bluuebunny/crossref_metadata_2025 huggingface dataset:
Embed-Search-Align: DNA Sequence Alignment using Transformer models
Authors: Holur Pavan , Enevoldsen K C , Rajesh Shreyas , Mboning Lajoyce , Georgiou Thalia , Bouchard Louis-S , Pellegrini Matteo , Roychowdhury Vwani
Published: February 2025

Motivation

DNA sequence alignment, an important genomic task, involves assigning short DNA reads to the most probable locations on an extensive reference genome. Conventional methods tackle this challenge in two steps: genome indexing followed by efficient search to locate likely positions for given reads. Building on the success of Large Language Models (LLM) in encoding text into embeddings, where the distance metric captures semantic similarity, recent efforts have encoded DNA sequences into vectors using Transformers and have shown promising results in tasks involving classification of short DNA sequences. Performance at sequence classification tasks does not, however, guarantee sequence alignment, where it is necessary to conduct a genome-wide search to align every read successfully, a significantly longer-range task by comparison.

Results

We bridge this gap by developing a “Embed-Search-Align” (ESA) framework, where a novel Reference-Free DNA Embedding (RDE) Transformer model generates vector embeddings of reads and fragments of the reference in a shared vector space; read-fragment distance metric is then used as a surrogate for sequence similarity. ESA introduces: (1) Contrastive loss for self-supervised training of DNA sequence representations, facilitating rich reference-free, sequence-level embeddings, and (2) a DNA vector store to enable search across fragments on a global scale. RDE is 99% accurate when aligning 250-length reads onto a human reference genome of 3 gigabases (single-haploid), rivaling conventional algorithmic sequence alignment methods such as Bowtie and BWA-Mem. RDE far exceeds the performance of 6 recent DNA-Transformer model baselines such as Nucleotide Transformer, Hyena-DNA, and shows task transfer across chromosomes and species.

Availability and Information

Please see https://anonymous.4open.science/r/dna2vec-7E4E/readme.md.

Supplementary Information

Please see attached file.
Four-year Loneliness Trajectory and Its Predictors in Older Adults
Authors: Huang Yan , Martire Lynn M , Jones Damon
Published: February 2025

Background and Objectives

Loneliness is a modifiable risk factor for health decline in older adults and its level may change over time. This study aimed to explore how loneliness changes across four years in older adults and investigate potential between-person and within-person predictors of this trajectory.

Research Design and Methods

Using growth curve modeling, we analyzed data collected annually between 2017 and 2020 from 128 older adults (Mage = 77.91) in independent-living or retirement communities.

Results

A quadratic model best fit the loneliness trajectory, showing loneliness decreased first and then increased over four years. At baseline, social relationship factors and health status, especially depressive symptoms, were correlated with the level of loneliness. None of the baseline variables had significant associations with the linear rate of change in loneliness. Increases in depressive symptoms and decreases in physical functioning were separately related to an increased level of loneliness. A secondary analysis showed the COVID-19 pandemic influenced the rate of change in loneliness.

Discussion and Implications

Findings suggest the loneliness trajectory for older adults follows a nonlinear trend, and that within-person variability exists in this trajectory. Social relationships and health indicators contribute to the trajectory of loneliness, and depressive symptoms were the most salient predictor of change in loneliness. The COVID-19 pandemic also influenced the uptick in loneliness in 2020. More attention and support should be offered to older adults who are less socially connected or experience health declines, to prevent loneliness and thus increase the healthy longevity of our older population.
Genetic architecture of cherry leaf spot (Blumeriella jaapii) resistance in sour cherry (P. Cerasus L.) uncovered by QTL analyses in a biparental population genotyped with the 6+9K SNP array
Authors: Emeriewen Ofere Francis , Wöhner Thomas Wolfgang , Braun Vincent , Schröpfer Susan , Schuster Mirko , Peil Andreas , Flachowsky Henryk
Published: February 2025

Sour cherry (Prunus cerasus L.) is an economically significant species in the Rosaceae family. Hitherto, there had been limited genetic and genomic resources to elucidate important horticultural traits in this species mainly because of the complex polyploid nature of its genome, a hybrid between Prunus avium and Prunus fruticosa. An important trait that has not been well studied in sour cherry is resistance to cherry leaf spot (CLS), caused by the fungus Blumeriella jaapii. This work took advantage of the RosBREED 6+9K SNP array to study the genetic basis of CLS resistance and inheritance in sour cherry. We established an F1 segregating population by crossing two cultivars, ‘Schattenmorelle’ and ‘Pc 2’ and genotyped both parents and the progeny with the cherry 6+9K SNP array and SSR markers. We evaluated both parents and progeny for resistance and susceptibility to CLS under field conditions. The applied marker systems facilitated the development of parental genetic maps, and the identification of two stable QTLs associated with CLS resistance, CLSR_1f in ‘Pc 2’ and susceptibility, CLSS_1f, in ‘Schattenmorelle’ explaining 40.9% and 21.5%, respectively of the phenotypic variation within the population. The mechanism of resistance in sour cherry appears to be independent of the CLS resistance QTL, CLSR_G4, previously identified in P. canescens, as the CLSR_G4-QTL and associated allele were not identified. Based on our findings, we propose a two-gene model for CLS resistance in sour cherry involving a susceptibility QTL, which might explain why some CLSR_G4-resistant plants in previous studies were susceptible.
Mammography Home Workstations and Remote Diagnostic Breast Imaging: Current Practice Patterns and Planned Future Directions
Authors: Dawar Ria , Grimm Lars J , Sonnenblick Emily B , Dontchos Brian N , Coffey Kristen , Goudreau Sally , Reig Beatriu , Jacobs Sarah A , Shah Zeeshan , Mullen Lisa , Dialani Vandana , Dawar Reema , Sayre James , Dodelzon Katerina , Parikh Jay R , Milch Hannah S
Published: February 2025

Objective

Assess current practices and plans regarding home workstations and remote diagnostic breast imaging in the United States.

