bluuebunny/crossref_metadata_2025 huggingface dataset:
OTHR-14 THE AFRICAN NEURO-ONCOLOGY ACCESS DISPARITY (ANAD) INDEX: A PUBLIC DATA-DRIVEN APPROACH TO MAPPING NATIONAL VARIATIONS IN NEURO-ONCOLOGY CARE BARRIERS
Authors: Kanmounye Ulrick Sidney , Avorgbedor Fortune Kekeli , Nuamah Jonathan Ayeyi , Asamoah Ernest Adu , Dadson Shirley Sarah , Benson Princess Yaa , Amoako Emmanuella Faith
Published: October 2024

INTRODUCTION

The burden of central nervous system tumors is unevenly distributed globally. In Africa, this burden is further compounded by a lack of cancer-focused health system strengthening. The authors sought to quantify these system-level challenges with a novel index.

METHODS

This prototype index was developed from publicly available data provided by the World Health Organization’s Global Health Observatory, the World Bank Group’s Country Database, and the Institute For Health Metrics and Evaluation’s Global Burden of Disease database. Metrics were selected based on their ability to represent health system components including workforce, service delivery, infrastructure, information management, health financing, and governance. The metrics were normalized either using standardization or min-max scaling. Next, they were weighted iteratively based on importance, relative impact, and expert judgment. Also, the weighted metrics were grouped into facilitators or obstructors. The difference between obstructors and facilitators for each country was percentile ranked to obtain the index score between 0 and 100. Finally, sensitivity analysis was conducted to test best- and worst-case scenarios based on uncertainty values. The t-test and ANOVA were used to evaluate association between country subregion/income and the index.

RESULTS

Data was found for 51 African countries. Ethiopia (98), Madagascar (96), and Mali (94) had the highest ANAD Index score whereas Gabon (0), Seychelles (2), and Mauritius (4) had the lowest scores. North African countries had lower ANAD Index scores than sub-Saharan African countries (mean (SD) 19 (4) vs. 54 (4), p=0.005). Also, low-income countries had higher ANAD Index scores than lower-middle- and upper-middle-income countries (72 (19) vs. 37 (27) vs. 9 (12), p<0.001).

CONCLUSION

This prototype will be further tested for face, construct, content, and criterion validity. The authors anticipate that expanding this metric globally will improve its validity while facilitating advocacy and allowing for impact assessment at the system level.
PDOC-02 SUB-SAHARAN AFRICAN EXPERIENCE OF NEUROSURGICAL-ONCOLOGIC CARE: CHALLENGES AND BARRIERS ENCOUNTERED AT 7 CANCER TREATMENT CENTERS
Authors: Shabani Hamisi Kimaro , Ashagere Yordanos , Labuschagne Jason , Copeland William , Sichizya Kachinga , Nketiah-Boakye Frank , Ahmad Misbahu Haruna , Belete Addisalem , Chotai Silky , Haizel-Cobbina Joseline a , Dewan Michael C
Published: October 2024

BACKGROUND

Wide disparities in neurosurgical-oncologic care and treatment outcomes exists globally despite recent improvements in diagnostics and cancer therapy. To better understand the challenges to neurosurgical-oncologic care in low resource settings, we collected data on national neurosurgery capacity and hospital diagnostic and treatment capacity across 7 national referral hospitals in 7 countries Sub-Saharan Africa (SSA).

METHODS

A 42-item self-administered questionnaire was distributed to partner neurosurgeons at the 7 sites via REDCap in April 2023 to provide country and hospital level capacity data on neurosurgical-oncologic care.

RESULTS

Neurosurgical and neurosurgical-oncologic care was reported to be available in a limited number of provinces/states/regions in 6 out of the 7 countries. The neurosurgery and pediatric neurosurgery workforce density across the 7 countries ranged between 0.03 – 0.67 per 100,000 and 0 – 0.05 per 100,000 respectively. Three hospitals had no pediatric ICU with the remaining four having between 2-8 bed-capacity pediatric ICU. One hospital did not have both CT and MRI scanner available and relied solely on private diagnostic facilities for neuroimaging. Histopathology services were largely limited to basic hematoxylin and eosin (H&E) and/or advanced histopathology staining. Molecular subtyping was available at only one hospital. None of the 7 hospitals had neurocritical care expertise, neuroradiologist, or neuropathologist. Four hospitals had a pediatric anesthesiologist. Only one hospital had a neuro-oncologist, but none had a pediatric neuro-oncologist. Both adjuvant chemotherapy and radiotherapy was unavailable at 3 hospitals. Rehabilitation was largely limited to basic physical and occupational therapy at all 7 hospitals. Although all 7 countries had a multiple health payer system, the payment structure differed across the 7 hospitals for different neurosurgical-oncologic services with patients making out-of-pocket payments for all services in some cases. Financial constraint was reported as a major barrier to care.

CONCLUSION

System-level interventions are needed to strengthen neurosurgical-oncologic care capacity in SSA.
PDOC-07 THE CLINICOPATHOLOGICAL PROFILE AND VALUE OF MULTIDISCIPLINARY MANAGEMENT OF PEDIATRIC BRAIN TUMORS IN A LOW-INCOME SETTING
Authors: Nyeko Richard , Angom Racheal , Senyonjo Hussen , Kibudde Solomon , Geriga Fadhil , Tusabe Tobias , Kalungi Sam , Nabbosa Valeria , Kambugu Joyce Balagadde , van Heerden Jaques
Published: October 2024

OBJECTIVE

The management of paediatric brain tumours in low-income countries is challenging, and survival rates are low, making multi-disciplinary teams (MDT) inevitable in quality management. In Uganda, paediatric neuro-oncology services are in their infancy. This study evaluated the management of paediatric brain tumours at the Uganda Cancer Institute (UCI) to assess the contributions of MDT management in improving patient care and outcomes.

