bluuebunny/crossref_metadata_2025 huggingface dataset:
Bordetella pertussis targets the basolateral membrane of polarized respiratory epithelial cells, gets internalized, and survives in intracellular locations
Authors: Baroli Carlos Manuel , Gorgojo Juan Pablo , Blancá Bruno Martín , Debandi Martina , Rodriguez Maria Eugenia
Published: November 2023

The airway epithelial barrier is a continuous highly organized cell layer that separates the exterior from the underlying mucosal tissue, preventing pathogen invasion. Several respiratory pathogens have evolved mechanisms to compromise this barrier, invade and even reside alive within the epithelium. Bordetella pertussis is a persistent pathogen that infects the human airway epithelium, causing whooping cough. Previous studies have shown that B. pertussis survives inside phagocytic and nonphagocytic cells, suggesting that there might be an intracellular stage involved in the bacterial infectious process and/or in the pathogen persistence inside the host. In this study we found evidence that B. pertussis is able to survive inside respiratory epithelial cells. According to our results, this pathogen preferentially attaches near or on top of the tight junctions in polarized human bronchial epithelial cells and disrupts these structures in an adenylate cyclase-dependent manner, exposing their basolateral membrane. We further found that the bacterial internalization is significantly higher in cells exposing this membrane compared with cells only exposing the apical membrane. Once internalized, B. pertussis mainly remains in nondegradative phagosomes with access to nutrients. Taken together, these results point at the respiratory epithelial cells as a potential niche of persistence.
Identifying and Prioritising the Causes of Medication Errors in the Pharmacy
Authors: Arslan M , Kağanoğlu İ
Published: November 2023

Introduction

Medication errors can negatively impact the health of numerous individuals worldwide and even lead to fatalities, from incorrect timing, dosages, or methods of administration of drugs to mismanagement of drug interactions. Such errors can arise from patients and healthcare professionals in all stages of patient care. Therefore, all healthcare workers must pay attention to preventing medication errors, correctly managing encountered errors, and reporting them appropriately to ensure patient safety. Parallel to these, one of the FIP's development goals for pharmacists was also determined as Patient Safety. Despite various studies that have analysed medication errors from different perspectives, no study has thoroughly evaluated the causes of medication errors specific to community pharmacists.

Aim

This project aimed to identify and prioritise the causes of medication errors encountered in community pharmacies.

Methods

According to the aim of the study, semi-structured qualitative interviews were conducted with 16 community pharmacists in Van. Thematic analysis was conducted on the qualitative interview findings. Additionally, at the end of the qualitative interviews, a questionnaire was applied due to the Analytical Hierarchy Process (AHP), to prioritize the causes of the medication errors.

This study was conducted after Van Yüzüncü Yıl University Non-interventional Research Ethics Committee approved the study ethically (Date:18/11/2022, Decision No: 2022/11-25). This study is supported by The Scientific and Technological Research Council of Türkiye (TUBITAK)’s 2209/2022 2nd term projects (Project No: 1919B012217783).

Results

Three main themes and 13 sub-themes were obtained. The study's results emphasise that communication gaps and manual prescriptions are the most significant causes of medication errors reported by pharmacists. As a result of the AHP, prescription errors (31.5%) were found to be the most encountered reason for medication errors, followed by medication knowledge gaps (25.7%).

Discussion/Conclusion

Pharmacists, aware of their responsibilities for patient and drug safety, also have an essential role in solving problems that cause medication errors. With this study, it is also seen that pharmacists show the necessary self-sacrifice and take precautions to minimize medication errors originating from the pharmacy. So, the findings obtained from this study are thought to have guiding implications for preventing medication errors.
A Single-Laboratory Validation of a UPLC Method for Determination of Folic Acid in Various Dietary Supplement Dosage Forms
Authors: A Lusi , Fakhary Mina , Gaeini Niloufar Rahimi , Solano Jennifer M , Koroma Mohamed
Published: November 2023

Background

Folic acid is an essential nutrient necessary for the synthesis of nucleic acids (DNA and RNA) and certain amino acids. There are no scientifically validated analytical methods for folic acid applicable to all dosage forms.

Objective

A single-laboratory method was validated for the determination of folic acid content in various dietary supplement dosage forms. This method used ultra-performance liquid chromatography/diode-array detector (UPLC/PDA) to determine the folic acid content in dietary supplements in the form of tablets, two-piece capsules, powder drinks, softgels, and gummies.

Method

The ultra-performance liquid chromatography/diode-array detector method was evaluated for linearity, limit of detection (LOD), limit of quantification (LOQ), repeatability, recovery, specificity, and system suitability.

Results

Linearity of the folic acid standard was shown to be linear in the range of 0.45 µg/mL to 7.37 µg/mL. LOD and LOQ of folic acid were 0.089 and 0.268 µg/mL, respectively. The repeatability of nine samples from five matrixes resulted in 1.15–4.82% relative standard deviation (RSD). Five samples with five different matrixes spiked with 25, 50, and 100% of working standard concentration and had a recovery range of 95.48–104.72%. The chromatograms and spectra of the blank, standard, and sample solutions showed that the method was free of interference for folic acid. The system suitability results of different matrixes showed that the UPLC/PDA system is suitable for folic acid analysis. All the AOAC INTERNATIONAL SMPR® 2022.002 requirements were fulfilled.