Methods

A 43-question survey relating to remote breast imaging was distributed to Society of Breast Imaging members from July 6, 2023, through August 2, 2023. A descriptive summary of responses was performed. Pearson’s chi-squared test was used to compare demographic variables of respondents and questions of interest.

Results

In total, 424 surveys were completed (response rate 13%, 424/3244). One-third of breast imaging radiologists (31%, 132/424) reported reading examinations from home or a personal remote site for a median of 25% of their clinical time. The most common types of examinations read from home were screening mammography (90%, 119/132), screening US (58%, 77/132), diagnostic mammography and MRI (both 53%, 70/132), and diagnostic US (49%, 65/132). Respondents from private practices were more likely than those from academic practices to read diagnostic imaging from home (67%, 35/52 vs 29%, 15/52; P <.001). Respondents practicing in the West were less likely to read breast imaging examinations from home compared with those in other geographic regions (18%, 12/67 vs 28%-43% for other regions; P = .023). No differences were found among respondents’ overall use of home workstations based on age, gender, or having dependents. Most respondents (75%, 318/424) felt that remote breast reading would be a significant practice pattern in the future.

Conclusion

Home workstations for mammography and remote diagnostic breast imaging are a considerable U.S. practice pattern. Further research should explore radiologist preferences regarding remote breast imaging and its impact on clinical care and radiologist well-being.
Changes in time-to-treatment initiation for breast, non-small cell lung, colon, or rectal cancers throughout the COVID-19 pandemic in the United States
Authors: Fan Qinjin , Dong Weichuan , Schafer Elizabeth J , Wagle Nikita Sandeep , Zhao Jingxuan , Shi Kewei Sylvia , Han Xuesong , Yabroff K Robin , Nogueira Leticia M
Published: February 2025

The COVID-19 pandemic disrupted health care and reduced cancer diagnoses in the United States, raising concerns about its impact on time-to-treatment initiation (TTI), a critical factor for survival. This study examined the changes in TTI for 1 213 481 individuals newly diagnosed with female breast, nonsmall cell lung, colon, or rectal cancer between 2019 and 2022, using the National Cancer Database. We compared TTI in 2020-2022 with 2019 by cancer site, diagnosis time of year, stage, and treatment modality. In 2020, TTI statistically significantly decreased for all cancers compared to 2019, especially in the second quarter (2.97-4.29 days). However, TTI increased across sites in 2021 (0.31-2.15 days) and in 2022 (1.43-5.07 days). Reduced diagnoses and efforts to prioritize cancer care during the pandemic may partly explain observed TTI decreases, whereas workforce constraints likely contributed to the later increases. Ongoing evaluation of TTI and associations with patient outcomes is warranted.
Genome-wide association study and Mendelian randomization analyses reveal insights into bladder cancer etiology
Authors: Larsson Susanna C , Chen Jie , Ruan Xixian , Li Xue , Yuan Shuai
Published: February 2025

Background

The causes of bladder cancer are not completely understood. Our objective was to identify blood proteins and modifiable causal risk factors for bladder cancer by combining genome-wide association studies (GWAS) and Mendelian randomization (MR) analyses.

Methods

We first performed a GWAS meta-analysis of 6984 bladder cancer cases and 708 432 controls from three European databases. Next, we conducted two-sample MR and colocalization analyses using data from the present GWAS and published GWAS meta-analyses on plasma proteins and modifiable factors.

Results

GWAS meta-analysis uncovered 17 bladder cancer susceptibility loci, of which 3 loci were novel. Genes were enriched in pathways related to the metabolic and catabolic processes of xenobiotics and cellular detoxification. Proteome-wide MR analysis based on cis-acting genetic variants revealed that higher plasma levels of glutathione S-transferases were strongly associated with a reduced risk of bladder cancer. There is strong evidence of colocalization between GSTM1 and bladder cancer. Finally, multivariable MR analyses of suspected risk factors for bladder cancer revealed independent causal associations between smoking and adiposity, particularly abdominal obesity, and risk of bladder cancer.