METHODS

A retrospective records review of paediatric brain tumours at the UCI between 2017 and 2021 was conducted. Patient and tumour characteristics, as well as MDT management, were sourced. A survey among MDT members was conducted to explore their perspectives.

RESULTS

Thirty-five paediatric brain tumour cases were treated at UCI, with a median age of 8.0 years (IQR 4.0–11.0) and a median duration of symptoms of six months (IQR 3.0-8.5). The majority (25.7%, n=9) were craniopharyngiomas, 14.3% (5/35) were astrocytomas, 11.4% (4/35) were medulloblastomas, and 8.6% (3/35) each were ependymomas and pineoblastomas. Overall, 22 (62.9%) of the cases were discussed on the MDT. The number of cases discussed in the MDT increased over the five years: 0/3 (0.0%) in 2017, 3/5 (60.0%) in 2018, 2/4 (50.0%) in 2019, 6/9 (66.7%) in 2020, and 11/14 (78.6%) in 2021. The proportion of multidisciplinary management decisions implemented also increased: 0% in 2018, 50% in 2019, 83.3% in 2020, and 81.8% in 2021. The majority of patients (12/15, 80.0%) for whom MDT recommendations were implemented were alive. Lack of neurosurgical resources (46.7%), imaging (46.6%), diversity of MDT roles (26.7%), access to radiotherapy (20.0%), and pathology (20.0%) were recognized as major impediments to paediatric neuro-oncology management.

CONCLUSIONS

Implementing multidisciplinary management decisions benefited children with brain tumours and decreased abandonment and patient loss to follow-up at the Uganda Cancer Institute. Greater emphasis should be placed on increasing resources and actionable treatment recommendations.
PDOC-09 EVALUATION OF HEALTH SERVICE DELAYS FOR CHILDREN WITH CENTRAL NERVOUS SYSTEM TUMORS AT BUGANDO REFERRAL HOSPITAL MWANZA, TANZANIA
Authors: Joas Heronima , Lubuulwa James , Mayays Gerald , Magambo Magreth , Schroeder Kristin
Published: October 2024

OBJECTIVE

Rapid diagnosis and treatment initiation is crucial for children with central nervous system tumors (CNS). Despite advancement in diagnostic modalities, health service delays persist in many LMICs. The current study evaluates the diagnostic and treatment delays experienced by children presenting to a zonal referral hospital in Mwanza Tanzania, with the goal of identifying breakpoints that can be addressed to improve quality of care through a multidisciplinary approach.

METHODS

All children age <18yrs with a diagnosis of a CNS tumor from 2020-2023 were included in the analysis. Data was extracted from hospital electronic medical system and clinical files and included demographics, diagnosis, and dates at first presentation to the hospital, diagnosis, surgical intervention, oncology presentation and treatment initiation. Treatment initiation included either surgical resection, chemotherapy or radiotherapy.

RESULTS

A total of 50 patients were included in the evaluation, with average age of 6.4yrs and equal M: F representation. Most of the cases (80%, n=40) were primary CNS tumors, with 20% metastatic disease. Low grade Glioma (LGG) and high-grade Glioma (HGG) tumors were similarly distributed (n=19, n=21). Among those who had a tumor resection, 56% (n=18) were completed before initial oncology evaluation. Delays were frequently experienced, with the average time from presentation to neurosurgery evaluation of 166 days, time to diagnosis of 121 days, time to oncology evaluation of 139 days, and time to treatment initiation of 127 days. 1yr overall survival for LGG was 67% (n=12/18) and 36% (n=8/22) for HGG, with a treatment abandonment rate of 38% overall (n=19/50).

CONCLUSIONS

There is significant delay in accessing services for patients presenting with CNS tumors. A multidisciplinary approach and social support of children with CNS tumor is necessary to facilitate early diagnosis and timely treatment to improve quality of care and leads to a higher survival rate.
PDOC-10 LIMITATIONS IN POST OPERATIVE- ADJUVANT CARE OF PATIENTS WITH BRAIN TUMOURS-A CASE OF SUPRATENTORIAL MEDULLOBLASTOMA IN A PAEDIATRIC PATIENT
Authors: Garapo Lilian , Kalangu Kazadi , Jokonya Luxwell , Madondoro Killion
Published: October 2024

OBJECTIVE

To highlight the challenges and limitations in accessing post-operative adjuvant care of patients with brain tumours in Zimbabwe and implications on patient outcomes and to discuss potential strategies to overcome these challenges.

METHODS

This is a case report on a 6 year old patient with a supratentorial medulloblastoma to demonstrate the challenges encountered on accessing post-operative adjuvant care at a Central hospital in Harare.

RESULTS

The patient had a near total resection of the tumour done and was managed in the Intensive care unit for 1 week. HE was discharged to the general ward for another week and eventually referred to the paediatric oncologists after a histological diagnosis of a supratentorial medulloblastoma was made. Patient received cycles of chemotherapy but failed to raise money for adjuvant radiotherapy. Patient returned 5 months later with the tumour having recurred.