Conclusions

The ultra-performance liquid chromatography/diode-array detector method compares favorably with the requirements of AOAC SMPR 2022.002.

Highlights

The UPLC/PDA method is fast and suitable for all dietary supplement matrixes studied. The method meets the requirements of SMPR 2022.002.
Maternal exercise during pregnancy modulates genotoxicity caused by high fructose consumption in mice offspring
Authors: Magenis Marina Lummertz , Damiani Adriani Paganini , Monteiro Isadora de Oliveira , Dagostin Ligia Salvan , Silva Nicollas dos Santos , Scussel Rahisa , Nagashima Seigo , Langie Sabine A S , Pinho Ricardo Aurino , de Andrade Vanessa Moraes
Published: November 2023

Pregnancy is a period that is characterized by several metabolic and physiological changes and requires special attention, especially with regard to the relationship between feeding and foetal development. Therefore, the objective of this study was to evaluate whether the practice of voluntary physical exercise (VPE) in combination with chronic consumption of fructose (FRU) from the beginning of life and/or until the gestational period causes genotoxic changes in pregnant females and in their offspring. Seventy Swiss female mice received FRU in the hydration bottle and/or practiced VPE for 8 weeks (prepregnancy/pregnancy). After the lactation period, the offspring groups were separated by sex. It was observed that the consumption of FRU affected the food consumption, serum concentration of FRU, and glycemic profile in the mothers and that the VPE decreases these parameters. In addition, FRU was genotoxic in the mothers’ peripheral tissues and VPE had a preventive effect on these parameters. The offspring showed changes in food consumption, serum FRU concentration, and body weight, in addition to an increase in the adiposity index in male offspring in the FRU (FRU) group and a decrease in the FRU + VPE group. FRU leads to hepatic steatosis in the offspring and VPE was able to decrease the area of steatosis. In addition, FRU led to genotoxicity in the offspring and VPE was able to modulate this effect, reducing damages. In conclusion, we observed that all interventions with VPE had nutritional, genetic, and biochemical benefits of the mother and her offspring.
Environmental and economic benefits of single-atom catalysts in energy conversion and storage
Authors: Velpandian Muthuraja , Sinhamahapatra Apurba , Basu Suddhasatwa
Published: November 2023

Single-atom catalysts have gained significant popularity in heterogeneous catalysis owing to their high activity and stability. The predominant focus of current research is centred around the dispersion of single-atom catalysts onto a support medium, aiming to enhance the efficiency of energy conversion and storage systems. The utilization of these catalysts has been associated with environmental and economic benefits. This perspective article provides an overview of the latest advancements in single-atom catalysts used for energy conversion and storage applications, with an emphasis on their potential environmental and economic benefits. It also provides insights into the future applications of single-atom catalysts in energy conversion and storage. In addition, the article investigates emerging opportunities for energy conversion and storage systems. Furthermore, the article provides a comprehensive analysis of the key benefits, challenges, and potential factors that may influence the advancement of energy conversion and storage technologies.
Does social communication make investors stay in the market?
Authors: Tong Xiaochuan , Preda Alex
Published: November 2023

The role of online discussions in rallying investors has been highlighted by the GameStop frenzy of 2021. We know little, however, about the effect of online discussions on investor survivorship. Previous studies have emphasized the role of communication with respect to market entry, but not with respect to market survival. Survivorship studies, in turn, have largely focused on the role of financial factors in the investors’ decision to quit trading, but have not investigated so far how social interactions and communication impact the decision to quit or stay. Using a dataset covering 1.1 million observations for 4,731 traders over 18 months, we examine the role of online discussions in traders’ decisions to stay in the market. We find that traders who actively engage in them tend to be 16 per cent to 30 per cent less likely to quit trading. We identify a positive Granger-causal relationship between online discussions and the probability of survival. Our results are robust to alternative measures of communication and different sets of control variables. Based on this evidence, we draw attention to the necessity of studying the nexus between finance and social media as an important component of platform capitalism.
Safety profile and signal detection of phosphodiesterase type 5 inhibitors for erectile dysfunction: a Food and Drug Administration Adverse Event Reporting System analysis
Authors: Shin Young Eun , Rojanasarot Sirikan , Hincapie Ana L , Guo Jeff Jianfei
Published: November 2023

Background

Phosphodiesterase type 5 inhibitors (PDE5Is) are generally well tolerated but have been associated with uncommon and significant adverse events (AEs).

Aim

This study aims to investigate and compare the characteristics of AEs associated with PDE5Is used for erectile dysfunction and identify any safety signals in a postmarketing surveillance database between 2010 and 2021.

Methods

A descriptive analysis was conducted for all AEs reported to the Food and Drug Administration Adverse Event Reporting System for 4 PDE5Is—avanafil, sildenafil, tadalafil, and vardenafil—indicated for erectile dysfunction between January 2010 and December 2021. The frequency of the most reported AEs and outcomes were identified. A disproportionality analysis based on proportional reporting ratio (PRR) and reporting odds ratio (ROR) was conducted for the most common and clinically important AEs to identify signals to gain insights into potential differences in safety profiles.

Outcomes

The outcome measures of the study are frequency of reported AEs and outcomes following AE.