Conclusions

Findings from this large-scale GWAS and multivariable MR analyses highlight the key role of detoxification processes, particularly glutathione S-transferase 1, as well as smoking and abdominal obesity in bladder cancer etiology.
William Gladstone’s Attitude Towards Islam
Authors: Yıldızeli Fahriye Begüm
Published: February 2025

During the heyday of British imperialism in the nineteenth century, perceptions and attitudes towards Islam were derived from the British Empire’s special relationship with the Eastern Question and long-standing trends in Victorian culture. This article explores the views of William Gladstone towards Islam, which have been the subject of a series of controversial debates among scholars. Although most studies of Gladstone have explored the links between his political development and his Christian faith, they have not analysed the grounds of his doctrines towards the Islamic world. In light of the inflammatory rhetoric that Gladstone employed in the ‘Bulgarian Horrors’ pamphlet, his indignation over Turkish rulers, and key elements of his policies towards Christian minorities, some historians have presented the view that he was antagonistic towards Muslims. This study argues that Gladstone had always regarded the Ottoman nation states with ethnic-religious differences independently from the Sublime Porte’s Islamic character of the state. The origins of his thoughts on Islamic civilization, self-government, and cumulative disillusionment with Ottoman reforms reveal the extent to which his humanitarian feelings, ‘religious nationality’, and moral foreign policy influenced his thinking about Islamic governance. It further considers how Gladstone’s liberal mindset and perceptions of Islam developed since his early life and how these later influenced his connections with other Muslim communities—Afghans, Bosnians, Egyptians, Indians, and Albanians.
A Preliminary Analysis of Psychological Strengths: Service Members’ Well-being Post-deployment
Authors: Bowles Stephen V , Neumaier Eric R , Hughes Evan R , Guberman Lucas , Cozzi Francesca M , Bartone Paul T , Switzer Paul , Mallonee Sybil D , Goyette Anna S , Seidler Dustin A , Kelly Julia , Hoyt Tim
Published: February 2025

Deployments are stressful for both service members and their families. To promote the overall health and welfare of those impacted by military deployment, it is important to identify individual resilience-building resources that service members can employ to strengthen their own well-being, the well-being of their families, and the readiness of the force. This pilot study examines different resilience-building skills that may impact individual well-being, relationship quality, and family satisfaction post-deployment. A cross-sectional sample of 78 married U.S. military enlisted service members (n = 24) and commissioned officers (n = 54) completed the Coping Self-Efficacy Scale, Resilience Scale for Adults, Humor Styles Questionnaire, Mindful Attention Awareness Scale, Dispositional Resilience Scale, the emotional well-being and spirituality subscales of the Work-Life Well-Being Inventory, and the Social Problem-Solving Inventory-Revised. The use of a positive humor style was significantly associated with individual well-being. Spirituality and religious practices were significantly predictive of a service member’s family satisfaction. Responding to qualitative open-ended questions, service members identified their top 6 subcategories of stress, which were communication, moving, finances, family separation, children, and future employment during post-deployment. The strengths and resources reported as contributing the most to family effectiveness and well-being were personal character traits, external relationship skills, emotional maturity, and the ability to work. The results identified unique individual resilience-building resources for service members, which contribute to their well-being and the well-being of their families. Findings suggest that training on individual resilience-building resources for service members can offer support to the entire family system following military deployment.
Local structural dynamics of Rad51 protomers revealed by cryo-electron microscopy of Rad51-ssDNA filaments
Authors: Liu Jie , Gore Steven K , Heyer Wolf-Dietrich
Published: February 2025

Homologous recombination (HR) is a high-fidelity repair mechanism for double-strand breaks. Rad51 is the key enzyme that forms filaments on single-stranded DNA (ssDNA) to catalyze homology search and DNA strand exchange in recombinational DNA repair. In this study, we employed single-particle cryogenic electron microscopy (cryo-EM) to ascertain the density map of the wild-type budding yeast Rad51-ssDNA filament bound to ADP-AlF3, achieving a resolution of 2.35 Å without imposing helical symmetry. The model assigned 6 Rad51 protomers, 24 nt of DNA, and 6 bound ADP-AlF3. It shows 6-fold symmetry implying monomeric building blocks, unlike the structure of the Rad51-I345T mutant filament with three-fold symmetry implying dimeric building blocks, for which the structural comparisons provide a satisfying mechanistic explanation. This image analysis enables comprehensive comparisons of individual Rad51 protomers within the filament and reveals local conformational movements of amino acid side chains. Notably, R293 in Loop 1 adopts multiple conformations to facilitate L296 and V331 in separating and twisting the DNA triplets. We also analyzed the crystal structure of Rad51-I345T and the predicted structure of yeast Rad51–K342E using the Rad51–ssDNA structure from this study as a reference.
The short conserved region-2 of LARP4 interacts with ribosome-associated RACK1 and promotes translation
Authors: Ranjan Amitabh , Mattijssen Sandy , Charlly Nithin , Gallardo Isabel Cruz , Pitman Leah F , Coleman Jennifer C , Conte Maria R , Maraia Richard J
Published: February 2025

LARP4 interacts with poly(A)-binding protein (PABP) to protect messenger RNAs (mRNAs) from deadenylation and decay, and recent data indicate it can direct the translation of functionally related mRNA subsets. LARP4 was known to bind RACK1, a ribosome-associated protein, although the specific regions involved and relevance had been undetermined. Here, through a combination of in-cell and in vitro methodologies, we identified positions 615–625 in conserved region-2 (CR2) of LARP4 (and 646–656 in LARP4B) as directly binding RACK1. Consistent with these results, AlphaFold2-Multimer predicted high-confidence interaction of CR2 with RACK1 propellers 5 and 6. CR2 mutations strongly decreased LARP4 association with cellular RACK1 and ribosomes by multiple assays, whereas PABP association was less affected, consistent with independent interactions. The CR2 mutations decreased LARP4’s ability to stabilize a β-globin mRNA reporter containing an AU-rich element (ARE) to higher degree than β-globin and GFP (green fluorescent protein) mRNAs lacking the ARE. We show LARP4 robustly increases translation of β-glo-ARE mRNA, whereas the LARP4 CR2 mutant is impaired. Analysis of nanoLuc-ARE mRNA for production of luciferase activity confirmed LARP4 promotes translation efficiency, while CR2 mutations are disabling. Thus, LARP4 CR2-mediated interaction with RACK1 can promote translational efficiency of some mRNAs.
The illegal trade of wild birds in a social network: A call for action from Argentina
Authors: López Fernando Gabriel , Rebollo María Emilia , Santillán Miguel Ángel , Berkunsky Igor , Cooper Nathan Wands , Tella José Luis , Grande Juan Manuel
Published: February 2025