CONCLUSION

Limitations in post-operative adjuvant care may have a negative impact on the overall patient outcomes, in this case lack of access to radiotherapy. Medulloblastomas are responsive to radiotherapy and their prognosis improves significantly with a combination of surgical resection and radiotherapy. Addressing these limitations at different levels involving government and non-governmental organizations helps in mitigating inaccessibility of radiotherapy to radio-sensitive brain tumours patients after surgical resection. This case report brings out the urgent need to implement cheaper and sustainable options to address challenges in post-operative adjuvant care in order to get good patient outcomes.
SPIN-02 AN INTRAMEDULLARY MYXOPAPILLARY EPENDYMOMA: A RARE OCCURANCE IN THE CERVICO-THORACIC SPINE
Authors: Kamabu Larrey Kasereka , Lekuya Hervé Monka , Kataka Louange Maha , Valimungighe Moise Muhindo , Galukande Moses
Published: October 2024

BACKGROUND

Spinal myxopapillary ependymomas are a rare variant of spinal ependymoma that are considered to occur exclusively in the conus medullaris and filum terminale. They account for about 13% of all spinal ependymomas and have a slight male predominance. Case presentation: We report a case of 38-year-old male, Muganda, that presented at the Neurosurgery department Mulago National Referral Hospital with progressive paresthesia and paraparesis, of the upper limbs and chronic neck pain for 2years. MRI showed an isointense lesion on TIWI extending from C4 to T2 levels and exhibited heterogenous enhancement on gadolinium administration. The lesion was hyperintense on T2WI with a syrinx above the tumor. A radiological diagnosis of an intramedullary neoplastic process was made with differentials of Ependymoma, Schwanomma, and Astrocytoma. The patient underwent posterior laminectomy, and the tumor was completely excised. He is currently under follow up by the Neurosurgery team.

CONCLUSION

This case underscores the rarity of intramedullary myxopapillary ependymomas highlighting diagnostic challenges and the critical role of tailored surgical interventions in managing rare spinal neoplasms.
When Socialist Chinese Law Meets Common Law Interpretation: Mandatory Sentencing and Mitigation Under the Hong Kong National Security Law
Authors: Chiu Urania , Wong Aaron H L
Published: October 2024

In HKSAR v Lui Sai Yu [2023] HKCFA 26, the Hong Kong Court of Final Appeal (CFA) delivered its first judgment on the mandatory sentencing regime under the newly introduced National Security Law (NSL). Adopting a common law approach to interpreting the NSL, the CFA held that mitigating factors not listed in the NSL cannot bring about a sentence below the minimum prescribed by the relevant provision. In this article, we propose an alternative approach to interpreting the NSL. We argue that, contrary to the CFA’s rejection of any reference to Mainland Chinese laws in constructing the NSL, both a common law purposive approach and the principle of ‘convergence, compatibility and complementarity’—one of the working principles in the enactment of NSL—would support such reference. The implications of our proposed approach would be to (i) recognize that the sui generis nature of the NSL, being a Chinese national law applied in its Special Administrative Region of Hong Kong, necessitates the consideration of relevant Chinese legal norms; and (ii) allow for a broader range of mitigating factors—those recognized by both Hong Kong common law and Mainland Chinese law—to be applied to the minimum sentencing regime in the interest of fairer and more principled outcomes for defendants.
‘Effective strategies’ for teaching mathematics in economics: testing prior knowledge, scaffolding and practical applications
Authors: Barile Lory
Published: October 2024

Recent literature highlights increasing concerns around various issues related to students transitioning from secondary to tertiary education and their learning of mathematics within economics courses. This article explores how scaffolding complex concepts offering students step-by-step guidance and mapping mathematical concepts to economic applications can provide effective pedagogical strategies that help to address problems occurring during the transition from school to mathematics for economics at university, such as a mismatch between expectations and actual demand or a perceived gap between abstract mathematical concepts and their applications in economics. Testing prior knowledge and modelling techniques such as using Excel are also considered in the article. The pedagogical techniques discussed in this article have the potential to address challenges related to students’ heterogeneity; the abstract nature of mathematical concepts and alleviate the discrepancy between expectations regarding mathematics prerequisites and the actual demand. These represent crucial aspects for the success of undergraduate courses.
Influence of CYP2C9 phenotypes on phenytoin plasma concentration in neurosurgical Brazilian patients
Authors: Kurtz Pedro , Elias Anna Beatriz Ribeiro , Suarez-Kurtz Guilherme
Published: October 2024

Aims

To investigate the association of CYP2C9 metabolic phenotypes with phenytoin plasma concentration ([PTH]) in neurosurgical patients from the Brazilian Public Health System.

Methods

Patients (n = 170) were treated with phenytoin (300 mg/day) perioperatively as prophylaxis for postoperative seizures. Two to 10 days after surgery, a blood sample was collected for quantification of [PTH] and genotyping of CYP2C9*2 and *3 alleles. CYP2C9 metabolic phenotypes, NM (normal), IM (intermediate), and PM (poor) metabolizer, were inferred from CYP2C9 diplotypes. Linear regression modeling was applied to identify predictors of [PTH].

Results

Wide (22-fold) interindividual variation in [PTH] was observed (2.2–47.5 mg/l). [PTH] associated significantly (Kruskal–Wallis P < 0.005) with CYP2C9 phenotypes and there was a significant trend (Jonckheere–Terpstra test, P < 0.0001) for [PTH] increase in the order NM < IM < PM. [PTH] was within the target therapeutic range (10–20 mg/l) in 34.7% of patients, while 39.4% and 25.9% had [PTH] below and above the range, respectively. CYP2C9 phenotypes associated significantly (chi-square P = 0.004) with the distribution of patients in [PHT] therapeutic categories and the Cramér’s V test pointed to moderate magnitude of the effect of CYP2C9 phenotypes (V = 0.211).