Results

A total of 29 236 AEs were reported for PDE5Is during the study period. The most reported AE was “drug ineffective” with 7115 reports (24.3%). Eight safety signals were detected across the 4 drugs. Key signals were sexual disorders (PRR, 3.13 [95% CI, 2.69-3.65]; ROR, 3.24 [95% CI, 2.77-3.79]) and death (PRR, 3.17 [2.5-4.01]; ROR, 3.211 [2.52-4.06]) for sildenafil, priapism (PRR, 3.63 [2.11-6.24]; ROR, 3.64 [2.12-6.26]) for tadalafil, and drug administration error (PRR, 2.54 [1.84-3.52]; ROR, 2.6 [1.86-3.63]) for vardenafil. The most reported outcomes were other serious events with 6685 events (67.2%) and hospitalization with 1939 events (19.5%).

Clinical Implications

The commonly reported AEs and detected signals may guide clinicians in treatment decision making for men with erectile dysfunction.

Strengths and Limitations

This is the first comprehensive report and disproportionality analysis on all types of AEs associated with PDE5Is used for erectile dysfunction in the United States. The findings should be interpreted cautiously due to limitations in the Adverse Event Reporting System, which includes self-reports, duplicate and incomplete reports, and biases in reporting and selection. Therefore, establishing a causal relationship between the reported AEs and the use of PDE5Is is uncertain, and the data may be confounded by other medications and indications.

Conclusion

PDE5Is demonstrate significantly increased risks of reporting certain clinically important AEs. While these events are not common, it is imperative to continually monitor PDE5I use at the levels of primary care to national surveillance to ensure safe utilization.
Spain: Private client tax landscape
Authors: Carreño Florentino , San Basilio Beatriz
Published: November 2023

This article provides an analysis of Spain’s current private client tax landscape, explored during the 2023 Vienna Conference by The International Academy of Estate and Trust Law. It offers insights into personal income, wealth, inheritance and gift taxation, as well as aspects of Spanish residence and citizenship. With a strong focus on family and estate planning, it sheds light on the tax opportunities presented by relocating to Spain.
Prognostic Factors of Perceived Disability and Perceived Recovery After Whiplash
Authors: Pedrero-Martin Yolanda , Falla Deborah , Rodriguez-Brazzarola Pablo , Torrontegui-Duarte Marcelino , Fernandez-Sanchez Manuel , Jerez-Aragones Jose Manuel , Bernard Liew , Luque-Suarez Alejandro
Published: November 2023

Objectives.

The understanding of the role that cognitive and emotional factors play in how an individual recovers from a whiplash injury, is important. Hence, we sought to evaluate if pain-related cognitions (self-efficacy beliefs, expectation of recovery, pain catastrophizing, optimism, and pessimism) and emotions (kinesiophobia) are longitudinally associated with the transition to chronic whiplash associated disorders (WAD) in terms of perceived disability, and perceived recovery at 6 and 12-months.

Methods:

One-hundred and sixty-one participants with acute or subacute WAD were included. The predictors were: self-efficacy beliefs, expectation of recovery, pain catastrophizing, optimism, and pessimism, pain intensity, and kinesiophobia. The two outcomes were the dichotomized scores of perceived disability and recovery expectations at six and twelve months. Stepwise regression with bootstrap resampling was performed to identify the predictors most strongly associated with the outcomes, and the stability of such selection.

Results.

Baseline perceived disability, pain catastrophizing, and expectation of recovery were the most likely to be statistically significant, with an overage frequency of 87.2%, 84.0%, and 84.0%, respectively.

Discussion:

Individuals with higher expectation of recovery and lower levels of pain catastrophizing and perceived disability at baseline, have higher perceived recovery and perceived disability at 6 and 12-months. These results have important clinical implications as both factors are modifiable via health education approaches.
Spinal Cord Signal Intensity Predicts Functional Outcomes in the Operative Management of Degenerative Cervical Myelopathy
Authors: Firempong Gaylinn Kwame , Sheppard William L. , Gelfand Yaroslav , Ellingson Benjamin M. , Holly Langston T.
Published: November 2023

Study Design:

Prospective single institutional cohort study on degenerative cervical myelopathy (DCM) from 2009 to 2022.

Objective:

This study aims to assess the relationship among preoperative spinal cord signal change, postoperative signal change evolution, and functional outcome in patients undergoing surgery for DCM.

Summary of Background Data:

There is conflicting evidence on whether spinal cord signal intensity influences functional outcomes in patients with DCM.

Patients and Methods:

This prospective study investigated 104 patients with DCM that underwent both preoperative and routine postoperative cervical spine magnetic resonance imaging (MRI) as part of a research protocol. Signal intensity/grade, modified Japanese Orthopedic Association (mJOA) scores, signal resolution, and patient demographics were assessed.

Results:

Sixty-eight of the subjects were found to have abnormal T2 spinal cord signal intensity changes on their preoperative MRI. The total mean preoperative mJOA score was 13.6, increasing postoperatively to 16 (P < 0.001). The presence or absence of preoperative spinal cord signal change was not associated with the change in mJOA score or neurological recovery rate after surgery. Of the 68 patients with preoperative T2 signal change, 36 were found to have an improvement in the T2-weighted signal grade after surgery and 32 had no change in postoperative signal grade. The mean improvement in mJOA score (3.7) and neurological recovery rate (70.3%) was significantly higher in the patients with preoperative signal change whose postoperative MRI signal change grade improved by at least one point compared with those that did not (2.0, 50.5%), (P < 0.001, P < 0.003).