The illegal trade of wild birds is a large threat to biodiversity and sellers often use social media to traffic wildlife. By monitoring and characterizing the trade of wild and domestic birds on Facebook, we show that this illegal e-commerce remains widespread throughout Argentina, despite a decrease in activity in 2023 compared to 2017, highlighting the persistence and magnitude of this issue. In 2017, we found 96,354 users in 127 buying/selling groups in 18 provinces, of which 61% were public. In 2023, we found 58,647 users in 76 groups in 14 provinces, of which 66% were public. Analyzing one group in 2017 and two groups in 2023, we found 67 bird species were offered for sale. All birds for sale in these groups had illegal origins (i.e., without authorized bands or permits), including two Endangered and one Near Threatened species. Passerines (mainly Thraupidae, Fringilidae, and Cardinalidae species) were the most offered group, but parrots, raptors, and other bird groups were also available. Saltator aurantiirostris (Golden-billed Saltator) was most frequently offered for sale and had the highest interest from users in the two largest analyzed groups. The Endangered Gubernatrix cristata (Yellow Cardinal) reached the highest price (up to 328 USD), it was also frequently offered for sale (5th position in 2017), and had high user interest (2nd in 2017). We found that Facebook was frequently used for illegal bird trade in Argentina, including species of conservation concern, which can threaten a number of species. We call for coordinated and interdisciplinary actions that engage authorities, social media companies, and local communities, which will be needed to enact top-down and bottom-up measures to continue reducing and eventually halting wildlife-related illegal activities. A translated Spanish version of this article is available in the Supplementary Material.
Systematic review and meta-analysis of conventional medical management in a patient population with refractory chronic pain suitable to receive a spinal cord stimulation system
Authors: Russo Marc , Nevitt Sarah , Santarelli Danielle , Eldabe Sam , Duarte Rui V
Published: February 2025

Aim

The aim of this review was to systematically identify all evidence that used conventional medical management (CMM) as a comparator in randomized controlled trials (RCTs) of spinal cord stimulation (SCS) therapy, and to conduct a meta-analysis to investigate if continued CMM provides statistical or clinically meaningful pain relief and whether CMM effects have improved over the last few decades.

Methods

Databases were searched from inception to June 2024 for RCTs that compared SCS to CMM. The primary outcome of the review was absolute change in pain intensity from baseline to the last available follow-up in the CMM group, measured using a visual analogue scale or numerical rating scale. The measure of treatment effect for absolute change and percentage change in pain intensity from baseline was mean difference (MD) and 95% confidence interval (CI). Risk of bias (RoB) was assessed by using the revised Cochrane RoB tool. The protocol for this review is registered on PROSPERO (CRD42023449215).

Results

Meta-analysis of absolute change in pain intensity from baseline to last follow-up shows that CMM is not associated with any significant reductions in pain intensity (MD −0.11; 95% CI: −0.32 to 0.11; moderate certainty). Similar results were observed for percent change in pain intensity from baseline to last follow-up (MD −3.22%; 95% CI: −12.59% to 6.14%; moderate certainty). No significant differences were observed when considering decade of publication of the RCT for absolute (P = .065; moderate certainty) or percent change in pain intensity (P = 0.524; moderate certainty). Meta-analysis for 6-month follow-up and sensitivity analysis shows similar numerical results.

Conclusion

Our findings show that continued CMM for a population eligible for SCS does not provide meaningful pain relief and has not considerably changed over the last few decades. The use of CMM as the control to evaluate relative SCS treatment effects should be reassessed.
Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study of ustekinumab in patients with Takayasu arteritis
Authors: Yoshifuji Hajime , Ishii Tomonori , Ohashi Hiroki , Yoshizawa Katsunori , Mihoya Maki , Nishikawa Kazuko , Nakaoka Yoshikazu
Published: February 2025

Objectives

Takayasu arteritis (TAK) is a rare, chronic large vessel vasculitis with unmet treatment needs. This phase 3 study aimed to evaluate efficacy, safety, pharmacokinetics, and immunogenicity of ustekinumab (UST) in Japanese patients with TAK.

Methods

Patients with TAK who had relapsed ≤12 weeks prior to study intervention administration and achieved remission thereafter with standard-of-care including corticosteroid intensification were randomized 1:1 to receive UST or matching placebo with protocol-defined oral glucocorticoid taper regimen. The double-blind (DB) phase was up to the patient’s relapse/total of 35 relapse events, followed by open-label extension (OLE) phase. Primary endpoint was the time to relapse of TAK per protocol-defined criteria through end of DB phase.