Conclusion

Diplotype-predicted CYP2C9 metabolic phenotypes are associated significantly with [PTH] in neurosurgical Brazilian patients receiving phenytoin for postsurgery seizure prophylaxis. [PHT] increased progressively in the phenotype order NM < IM < PM, and all PM patients had [PHT] above the target therapeutic range, consistent with the CPIC guideline ‘strong’ recommendation for phenytoin dosing adjustments in PMs.
The role of advanced physiological guidance in contemporary coronary artery disease management
Authors: Munhoz Daniel , Ikeda Kazumasa , Bouisset Frederic , Sakai Koshiro , Tajima Atomu , Mizukami Takuya , Sonck Jeroen , Johnson Nils P. , Collet Carlos
Published: October 2024

Purpose of review

This review evaluates the emerging role of the pullback pressure gradient (PPG) as a standardized metric for assessing coronary artery disease (CAD) patterns and its implications for clinical decision-making when managing patients undergoing percutaneous coronary interventions (PCIs). By integrating PPG with existing physiological assessments, this review highlights the potential benefits of PPG in predicting treatment outcomes and refining therapeutic strategies for CAD.

Recent findings

Recent studies, particularly the PPG Global study have demonstrated a strong correlation between PPG values and post-PCI outcomes, revealing that focal disease is associated with improved fractional flow reserve (FFR) and lower rates of adverse events than vessels with diffuse disease (low PPG). Additionally, PPG has been linked to specific atherosclerotic plaque characteristics, indicating its utility in identifying high-risk plaques. The integration of PPG with advanced imaging techniques further enhances the understanding of CAD patterns and their implications for treatment planning.

The PPG represents a significant advancement in the management of CAD, providing a reproducible and objective assessment of coronary artery disease patterns that can inform clinical decision-making. As research continues to explore the relationship among PPG, atherosclerotic characteristics, and patient outcomes, its integration into routine practice is expected to improve the effectiveness of PCI and optimize patient management strategies. Future studies are warranted to establish specific PPG thresholds and further investigate its potential in identifying vulnerable plaques and guiding treatment decisions.
CARTp/GPR160 mediates behavioral hypersensitivities in mice through NOD2
Authors: Schafer Rachel M. , Giancotti Luigino A. , Chrivia John C. , Li Ying , Mufti Fatma , Kufer Thomas A. , Zhang Jinsong , Doyle Timothy M. , Salvemini Daniela
Published: October 2024

Neuropathic pain is a debilitating chronic condition that remains difficult to treat. More efficacious and safer therapeutics are needed. A potential target for therapeutic intervention recently identified by our group is the G-protein coupled receptor 160 (GPR160) and the cocaine- and amphetamine-regulated transcript peptide (CARTp) as a ligand for GPR160. Intrathecal administration of CARTp in rodents causes GPR160-dependent behavioral hypersensitivities. However, the molecular and biochemical mechanisms underpinning GPR160/CARTp-induced behavioral hypersensitivities in the spinal cord remain poorly understood. Therefore, we performed an unbiased RNA transcriptomics screen of dorsal horn spinal cord (DH-SC) tissues harvested at the time of peak CARTp-induced hypersensitivities and identified nucleotide-binding oligomerization domain-containing protein 2 (Nod2) as a gene that is significantly upregulated. Nucleotide-binding oligomerization domain-containing protein 2 is a cytosolic pattern-recognition receptor involved in activating the immune system in response to bacterial pathogens. While NOD2 is well studied under pathogenic conditions, the role of NOD2-mediated responses in nonpathogenic settings is still not well characterized. Genetic and pharmacological approaches reveal that CARTp-induced behavioral hypersensitivities are driven by NOD2, with co-immunoprecipitation studies indicating an interaction between GPR160 and NOD2. Cocaine- and amphetamine-regulated transcript peptide–induced behavioral hypersensitivities are independent of receptor-interacting protein kinase 2 (RIPK2), a common adaptor protein to NOD2. Immunofluorescence studies found NOD2 co-expressed with endothelial cells rather than glial cells, implicating potential roles for CARTp/NOD2 signaling in these cells. While these findings are based only on studies with male mice, our results identify a novel pathway by which CARTp causes behavioral hypersensitivities in the DH-SC through NOD2 and highlights the importance of NOD2-mediated responses in nonpathogenic settings.
Elucidation of neuronal activity in mouse models of temporomandibular joint injury and inflammation by in vivo GCaMP Ca2+ imaging of intact trigeminal ganglion neurons
Authors: Son Hyeonwi , Shannonhouse John , Zhang Yan , Gomez Ruben , Amarista Felix , Perez Daniel , Ellis Edward , Chung Man-Kyo , Kim Yu Shin
Published: October 2024