Conclusions:

The presence of preoperative T2-weighted signal change was associated with lower preoperative mJOA scores, but no change in mJOA after surgery or postoperative neurological recovery rate. However, improvement in T2-weighted spinal cord signal grade on postoperative MRI was significantly associated with a degree of neurological improvement after surgery.
An Integrative Review
Authors: Tam Derrick , Norman Hollie , Chen Leon L.
Published: November 2023

The onset of the COVID-19 pandemic has led to an increased use of extracorporeal membrane oxygenation (ECMO) for severe acute respiratory distress syndrome (ARDS); however, there are ongoing concerns about its associated risks and benefits, making a comprehensive understanding vital for clinical decision-making. This review aims to evaluate the efficacy, risks, and practical implications of ECMO as a therapeutic intervention in severe ARDS secondary to COVID-19. The results indicate that ECMO is a key therapeutic intervention for managing severe COVID-19, but due to its associated risks and resource constraints, its application needs careful consideration. Nurse practitioners need to acquire specialized skills to manage ECMO and stay updated with ongoing research and revised protocols. Given the potential for future virus mutations or pandemics, and finite resources, a multidisciplinary approach to ECMO therapy is necessary. Careful patient selection, strategic resource allocation, and continuous education are pivotal elements for improved patient outcomes.
Early Identification of Developmental Language Delay
Authors: Wiefferink Carin H. , Adriaanse Conja , van Denderen Margot , van Schie Carla , Uilenburg Noëlle N.
Published: November 2023

Despite the importance of identifying children with developmental language delay, no accurate screening instruments are available for 3-year-olds. The aim of the present study is to compare the accuracy of the General Language Screen (GLS), focusing on receptive and expressive language and intelligibility with the accuracy of the VTO Language Screening Instrument (VTO-LSI)-3-year, focusing on expressive language and intelligibility. We hypothesize that the GLS is more accurate in identifying children with language delay, because it also assesses receptive language. Ninety-seven 3-year-old children were included based on their language screening score at the age of 2. At the age of 3, children were assessed with the VTO-LSI-3-year and the GLS. Diagnostic tests were used as reference tests. The GLS was better than the VTO-LSI-3-year in identifying children with language delay. Receiver operating characteristic analysis of the discriminative power showed higher areas under the receiver operating characteristic curve for the GLS. Moreover, the GLS was better in detecting receptive language concerns. Given these results the GLS may serve as a reliable screening tool, especially for children with receptive problems. Because receptive language problems are persistent, early diagnosis and intervention is very important for these children.
Correlations Between State-Level Monitoring and Screening Rates and Early Identified ASD/DD Across Racial and Ethnic Groups
Authors: Barger Brian , Salmon Ashley , Chödrön Gail
Published: November 2023

This study combined data from the National Survey of Children's Health (NSCH; 2016–2019) to develop state-level percentages of Hispanic, non-Hispanic Black, non-Hispanic other race, and non-Hispanic White children receiving developmental screening and/or monitoring and diagnosed with an autism spectrum disorder or developmental delay (ASD/DD). Analyses for the entire sample indicated no significant correlations between state-level screening/monitoring and ASD/DD; stratified analyses indicated correlations between monitoring and ASD/DD for Black populations and conjoint monitoring/screening and ASD/DD for Hispanic populations. Findings are contextualized around the limitations of the NSCH items, scope of community partners engaged in screening and monitoring, the importance of monitoring for identifying Black and Hispanic children with ASD/DD, and the utility of the NSCH's multiyear design.
Early Initiation of Antiretroviral Therapy is Protective Against Seizures in Children With HIV in Zambia: A Prospective Case–Control Study
Authors: Bearden David R. , Mwanza-Kabaghe Sylvia , Bositis Christopher M. , Dallah Ifunanya , Johnson Brent A. , Siddiqi Omar K. , Elafros Melissa A. , Gelbard Harris A. , Okulicz Jason F. , Kalungwana Lisa , Musonda Nkhoma , Theodore William H. , Mwenechanya Musaku , Mathews Manoj , Sikazwe Izukanji T. , Birbeck Gretchen L.
Published: November 2023

Background:

Seizures are relatively common among children with HIV in low- and middle-income countries and are associated with significant morbidity and mortality. Early treatment with antiretroviral therapy (ART) may reduce this risk by decreasing rates of central nervous system infections and HIV encephalopathy.

Methods:

We conducted a prospective, unmatched case–control study. We enrolled children with new-onset seizure from University Teaching Hospital in Lusaka, Zambia and 2 regional hospitals in rural Zambia. Controls were children with HIV and no history of seizures. Recruitment took place from 2016 to 2019. Early treatment was defined as initiation of ART before 12 months of age, at a CD4 percentage >15% in children aged 12–60 months or a CD4 count >350 cells/mm3 for children aged 60 months or older. Logistic regression models were used to evaluate the association between potential risk factors and seizures.