Results

The study was terminated early due to patient recruitment challenge. Of 14 patients randomized, 8 relapsed during DB phase (UST : 4/6; placebo : 4/8). The median time to relapse (weeks) was 11.14 (95%CI: 4.14, NE[not estimated]) for UST and 12.64 (95%CI: 12.14, NE) for placebo; (hazard ratio = 1.86 [95%CI: 0.41, 8.47]). In DB phase, one patient in each group reported SAE (UST: vascular pseudoaneurysm and brachiocephalic artery stenosis; placebo: cholecystitis); none were related to study intervention. Through OLE phase, 1/4 (25.0%) patient in UST-UST group (vascular graft infection considered related to study intervention) and none in the placebo-UST had SAEs. There were no serious infections/deaths throughout the study.

Conclusion

The efficacy of UST in patients with TAK cannot be adequately assessed as the pre-determined sample size was not reached, and study was prematurely terminated. No new safety signal of UST was identified.

Clinical trial registration number

Clinicaltrials.gov, NCT04882072; jrct.niph.go.jp, jRCT2061210007; Clinical Registry, CR108981
Models behaving badly: The limits of data-driven lending
Authors: Ben-David Itzhak , Johnson Mark J , Stulz René M
Published: February 2025

Data-driven lending relies on the calibration of models using training periods. We find that this type of lending is not resilient in the presence of economic conditions that are materially different from those experienced during the training period. Using data from a small business fintech lending platform, we document that the small business credit supply collapsed during the COVID-19 crisis of March 2020 even though the demand for loans doubled relative to pre-pandemic levels. As the month progressed, most lenders significantly reduced or halted their lending activities, likely due to the heightened risk of model miscalibration under the new economic conditions.
Exploring Preferences for Communication and Care among Hospitalized Patients with Opioid Use Disorder: A Qualitative Descriptive Study
Authors: Davis M Holliday , French Rachel , Crowe Molly , Abrams Matthew , Edwards Grace , Aronowitz Shoshana , Mandell David S. , Lowenstein Margaret
Published: February 2025

Objective:

The aim of the study was to explore hospitalized patient priorities for effective communication and care in opioid use disorder (OUD).

Methods:

In this qualitative descriptive study, we conducted semistructured interviews from April to August 2022 focusing on communication values with inpatient care teams among hospitalized patients with OUD in Philadelphia, PA. Interviews were recorded, transcribed, and analyzed with thematic content analysis.

Results:

We identified 3 key themes in the communication and care planning preferences of the 21 patients we interviewed: effectiveness, reciprocity, and empathy. Patients emphasized the need for clear, reliable, and frequent communication from healthcare providers, valuing collaborative dialog, shared decision making, and empathic nonstigmatized interactions that incorporated their prior experiences, full personhood, and current symptoms. Participants reported negative experiences with inconsistent or dismissive communication but appreciated care that incorporated their input and was nonjudgmental, fostering a sense of trust in their healthcare teams.

Conclusions:

Effective, empathic communication, and shared decision making were favored by hospitalized patients with OUD and may be a way to improve treatment for hospitalized patients with OUD. Our findings underscore the need for stigma reduction strategies in clinical education and the expansion of both generalist resources for the treatment of OUD and specialized addiction care services.
The Use of Extended-Release Buprenorphine in the Treatment of Adolescent Opioid Use Disorder: A Case Series
Authors: Neptune Asha , Kaliamurthy Sivabalaji
Published: February 2025

Objectives:

Opioid use disorder (OUD) is rising among adolescents, highlighting a need for additional treatment approaches in this population. Buprenorphine, a medication for opioid use disorder, is available in multiple formulations. Sublingual buprenorphine is approved for use in patients ages 16 and older. Extended-release buprenorphine is approved only for adults, and studies have not established the safety and efficacy of its use in adolescents younger than age 18. This case series reviews the medical records of adolescents with OUD receiving monthly extended-release buprenorphine subcutaneous injections.

Methods:

The electronic medical records of six adolescents, younger than 18 years, receiving monthly extended-release buprenorphine in an outpatient setting from February 2022 to April 2024 were reviewed. The primary outcomes of interest were treatment retention, complications, and opioid abstinence during treatment.

Results:

The patients included in this case series ranged in age from 15 to 17 years at the onset of treatment. The majority of patients, four of the six, were female. At the conclusion of the chart review period in April 2024, all six patients remained on treatment with extended-release buprenorphine. The duration of treatment with extended-release buprenorphine varied among patients from 2 to 13 months. No significant complications were noted. Five patients achieved opioid abstinence for greater than 2 months during treatment.

Conclusions:

Treatment of OUD in adolescents remains challenging. This case series highlights a need for larger studies to establish the safety and efficacy of extended-release buprenorphine in adolescents younger than 18 years of age.
Cranio-Vertebral Junction Anomalies
Authors: Alves Óscar L. , Zileli Mehmet , Sharif Salman , Botelho Ricardo
Published: February 2025

Introduction.

The published literature on Cranio-vertebral Junction (CVJ) anomalies lacks a comprehensive appraisal that integrates common diagnostic, management and treatment concepts for different conditions, such as Chiari Malformation (CM), Basilar Invagination (BI), Os Odontoideum (OO) and Syndromic Malformations. The authors aimed to fill this knowledge gap offering guidelines and recommendations with a global outreach and applicability.

Methods.

