data were obtained from the National COVID Cohort Collaborative (N3C), which has EHR data from 65 clinical organizations. EHR codes were mapped to 151 non-psychiatric PASC-AMs recorded 28-120 days following SARS-CoV-2 diagnosis and before diagnosis of new-onset psychiatric disease. Association of newly diagnosed psychiatric disease with age, sex, race, pre-existing comorbidities, and PASC-AMs in seven categories was assessed by logistic regression.

There was a significant association between six categories and newly diagnosed anxiety, mood, and psychotic disorders, with odds ratios highest for cardiovascular (1.35, 1.27-1.42) PASC-AMs. Secondary analysis revealed that the proportions of 95 individual clinical features significantly differed between patients diagnosed with different psychiatric disorders.

Our study provides evidence for association between non-psychiatric PASC-AMs and the incidence of newly diagnosed psychiatric disease. Significant associations were found for features related to multiple organ systems. This information could prove useful in understanding risk stratification for new-onset psychiatric disease following COVID-19. Prospective studies are needed to corroborate these findings.

Funding

NCATS U24 TR002306
Colonization of intervertebral discs byCutibacterium acnesin patients with low back pain: protocol for an analytical study with microbiological, phenotypic, genotypic, and multiomic techniques
Authors: Magno da Rocha Vinícius , Ormundo Gonçalves Ximenes Lima Carla , de Oliveira Ferreira Eliane , de Farias Gabriel Corrêa , Nogueira Fábio César Sousa , Martha Antunes Luis Caetano , Cassiano Keila Mara , Fiorelli Rossano Kepler Alvim
Published: July 2022

Lumbar disc degeneration (LDD) and low back pain (LBP) are two conditions that are closely related. Several studies have shownCutibacterium acnescolonization of degenerated discs, but whether and how these finding correlates with LBP is unknown. A prospective study was planned to identify molecules present in lumbar intervertebral discs (LLIVD) colonized byC. acnesin patients with LDD and LBP and correlate them with their clinical, radiological, and demographic profiles. The clinical manifestations, risk factors, and demographic characteristics of participants undergoing surgical microdiscectomy will be tracked. Samples will be isolated and pathogens found in LLIVD will be characterized phenotypically and genotypically. Whole genome sequencing (WGS) of isolated species will be used to phylotype and detect genes associated with virulence, resistance, and oxidative stress. Multiomic analyses of LLIVD colonized and non-colonized will be carried out to explain not only the pathogen’s role in LDD, but also its involvement in the pathophysiology of LBP. This study was approved by the Institutional Review Board (CAAE 50077521.0.0000.5258). All patients who agree to participate in the study will sign an informed consent form. Regardless of the study’s findings, the results will be published in a peer-reviewed medical journal. Trials registration numberNCT05090553; pre-results.
Dual therapy with Atazanavir/ritonavir plus Raltegravir versus triple therapy with Atazanavir/ritonavir plus Tenofovir-Emtricitabine after failure to an NNRTI regimen: 48-week results of the randomized pilot study ARTE trial
Authors: Inés Figueroa María , Sued Omar , Cesar Carina , Patterson Patricia , Yamamoto Cleyton , Fink Valeria , Luna Norma , Camiro-Zúñiga Antonio , Gun Ana , Cahn Pedro
Published: July 2022

Background

Dual therapy has emerged as a novel concept for HIV treatment. The ARTE study was aimed at comparing a nucleoside-sparing dual regimen consisting of ATV/r + RAL (DT) vs standard therapy of ATV/r + TDF/FTC (TT) among individuals failing first NNRTI-containing treatment.

Methods

Randomized multicenter open-label pilot study. Primary outcome: proportion of subjects with plasma HIV-1 RNA below the limit of detection (<50 copies/mL) at 48 weeks (W48). Secondary outcomes: proportion of discontinuation due to adverse events (AEs), time until viral suppression, time until loss of virological response, development of integrase resistance mutations, and absolute change in CD4 counts. The primary outcome was analyzed using the FDA snapshot analysis.

Results

Out of 57 participants screened, 34 were randomized to receive: DT (n: 18) or TT (n: 16). At W48, virological response was achieved in 67% (n: 12/18) of participants receiving DT and 88% (n: 14/16) receiving TT by FDA snapshot analysis (p = NS) and, 73% and 93% by per-protocol analysis (p = NS). CD4 cell count median change from baseline to W48 was +119 and + 52 cell/μL in DT and TT, respectively. Four participants receiving DT and one TT presented virological failure at W48, with low pVL. One participant developed an integrase resistance mutation (155H) and suppressed later on TT.

Conclusion

ATV/r+RAL as second-line therapy showed a trend to more frequent virological failure, compared to TT, although the study was unpowered to prove this difference. No major differences were seen in tolerance or toxicity.