Results:

We identified 73 children with new-onset seizure and compared them with 254 control children with HIV but no seizures. Early treatment with ART was associated with a significant reduction in the odds of seizures [odds ratio (OR) 0.04, 95% confidence interval: 0.02 to 0.09; P < 0.001]. Having an undetectable viral load at the time of enrollment was strongly protective against seizures (OR 0.03, P < 0.001), whereas history of World Health Organization Stage 4 disease (OR 2.2, P = 0.05) or CD4 count <200 cells/mm3 (OR 3.6, P < 0.001) increased risk of seizures.

Conclusions:

Early initiation of ART and successful viral suppression would likely reduce much of the excess seizure burden in children with HIV.
Triangulation of a Needs Assessment on High-Tone Pelvic Floor Dysfunction
Authors: Smith Devon , Gugerty Lindsey , Schug Seran , Lipetskaia Lioudmila
Published: November 2023

Importance

High-tone pelvic floor dysfunction is a complex condition that is challenging to manage effectively. Pelvic floor physical therapy (PFPT) is often used in the treatment and relies on a coordinated effort between the physician, patient, and physical therapist. Collaboration is crucial for therapy success, but there is limited research that includes personal perspectives from these individuals.

Objective

The objective of this qualitative study was to gain further insight from these groups to identify areas for improvement in patient counseling and understanding of the diagnosis of high-tone pelvic floor dysfunction and the role of physical therapy.

Study Design

The following participants were recruited: urogynecologists, pelvic floor physical therapists, and patients. Semistructured interviews were conducted exploring participant experiences with therapy and management of the condition and surrounding phenomena.

Results

Participants interviewed included 5 urogynecologists, 5 pelvic floor physical therapists, and 15 patients. Similarities in key themes were identified: (1) the usefulness of pelvic models and illustrations in counseling, (2) appropriate descriptions of therapy, (3) motivating factors for patients, and (4) patient barriers to completing therapy. Several emergent themes revealed a misalignment in perspectives, including (1) patients reporting an unclear understanding of PFPT, (2) patient unawareness of the intimacy of therapy, and (3) reports of unsupportive and unempathetic physician providers.

Conclusions

There are both similarities and discrepancies in the perspectives among physicians, pelvic floor physical therapists, and patients regarding high-tone pelvic floor dysfunction and PFPT. Acknowledging these comparisons and adapting practices could facilitate patient-centered care and improve patient understanding of their diagnosis.
Empowering nurses to increase engagement in advance care planning in a medicine transitional care unit: a best practice implementation project
Authors: Garcia Philip , Kim Hannah Jang , Barbour Susan , Cooper Adam S.
Published: November 2023

Introduction and objective:

Advance care planning (ACP) communication and documentation are often inadequate, leading to care that is inconsistent with patients’ preferences and moral dilemmas for family members. Nurses are patient advocates optimally positioned to initiate ACP but many feel that they lack the training and skills to navigate these conversations. The objective of this project was to increase nurses’ capacity to engage in ACP.

Methods:

This project used the JBI audit and feedback method to implement evidence into practice. The JBI Practical Application of Clinical Evidence System and Getting Research into Practice audit tools were used to incorporate ACP into nursing workflow. Eight audit criteria were created based on a JBI evidence summary. Compliance was measured by reviewing ACP notes from electronic health records and online survey responses. A baseline audit was followed by educational presentations and development of posted materials. Three follow-up audits examined sustainability.

Results:

Compliance with the best practice recommendation for nurses to engage in ACP discussions increased from 55% to 80%. There was improvement from zero ACP notes at baseline (0% compliance) to 12 ACP notes in the final audit. Of these notes, 42% included all best practice elements and 92% included patients’ treatment preferences.

Conclusions:

Development of an integrative nursing education plan for ACP empowers nurses to engage in vital conversations. Informing nurses of their scope of practice, defining terms and expectations, and encouraging them to attempt and document conversations will benefit patients. Future initiatives would benefit from incorporating practical opportunities without real-life implications and providing continued support to cohorts.
COVID-19 infection wave mortality from surveillance data in the Philippines using machine learning
Authors: Migriño Julius R , Batangan Ani Regina U , Abello Rizal Michael R
Published: November 2023

Objective

The Philippines has had several COVID-19 infection waves brought about by different strains and variants of SARS-CoV-2. This study aimed to describe COVID-19 outcomes by infection waves using machine learning.

Methods

We used a cross-sectional surveillance data review design using the DOH COVID DataDrop data set as of September 24, 2022. We divided the data set into infection wave data sets based on the predominant COVID-19 variant(s) of concern during the identified time intervals: ancestral strain (A0), Alpha/Beta variant (AB), Delta variant (D), and Omicron variant (O). Descriptive statistics and machine learning models were generated from each infection wave data set.

Results

Our final data set consisted of 3 896 206 cases and ten attributes including one label attribute. Overall, 98.39% of cases recovered while 1.61% died. The Delta wave reported the most deaths (43.52%), while the Omicron wave reported the least (10.36%). The highest CFR was observed during the ancestral wave (2.49%), while the lowest was seen during the Omicron wave (0.61%). Higher age groups generally had higher CFRs across all infection waves. The A0, AB and D models had up to four levels with two or three splits for each node. The O model had eight levels, with up to 16 splits in some nodes. Of the ten attributes, only age was included in all the decision tree models, while region of residence was included in the O model. F-score and specificity were highest using naïve Bayes in all four data sets. Area under the curve (AUC) was highest in the naïve Bayes models for the A0, AB and D models, while sensitivity was highest in the decision tree models for the A0, AB and O models.

