bluuebunny/crossref_metadata_2025 huggingface dataset:
Survival outcomes after breast cancer surgery among older women with early invasive breast cancer in England: population-based cohort study
Authors: Miller Katie , Gannon Melissa Ruth , Medina Jibby , Clements Karen , Dodwell David , Horgan Kieran , Park Min Hae , Cromwell David Alan
Published: July 2024

Background

This study assessed the influence of age, co-morbidity and frailty on 5-year survival outcomes after breast conservation surgery (BCS) with radiotherapy (RT) versus mastectomy (with or without RT) in women with early invasive breast cancer.

Methods

Women aged over 50 years with early invasive breast cancer diagnosed in England (2014–2019) who had breast surgery were identified from Cancer Registry data. Survival estimates were calculated from a flexible parametric survival model. A competing risk approach was used for breast cancer–specific survival (BCSS). Standardized survival probabilities and cumulative incidence functions for breast cancer death were calculated for each treatment by age.

Results

Among 101 654 women, 72.2% received BCS + RT and 27.8% received mastectomy. Age, co-morbidity and frailty were associated with overall survival (OS), but only age and co-morbidity were associated with BCSS. Survival probabilities for OS were greater for BCS + RT (90.3%) versus mastectomy (87.0%), and the difference between treatments varied by age (50 years: 1.9% versus 80 years: 6.5%). Cumulative incidence functions for breast cancer death were higher after mastectomy (5.1%) versus BCS + RT (3.9%), but there was little change in the difference by age (50 years: 0.9% versus 80 years: 1.2%). The results highlight the change in baseline mortality risk by age for OS compared to the stable baseline for BCSS.

Conclusion

For OS, the difference in survival probabilities for BCS + RT and mastectomy increased slightly with age. The difference in cumulative incidence functions for breast cancer death by surgery type was small regardless of age. Evidence on real-world survival outcomes among older populations with breast cancer is informative for treatment decision-making.
Prosthetic home intervention induces cortical plasticity in paediatrics with congenital limb reduction
Authors: Borrell Jordan A , Karumattu Manattu Arun , Copeland Christopher , Fraser Kaitlin , D’Ovidio Andrew , Granatowicz Zach , Delgado Liliana , Zuniga Jorge M
Published: July 2024

Paediatrics with congenital upper-limb reduction deficiency often face difficulties with normal development such as motor skills, needing assistance with daily activities such as self-care limitations with certain movements, sports, or activities. The purpose of this non-randomized longitudinal controlled trial was to assess, using intent-to-treat analysis, the effects of an 8-week home intervention of prosthetic use on the sensorimotor cortex in paediatrics with congenital upper-limb reduction deficiency. A paediatric population with congenital upper-limb reduction deficiency (n = 14) who were aged 6–18 years and who had a 20° or greater range of motion in the appropriate joint of the affected arm to move the body-powered prosthesis were enrolled. An age- and sex-matched control group (n = 14) was also enrolled. Participants were non-randomized and fitted with a custom low-cost 3D printed prosthesis and participated in 8 weeks of prosthetic use training at home. Control participants utilized a prosthetic simulator. The home intervention incorporated daily use training and exercises utilizing the prosthesis in direct use and assistive tasks explained by the researchers. After the home intervention, both groups displayed significant improvements in gross manual dexterity. During prosthetic use with the affected limb, significant increases in oxygenated hemodynamic responses were only displayed in the left premotor cortex of the upper-limb reduction deficiency group. The novel findings of this non-randomized longitudinal controlled trial suggest that the intervention may have improved the functional role of the left hemisphere which translated to the improvement of learning direction during adaptation to visuomotor control. The prosthetic home intervention was assumed to provide closed-loop training which could provide a direct benefit to the motor development of paediatrics with upper-limb reduction deficiency.
Artificial intelligence-based fully automated stress left ventricular ejection fraction as a prognostic marker in patients undergoing stress cardiovascular magnetic resonance
Authors: Toupin Solenn , Pezel Théo , Hovasse Thomas , Sanguineti Francesca , Champagne Stéphane , Unterseeh Thierry , Duhamel Suzanne , Chitiboi Teodora , Jacob Athira J , Borgohain Indraneel , Sharma Puneet , Gonçalves Trecy , Martial Paul-Jun , Gall Emmanuel , Florence Jeremy , Unger Alexandre , Garot Philippe , Garot Jérôme
Published: July 2024

Aims

This study aimed to determine in patients undergoing stress cardiovascular magnetic resonance (CMR) whether fully automated stress artificial intelligence (AI)-based left ventricular ejection fraction (LVEFAI) can provide incremental prognostic value to predict death above traditional prognosticators.

