bluuebunny/crossref_metadata_2025 huggingface dataset:
LMIC-25. EXPANDING THE PEDIATRIC NEURO-ONCOLOGY TELECONFERENCE EXPERIENCES, A LUXURY, OR A NECESSITY?
Authors: Badarin Essra’ Al , Chamdine Omar , El-Ayadi Moatasem , Al-Battashi Abeer , Nuaimi Mohammed Al , Alshamsi Emam , Hessissen Laila , Al-Tarrah Hiba , Maher Eslam , farah Roula , Maaz Ata Ur Rehman , Saed Waleed , Haziemeh Ruba , Mustafa Maher Khader , Salami Khadra , Hawkins Cynthia , Abdelbaki Mohamed , Bartels Ute , tabori Uri , Bouffet Eric , Amayiri Nisreen
Published: June 2024

INTRODUCTION

Videoteleconference in neurooncology is feasible and sustainable. The well-established 20 years’ Sickkids/KHCC teleconferencing is an example. Since 2018, several regional centers joined these meetings to discuss their patients’ management plans. We aimed to evaluate the impact of this experience.

METHODS

We retrospectively reviewed the 56 meetings’ minutes (9/2018-12/2023) and compared the pre-conference suggested plans with the post-conference recommendations. We recorded if the recommendations were implemented and the impact perceived.

RESULTS

In total, 251 patients were discussed: KHCC (137) and non-KHCC (114). Four of the regional participating oncologists had dedicated pediatric neuro-oncology training. Patients were selected for discussion due to challenges in their management (i.e. with relapsed tumors, rare diagnoses, unexpected tumor behavior). Main diagnoses were: Low-grade-glioma (28%), High-grade-glioma (21%), and Medulloblastoma (17%). Of the 227 patients where the local team suggested a care plan, the teleconference recommendations concurred with the proposed plan in 50% of the cases, agreed on but provided an alternative plan option in 18% and disagreed on in 32% of the cases. The difference in recommendations mostly affected the proposed treatment modality (15%). In 64% of the discordant plans and 50% of the alternative plans, the treating team applied the recommendations. Challenges to apply the recommendations were mainly linked to patients’ factors (53%, plan refusal, traveling abroad, clinical deterioration), local multidisciplinary team consensus on a different plan (29%) or logistic difficulties (18%, e.g. drug access).

CONCLUSIONS

Improvement in patients’ care was likely achieved with the continuous effort of the local teams to implement the recommendations. Participating oncologists valued the shared educational experience learned from each other’s case discussions, especially those related to molecular-testing and implications on treatment. Joining such regional teleconferences is of particular importance to small-volume centers or those lacking a pediatric neurooncologist. Regional and international collaborations are a necessity when it comes to improving the care of children with CNS tumors.
MODL-02. ESTABLISHING THE TIME-DEPENDENCE OF CDK4/6 INHIBITOR EFFICACY IN PEDIATRIC BRAIN TUMORS AND FEASIBILITY OF METRONOMIC INTRATHECAL DELIVERY IN A PRECLINICAL MODEL
Authors: Martin Brice , Guadix Sergio , Sathian Rekha , Laramee Madeline , Pandey Abhinav , Ray Ishani , Chen-Kiang Selina , Wang Amy , Davuluri Ramana , Dahmane Nadia , Thomas Craig , Souweidane Mark
Published: June 2024

This comprehensive study delves into the intricate dynamics of CDK4/6 inhibitors (abemaciclib, ribociclib, palbociclib) efficacy in the context of pediatric brain tumors, with a specific focus on establishing the temporal dependencies of their effectiveness. Beyond elucidating the time-dependent aspects, the research also explores into the feasibility and safety considerations associated with a metronomic intrathecal delivery with Palbociclib. This involves a thorough examination of pharmacokinetics and an analysis of liver and renal function through a panel assessment in vivo. By methodically exploring the optimal dosing within the brain after administration of Palbociclib via a systemic or intrathecal administration; the study aims to provide nuanced insights into enhancing therapeutic outcomes for pediatric brain tumors. Ultimately, we also provide a mechanistic understanding of the inhibition of CDK4/6 over time using RNAseq analysis; and an assessment of the efficacy of the proposed metronomic intrathecal delivery strategy in a preclinical mouse model of leptomeningeal ATRT. This multifaceted study not only expands our understanding of the temporal dynamics of CDK4/6 inhibitors but also lays the foundation for informed decision-making regarding the potential of this innovative therapeutic delivery method in the realm of pediatric brain tumor treatment.
MODL-11. LOW-GRADE GLIOMA 3D PATIENT-DERIVED ORGANOID PLATFORM AS TRANSFORMATIVE TOOL FOR TUMOR BIOLOGY AND TRANSLATIONAL RESEARCH
Authors: Beale David R , Alonso Alana Martinez , Baubet Valerie P , Santi-Vicini Mariarita , Viaene Angela , Madsen Peter , Koptyra Mateusz P , Storm Phillip B , Resnick Adam C
Published: June 2024