Discussion

The ancestral, Alpha/Beta and Delta variants seem to have similar transmission and mortality profiles. The Omicron variant caused lesser deaths despite being more transmissible. Age remained a significant predictor of death regardless of infection wave. We recommend constant timely analysis of available data especially during public health events and emergencies.
Expansion of human hematopoietic stem cells by inhibiting translation
Authors: Li Chenchen , Shin Hanna , Bhavanasi Dheeraj , Liu Mai , Yu Xiang , Peslak Scott A. , Liu Xiaolei , Alvarez-Dominguez Juan R. , Blobel Gerd A. , Gregory Brian D. , Huang Jian , Klein Peter S.
Published: November 2023

Hematopoietic stem cell (HSC) transplantation using umbilical cord blood (UCB) is a potentially life-saving treatment for leukemia and bone marrow failure but is limited by the low number of HSCs in UCB. The loss of HSCs after ex vivo manipulation is also a major obstacle to gene editing for inherited blood disorders. HSCs require a low rate of translation to maintain their capacity for self-renewal, but hematopoietic cytokines used to expand HSCs stimulate protein synthesis and impair long-term self-renewal. We previously described cytokine-free conditions that maintain but do not expand human and mouse HSCs ex vivo. Here we performed a high throughput screen and identified translation inhibitors that allow ex vivo expansion of human HSCs while minimizing cytokine exposure. Transplantation assays show a ∼5-fold expansion of long-term HSCs from UCB after one week of culture in low cytokine conditions. Single cell transcriptomic analysis demonstrates maintenance of HSCs expressing mediators of the unfolded protein stress response, further supporting the importance of regulated proteostasis in HSC maintenance and expansion. This expansion method maintains and expands human HSCs after CRISPR/Cas9 editing of theBCL11A+58enhancer, overcoming a major obstacle to ex vivo gene correction for human hemoglobinopathies.
Behavioural pharmacology predicts disrupted signalling pathways and candidate therapeutics from zebrafish mutants of Alzheimer’s disease risk genes
Authors: Kroll François , Donnelly Joshua , Özcan Güliz Gürel , Mackay Eirinn , Rihel Jason
Published: November 2023

By exposing genes associated with disease, genomic studies provide hundreds of starting points that should lead to druggable processes. However, our ability to systematically translate these genomic findings into biological pathways remains limited. Here, we combine rapid loss-of-function mutagenesis of Alzheimer’s risk genes and behavioural pharmacology in zebrafish to predict disrupted processes and candidate therapeutics.FramebyFrame, our expanded package for the analysis of larval behaviours, revealed that decreased night-time sleep was common to F0 knockouts of all four late-onset Alzheimer’s risk genes tested. We developed an online tool,ZOLTAR, which compares any behavioural fingerprint to a library of fingerprints from larvae treated with 3,677 compounds. ZOLTAR successfully predicted thatsorl1mutants have disrupted serotonin signalling and identified betamethasone as a drug which normalises the excessive day-time sleep ofpresenilin-2knockout larvae with minimal side effects. Predictive behavioural pharmacology offers a general framework to rapidly link disease-associated genes to druggable pathways.
Acute loss of fingertip sensation leads to general compensatory changes in eye-hand coordination
Authors: Ung Kevin , Yau Jeffrey M. , Nordmark Per F
Published: November 2023

The role of sensory feedback is well established in current models of motor control, evidenced by deficits in movement coordination resulting from impaired sensory function. When vision and touch are both available for object-oriented manual behaviors, these senses can be distinctly leveraged; vision guides movement planning while touch provides feedback on hand-object interactions. How eye-hand coordination changes with the loss of somatosensory feedback has not been well studied. Conceivably, vision is recruited to compensate for the feedback lost when touch is abolished. We tested healthy participants on a manual dexterity task, consisting of moving small metal pegs. The task was performed before and after administration of digital anesthesia that abolished cutaneous sensations while preserving motor function with the acting hand. During peg collection, transport, and placement epochs, we tracked gaze direction and hand positions while also recording forces applied to the pegboard. We hypothesized that the nervous system selectively adapts eye-hand coordination according to the dexterity demands of the task epochs. We found that participants maintained the ability to perform the pegboard task following the loss of cutaneous feedback, albeit with longer trial times and altered force profiles. Notably, somatosensory loss was accompanied by a shift in visual behavior marked by a closer alignment between gaze and hand positions during all task epochs, even those that did not involve object manipulation. Together, these data affirm the contributions of sensory feedback to force control in service of dexterous object manipulation and reveal the non-selective nature of compensatory eye-hand coordination processes.