Methods and results

Between 2016 and 2018, we conducted a longitudinal study that included all consecutive patients referred for vasodilator stress CMR. LVEFAI was assessed using AI algorithm combines multiple deep learning networks for LV segmentation. The primary outcome was all-cause death assessed using the French National Registry of Death. Cox regression was used to evaluate the association of stress LVEFAI with death after adjustment for traditional risk factors and CMR findings. In 9712 patients (66 ± 15 years, 67% men), there was an excellent correlation between stress LVEFAI and LVEF measured by expert (LVEFexpert) (r = 0.94, P < 0.001). Stress LVEFAI was associated with death [median (interquartile range) follow-up 4.5 (3.7–5.2) years] before and after adjustment for risk factors [adjusted hazard ratio, 0.84 (95% confidence interval, 0.82–0.87) per 5% increment, P < 0.001]. Stress LVEFAI had similar significant association with death occurrence compared with LVEFexpert. After adjustment, stress LVEFAI value showed the greatest improvement in model discrimination and reclassification over and above traditional risk factors and stress CMR findings (C-statistic improvement: 0.11; net reclassification improvement = 0.250; integrative discrimination index = 0.049, all P < 0.001; likelihood-ratio test P < 0.001), with an incremental prognostic value over LVEFAI determined at rest.

Conclusion

AI-based fully automated LVEF measured at stress is independently associated with the occurrence of death in patients undergoing stress CMR, with an additional prognostic value above traditional risk factors, inducible ischaemia and late gadolinium enhancement.
Leveraging the ETAS model to forecast mining microseismicity
Authors: Sedghizadeh Mohammadamin , van den Berghe Matthew , Shcherbakov Robert
Published: July 2024

Mining operations result in changes of the subsurface stress field that can lead to the occurrence of microseismic events. The development of strategies for forecasting and avoidance of significant events is crucial for safe and efficient operations of mines. One such example, discussed here is the observed induced microseismicity in soft rock potash mines. It is primarily driven by the rock excavations but can also be triggered by preceding events or can result from the delayed effects of plastic creep of soft rocks. Therefore, it is important from seismic hazard assessment and risk mitigation points of view to understand the statistical aspects of microseismicity in potash or other types of mines. In this study, the temporal evolution of the induced microseismicity from a potash mine in Saskatchewan is analysed and modelled. Specifically, the epidemic type aftershock sequence model is used to approximate the occurrence rate of the induced mining microseismicity. The estimated parameters signify that the microseismicity displays swarm-type characteristics with limited inter-event triggering. Moreover, the Bayesian predictive framework is used to compute the probabilities of the occurrences of the largest expected events above a certain magnitude for prescribed forecasting time intervals during the evolution of the sequence. This approach for computing the probabilities allows one to incorporate fully the uncertainties of the model parameters. The Markov Chain Monte Carlo sampling of the posterior distribution are used to generate parameter chains to quantify their variability. Furthermore, several statistical tests are conducted to assess the credibility of the obtained retrospective forecasts compared to the observed microseismicity. The obtained results show that the developed approach can accurately forecast the number of events and intensity of the sequence. It also provides a framework for computing the probabilities for the largest expected events.
The Soft Palate Enables Extreme Feeding and Explosive Breathing in the Fin Whale (Balaenoptera physalus)
Authors: Vogl A W , Petersen H , Gil K N , Cieri R L , Shadwick R E
Published: July 2024

Synopsis

The evolution of lunge feeding in rorqual whales was associated with the evolution of several unique morphological features that include non-synovial ligamentous temporomandibular joints, a tongue that can invert and extend backward to the umbilicus, walls of the oral cavity that can dramatically expand, and muscles and nerves that are stretchy. Also, among the acquired features was an enlargement of the rostral end of the soft palate into an oral plug that occludes the opening between the oral cavity and pharynx and prevents water incursion into the pharynx during the engulfment phase of a feeding lunge. During this engulfment phase of a lunge, the volume of water entering the oral cavity can exceed the volume of the whale itself. Here, using dissection of fetuses and adults and a magnetic resonance imaging dataset of a fetus, we examine the detailed anatomy of the soft palate in fin whales. We describe several innovative features relative to other mammals, including changes in the attachment and positions of the major extrinsic muscles of the palate, alterations in the morphology of the pterygoid processes related to the palate and pharynx, and the presence of distinct muscle layers in the part of the palate caudal to the oral plug. Based on the anatomy, we present a model for how the soft palate is positioned at rest, and how it functions during feeding, breathing, and swallowing.
Barriers and facilitators to effective electronic health record-based sepsis screening in the pediatric intensive care unit
Authors: Sears Stacey M , Coughlin Anisha K , Nelson Kathryn , Stillwell Terri , Carlton Erin F , Flori Heidi R
Published: July 2024

Introduction

The Pediatric Surviving Sepsis Campaign supports the implementation of automated tools for early sepsis recognition. In 2019 the C.S. Mott Children’s Hospital Pediatric Intensive Care Unit deployed an electronic medical record (EMR)-based screening for early recognition and treatment of sepsis.

Materials and Methods

We analyzed all automated primary sepsis alerts, secondary screens, and bedside huddles from November 2019 to January 2020 (Cohort 1) and from November 2020 to January 2021 (Cohort 2) to identify barriers and facilitators for the use of this tool. We distributed surveys to frontline providers to gather feedback on end-user experience.