Patients with temporomandibular disorders (TMDs) typically experience facial pain and discomfort or tenderness in the temporomandibular joint (TMJ), causing disability in daily life. Unfortunately, existing treatments for TMD are not always effective, creating a need for more advanced, mechanism-based therapies. In this study, we used in vivo GCaMP3 Ca2+ imaging of intact trigeminal ganglia (TG) to characterize functional activity of the TG neurons in vivo, specifically in mouse models of TMJ injury and inflammation. This system allows us to observe neuronal activity in intact anatomical, physiological, and clinical conditions and to assess neuronal function and response to various stimuli. We observed a significant increase in spontaneously and transiently activated neurons responding to mechanical, thermal, and chemical stimuli in the TG of mice with TMJ injection of complete Freund adjuvant or with forced mouth opening (FMO). An inhibitor of the calcitonin gene–related peptide receptor significantly attenuated FMO-induced facial hypersensitivity. In addition, we confirmed the attenuating effect of calcitonin gene–related peptide antagonist on FMO-induced sensitization by in vivo GCaMP3 Ca2+ imaging of intact TG. Our results contribute to unraveling the role and activity of TG neurons in the TMJ pain, bringing us closer to understanding the pathophysiological processes underlying TMJ pain after TMJ injury. Our study also illustrates the utility of in vivo GCaMP3 Ca2+ imaging of intact TG for studies aimed at developing more targeted and effective treatments for TMJ pain.
Differences in Attentional Bias Toward e-Cigarette Cues Between e-Cigarette Users and Nonusers
Authors: Gwon Seok Hyun , Cho Youngjoo , Kim Yourim , Paek Suna , Lee Han-Joo
Published: October 2024

The use of electronic nicotine delivery systems (ENDS) has increased rapidly in recent years, particularly among young adults. There is a dearth of research on the cognitive factors that contribute to ENDS use. One of the possible cognitive mechanisms involved with addictive behavior is attentional bias (AB). AB can manifest as either facilitated attention engagement toward or delayed attention disengagement from a relevant stimulus. The purpose of this study was to examine the difference in AB toward ENDS-related cues between ENDS users and non-ENDS users. ENDS users (n = 29) and nonusers (n = 24) between the ages of 18 and 29 years participated in the dot-probe and eye-tracking picture-viewing tasks. The results showed that there was a significant difference in the variance of AB between the two groups. In the eye-tracking task, ENDS users displayed significantly greater net dwell time and fixation time at time frames of 6–9, 9–12, and 12–15 seconds, compared to nonusers. It is noteworthy that ENDS users exhibited attentional fluctuation toward ENDS cues as well as difficulties disengaging attention from ENDS cues. The current findings offer insight into the nature of attentional processes associated with ENDS cues and provide useful data to guide the development of a nurse-led cognitive intervention focusing on biased attentional processing related to ENDS cues.
Management of Psychiatric Diagnoses in Reversible Cerebral Vasoconstriction Syndrome: The Dangers of Worsening Pathology with Serotonergic Medications: A Case Report and Literature Review
Authors: Wang Chris , Iftekharuddin Anika , Fipps David C.
Published: October 2024

Reversible cerebral vasoconstriction syndrome (RCVS) represents a group of conditions that show reversible multifocal narrowing or constriction of the cerebral arteries that supply blood to the brain. The initial manifestation of RCVS often includes a “thunderclap” headache that is sudden, severe, and often disabling. Stimulants, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and antipsychotics with serotonergic activity can alter the cerebral arterial tone, trigger vasoconstriction, and place patients at risk of a cerebrovascular accident. Thus, psychiatric medications are commonly discontinued on admission for RCVS, and psychiatry is often consulted for input on acute medication management and longitudinal treatment options. Currently, there is a dearth of literature on managing psychiatric medications in RCVS, resulting in variable practice patterns that place patients at risk of withdrawal, decompensation, and relapse. In this article, we provide a case example and aim to consolidate the limited data surrounding the management of psychiatric illness with comorbid RCVS in our discussion. There is a clear concern about worsening and even potentially lethal consequences due to serotonin or stimulant-induced vasospasm both during an acute episode and in long-term management of RCVS. We discuss the underlying pathophysiologic mechanisms proposed for serotonergic-, noradrenergic-, and dopaminergic-induced cerebral vasospasm and how this correlates with the clinical management of patients on psychiatric medications. These data will then be organized to create a risks versus benefits outline to equip psychiatrists to make decisions about when to stop and when to restart psychiatric medications in the setting of RCVS.
The Role of Hopelessness in Patients With Borderline Personality Disorder
Authors: Aguglia Andrea , Cioci Daniele , Meinero Matteo , Placenti Valeria , Verrina Edoardo , Bianchi Davide , Fusar-Poli Laura , Costanza Alessandra , Schiavetti Irene , Amerio Andrea , Amore Mario , Serafini Gianluca
Published: October 2024

Background:

The goal of this study was to evaluate specific characteristics associated with hopelessness, potentially correlated with coping strategies, sensory profile, and alexithymia in patients with borderline personality disorder (BPD).

Materials and Methods:

Two hundred twenty-four (N=224) inpatients completed a clinical interview with administration of the Beck Hopelessness Scale (BHS), the Adolescent/Adult Sensory Profile (AASP), the Coping Orientation to Problems Experienced Inventory (COPE), and the Toronto Alexithymia Scale (TAS).

Results:

Hopelessness was significantly associated with female gender, more hospitalizations, current suicidal ideation, number of suicide attempts, current and lifetime medication abuse, and alcohol misuse. Furthermore, patients with BHS ≥ 9 had higher scores in low registration, sensory sensitivity and sensation avoiding in AASP, higher rate of alexithymia, and the use of maladaptive coping strategies.