Significance Statement

Touch and vision typically support distinct, but coordinated aspects of dexterous manual behaviors. Here, we evaluated how acute removal of tactile feedback using digital anesthesia affected performance and eye-hand coordination in a manual dexterity task. With insensate fingers and intact vision, participants continued to perform the task successfully, albeit with longer trial times and altered force profiles. We also observed closer alignment between gaze and hand positions during all task epochs, even those that did not involve object manipulation. Our results reveal the consequences of acute somatosensory loss and the general nature of compensatory eye-hand coordination processes.
Intermittent cell division dynamics in regenerating Arabidopsis roots reveals complex long-range interactions
Authors: Fallesen T. , Amarteifio S. , Pruessner G. , Jensen H. J. , Sena G.
Published: November 2023

In this work, we present a quantitative comparison of the cell division dynamics between populations of intact and regenerating root tips in the plant model systemArabidopsis thaliana. To achieve the required temporal resolution and to sustain it for the duration of the regeneration process, we adopted a live imaging system based on light-sheet fluorescence microscopy, previously developed in the laboratory. We offer a straightforward quantitative analysis of the temporal and spatial patterns of cell division events showing a statistically significant difference in the frequency of mitotic events and spatial separation of mitotic event clusters between intact and regenerating roots.
VHL loss enables immune checkpoint blockade therapy by boosting type I interferon response
Authors: Jiao Meng , Bao Xuhui , Hu Mengjie , Pan Dong , Liu Xinjian , Kim Jonathan , Li Fang , Li Chuan-Yuan
Published: November 2023

Despite a moderate mutation burden, clear cell renal cell carcinoma (ccRCC) responds well to immune checkpoint blockade (ICB) therapy. Here we report that loss-of-function mutations in the von Hippel-Lindau (VHL) gene, the most frequent in ccRCC, underlies its responsiveness to ICB therapy. We demonstrate that genetic knockout of theVHLgene enhanced the efficacy of anti-PD-1 therapy in multiple murine tumor models in a T cell-dependent manner. Mechanistically, we discovered that upregulation of HIF1α and HIF2α induced by VHL gene loss decreased mitochondrial outer membrane potential and caused the cytoplasmic leakage of mitochondrial DNA (mtDNA), which triggered cGAS-STING activation and induced type I interferons. Our study thus provided novel mechanistic insights into the role of VHL gene loss in potentiating ccRCC immunotherapy.
Role of a holo-insertase complex in the biogenesis of biophysically diverse ER membrane proteins
Authors: Page Katharine R. , Nguyen Vy N. , Pleiner Tino , Tomaleri Giovani Pinton , Wang Maxine L. , Guna Alina , Wang Ting-Yu , Chou Tsui-Fen , Voorhees Rebecca M.
Published: November 2023

Mammalian membrane proteins perform essential physiologic functions that rely on their accurate insertion and folding at the endoplasmic reticulum (ER). Using forward and arrayed genetic screens, we systematically studied the biogenesis of a panel of membrane proteins, including several G-protein coupled receptors (GPCRs). We observed a central role for the insertase, the ER membrane protein complex (EMC), and developed a dual-guide approach to identify genetic modifiers of the EMC. We found that the back of sec61 (BOS) complex, a component of the ‘multipass translocon’, was a physical and genetic interactor of the EMC. Functional and structural analysis of the EMC•BOS holocomplex showed that characteristics of a GPCR’s soluble domain determine its biogenesis pathway. In contrast to prevailing models, no single insertase handles all substrates. We instead propose a unifying model for coordination between the EMC, multipass translocon, and Sec61 for biogenesis of diverse membrane proteins in human cells.
Exploring the molecular composition of the multipass translocon in its native membrane environment
Authors: Gemmer Max , Chaillet Marten L. , Förster Friedrich
Published: November 2023

Multispanning membrane proteins are inserted into the endoplasmic reticulum membrane by the ribosome-bound multipass translocon machinery. Based on cryo-electron tomography and extensive subtomogram analysis, we reveal the composition and arrangement of multipass translocon components in their native membrane environment. The intramembrane chaperone complex PAT and the translocon associated protein (TRAP) complex associate substoichiometrically with the multipass translocon in a translation-dependent manner. While PAT is preferentially recruited to active complexes, TRAP primarily associates with inactive translocons. The subtomogram average of the TRAP-multipass translocon reveals intermolecular contacts between the luminal domains of TRAP and an unknown subunit of the BOS complex. AlphaFold modeling suggests this protein is NOMO, bridging the luminal domains of nicalin and TRAPα. Collectively, our results visualize the interplay of accessory factors associated with multipass membrane protein biogenesis under near-native conditions.
Coexpression enhances cross-species integration of scRNA-seq across diverse plant species
Authors: Passalacqua Michael John , Gillis Jesse
Published: November 2023

Single-cell RNA sequencing is increasingly used to investigate cross-species differences driven by gene expression and cell-type composition in plants. However, the frequent expansion of plant gene families due to whole genome duplications makes identification of one-to-one orthologs difficult, complicating integration. Here, we demonstrate that coexpression can be used to identify non-orthologous gene pairs with proxy expression profiles, improving the performance of traditional integration methods and reducing barriers to integration across a diverse array of plant species.
Incidence, prevalence, and survival of breast cancer in the United Kingdom from 2000-2021: a population-based cohort study
Authors: Barclay Nicola L , Burn Edward , Delmestri Antonella , Duarte-Salles Talita , Golozar Asieh , Man Wai Yi , Tan Eng Hooi , Tietzova Ilona ,   OPTIMA Consortium, Prieto-Alhambra Daniel , Newby Danielle
Published: November 2023

Background

Breast cancer is the most frequently diagnosed cancer in females globally. However, we know relatively little about trends in males. This study describes UK secular trends in breast cancer from 2000-2021 for both sexes.