Results

In Cohort 1, 895 primary alerts were triggered, yielding 503 completed secondary screens and 40 bedside huddles. In Cohort 2, 925 primary alerts were triggered, yielding 532 completed secondary screens and 12 bedside huddles. Surveys assessing end-user experience identified the following facilitators: (1) 73% of nurses endorsed the bedside huddle as value added; (2) 74% of medical providers agreed the bedside huddle increased the likelihood of interventions. The greatest barriers to successful implementation included the (1) overall large number of primary alerts from the automated tool and (2) rate of false alerts, many due to routine respiratory therapy interventions.

Discussion

Our data suggests that the successful implementation of EMR-based sepsis screening tools requires countermeasures focusing on 3 key drivers for change: education, technology, and patient safety.

Conclusion

While both medical providers and bedside nurses found merit in our EMR-based sepsis early recognition system, continued refinement is necessary to avoid sepsis alert fatigue.
Pectoral major myocutaneous flap in our practice: about 25 cases
Authors: Opango Alban Déo Christian , Aziz Zakaria , Jaifi Abdelghafour , Ndelafei Divina , El Fatihi Meriem , Mansouri Hattab Nadia
Published: July 2024

The pectoralis major myocutaneous flap (PMMF) was described by Ariyan in 1979 for head and neck reconstructions. It is a safe flap, currently supplanted by free flaps in developed countries, but which remains very useful in developing countries. We report a series of 25 cases of PMMF reconstruction. All patients were treated for advanced stages of oral cavity cancer, where tumor excision left significant tissue loss. The reconstruction used PMMF, taken using the same technique. Supplanted by free flaps in developed countries, PMMF remains useful in developing countries. It is a flap that has numerous advantages (ease of collection, viability, low requirements in terms of instrumentation, etc.). Many variations have been described over the years.
Clinical outcomes of the Burnett “snake” maneuver shunt modification for ischemic priapism
Authors: Unal Selman , Karakus Serkan , Du Comb William , Burnett Arthur L
Published: July 2024

Background

Major ischemic priapism (IP) is defined as a persistent penile erection for >4 hours. IP may cause serious complications, especially if prompt resolution is not achieved. Therefore, selecting the most effective and usable shunt technique is crucial in IP cases that are refractory to medical therapy.

Aim

To compare the effectiveness and complication risks of distal corporoglanular shunt procedures with and without the Burnett “snake” maneuver.

Methods

We conducted a retrospective study of patients who presented with IP and underwent surgical treatment at our institution between 2005 and 2021. The patients were categorized into 2 groups: group 1 (n = 26) underwent distal shunt + Burnett snake maneuver, and group 2 (n = 56) underwent distal shunt-only. Clinical history, parameters of IP, details of medical and surgical treatments, and follow-up information were evaluated.

Outcomes

Outcomes included differences in IP resolution and recurrence, functional erections, and complications between corporoglanular shunt procedures with and without the Burnett snake maneuver.

Results

In group 1, 24 of 26 patients (92.3%) experienced priapism resolution with a single surgical intervention, while this outcome was observed in 30 of 56 patients (53.6%) in group 2 (P < .001). Notably, priapism recurrence was significantly lower in group 1, occurring in 1 of 24 patients (4.2%), as opposed to 8 of 30 patients (26.6%) in group 2 (P < .001). Of the patients with documented sexual function status at follow-up, functional erections (capable of penetration with or without phosphodiesterase 5 inhibitors) were noted in 6 of 14 patients (42.8%) in group 1 and 13 of 26 patients (50%) in group 2 (P = .66).

Clinical Implications

This study provides valuable insights regarding technical aspects of distal shunt procedures with and without the Burnett snake maneuver for treating major IP episodes. These results can help surgeons with clinical decision making for patients who present with IP.

Strength and Limitations

Limitations include the single-site retrospective design with potential selection bias, inaccuracies in medical record data, challenges in controlling confounding variables, and the lack of validated questionnaire scores for erectile function evaluation.

Conclusion

Our study demonstrates that modifying distal shunt procedures using the Burnett snake maneuver significantly improves priapism resolution and effectively prevents further priapism episodes without introducing additional complications or erectile function loss, thereby distinguishing it from distal shunt–only procedures.
Assessing the interplay between off-target promiscuity, cytotoxicity, and tolerability in rodents to improve the safety profile of novel anti-malarial plasmepsin X inhibitors
Authors: Gerets Helga H J , Delaunois Annie , Cardenas Alvaro , Class Reiner , Fleurance Renaud , de Haro Teresa , Laleu Benoît , Lowe Martin A , Rosseels Marie-Luce , Valentin Jean-Pierre
Published: July 2024