Unlike many high-grade tumors, low-grade glioma (LGG) has faced challenges in advancing scientific and clinical breakthroughs, affected by the limited capacity to develop representative preclinical tumor models. Major barriers to establishing traditional LGG cell culture systems have been cellular senescence and the need to introduce additional genetic modifications to obtain cultured growth. Such LGG models, while extremely valuable, require extensive periods for development and result in clonally selected lines which may not present the complexity of LGG tumor biology. To mitigate such challenges in LGG model development and address the need for three-dimensional tissue cultures, we have successfully generated organoids from fresh tissue specimens obtained from surgical resection. We have demonstrated success of this method on various pediatric brain tumor histologies and have expanded these approaches successfully to LGG. Through such efforts, we have developed 14 LGG tumors’ organoid models as well as other low-grade tumor’s models such as craniopharyngioma, schwannoma, meningioma, optic glioma, and oligodendroglioma. The tissue was processed immediately post-extraction and cultured in media solution on rotating platform. Organoid growth was observed within 1-3 weeks of initiation and tested for growth for up to 3 months. Phenotypic analysis revealed organoid cell composition representing clinical histology. The immune component was preserved in organoids for up to 40 days. MAPK pathway activity, a hallmark marker for KIAA-BRAF fusion positive pilocytic astrocytoma was preserved for up to 4 weeks. Our successful deployment of three-dimensional patient-tissue derived organoids provides for an efficient, simple workflow for the generation of unique and transformative preclinical models for the LGG field. Supported by the Children’s Brain Tumor network’s open science model, 3D organoids will provide investigations with broader resources for LGG tumor biology preclinical testing and support translational studies on behalf of the development of novel clinical trials.
MODL-13. ORGANOTYPIC BRAIN SLICE CULTURE PLATFORM AS A MODEL OF PEDIATRIC LOW GRADE GLIOMAS
Authors: Mann Breanna , Artz Nichole , Adefolaju Adebimpe , Dasari Rajaneekar , Bell Noah , Buckley Andrew , Kram David , Hingtgen Shawn , Satterlee Andrew
Published: June 2024

BACKGROUND

Pediatric low grade glioma (pLGG), the most common subgroup of central nervous system tumors in children, suffers from a paucity of models that support pLGG biological discovery, preclinical target identification, and drug screening studies.

METHODS

We propose the use of an organotypic brain slice culture (OBSC) platform as a novel model in which we are able to reliably support fresh, zero-passage pLGG patient tumor tissue for preclinical testing. We performed individualized drug screening with the frequently used up-front agents: carboplatin, vincristine, trametinib, and dabrafenib.

RESULTS

We have collected and established on OBSCs 100% (3/3) pLGGs since 2023. With these three patient samples, we have applied our quantitative drug screening algorithm, which combines tumor killing efficacy with healthy tissue toxicity, and yielded resultant drug sensitivity scores (DSS) to quantify patient-specific treatment efficacies.

CONCLUSIONS

Overall, these early results suggest that the OBSC platform may serve as a novel and reliable model for pLGG, filling a critical void in representative models for this common and often highly morbid pediatric tumor.
RADT-05. MATURE OUTCOMES OF A PHASE II PROSPECTIVE STUDY OF PROTON RADIOTHERAPY FOR LOCALIZED BRAIN TUMORS
Authors: Kang Soo , Anderson Emily , Bajaj Benjamin , Allison Keith , Gallotto Sara , Lawell Miranda , Perry Alisa , Yock Torunn
Published: June 2024

BACKGROUND

Proton radiotherapy (PRT) is a highly targeted form of radiation that spares more normal brain tissue compared to modern photon radiotherapy. Therefore, we expect the late effect profile in children treated with PRT with curable brain tumors should be improved.