Conclusions:

Hopelessness in BPD was associated with higher severity of illness, alternative process sensory input from the environment, reduced ability to cope with stressful events, and alexithymia. Therefore, a routine assessment of hopelessness in patients with BPD could lead to better and more specific therapeutic strategies.
The potential for evolutionary rescue in an Arctic seashore plant threatened by climate change
Authors: Mattila Anniina L. K. , Opedal Øystein H. , Hällfors Maria H. , Pietikäinen Laura , Koivusaari Susanna H. M. , Hyvärinen Marko-Tapio
Published: October 2024

The impacts of climate change may be particularly severe for geographically isolated populations, which must adjust through plastic responses or evolve. Here, we study an endangered Arctic plant,
Primula nutans
ssp.
finmarchica
, confined to Fennoscandian seashores and showing indications of maladaptation to warming climate. We evaluate the potential of these populations to evolve to facilitate survival in the rapidly warming Arctic (i.e. evolutionary rescue) by utilizing manual crossing experiments in a nested half-sibling breeding design. We estimate G-matrices, evolvability and genetic constraints in traits with potentially conflicting selection pressures. To explicitly evaluate the potential for climate change adaptation, we infer the expected time to evolve from a northern to a southern phenotype under different selection scenarios, using demographic and climatic data to relate expected evolutionary rates to projected rates of climate change. Our results indicate that, given the nearly 10-fold greater evolvability of vegetative than of floral traits, adaptation in these traits may take place nearly in concert with changing climate, given effective climate mitigation. However, the comparatively slow expected evolutionary modification of floral traits may hamper the evolution of floral traits to track climate-induced changes in pollination environment, compromising sexual reproduction and thus reducing the likelihood of evolutionary rescue.
SeqFirst: Building equity access to a precise genetic diagnosis in critically ill newborns
Authors: Wenger Tara L. , Scott Abbey , Kruidenier Lukas , Sikes Megan , Keefe Alexandra , Buckingham Kati J. , Marvin Colby T. , Shively Kathryn M. , Bacus Tamara , Sommerland Olivia M. , Anderson Kailyn , Gildersleeve Heidi , Davis Chayna J. , Love-Nichols Jamie , MacDuffie Katherine E. , Miller Danny E. , Yu Joon-Ho , Snook Amy , Johnson Britt , Veenstra David L. , Parish-Morris Julia , McWalter Kirsty , Retterer Kyle , Copenheaver Deborah , Friedman Bethany , Juusola Jane , Ryan Erin , Varga Renee , Doherty Dan , Dipple Katrina , Chong Jessica X. , Kruszka Paul , Bamshad Michael J.
Published: October 2024

Access to a precise genetic diagnosis (PrGD) in critically ill newborns is limited and inequitable because complex inclusion criteria used to prioritize testing eligibility omits many patients at high risk for a genetic condition. SeqFirst-neo is a program to test whether a genotype-driven workflow using simple, broad exclusion criteria to assess eligibility for rapid whole genome sequencing (rWGS) increases access to a PrGD in critically ill newborns. All 408 newborns admitted to a neonatal intensive care unit between January 2021 and February 2022 were assessed and of 240 eligible infants, 126 were offered rWGS (i.e., intervention group [IG]) and compared to 114 infants who received conventional care in parallel (i.e., conventional care group [CCG]). A PrGD was made in 62/126 (49.2%) IG neonates compared to 11/114 (9.7%) CCG infants. The odds of receiving a PrGD was ∼9 times greater in the IG vs. the CCG, and this difference was maintained at 12 months follow up. Access to a PrGD in the IG versus CCG differed significantly between infants identified as non-white (34/74, 45.9% vs. 6/29, 20.7%; p=0.024) and Black (8/10, 80.0% vs. 0/4; p=0.015). Neonatologists were significantly less successful at predicting a PrGD in non-white than non-Hispanic white patients. Use of a standard workflow in the IG with a PrGD revealed that a PrGD would have been missed in 26/62 (42%) of infants. Use of simple, broad exclusion criteria that increases access to genetic testing significantly increases access to a PrGD, improves access equity and results in fewer missed diagnoses.
Anthocyanin-rich extract mitigates the contribution of the pathobiont genusHaemophilusin mild-to-moderate ulcerative colitis patients
Authors: Zobrist Yannik , Doulberis Michael , Biedermann Luc , Leventhal Gabriel E , Rogler Gerhard
Published: October 2024

Objective

Anthocyanins (AC) have been shown to elicit anti-inflammatory and antioxidant effects in several animal models of colitis. Furthermore, AC lowered biochemical disease activity in our double-blind randomized trial in patients with ulcerative colitis. Here, we report on the changes in the faecal microbiome composition in the patient upon AC exposure in this trial.

Methods

Ulcerative colitis patients received a 3g daily dose of an AC-rich bilberry extract (ACRE) for eight weeks. We determined the microbiome composition in longitudinal stool samples from 24 patients and quantified the degree of change over time. We also correlated the relative abundances of individual microbial taxa at different time points to faecal concentration measurements of calprotectin.

Results

Microbiome compositions did not change over time as a result of the intervention, both in terms of alpha and beta diversity. Before the intervention, Haemophilus parainfluenzae was positively correlated with faecal calprotectin concentrations, and this correlation persisted in placebo-treated subjects throughout the study. In contrast, the correlation between H. parainfluenzae and the concentration of faecal calprotectin vanished in ACRE-treated subjects, while the relative abundance of H. parainfluenzaae did not change. Conclusion: Our results suggest that ACRE treatment mitigates the contribution of H. parainfluenzae to inflammation. Further research is warranted to better comprehend the role of microbial composition in response to medical therapy including AC-rich extract in ulcerative colitis patients.