Within drug development, high off-target promiscuity as well as potent cytotoxicity, are associated with a high attrition rate. We investigated the safety profile of novel plasmepsin X (PMX) inhibitors for the treatment of malaria. In our screening cascade, a total of 249 PMX compounds were profiled in a panel of in vitro secondary pharmacology assays containing 44 targets (SafetyScreen44 panel) and in a cytotoxicity assay in HepG2 cells using ATP as an endpoint. Six of the lead compounds were subsequently tested in a 7-d rat toxicology study, and/or in a cardiovascular study in guinea pigs. Overall, compounds with high cytotoxicity in HepG2 cells correlated with high promiscuity (off-target hit rate >20%) in the SafetyScreen44 panel and were associated with poor tolerability in vivo (decedents, morbidity, adverse clinical signs, or severe cardiovascular effects). Some side effects observed in rats or guinea pigs could putatively be linked with hits in the secondary pharmacological profiling, such as the M1 or M2 muscarinic acetylcholine receptor, opioid µ and/or κ receptors or hERG/CaV1.2/Na+ channels, which were common to >50% the compounds tested in vivo. In summary, compounds showing high cytotoxicity and high promiscuity are likely to be poorly tolerated in vivo. However, such associations do not necessarily imply a causal relationship. Identifying the targets that cause these undesirable effects is key for early safety risk assessment. A tiered approach, based on a set of in vitro assays, helps selecting the compounds with highest likelihood of success to proceed to in vivo toxicology studies.
Comparative Fitness of Monilinia fructicola Isolates with Multiple Fungicide-Resistant Phenotypes
Authors: Dutra Pamela S. S. , Carraro Thiago A. , Nesi Cristiano N. , Amorim Lilian , May De Mio Louise L.
Published: July 2024

This study characterized 52 isolates of Monilinia fructicola from peach and nectarine orchards for their multiresistance patterns to thiophanate-methyl (TF), tebuconazole (TEB), and azoxystrobin (AZO) using in vitro sensitivity assays and molecular analysis. The radial growth of M. fructicola isolates was measured on media amended with a single discriminatory dose of 1 μg/ml for TF and AZO and 0.3 μg/ml for TEB. Cyt b, CYP51, and β-tubulin were tested for point mutations that confer resistance to quinone outside inhibitors (QoIs), demethylation inhibitors (DMIs), and methyl benzimidazole carbamates (MBCs), respectively. Eight phenotypes were identified, including isolates with single, double, and triple in vitro resistance to QoI, MBC, and DMI fungicides. All resistant phenotypes to TF and TEB presented the H6Y mutation in β-tubulin and the G641S mutation in CYP51. None of the point mutations typically linked to QoI resistance were present in the Monilinia isolates examined. Moreover, fitness of the M. fructicola phenotypes was examined in vitro and in detached fruit assays. Phenotypes with single resistance displayed equal fitness in vitro and in fruit assays compared with the wild type. In contrast, the dual- and triple-resistance phenotypes suffered fitness penalties based on osmotic sensitivity and aggressiveness on peach fruit. In this study, multiple resistance to MBC, DMI, and QoI fungicide groups was confirmed in M. fructicola. Results suggest that Monilinia populations with multiple resistance phenotypes are likely to be less competitive in the field than those with single resistance, thereby impeding their establishment over time and facilitating disease management.
Mediating effects of BMI on the association between DNA methylation regions and 24-h blood pressure in African Americans
Authors: Pan Xiaoqing , Chen Yuru , Yang Yifan , Kidambi Srividya , Liang Mingyu , Liu Pengyuan
Published: July 2024

Background:

DNA methylation is an important epigenetic mechanism that may influence blood pressure (BP) regulation and hypertension risk. Obesity, a major lifestyle factor associated with hypertension, may interact with DNA methylation to affect BP. However, the indirect effect of DNA methylation on 24-h BP measurements mediated by obesity-related phenotypes such as BMI has not been investigated.

Methods:

Causal mediation analysis was applied to examine the mediating role of BMI in the relation between DNA methylation and 24-h BP phenotypes, including SBP, DBP and mean arterial blood pressure (MAP), in 281 African American participants.

Results:

Analysis of 38 215 DNA methylation regions, derived from 1 549 368 CpG sites across the genome, identified up to 138 methylation regions that were significantly associated with 24-h BP measurements through BMI mediation. Among them, 38 (19.2%) methylation regions were concurrently associated with SBP, DBP and MAP. Genes associated with BMI-mediated methylation regions are potentially involved in various chronic diseases such as coronary artery disease and renal disease, which are often caused or exacerbated by hypertension. Notably, three genes (CDH4, NOTCH1 and COLGALT1) showed both direct associations with 24-h BP measurements and indirect associations through BMI after adjusting for age and sex covariates.

Conclusion:

Our findings suggest that DNA methylation may contribute to the regulation of 24-h BP in African Americans both directly and indirectly through BMI mediation.
Patient Surveys Are Used Most Often to Assess Health Care Innovations, Rigorous Methods Are Less Common
Authors: Qureshi Nabeel , Quigley Denise D.
Published: July 2024

The Agency of Healthcare Research and Quality Healthcare Innovations Exchange (IE) was developed to collect and report on innovative approaches to improving health care. The team reviewed 348 IE innovations including patient-reported satisfaction or experience measures. Innovations most often measured overall rating of care (61% of innovations), followed by access (52%) and provider-patient communication (12%). More than half used patient satisfaction surveys (n = 187) rather than patient experience surveys (n = 64). Innovations using patient experience surveys more often measured specific aspects of patient care, for example, access, versus a general overall rating of care. Most innovations using patient experience surveys administered nonvalidated, homegrown surveys, with few using the Agency of Healthcare Research and Quality-endorsed, psychometrically-tested CAHPS (Consumer Assessment of Healthcare Providers and Systems) survey. The most common study design was postimplementation-only (65%), highlighting that methodological rigor used to assess patient-centeredness in the IE is low. Broad use of patient experience surveys and more rigorous evaluation study designs has increased some over time but is still lacking.
Attitudes and Knowledge of Medical Students in South of Israel Toward Medical Cannabis
Authors: Mirzayov Shira , Peleg Roni , Freud Tamar
Published: July 2024

Background:

Public and medical interest in the use of cannabis has increased in Israel and the world over recent years.