This study is registered with ClinicalTrials.gov, Number: NCT01829802
Looking for a needle in a haystack: magnetotactic bacteria help in “rare biosphere” investigations
Authors: Uzun Maria , Koziaeva Veronika , Dziuba Marina , Alekseeva Lolita , Krutkina Maria , Sukhacheva Marina , Baslerov Roman , Grouzdev Denis
Published: July 2022

Studying the minor part of the uncultivated microbial majority (“rare biosphere”) is difficult even with modern culture-independent techniques. The enormity of microbial diversity creates particular challenges for investigating low-abundance microbial populations in soils. Strategies for selective sample enrichment to reduce community complexity can aid in studying the rare biosphere. Magnetotactic bacteria, apart from being a minor part of the microbial community, are also found in poorly studied bacterial phyla and certainly belong to a rare biosphere. The presence of intracellular magnetic crystals within magnetotactic bacteria allows for their significant enrichment using magnetic separation techniques for studies using a metagenomic approach. This work investigated the microbial diversity of a black bog soil and its magnetically enriched fraction. The poorly studied phylum representatives in the magnetic fraction were enriched compared to the original soil community. Two new magnetotactic species,CandidatusLiberimonas magnetica DUR002 andCandidatusObscuribacterium magneticum DUR003, belonging to different classes of the relatively little-studied phylumElusimicrobiota, were proposed. Their genomes contain clusters of magnetosome genes that differ from the previously described ones by the absence of genes encoding magnetochrome-containing proteins and the presence of uniqueElusimicrobiota-specific genes, termedmae. The predicted obligately fermentative metabolism in DUR002 and lack of flagellar motility in the magnetotacticElusimicrobiotabroadens our understanding of the lifestyles of magnetotactic bacteria and raises new questions about the evolutionary advantages of magnetotaxis. The findings presented here increase our understanding of magnetotactic bacteria, soil microbial communities, and the rare biosphere.
UPF1 mutants with intact ATPase but deficient helicase activities promote efficient nonsense-mediated mRNA decay
Authors: Chapman Joseph H. , Craig Jonathan M. , Wang Clara D. , Gundlach Jens H. , Neuman Keir C. , Hogg J. Robert
Published: July 2022

The conserved RNA helicase UPF1 coordinates nonsense-mediated mRNA decay (NMD) by engaging with mRNAs, RNA decay machinery, and the terminating ribosome. UPF1 ATPase activity is necessary for mRNA target discrimination and completion of decay, but the mechanisms through which UPF1 enzymatic activities such as helicase, translocase, RNP remodeling, and ATPase-stimulated dissociation influence NMD remain poorly defined. Using high-throughput biochemical assays to quantify UPF1 enzymatic activities, we show that UPF1 is only moderately processive (< 200 nt) in physiological contexts and undergoes ATPase-stimulated dissociation from RNA. We combine an in silico screen with these assays to identify and characterize known and novel UPF1 mutants with altered helicase, ATPase, and RNA binding properties. We find that UPF1 mutants with substantially impaired processivity, slower unwinding rate, and reduced mechanochemical coupling (i.e. the ability to harness ATP hydrolysis for work) still support efficient NMD in human cells. These data are consistent with a central role for UPF1 ATPase activity in driving cycles of RNA binding and dissociation to ensure accurate NMD target selection.
A population modification gene drive targeting bothSaglinandLipophorinimpairsPlasmodiumtransmission inAnophelesmosquitoes
Authors: Green Emily , Jaouen Etienne , Klug Dennis , Olmo Roenick Proveti , Gautier Amandine , Blandin Stéphanie , Marois Eric
Published: July 2022

Lipophorin is an essential, highly expressed lipid transport protein that is secreted and circulates in insect hemolymph. We hijacked theAnopheles coluzzii Lipophoringene to make it co-express a single-chain version of antibody 2A10, which binds sporozoites of the malaria parasitePlasmodium falciparum. The resulting transgenic mosquitoes show a markedly decreased ability to transmitPlasmodium bergheiexpressing theP. falciparumcircumsporozoite protein. To force the spread of this anti-malarial transgene in a mosquito population, we designed and tested several CRISPR/Cas9-based gene drives. One of these is installed in, and disrupts, the pro-parasitic geneSaglinand also cleaves wild-typeLipophorin,causing the anti-malarial modifiedLipophorinversion to replace the wild type and hitch-hike together with theSaglindrive. Although generating drive-resistant alleles and showing instability in its gRNA-encoding multiplex array, theSaglin-based gene drive reached high levels in caged mosquito populations and efficiently promoted the simultaneous spread of the antimalarialLipophorin::Sc2A10allele. This combination is expected to decrease parasite transmission via two different mechanisms. This work contributes to the design of novel strategies to spread antimalarial transgenes in mosquitoes, and illustrates some expected and unexpected outcomes encountered when establishing a population modification gene drive.