Key messages

1. What is already known on this topic

Anthocyanins are a promising therapeutic alternative for ulcerative colitis patients given their effect on faecal calprotectin, excellent safety profile, and low costs.

2. What this study adds

The administration of anthocyanin-rich extract to ulcerative colitis patients in a Phase 2a study reduced faecal calprotectin concentrations by mitigating the contribution from the pathobiont genus Haemophilus but did not affect the overall microbiome composition.

3. How this study might affect research, practice or policy

Our results could aid in targeted treatment of ulcerative colitis patients with anthocyanins, according to individual microbial composition.
Biomedical Text Normalization through Generative Modeling
Authors: Berkowitz Jacob S. , Fatapour Yasaman , Srinivasan Apoorva , Cortina Jose Miguel Acitores , Tatonetti Nicholas P
Published: October 2024

Objective

Around 80% of electronic health record (EHR) data consists of unstructured medical language text. By its nature, this text is flexible and inconsistent, making it challenging to use for clinical trial matching, decision support, and predictive modeling. In this study, we develop and assess text normalization pipelines built using large-language models.

Materials and Methods

Here, we evaluated four LLM-based normalization strategies: Zero-Shot Recall, Prompt Recall, Semantic Search, and Retrieval-Augmented Generation (RAG) and one baseline, TF-IDF based String Matching. We compared normalization performance across two datasets of condition terms mapped to SNOMED, one tailored to oncology, and one covering a wide range of medical conditions. Additionally, we benchmarked our models against the TAC 2017 drug label annotations, which normalizes terms to the Medical Dictionary for Regulatory Activities (MedDRA) Preferred Terms.

Results

RAG, which effectively combines Prompt Recall and Semantic Search, was the most effective, accurately identifying the correct term 88.31% of the time for the domain-specific dataset and 79.97% for the broader dataset. Our model achieved a micro F1 score of 88.01 on task 4 of the TAC2017 conference, surpassing all other models without relying on the provided training data.

Discussion

These findings demonstrate the potential of LLMs in medical text normalization. We find that retrieval-focused approaches overcome traditional LLM limitations for this task.

Conclusion

Large language models combined with retrieval-augmented generation should be explored for text normalization of biomedical free text.
Real-time prediction of drug-induced proarrhythmic risk with sex-specific cardiac emulators
Authors: Dominguez-Gomez Paula , Zingaro Alberto , Baldo-Canut Laura , Balzotti Caterina , Darpo Borje , Morton Christopher , Vázquez Mariano , Aguado-Sierra Jazmin
Published: October 2024

In silicotrials for drug safety assessment require a large number of high-fidelity 3D cardiac electrophysiological simulations to predict drug-induced QT interval prolongation, making the process computationally expensive and time-consuming. These simulations, while necessary to accurately model the complex physiological conditions of the human heart, are often cost-prohibitive when scaled to large populations or diverse conditions. To overcome this challenge, we develop sex-specific emulators for the real-time prediction of QT interval prolongation, with separate models for each sex. Building an extensive dataset from 900 simulations allows us to show the superior sensitivity of 3D models over 0D single-cell models in detecting abnormal electrical propagation in response to drug effects as the risk level increases. The resulting emulators trained on this dataset showed high accuracy level, with an average relative error of 4% compared to simulation results. This enables global sensitivity analysis and the replication ofin silicocardiac safety clinical trials with accuracy comparable to that of simulations when validated againstin vivodata. With our emulators, we carry outin silicoclinical trials in seconds on a standard laptop, drastically reducing computational time compared to traditional high-performance computing methods. This efficiency enables the rapid testing of drugs across multiple concentration ranges without additional computational cost. This approach directly addresses several key challenges faced by the biopharmaceutical industry: optimizing trial designs, accounting for variability in biological assays, and enabling rapid, cost-effective drug safety evaluations. By integrating these emulators into the drug development process, we can enhance the reliability of preclinical assessments, streamline regulatory submissions, and advance the practical application of digital twins in biomedicine. This work represents a significant step toward more efficient and personalized drug development, ultimately benefiting patient safety and accelerating the path to market.
Human bioaccumulation of micro- and nanoplastics is primarily determined by the organs’ vascular volume
Authors: Gañán-Calvo Alfonso M.
Published: October 2024

Recent studies have demonstrated the accumulation of micro- and nanoplastics (MNPs) in human organs, particularly in the brain, at an alarming rate (Campen et al., 2024, doi.org/10.21203/rs.3.rs-4345687/v1). This study examines the phenomenon of bioaccumulation in relation to up to six distinct biological and biomedical parameters pertaining to vascular structure and composition in seven organ tissues: the brain cortex, kidney, liver, testis, and three arteries (coronary, carotid and aorta). As anticipated based on fundamental mechanistic considerations of bioaccumulation (washing rate), the MNP content appears to be proportional to the inverse of the capillary volume fraction (Vc), exhibiting no correlation with any other geometric variable, such as capillary diameter or capillary segment length. This finding is consistent with the small size spectra of MNPs in comparison to these dimensions. However, contrary to expectations, no correlation was observed between MNP content and biological composition (lipid, water, or carbohydrate content), while a likely non-causal correlation was observed between MNP content and protein content, which may be simply attributed to the non-linear correlation between protein content andVc. The conclusions that point to a possibly exceedingly large number of MNP particles currently in our brains call for urgent further investigation and the revision of the published data.
Yearly trends in cause-specific age-adjusted mortality from 1999-2020 in Black and White Non-Hispanic Americans
Authors: Arun Adith S. , Krumholz Harlan M.
Published: October 2024