A group of expert spine surgeons and WFNS Spine Committee members, most of which extensively published on CVJ anomalies in the past, reviewed the literature issued from 2011 to 2022. Following a common methodology, based on the Delphi method, the authors analyzed the strength of the literature and voted statements concerning diagnosis and management of these conditions.

Results.

A total of eight papers were produced: (1) Chiari Malformation diagnosis, classifications, natural history, and conservative management, (2) Chiari malformation: indications for surgery and surgical options, (3) Pediatric Chiari malformation, (4) Syndromic atlanto-axial instability, (5) Os odontoideum, (6) Basilar invagination: diagnosis, radiology, and classification, (7) Surgical treatment of Basilar Invagination, and (8) Basilar invagination with associated Chiari malformation.

Conclusions.

Despite grey zones on natural history of CVJ anomalies and controversies on timing and type of surgical treatments, whenever atlantoaxial instability is present, C1-C2 stabilization through instrumentation and fusion is necessary. If only recurrent pain and neurological dysfunction occurs, surgical decompression is appropriate. If no atlantoaxial instability is present, Down’s patients can participate in competitive sports. In general, contact sports are not recommended.
Investigating the Relationship Between Sodium–Glucose Cotransporter-2 (SGLT2) Inhibitors and Blood Pressure
Authors: Kallash Mohammed , Frishman William
Published: February 2025

Sodium–glucose cotransporter-2 (SGLT2) inhibitors were originally approved for use in type 2 diabetes, but in recent years, these medications were found to also have significant cardiovascular benefits in patients with heart failure with reduced and preserved ejection fraction and chronic kidney disease. Part of the cardiovascular benefits of SGLT2 inhibitors likely comes from their antihypertensive effect in addition to other unknown effects, but the mechanism by which these medications reduce blood pressure has not been identified yet. Multiple mechanisms have been proposed to describe SGLT2 inhibitors’ antihypertensive effect, including their associated weight loss and diuretic effect. However, studies have shown that these indirect mechanisms alone do not account for the antihypertensive effect seen with this medication, with more recent studies identifying a new potential mechanism by which SGLT2 inhibitors may derive their direct antihypertensive and cardiovascular benefits. In animal models, SGLT2 receptors were identified in parts of the brain responsible for regulating the sympathetic nervous system and adjusting blood pressure. In these studies, SGLT2 inhibitors suppressed the neuronal activity in these brain regions, reducing the sympathetic nervous system activity and blood pressure of the animals. Further investigation is needed to identify whether there are SGLT2 receptors in the central nervous system of humans and whether SGLT2 inhibitors can suppress neuronal activity in these brain regions. This information could be significant in learning more about the susceptibility and severity of primary hypertension in certain patient populations, as well as identifying whether SGLT2 inhibitors can be considered as a primary antihypertensive agent.
Clinical Outcomes With Postprocedural Anticoagulation Versus No Anticoagulation in Patients With Acute Myocardial Infarction After Percutaneous Coronary Intervention: A Meta-Analysis
Authors: Jain Hritvik , Odat Ramez M. , Mody Shefali , Dey Debankur , Singh Jagjot , Passey Siddhant , Ahmed Mushood , Jain Jyoti , Mehta Aryan , Ahmed Raheel
Published: February 2025

Postprocedural anticoagulation (PPAC) after percutaneous coronary intervention (PCI) in patients with acute myocardial infarction (AMI) can mitigate thrombotic events. However, current clinical guidelines do not recommend PPAC after PCI considering the scarce evidence supporting its use. A comprehensive literature search of electronic databases was conducted to identify studies comparing PPAC to no anticoagulation (AC) after PCI for AMI. Using the inverse-variance random-effects model, we pooled risk ratios (RRs) with 95% confidence intervals (CIs), with P < 0.05 considered statistically significant. Seven studies with a total of 47,981 patients (32,010: PPAC and 15,971: no AC) were included in the final analysis. PPAC administration demonstrated no significant difference in 30-day all-cause mortality [RR, 0.73 (95% CI, 0.47–1.16); P = 0.19], 30-day cardiovascular mortality [RR, 0.76 (95% CI, 0.45–1.30); P = 0.32], 30-day myocardial infarction [RR, 0.68 (95% CI, 0.41–1.12); P = 0.13], 30-day stroke [RR, 0.89 (95% CI, 0.47–1.67); P = 0.71], 30-day target vessel revascularization [RR, 0.74 (95% CI, 0.37–1.47); P = 0.39], 30-day stent thrombosis [RR, 1.08 (95% CI, 0.75–1.57); P = 0.67], and 30-day bleeding [RR, 1.25 (95% CI, 0.83–1.88); P = 0.29] compared with no AC. This meta-analysis concludes that there are no benefits of routine PPAC after PCI in AMI. The decision to prolong anticoagulant use post-PCI depends on risk versus benefits, which vary from case to case. Future large-scale multicentric randomized trials are warranted to corroborate the results of this meta-analysis.
Evaluating the effect of public health and social measures under rapid changes in population-level immunity against SARS-CoV-2: a mathematical modeling study
Authors: Jung Sung-mok , Jung Jaehun , Lessler Justin
Published: February 2025

Background:

Public health and social measures are crucial for controlling the spread of pathogens. However, well-tailored assessments of their impact remain elusive, particularly considering time-varying immunity established from prior exposures and its waning.