Study Question:

The aim of the study was to assess the attitudes of medical students from the Faculty of Health Sciences of Ben-Gurion University of the Negev on the use of medical cannabis.

Study Design:

This is a cross-sectional study using a self-administered questionnaire completed by medical students from Ben-Gurion University of the Negev, Beer-Sheva, Israel.

Measures and Outcomes:

Attitudes and knowledge toward the use of medical cannabis were evaluated.

Results:

A total of 243 medical students participated in the study. Of these, 111 (46.1%) were from preclinical years. The mean age was 27.31 ± 3.07, and 138 (57.3%) were female students. Most students (N = 193, 79.4%) agreed to a great degree or to a very great degree that there was a role for cannabis for medical purposes. Most students thought that medical cannabis should be recommended for use by pain specialists (N = 231, 95.1%), by oncologists (N = 208, 85.6%), and by psychiatrists (N = 192, 79%). A little more than half of the participants (N = 127, 52.5%) would agree to be licensed, as future physicians, to prescribe medical cannabis. A logistic regression analysis found that the students strongly agreed with legalization of medical cannabis and students who strongly agreed that medical cannabis should be in the health basket predicted a very strong agreement about its use (OR = 2.623, P ≤ 0.002, and OR = 3.285, P ≤ 0.001, respectively).

Conclusions:

Most medical students support the use of medical cannabis for medical purposes and are in favor of its legalization. As physicians of the future, it is important to assess the attitudes of medical students on medical cannabis.
H5 and H9 avian influenza – potential re-emergent zoonotic threats to humans
Authors: Dabrera Gavin
Published: July 2024

Purpose of review

This review aims to discuss the current state of human infections with Avian Influenza A (H5) and (H9) viruses, to support awareness of the global epidemiology among clinicians and public health professionals interested in emerging respiratory infections.

Recent findings

Among increasing numbers of detections in avian species of Avian Influenza A(H5N1) clade 2.3.4.4b globally, reported human cases of severe infection have been rare.

Enhanced surveillance of persons exposed to avian species infected with Influenza A (H5N1) clade 2.3.4.4b in different countries has identified small numbers of asymptomatic individuals with Avian Influenza A (H5N1) detected by PCR from the upper respiratory tract; some of these instances have been considered to represent contamination rather than infection.

There have also been recent sporadic human cases of Avian Influenza A(H9N2) internationally, including in China and Cambodia.

Human infections with Avian Influenza A(H5) and (H9) viruses remain of interest as an emerging infection both to clinicians and public health professionals. While maintaining effective surveillance is essential, one health strategies to control infection in avian species will be key to mitigating these risks.
Effectiveness of Mindfulness-Based Cognitive Therapy on Depressive Symptoms, Brain Potential, and Neuroimmunoinflammatory Factors in Depressed Patients
Authors: Qiu Jiancheng , Gong Yifei , Zhang Xiucui , Mao Weibing
Published: July 2024

Objective

This study was aimed to investigate the effectiveness of mindfulness-based cognitive therapy (MBCT) on depressive symptoms, brain potential, and neuroimmunoinflammatory factors in patients with depression.

Methods

Sixty-four eligible patients according to the inclusion criteria were randomly divided into the control group and the observation group, with 32 patients in each group. The control group received conventional therapy, while the observation group received MBCT on top of conventional therapy. The depressive symptoms, brain potential, and neuroimmunoinflammatory factors were measured in the two groups.

Results

After treatment, the Hamilton Depression Rating Scale score, tumor necrosis factor α, and interleukin-6 levels were decreased, while the World Health Organization Quality of Life Scale score, total number of response execution score, and 5-hydroxy tryptamine level were increased in both groups. Moreover, the Hamilton Depression Rating Scale score, tumor necrosis factor α, and interleukin-6 levels were decreased more significantly, while the World Health Organization Quality of Life Scale score, total number of response execution score, and 5-hydroxy tryptamine level were increased more significantly in the observation group compare to the control group (P < 0.01). In addition, the latency in the observation group was shorter and the amplitude was longer than those in the control group (P < 0.01).