METHODS

Between 2010-2022, 100 patients were enrolled, treated with PRT, and then followed for disease control, hearing, neurocognitive and endocrine outcomes. Late effects of the tumor and treatment delivered were graded using CTCAE v4.0.

RESULTS

Median age at PRT was 8.0 years (1.1-20.8) and median follow up was 8.7 years (0.3-12.7). Tumor types included 40 (40%) ependymomas, 19 (19%) low grade gliomas (LGG), 21 (21%) craniopharyngiomas, and 20 (20%) other histologies. 26% of patients were treated with chemotherapy in addition to PRT. The location of PRT was 38 (38%) infratentorial, 56 (56%) supratentorial, and 6 (6%) both. The median radiation dose was 52.2 GyRBE (48.6-59.4). 8-year event-free survival (EFS) and overall survival (OS) was 71.7% and 86.2% for all patients. 8-year EFS and OS was 59.9% and 82.4% for ependymomas, 78.2% and 94.7% for LGG, 80.0% and 87.7% for craniopharyngiomas and 79.1% and 84.7% for all other tumor types. 19% of patients had new grade 3+ toxicities that were at least possibly related to radiotherapy. Baseline full-scale intelligence quotient (FSIQ) was 98.0 and follow-up FSIQ was 101.8 (p=0.14). 43% of patients had new endocrine deficiencies after radiation. 8 patients suffered new high-grade hearing loss after PRT. Dosimetry on critical brain structures was collected and correlated with late effects. More details will be presented at the conference.

CONCLUSION

PRT remains an effective treatment for children with curable brain tumors. While late effects of the tumor and treatment are still present, the overall burden of late effects is lower than other reports.
STEM-05. CREATING PATIENT-DERIVED TUMOROIDS TO INVESTIGATE RADIORESISTANCE IN PEDIATRIC BRAIN TUMORS
Authors: Deschuyter Marlène , Pelletier Rémi , Salmanli Chinar , Wolf Thibaut , Lhermitte Benoit , Reita Damien , Guerin Eric , Foppolo Sophie , Klymchenko Andrey , Dontenwill Monique , Martin Sophie , Entz-Werle Natacha
Published: June 2024

BACKGROUND

Brain cancers are the most frequently diagnosed tumor types in pediatric and young adult populations. Unfortunately, they often carry a poor prognosis and face common challenges such as treatment resistances due to intra- and intertumoral heterogeneity. To fully understand the intrinsic and extrinsic mechanisms which might hinder proper care, there is an emerging need to develop precise models of brain tumors to understand resistances and to predict therapeutic responses. While tumor-derived primary cell lines are relatively easy to produce, fully replicate the complexity of tumors as they grow without interactions with and from the microenvironment. Therefore, the advent of organoid cultures represents a significant advancement in modelling development. Derived from this technology, tumoroids offer a promising solution for modeling 3D tumors and their complex microenvironment.

METHODS

We develop tumoroids from fresh biopsies and patient-derived tumor xenografts. These models were rigorously validated against to initial tumor using confocal microscopy, methylome analyses, metabolomics and single-cell RNAseq. To assess the intrinsic hypoxic environment and its spatial heterogeneity, characteristic of aggressive cancers, we employed fluorescent oxygen-sensitive dye loaded polymeric nanorods.

RESULTS

We successfully generated tumoroids using PDX of ependymomas (BT39) and it paired relapse (BT42), two H3.3 mutated high-grade gliomas (BT35 and BT69), one ganglioglioma (BT63) and directly from fresh biopsies of DIPG sample (BT140). Several passages were obtained after primary derivation, and cryopreservation demonstrating the stability of the models over time. Tumoroids displayed similar protein and omics markers as their parental tumors and harbored specific stem cell and neural progenitor markers. The methylation patterns were entirely preserved comparing 3D models and their parental tumors, and other multiomics and metabolic approaches confirmed the accurate reconstitution of tumor complexity. The study of oxygen-sensitive nanorods highlighted the heterogeneous oxygen gradient within tumoroids.