From 1999 to 2020, disparities in all-cause age-adjusted mortality rates between Black and White Non-Hispanic Americans decreased then stagnated and increased. Consistent improvement in racial disparities were made for cancer, HIV, and sepsis regardless of all-cause trends. In contrast, conditions like heart disease and external causes of death mirrored the overall trends.
Large language models for abstract screening in systematic- and scoping reviews: A diagnostic test accuracy study
Authors: Krag Christian Hedeager , Balschmidt Trine , Bruun Frederik , Brejnebøl Mathias , Xu Jack Junchi , Boesen Mikael , Andersen Michael Brun , Müller Felix Christoph
Published: October 2024

Introduction

We investigated if large language models (LLMs) can be used for abstract screening in systematic- and scoping reviews.

Methods

Two broad reviews were designed: a systematic review structured according to the PRISMA guideline with abstract inclusion based on PICO criteria; and a scoping review, where we defined abstract characteristics and features of interest to look for. For both reviews 500 abstracts were sampled. Two readers independently screened abstracts with disagreements handled with arbitrations or consensus, which served as the reference standard. The abstracts were analysed by six LLMs (GPT-4o, GPT-4T, GPT-3.5, Claude3-Opus, Claude3-Sonnet, and Claude3-Haiku). Primary outcomes were diagnostic test accuracy measures for abstract inclusion, abstract characterisation and feature of interest detection. Secondary outcome was the degree of automation using LLMs as a function of the error rate.

Results

In the systematic review 12 studies were marked asincludeby the human consensus. GPT-4o, GPT-4T, and Claude3-Opus achieved the highest accuracies (97% to 98%) comparable to the human readers (96% and 98%), although sensitivity was low (33% to 50%). In the scoping review 130 features of interest were present and the LLMs achieved sensitivities between 74-84%, comparable to the human readers (73% and 86%). The specificity of GPT-4o (98%) and GPT-4T (>99%) greatly surpassed the other LLMs (between 33% and 93%). For abstract characterization all LLMs achieved above 95% accuracy for language, manuscript type and study participant characterisation. For characterisation of disease-specific features only GPT-4T and GPT-4o showed very high accuracy. For abstract inclusion the highest automation rate (91%) at the lowest error rate (8%) was achieved by use of two LLMs with disagreement solved by human arbitration. An LLM pre screening before human abstract screening achieved an automation rate of 55% with no missed abstracts.

Conclusion

Abstract characterisation and specific feature of interest detection with LLMs is feasible and accurate with GPT-4o and GPT-4T. The majority of abstract screenings for systematic reviews can be automated with use of LLMs, at low error rates.
Atherosclerotic fibrous plaques in females are characterized by endothelial-to-mesenchymal transition and linked to smoking
Authors: Sakkers Tim R. , Mili Eloi , Meteva Denitsa , Wesseling Marian , Kapteijn Daniek , Mol Barend M. , de Borst Gert J. , de Kleijn Dominique P.V. , van der Laan Sander W. , Civelek Mete , Mayr Manuel , Pasterkamp Gerard , Mokry Michal , Benavente Ernest Diez , den Ruijter Hester M.
Published: October 2024

Background

Sex and plaque histology are intertwined, with fibrous atherosclerotic plaques being more prevalent in women and pointing to general smooth muscle cell plasticity and estrogen signaling. Plaque erosion, a significant contributor to acute coronary syndromes (ACSs), is linked to fibrous plaques and is more prevalent in women as compared to men. We hypothesize that the molecular drivers of histologically determined fibrous plaques differ between men and women.

Methods

Human end-stage atherosclerotic plaques were isolated from consecutive patients who underwent carotid endarterectomy and were included in the Athero-Express biobank. Fibrous plaques from both female and male patients were histologically assessed and further processed to obtain protein, bulk RNA, single-cell RNA and DNA methylation data. We leveraged sex-differential expression and deconvolution analyses to uncover sex-biased molecular mechanisms and cellular dynamics which were experimentally validated using an EndMT in vitro model.

Results

Out of 1,889 atherosclerotic plaques (1,309 male and 580 female), fibrous lesions were observed in 50% of female (n=290) and 31% of male patients (n=416). Compared to patients with atheromatous plaques (n=494), women with fibrous plaques exhibited a higher prevalence of smoking (41% vs. 33%), while men with fibrous plaques presented more often with diabetes (29% vs. 20%). Transcriptional and proteomic phenotyping highlighted more immune-dependent and inflammatory processes in male fibrous plaques. Genes and proteins with higher abundance in female fibrous plaques pointed to endothelial-to-mesenchymal transition (EndMT) and extracellular matrix remodelling. Using single-cell RNA sequencing, we identified a dominant role of endothelial and smooth muscle cells in female plaques, and more macrophages in males. Finally, at the cellular level, we show that sex - specific, smoking-mediated promoter methylation changes may explain these differences.

Conclusions

Patients with end-stage fibrous atherosclerotic plaques have a distinct clinical profile, with men more often having diabetes and women more often smoking. This clinical profile associates with sex differences that point to different cellular and molecular compositions of fibrous plaques. These mechanisms might be candidate pathways to understand plaque erosion from a molecular point of view and may provide promising targets for atherosclerosis therapies, as they account for the sex-specific differences in plaque phenotype.

Graphical abstract