Conclusions

Compared with conventional therapy, the use of MBCT combined with conventional therapy can effectively reduce depressive symptoms, suppresses inflammatory responses, and optimize attention and response to target stimulation and is worthy of wide clinical implementation.
Evaluation of the efficacy of Cephalosporin antibiotics Sold in Kano Nigeria against Some Clinical Bacterial Isolates.
Authors: Ibrahim Safiyya Atiku , Muhammad Bashir , Rabiu Ismail , Muhammed Abdulazeez
Published: July 2024

Introduction: The circulation of substandard antibiotics is believed to aggravate the evil effect of Antibiotic resistance (AR) globally.  AR knows no boundaries and pose a serious threat to existing antibiotics.
Gap statement: Sabon Gari market is chosen due to several formal and informal reports of substandard antibiotics. It's a major distribution centre for pharmaceuticals, yet research on its impact and extent of substandard drugs is lacking.
Aim: This study aims to evaluate the susceptibility status of some clinical Bacterial isolates (E. coli, K. pneumoniae, S. aureus, S. pneumoniae, P. aeruginosa and Salmonella sp.) to generations of Cephalosporins purchased from drug distributors in Sabon Gari Market Kano.
Methodology: Antimicrobial susceptibility pattern of the test isolates was determined by disc diffusion method. Fourier Transform Infrared Spectroscopy (FT-IR) analysis was used to confirm the functional group of the active ingredients of all the antibiotics tested. Molecular identification of resistant gene (CTX-M1) were carried out using PCR.
Results: Market survey reveals that Cephalexin 61% (first generation), Cefuroxime 72% (Second generation) and Cefixime 68%, Cefpodoxime 79%, Ceftriaxone 63%, Ceftazidime 70% and Cefotaxime 45% (third generation) and Cefepime 84% (fourth generation) were the most commonly sold Cephalosporins, with different brands and company names.  In all the antibiotics tested, similar activity was observed in the branded antibiotics as compared with the standard antibiotics, with no significant difference observed. Exactly 20% of E. coli and K. pneumoniae were resistant while 80% of S. aureus, S. pneumoniae, Pseudomonas, and Salmonella sp. were susceptible. CTX-M1 resistant gene was identified E. coli and K. pneumoniae which further confirms their resistance to Cefotaxime and ceftriaxone antibiotics.
Conclusion: Branded cephalosporins sold in Kano were effective as standard antibiotics with good bioavailability and compliance with the standard formulation of medicine, thus fit for human intake.
Proteomics and personalized patient-derived xenograft models identify treatment opportunities for a progressive malignancy within a clinically actionable timeframe and change care
Authors: Barnabas Georgina D. , Bhat Tariq A. , Goebeler Verena , Leclair Pascal , Azzam Nadine , Melong Nicole , Anderson Colleen , Gom Alexis , An Seohee , Ergin Enes K. , Shen Yaoqing , Mungall Andy J. , Mungall Karen L. , Maxwell Christopher A. , Reid Gregor S.D. , Hirst Martin , Jones Steven , Chan Jennifer A. , Senger Donna L. , Berman Jason N. , Parker Seth J. , Bush Jonathan W. , Strahlendorf Caron , Deyell Rebecca J. , Lim Chinten J. , Lange Philipp F. ,   PROFYLE Program
Published: July 2024

Increased access to high-throughput DNA sequencing platforms has transformed the diagnostic landscape of pediatric malignancies by identifying and integrating actionable genomic or transcriptional features that refine diagnosis, classification, and treatment. Yet less than 10% of treated patients show a positive response and translating precision oncology data into feasible and effective therapies for hard-to-cure childhood, adolescent, and young adult malignancies remains a significant challenge. Combining the identification of therapeutic targets at the protein and pathway levels with demonstration of treatment response in personalized models holds great promise. Here we present the case for combining proteomics with patient-derived xenograft (PDX) models to identify personalized treatment options that were not apparent at genomic and transcriptomic levels. Proteome analysis with immunohistochemistry (IHC) validation of formalin-fixed paraffin-embedded sections from an adolescent with primary and metastatic spindle epithelial tumor with thymus-like elements (SETTLE) was completed within two weeks of biopsy.

The results identified an elevated protein level of SHMT2 as a possible target for therapy with the commercially available anti-depressant sertraline. Within 2 months and ahead of a molecular tumor board, we confirmed a positive drug response in a personalized chick chorioallantoic membrane (CAM) model of the SETTLE tumor (CAM-PDX). Following the failure of cytotoxic chemotherapy and second-line therapy, a treatment of sertraline was initiated for the patient. After 3 months of sertraline treatment the patient showed decreased tumor growth rates, albeit with clinically progressive disease.

Significance: Overall, we demonstrate that proteomics and fast-track personalized xenograft models can provide supportive pre-clinical data in a clinically meaningful timeframe to support medical decision-making and impact the clinical practice. By this we show that proteome-guided and functional precision oncology are feasible and valuable complements to the current genome-driven precision oncology practices.
Benchmarking algorithms for spatially variable gene identification in spatial transcriptomics
Authors: Chen Xuanwei , Ran Qinghua , Tang Junjie , Chen Zihao , Huang Siyuan , Shi Xingjie , Xi Ruibin
Published: July 2024