CONCLUSIONS

All these initial characterized tumoroids helped us to develop radioresistant paired models.
STEM-07. CONSERVATION AND FAITHFUL REPRESENTATION OF CIRCULAR EXTRACHROMOSOMAL DNA IN ORTHOTOPIC PATIENT-DERIVED MEDULLOBLASTOMA XENOGRAFTS
Authors: Kenkre Rishaan , Chapman Owen , Luebeck Jens , Bafna Vineet , Wechsler-Reya Robert J , Mesirov Jill , Chavez Lukas
Published: June 2024

BACKGROUND

Extrachromosomal DNA (ecDNA) drives tumor heterogeneity and correlates with poor survival across various cancer types. Patient-derived xenograft (PDX) models facilitate preclinical drug testing in vivo, enabling tumor growth analysis and molecular tumor profiling. These models, combined with single-cell profiling, offer insights into intratumoral heterogeneity under therapeutic pressure and the emergence of drug resistance. We investigate the abundance and conservation of ecDNA in PDX models to assess the faithful representation of ecDNA compared to their corresponding primary tumors.

METHODS

Whole-genome sequencing (WGS) was applied to 27 medulloblastoma (MB) PDX models and their tumors of origin using Amplicon Architect. ecDNA frequency in these models was also compared to that in the MB patient population. Optical genome mapping enabled accurate and reliable ecDNA sequence reconstructions. Multiome single-cell RNA and ATAC-sequencing of a PDX tumor enabled analysis of ecDNA conservation and intratumoral heterogeneity compared to similar data previously obtained from the primary tumor.

RESULTS

ecDNA is largely conserved in PDX models, emphasizing their relevance as faithful models of the primary tumors. MB PDX models exhibit significant higher ecDNA frequency (16 out of 27 tumors) as compared to their frequency in the overall patient population (~18%), suggesting ecDNA as a driver for successful establishment of MB PDX models. Single-cell analysis revealed that ecDNA is omnipresent in almost all PDX tumor cells, contrasting with only ~9% of tumor cells in the primary tumor.

CONCLUSIONS

ecDNA analysis in medulloblastoma primary tumors and in PDX models revealed that ecDNA is preserved in PDX models. These findings emphasize the relevance of PDX models in preclinical in vivo studies aimed at analyzing the role of ecDNA under therapeutic pressure and for analyzing clonal selection along with molecular evolution of ecDNA during the development of therapeutic resistance.
Science and the nation-state: What China’s experience reveals about the role of policy in science
Authors: Wagner Caroline S
Published: June 2024

China’s rapid rise and spectacular growth in science capacity reopens a discussion about the relationship between science and the nation-state. Literature suggests that science thrives within a democratic system and that scientific activities tend to have a liberalizing effect on governments. Neither of these phenomena appears evident in China’s case. Three policies, present in the earliest days of the growth of modern science, ones in common with other nations, factor into China’s science policy: (1) policies enabling protection of intellectual property, (2) encouraging mobility and skills development, and (3) government procurement of science and technology, especially through military purchases. Using Graham’s interactionist model, I suggest that policies instituted by the state-created conditions for emergence of modern science.
Blending gestation and lactation diets during the transition period reduces energy mobilization by sows in late gestation, with no impact on subsequent lactation performance
Authors: Gregory N , Huber L
Published: June 2024