Methods:

We developed a mathematical model to estimate the time-varying basic reproduction number, accounting for the dynamics of underlying immunity. Applying this framework, we retrospectively assessed the impact of public health and social measures implemented from November 2021–April 2022 on SARS-CoV-2 transmission in Korea and discussed potential biases from ignoring underlying immunity.

Results:

Our proposed model estimated a notable attenuation in the impact of public health on social measures on SARS-CoV-2 transmission in Korea with the emergence of the Omicron variants while remaining effective throughout the Delta and Omicron periods. These changes during the Omicron period became evident only upon adjusting for underlying immunity and were correlated with observed human mobility patterns in Korea.

Conclusions:

Our findings support the importance of incorporating underlying immunity in evaluating public health and social measures, particularly in the presence of substantial changes over a short period such as widespread infections or vaccination. This model would stand as a tool for informing public health planning, capable of mitigating the overall disease burden in future epidemics.
Delayed Drug–Drug Interaction Between Antiviral Drugs and Tacrolimus in a Pancreatic Islet Transplant Recipient with SARS-CoV-2 Pneumonia—A Case Study
Authors: Sabo Amelia-Naomi , Cunat Sibylle , Kemmel Véronique
Published: February 2025

Background:

PAXLOVID (nirmatrelvir and ritonavir) and VEKLURY (remdesivir) are the first- and second-line antivirals administered to adult patients at risk of severe forms of SARS-CoV-2 infection (COVID-19), such as transplant recipients. As this specific population requires lifelong immunosuppressive treatments, the administration of antivirals with cytochrome P450-modulating properties exposes patients to a high risk of drug–drug interactions (DDI).

Case Presentation:

A 72-year-old male patient who underwent a pancreatic islet transplant experienced DDI between antiviral treatment and tacrolimus during the management of SARS-CoV-2 pneumonia. The patient received a single dose of nirmatelvir/ritonavir followed by a single dose of remdesivir. Tacrolimus treatment was interrupted for the duration of the antiviral treatment, and the concentration of tacrolimus was within the target range for this patient. Once antiviral treatment was stopped, tacrolimus was reintroduced at the initial dose. On day 6, the patient presented with clinical and biological parameters consistent with a tacrolimus overdose. A trough concentration 18 times higher than the therapeutic target was found, prompting tacrolimus to be discontinued for 9 days and reintroduced at a lower dose, followed by a gradual increase based on therapeutic drug monitoring to the initial dose. Clinical and biological parameters gradually returned to baseline levels.

Conclusions:

Management of DDI between tacrolimus and anti-SARS-CoV-2 drugs requires a substantial therapeutic intervention and close therapeutic drug monitoring during and for several days after antiviral treatment.
National Survey on Corneal Transplantation in Japan
Authors: Shimazaki Jun , Soma Takeshi , Yamada Keiko , Kobayashi Akira , Usui Tomohiko , Inatomi Tsutomu ,   The Japan Corneal Transplantation Study Group
Published: February 2025

Purpose:

To report the results of a national survey on corneal transplantation in Japan.

Methods:

The Japan Cornea Society conducted a national survey on corneal transplantation performed from 2017 to 2019. Data from various institutions were collected through an online database and subsequently analyzed.

Results:

In total, 4951 cases from 44 facilities were documented. The leading cause of corneal transplantation was corneal edema (CE), which accounted for 39.3% of cases, followed by repeat keratoplasty at 27.7%. Among CE cases, postcataract surgery was the most prevalent (25.1%), followed by postglaucoma surgery (20.8%) and laser iridotomy–induced CE (18.2%). Fuchs endothelial corneal dystrophy was the fourth most common cause (10.9%). Regarding surgical methods, Descemet stripping automated endothelial keratoplasty was the most common, used in 41.3% of procedures, followed by penetrating keratoplasty at 37.1%. Deep anterior lamellar keratoplasty and Descemet membrane endothelial keratoplasty were used in 8.1% and 2.6% of cases, respectively. One year after transplantation, graft clarity was maintained in 80.5% of cases, and regrafting was necessary in 15.2% of instances.

Conclusions:

The national survey reveals that CE is the most frequent indication for corneal transplantation in Japan. Increases in cases from glaucoma surgery and Fuchs endothelial corneal dystrophy were noted among patients with CE. Endothelial keratoplasty, especially Descemet stripping automated endothelial keratoplasty, is now the preferred surgical technique for these transplants.
Elevated Cerebrospinal Fluid CXCL13 Is a Helpful Marker for the Early Diagnosis of Neuroborreliosis in Children
Authors: Jung Lisa , Lâm Thiên-Trí , Streng Andrea , Fingerle Volker , Liese Johannes
Published: February 2025

Background:

Lyme neuroborreliosis (LNB) is an early systemic manifestation of Lyme disease in children, but standard diagnostic measures have constraints that limit early LNB diagnosis. Elevated cerebrospinal fluid (CSF) concentrations of the chemokine CXCL13 are considered a useful marker for early LNB diagnosis in adults, however, few studies have evaluated their diagnostic value in children.

Methods:

In this retrospective analysis, stored CSF samples of 232 hospitalized pediatric patients tested for LNB with standard serological methods were re-analyzed for CXCL13. CXCL13 levels were compared in children classified as definite, possible or no LNB patients according to European Federation of Neurological Societies guidelines. Specificity and sensitivity of CSF CXCL13 were determined for the diagnosis of early LNB, using previously published cutoff levels for pediatric patients.