The rapid development of spatial transcriptomics has underscored the importance of identifying spatially variable genes. As a fundamental task in spatial transcriptomic data analysis, spatially variable gene identification has been extensively studied. However, the lack of comprehensive benchmark makes it difficult to validate the effectiveness of various algorithms scattered across a large number of studies with real-world datasets. In response, this article proposes a benchmark framework to evaluate algorithms for identifying spatially variable genes through the analysis of synthesized and real-world datasets, aiming to identify the best algorithms and their corresponding application scenarios. This framework can assist medical and life scientists in selecting suitable algorithms for their research, while also aid bioinformatics scientists in developing more powerful and efficient computational methods in spatial transcriptomic research.
A Machine Learning Decision Support Tool Optimizes Whole Genome Sequencing Utilization in a Neonatal Intensive Care Unit
Authors: Juarez Edwin F. , Peterson Bennet , Sanford Kobayashi Erica , Gilmer Sheldon , Tobin Laura E. , Schultz Brandan , Lenberg Jerica , Carroll Jeanne , Bai-Tong Shiyu , Sweeney Nathaly M. , Beebe Curtis , Stewart Lawrence , Olsen Lauren , Reinke Julie , Kiernan Elizabeth A. , Reimers Rebecca , Wigby Kristen , Tackaberry Chris , Yandell Mark , Hobbs Charlotte , Bainbridge Matthew N.
Published: July 2024

The Mendelian Phenotype Search Engine (MPSE), a clinical decision support tool using Natural Language Processing and Machine Learning, helped neonatologists expedite decisions to whole genome sequencing (WGS) to diagnose patients in the Neonatal Intensive Care Unit. After the MPSE was introduced, utilization of WGS increased, time to ordering WGS decreased, and WGS diagnostic yield increased.
GeneSurfer Enables Transcriptome-wide Exploration and Functional Annotation of Gene Co-expression Modules in 3D Spatial Transcriptomics Data
Authors: Li Chang , Thijssen Julian , Kroes Thomas , van der Burg Ximaine , van der Weerd Louise , Höllt Thomas , Lelieveldt Boudewijn
Published: July 2024

Gene co-expression provides crucial insights into biological functions, however, there is a lack of exploratory analysis tools for localized gene co-expression in large-scale datasets. We present GeneSurfer, an interactive interface designed to explore localized transcriptome-wide gene co-expression patterns in the 3D spatial domain. Key features of GeneSurfer include transcriptome-wide gene filtering and gene clustering based on spatial local co-expression within transcriptomically similar cells, multi-slice 3D rendering of average expression of gene clusters, and on-the-fly Gene Ontology term annotation of co-expressed gene sets. Additionally, GeneSurfer offers multiple linked views for investigating individual genes or gene co-expression in the spatial domain at each exploration stage. Demonstrating its utility with both spatial transcriptomics and single-cell RNA sequencing data from the Allen Brain Cell Atlas, GeneSurfer effectively identifies and annotates localized transcriptome-wide co-expression, providing biological insights and facilitating hypothesis generation and validation.
Frequent transitions in self-assembly across the evolution of a central metabolic enzyme
Authors: Sendker Franziska L. , Schlotthauer Tabea , Mais Christopher-Nils , Lo Yat Kei , Girbig Mathias , Bohn Stefan , Heimerl Thomas , Schindler Daniel , Weinstein Arielle , Metzger Brain P. , Thornton Joseph W. , Pillai Arvind , Bange Gert , Schuller Jan M. , Hochberg Georg K.A.
Published: July 2024

Many enzymes assemble into homomeric protein complexes comprising multiple copies of one protein. Because structural form is usually assumed to follow function in biochemistry, these assemblies are thought to evolve because they provide some functional advantage. In many cases, however, no specific advantage is known and, in some cases, quaternary structure varies among orthologs. This has led to the proposition that self-assembly may instead vary neutrally within protein families. The extent of such variation has been difficult to ascertain because quaternary structure has until recently been difficult to measure on large scales. Here, we employ mass photometry, phylogenetics, and structural biology to interrogate the evolution of homo-oligomeric assembly across the entire phylogeny of prokaryotic citrate synthases – an enzyme with a highly conserved function. We discover a menagerie of different assembly types that come and go over the course of evolution, including cases of parallel evolution and reversions from complex to simple assemblies. Functional experiments in vitro and in vivo indicate that evolutionary transitions between different assemblies do not strongly influence enzyme catalysis. Our work suggests that enzymes can wander relatively freely through a large space of possible assemblies and demonstrates the power of characterizing structure-function relationships across entire phylogenies.
Infant- and child-level predictors of mortality in low-resource settings: the WHO Child Mortality Risk Stratification Multi-Country Pooled Cohort
Authors:   The WHO Risk Stratification Working Group (WHO-RSWG), Schwinger Catherine
Published: July 2024

Background

Despite impressive reductions in overall global child mortality, rates of decline have slowed during the last decade. Current guidelines for the care of at-risk children in low-resource settings mostly focus on broad clinical syndromes or undernutrition rather than children’s individual contextualized risk. We aimed to identify readily assessable child-level characteristics that can predict child mortality risk in a range of community and healthcare settings in high-burden settings.

Methods

We analysed pooled data from 33 cohorts including 75,287 children under five years of age living in low resource settings to estimate the absolute risks of death associated with risk exposures separately and combined with anthropometry. Children were grouped according to population types studied: general population (GP), selected on anthropometric criteria (A-S), and selected on the presence of illness (I-S).