Fifty-three gilts and fifty-three multiparous (MP) sows were used to evaluate a blended feeding program using gestation and lactation diets during the transition period on changes in sow back fat (BF) depth and BW, blood metabolites, and litter growth performance in the subsequent lactation period. A 2 × 2 factorial experimental design was generated including the factors of parity and feeding program. The MP sows and gilts were assigned to one of two feeding programs on day 104 ± 1 of gestation: 1) 2 kg/d of a standard lactation diet until farrowing when sows received step-up access to the lactation diet until ad libitum access was given on day 4 of lactation (CON) and 2) a dynamic blend of standard gestation and lactation diets that met estimated daily requirements for standardized ileal digestible Lys and net energy according to the NRC (2012) until day 4 of lactation where sows were provided ad libitum access to the lactation diet (TRAN). Litters were standardized to 13 ± 1 piglets within 24-h of birth. In gestation, ADFI was greatest for TRAN-MP sows (interaction; P < 0.05), with greater ADFI for TRAN versus CON sows (main effect; 2.95 vs. 2.13 ± 0.08 kg; P < 0.05). Feeding program did not influence ADFI in lactation, but MP sows had greater ADFI versus gilts (main effect; 5.96 vs. 4.47 ± 0.28 kg; P < 0.001). Immediately after farrowing, TRAN sows had greater BW and BF vs. CON sows, regardless of parity (main effect; 224.1 vs. 215.4 ± 4.1 kg and 17.3 vs. 16.2 ± 0.4 mm, respectively; P < 0.05). At weaning, no feeding program-related differences were observed for BW or BF, but MP sows had thicker BF compared to gilts (main effect; 14.4 vs. 13.4 ± 0.5 mm; P < 0.05). The TRAN-MP sows had heavier piglets at birth compared to all other groups (interaction; P < 0.05) and MP sows had greater litter birth weight and average piglet BW at birth versus gilts (main effect; P < 0.05). No effect of feeding program was observed for piglet BW at weaning. On lactation day 1, serum beta-hydroxybutyric acid and non-esterified fatty acid concentrations were lower for TRAN compared to CON sows (main effect; 12.0 vs. 19.4 ± 7.8 mmol/L and 0.35 vs. 0.57 ± 0.10 mmol/L, respectively; P < 0.05) and serum glucose concentration was greater for TRAN compared to CON sows (main effect; 4.41 vs. 3.88 ± 0.22 mmol/L; P < 0.05), but these differences were no longer detectable at weaning. Therefore, a simple transition feeding program using a blend of a standard gestation and lactation diets reduced energy mobilization by sows in late gestation, with no impact on subsequent lactation performance.
Listening Effort Measured With Pupillometry in Cochlear Implant Users Depends on Sound Level, But Not on the Signal to Noise Ratio When Using the Matrix Test
Authors: Stronks Hendrik Christiaan , Tops Annemijn Laura , Quach Kwong Wing , Briaire Jeroen Johannes , Frijns Johan Hubertus Maria
Published: June 2024

Objectives:

We investigated whether listening effort is dependent on task difficulty for cochlear implant (CI) users when using the Matrix speech-in-noise test. To this end, we measured peak pupil dilation (PPD) at a wide range of signal to noise ratios (SNR) by systematically changing the noise level at a constant speech level, and vice versa.

Design:

A group of mostly elderly CI users performed the Dutch/Flemish Matrix test in quiet and in multitalker babble at different SNRs. SNRs were set relative to the speech-recognition threshold (SRT), namely at SRT, and 5 and 10 dB above SRT (0 dB, +5 dB, and +10 dB re SRT). The latter 2 conditions were obtained by either varying speech level (at a fixed noise level of 60 dBA) or by varying noise level (with a fixed speech level). We compared these PPDs with those of a group of typical hearing (TH) listeners. In addition, listening effort was assessed with subjective ratings on a Likert scale.

Results:

PPD for the CI group did not significantly depend on SNR, whereas SNR significantly affected PPDs for TH listeners. Subjective effort ratings depended significantly on SNR for both groups. For CI users, PPDs were significantly larger, and effort was rated higher when speech was varied, and noise was fixed for CI users. By contrast, for TH listeners effort ratings were significantly higher and performance scores lower when noise was varied, and speech was fixed.

Conclusions:

The lack of a significant effect of varying SNR on PPD suggests that the Matrix test may not be a feasible speech test for measuring listening effort with pupillometric measures for CI users. A rating test appeared more promising in this population, corroborating earlier reports that subjective measures may reflect different dimensions of listening effort than pupil dilation. Establishing the SNR by varying speech or noise level can have subtle, but significant effects on measures of listening effort, and these effects can differ between TH listeners and CI users.
Practices in Pediatric Cosmetic Dermatologic Procedures: A National Survey
Authors: Hoffman Lauren , Ahmed Sarah , Krakowski Andrew C. , Chapas Anne
Published: June 2024

BACKGROUND

Adult populations have traditionally been the primary recipients of cosmetic treatments, but a growing trend shows an increase in such procedures among pediatric patients.

OBJECTIVE

The objective of the authors' study was to investigate types of procedures currently being performed by pediatric and cosmetic dermatologists and factors that may influence their choice of treatments in a pediatric population.