Results:

CSF CXCL13 levels differed significantly between 25 patients with definite LNB (all >7.8 pg/mL; range: 37.9–>500 pg/mL) and 174 patients without LNB [160 (92%) <7.8 pg/mL; 13 (7%) with a range of 7.8–59.3 pg/mL; 1 (1%) with >500 pg/mL and Ureaplasma parvum CNS infection]. Using a cutoff of 55 pg/mL, CSF CXCL13 resulted in a specificity of 98.9% (95% CI: 97.4–100) and sensitivity of 92.0% (95% CI: 81.4–100).

Conclusions:

This study confirms the high sensitivity and specificity of CSF CXCL13 for the diagnosis of pediatric LNB using a cutoff value of 55 pg/mL. The use of CSF CXCL13 as an additional diagnostic measure in children with suspected LNB could improve diagnostic specificity and thereby reduce unnecessary antibiotic treatment, especially in the early phases of the disease.
Viral Codetection and Clinical Outcomes of Infants Hospitalized With Bronchiolitis: A Multicenter Cohort Study
Authors: Milani Gregorio Paolo , Ronchi Andrea , Agostoni Carlo , Marchisio Paola , Chidini Giovanna , Pesenti Nicola , Bellotti Anita Sofia , Cugliari Marco , Crimi Riccardo , Fabiano Valentina , Pietrasanta Carlo , Pugni Lorenza , Mosca Fabio ,   on behalf of the IRIDE Study Group listed in the Appendix
Published: February 2025

Background:

The simultaneous identification of multiple respiratory viruses is common in infants hospitalized with respiratory tract infections. Respiratory syncytial virus (RSV) is one of the main pathogens in bronchiolitis, although codetection of rhinovirus, influenza and other respiratory viruses may occur in about one-third of cases. The relevance of viral codetection on disease severity is still controversial. This multicenter cohort study aimed to assess the clinical outcomes of infants under 24 months hospitalized with bronchiolitis, comparing those testing positive for RSV alone, RSV plus another virus and ≥2 viruses distinct from RSV.

Methods:

Data were collected across 13 hospitals in Lombardy, Italy, both in the prepandemic and pandemic years. Random effect regression models were also employed to test the association between 3 groups (infants testing positive for RSV alone, RSV plus another respiratory virus and no RSV but ≥2 respiratory viruses other than RSV) and course of bronchiolitis, adjusted for potential confounders.

Results:

Among 1788 infants, 86.7% tested positive for RSV alone, 6.9% for RSV plus another virus and 6.3% for ≥2 other viruses. Significant differences were found in clinical outcomes: infants with multiple non-RSV viruses had shorter oxygen supplementation, intensive care and hospital stay compared with those with RSV alone. Notably, codetection of RSV and another virus was associated with a higher risk of radiologically confirmed pneumonia, whereas detection of ≥2 non-RSV viruses was inversely associated with pneumonia.

Conclusions:

These findings point out that codetection of viruses other than RSV is associated with milder disease courses than detection of RSV alone in infants with bronchiolitis. On the other hand, patients with RSV and another virus are at higher risk of pneumonia than infants affected by RSV alone. Further research is required to understand the underlying mechanisms and optimize management strategies in infants with bronchiolitis testing positive for multiple viruses.
Birth Defects and Adverse Pregnancy Outcomes in Hospital-based Birth Surveillance in Eswatini
Authors: Gill Michelle M. , Khumalo Philisiwe Ntombenhle , Hoffman Heather J. , Chouraya Caspian , Kunene Mthokozisi , Dlamini Futhi , Tukei Vincent , Scheuerle Angela E. , Nhlabatsi Bonisile , Mofenson Lynne
Published: February 2025

Background:

The Botswana Tsepamo study identified an initial neural tube defect (NTD) safety signal with dolutegravir antiretroviral therapy (ART) exposure at conception. We conducted similar surveillance in 5 hospitals in Eswatini from September 2021 to September 2023 to evaluate the prevalence of birth defects and adverse pregnancy outcomes by maternal HIV status and ART regimen/timing.

Methods:

Routine pregnancy history and HIV/ART status were collected from clinic records. Women of live or stillborn infants with birth defects consented for interviews and photographs of defects. A medical geneticist reviewed blinded interview data and photographs.

Results:

Of 45,836 women with live-born or stillborn infants, 13,577 (29.6%) were living with HIV; 11,581 (86.0%) were receiving ART at conception (84.1% dolutegravir). Overall, birth defects were confirmed in 387 (0.8%) women. Comparing women with and without HIV, there were no significant differences in major defects (0.48% vs. 0.38%) or NTD (0.10% vs. 0.08%). In women with HIV, there were no significant differences between those on dolutegravir versus non-dolutegravir at conception for major defects (0.53% vs. 0.49%) or NTD (0.08% vs. 0.22%). Stillbirths were significantly higher in women with HIV than those without (2.6% vs. 1.9%, P < 0.001), as was low birthweight and preterm delivery (11.8% vs. 10.4%, P < 0.001; 12.5% vs. 10.7%, P < 0.001, respectively). There were no significant differences in outcomes by ART regimen.

Conclusions:

While these data from sub-Saharan Africa further strengthen the lack of a NTD safety signal in women with HIV on ART, there remained elevated adverse birth outcomes despite treatment compared to women without HIV.