Findings

During a total of 69,085 child-years of follow-up in the pooled dataset, 2,805 (3.7%) children died. Age <24 months, low anthropometry, preterm birth, low birthweight, and absence of breastfeeding were each associated with increased mortality: risks were additive and declined with increasing age. However, overall mortality and the association between child-level characteristics and mortality differed according to the type of study population and child age.

Interpretation

Risk assessments combining individual child-level characteristics including anthropometry can enable programmes to identify children at high and lower risk of mortality and, thereafter, differentiate care accordingly. Such a strategy may reduce mortality and optimise health system efficiency and effectiveness.
DeepDrug: An Expert-led Domain-specific AI-Driven Drug-Repurposing Mechanism for Selecting the Lead Combination of Drugs for Alzheimer’s Disease
Authors: Li Victor OK , Han Yang , Kaistha Tushar , Zhang Qi , Downey Jocelyn , Gozes Illana , Lam Jacqueline CK
Published: July 2024

Alzheimer’s Disease (AD) significantly aggravates human dignity and quality of life. While newly approved amyloid immunotherapy has been reported, effective AD drugs remain to be identified. Here, we propose a novel AI-driven drug-repurposing method, DeepDrug, to identify a lead combination of approved drugs to treat AD patients. DeepDrug advances drug-repurposing methodology in four aspects. Firstly, it incorporates expert knowledge to extend candidate targets to include long genes, immunological and aging pathways, and somatic mutation markers that are associated with AD. Secondly, it incorporates a signed directed heterogeneous biomedical graph encompassing a rich set of nodes and edges, and node/edge weighting to capture crucial pathways associated with AD. Thirdly, it encodes the weighted biomedical graph through a Graph Neural Network into a new embedding space to capture the granular relationships across different nodes. Fourthly, it systematically selects the high-order drug combinations via diminishing return-based thresholds. A five-drug lead combination, consisting of Tofacitinib, Niraparib, Baricitinib, Empagliflozin, and Doxercalciferol, has been selected from the top drug candidates based on DeepDrug scores to achieve the maximum synergistic effect. These five drugs target neuroinflammation, mitochondrial dysfunction, and glucose metabolism, which are all related to AD pathology. DeepDrug offers a novel AI-and-big-data, expert-guided mechanism for new drug combination discovery and drug-repurposing across AD and other neuro-degenerative diseases, with immediate clinical applications.
Which social media platforms facilitate monitoring the opioid crisis?
Authors: Carpenter Kristy A. , Nguyen Anna T. , Smith Delaney A. , Samori Issah A. , Humphreys Keith , Lembke Anna , Kiang Mathew V. , Eichstaedt Johannes C. , Altman Russ B.
Published: July 2024

Social media can provide real-time insight into trends in substance use, addiction, and recovery. Prior studies have used platforms such as Reddit and X (formerly Twitter), but evolving policies around data access have threatened these platforms’ usability in research. We evaluate the potential of a broad set of platforms to detect emerging trends in the opioid epidemic. From these, we created a shortlist of 11 platforms, for which we documented official policies regulating drug-related discussion, data accessibility, geolocatability, and prior use in opioid-related studies. We quantified their volumes of opioid discussion, capturing informal language by including slang generated using a large language model. Beyond the most commonly used Reddit and X, the platforms with high potential for use in opioid-related surveillance are TikTok, YouTube, and Facebook. Leveraging many different social platforms, instead of a single platform, safeguards against sudden changes to data access and may better capture all populations that use opioids than any single platform.

Teaser

TikTok, Facebook, and YouTube may complement Reddit and X as text sources to monitor trends in the opioid epidemic.
Quantification and site-specific analysis of co-occupied N- and O-glycopeptides
Authors: Chongsaritsinsuk Joann , Rangel-Angarita Valentina , Mahoney Keira E. , Lucas Taryn M. , Enny Olivia M. , Katemauswa Mitchelle , Malaker Stacy A.
Published: July 2024

Protein glycosylation is a complex post-translational modification that is generally classified as N- or O-linked. Site-specific analysis of glycopeptides is accomplished with a variety of fragmentation methods, depending on the type of glycosylation being investigated and the instrumentation available. For instance, collisional dissociation methods are frequently used for N-glycoproteomic analysis with the assumption that one N-sequon exists per tryptic peptide. Alternatively, electron-based methods are indispensable for O-glycosite localization. However, the presence of simultaneously N- and O-glycosylated peptides could suggest the necessity of electron-based fragmentation methods for N-glycoproteomics, which is not commonly performed. Thus, we quantified the prevalence of N- and O-glycopeptides in mucins and other glycoproteins. A much higher frequency of co-occupancy within mucins was detected whereas only a negligible occurrence occurred within non-mucin glycoproteins. This was demonstrated from analyses of recombinant and/or purified proteins, as well as more complex samples. Where co-occupancy occurred, O-glycosites were frequently localized to the Ser/Thr within the N-sequon. Additionally, we found that O-glycans in close proximity to the occupied Asn were predominantly unelaborated core 1 structures, while those further away were more extended. Overall, we demonstrate electron-based methods are required for robust site-specific analysis of mucins, wherein co-occupancy is more prevalent. Conversely, collisional methods are generally sufficient for analyses of other types of glycoproteins.

Abstract Figure