Methods

Population-based cohort study using UK primary care Clinical Practice Research Datalink (CPRD) GOLD database and validated in Aurum. There were 5848436 eligible females and 5539681 males aged 18+ years, with ≥one year of prior data availability in the study period. We estimated breast cancer incidence rates (IR), period prevalence (PP) and survival at one-, five- and 10-years after diagnosis using the Kaplan-Meier method. Analyses were further stratified by age.

Results

IR of breast cancer from 2000-2021 was 194.4 per 100000 person-years for females and 1.16 for males. PP in 2021 was 2.1% for females and 0.009% for males. Both sexes have seen around a 2.5-fold increase in PP across time. Incidence increased with age for both sexes, peaking in females aged 60-69 years and males 90+. There was a drop in incidence for females aged 70-79 years. From 2003-2019, incidence increased >2-fold in younger females (aged 18-29: IR 2.12 in 2003 vs. 4.58 in 2018); decreased in females aged 50-69 years; and further declined from 2015 onwards in females aged 70-89 years. Survival for females after one-, five-, and ten-years after diagnosis was 95.1%, 80.2%, and 68.4%, and for males 92.9%, 69.0%, and 51.3%. Survival at one-year increased by 2.08% points, and survival at five years increased by 5.39% from 2000-2004 to 2015-2019 for females, particularly those aged 50-70 years. For males, there were no clear time-trends for short-term and long-term survival.

Conclusion

Changes in incidence of breast cancer in females largely reflect the success of screening programmes, as rates rise and fall in synchronicity with ages of eligibility for such programmes. Overall survival from breast cancer for females has improved from 2000 to 2021, again reflecting the success of screening programmes, early diagnosis, and improvements in treatments. Male breast cancer patients have worse survival outcomes compared to females, highlighting the need to develop male-specific diagnosis and treatment strategies to improve long-term survival in line with females.
Hearing Progression of Children with Enlarged Vestibular Aqueduct (EVA) According toSLC26A4Genetic Mutation Status
Authors: Osborne Madeline Hocking , Koeritzer Margaret , Herd Hannah , Polonenko Melissa Jane
Published: November 2023

Enlarged vestibular aqueduct (EVA) is a malformation associated with sensorineural hearing loss in children. Mutations in theSLC26A4gene are also associated with EVA and may contribute to more severe hearing losses that progress, but the timescale of this progression remains unknown. Given that children undergo significant speech and language development, a better understanding of the timing and extent of hearing loss is needed for individuals who have EVA. Through a retrospective review of records in a local database, we aimed to 1) estimate the prevalence of aSLC26A4mutation in this pediatric EVA cohort; and 2) compare hearing threshold severity and timing of progression across children who have EVA and differentSLC26A4statuses. Of 62 children with EVA, 39 had available genetic results and of these, 15 had at least one mutation of theSLC26A4gene (38%). The children with aSLC26A4mutation had a more severe onset of hearing loss and a more rapid progression of hearing loss over time, especially for higher frequencies, than children without a mutation in this gene. This longitudinal information may facilitate prognostic counseling to pediatric patients and better inform the audiology follow-up appointments for these families.
Quantitative and radiological assessment of post-cardiac arrest comatose patients with diffusion-weighted magnetic resonance imaging
Authors: Van Roy Sam , Hsu Liangge , Ho Joseph , Scirica Benjamin , Fischer David , Snider Samuel , Lee Jong Woo
Published: November 2023

Background

Although MR imaging, particularly diffusion weighted imaging, has increasingly been utilized as part of a multimodal approach to prognostication in patients comatose after cardiac arrest, the performance of quantitative analysis of apparent diffusion coefficient (ADC) maps, as compared to standard radiologist impression, has not been well characterized. This retrospective study evaluated quantitative ADC analysis to the identification of anoxic brain injury by diffusion abnormalities on standard clinical MRI reports.

Methods

The cohort included 204 previously described comatose patient post-cardiac arrest. Clinical outcome was assessed by 1) 3-6 month cerebral performance category (CPC); 2) Coma recovery to following commands. Radiological evaluation was obtained from clinical reports and characterized as diffuse, cortex only, deep gray matter structures only, or no injury. Quantitative analysis of ADC maps were obtained in specific regions of interest (ROI), whole cortex, and whole brain. A subgroup analysis of 172 was performed after eliminating images with artifacts and pre-existing lesions.

Results

Radiological assessment outperformed quantitative assessment over all evaluated regions (AUC 0.80 for radiological interpretation, 0.70 for occipital region, the best-performing ROI, p=0.11); agreement was substantial for all regions. Radiological assessment still outperformed quantitative analysis in the subgroup analysis, though by smaller margins, and with substantial to near-perfect agreement. When assessing for coma recovery only, the difference was no longer significant (AUC 0.83 vs 0.81, p=0.70).

Discussion

Although quantitative analysis eliminates interrater differences in the interpretation of abnormal diffusion imaging and avoids bias from other prediction modalities, clinical radiologist interpretation has a higher predictive value for outcome. This difference appears to be driven by poor scan quality, foreign body artifacts, and pre-existing stroke and white matter disease. Quantitative analysis is comparable to clinical interpretation after eliminating such scans. Further research is required into improving quantitative imaging techniques to account for such variability.