METHODS

The authors conducted an anonymous online survey targeting healthcare practitioners who frequently use lasers for pediatric cutaneous conditions. The survey collected information on participants' primary scope of practice, pediatric cosmetic procedures they performed, counseling topics, and procedural details.

RESULTS

Of 85 survey respondents, 73 (86.00%) completed all questions. Most respondents identified as pediatric dermatologists (77.65%), followed by general dermatologists (18.82%), cosmetic dermatologists (8.24%), and dermatologic/Mohs surgeons (1.18%). Top pediatric cosmetic conditions treated included hypertrophic/traumatic scars (95.29%), acne (89.41%), axillary and facial hyperhidrosis (77.65%), hypertrichosis/hirsutism (67.06%), and pigmented lesion removal (64.71%). Commonly performed procedures were vascular lasers (77.65%), laser hair removal (50.59%), and pigmented lasers (28.24%), among others. Respondents prioritized understanding risks/benefits, clinically indicated treatment, and the natural course of the condition.

CONCLUSION

As the first multisociety, national survey, these results offer valuable insight into the current landscape of pediatric cosmetic treatments from the perspective of dermatologists.
Bruxism, temporomandibular disorders, and headache: a narrative review of correlations and causalities
Authors: Voß Leonie Caroline , Basedau Hauke , Svensson Peter , May Arne
Published: June 2024

The co-occurrence of bruxism, temporomandibular disorders (TMDs), and headache is common in patients. However, there is conflicting evidence regarding whether this association is simply a result of their high prevalence or whether there are indeed causal relationships. This review provides an overview of the current state of research while taking into account the controversies surrounding research methods, particularly in definitions and diagnostic standards. Bruxism—defined as repetitive jaw muscle activity during sleep or wakefulness—is not a painful disorder but may—particularly in co-occurrence with TMD—worsen pre-existing headache. It seems important to differentiate between sleep and awake bruxism because of different impact on pathophysiological processes in different primary headache disorders such as migraine and tension-type headache. Temporomandibular disorder is a heterogenous entity with both myofascial and arthrogenous types of pain in addition to nonpainful disorders. Research suggests a correlation between TMD pain and migraine, as well as between awake bruxism and tension-type headache. However, psychosocial factors may act as confounders in these relationships. Determining causality is challenging because of the limited number of experimental and clinical studies conducted on this topic. The main finding is an apparent lack of consensus on the definition and assessment criteria for bruxism. Treatment wise, it is important to differentiate all 3 conditions because treatment of one condition may have an effect on the other 2 without proving causality. For future research, it is crucial to establish greater consistency and applicability in diagnostic procedures and definitions. In addition, more experimental and clinical studies investigating the question of causality are needed.
Educational needs and preferences of adult patients with acute pain: a mixed-methods systematic review
Authors: Bérubé Mélanie , Verret Michael , Bourque Laurence , Côté Caroline , Guénette Line , Richard-Denis Andréane , Ouellet Simon , Singer Lesley Norris , Gauthier Lynn , Gagnon Marie-Pierre , Gagnon Marc-Aurèle , Martorella Géraldine
Published: June 2024

Many patients experience acute pain, which has been associated with numerous negative consequences. Pain education has been proposed as a strategy to improve acute pain management. However, studies report limited effects with educational interventions for acute pain in adults, which can be explained by the underuse of the person-centered approach. Thus, we aimed to systematically review and synthetize current evidence from quantitative, qualitative and mixed-methods studies describing patients' needs and preferences for acute pain education in adults. We searched original studies and gray literature in 7 databases, from January 1990 to October 2023. Methodological quality was assessed with the Mixed Methods Appraisal Tool. A total of 32 studies were included (n = 1847 patients), two-thirds of which were qualitative studies of high methodological quality. Most of the studies were conducted over the last 15 years in patients with postsurgical and posttraumatic pain, identified as White, with a low level of education. Patients expressed the greatest need for education when it came to what to expect in pain intensity and duration, as well how to take the medication and its associated adverse effects. The most frequently reported educational preferences were for in-person education while involving caregivers and to obtain information first from physicians, then by other professionals. This review has highlighted the needs and preferences to be considered in pain education interventions, which should be embedded in an approach cultivating communication and partnership with patients and their caregivers. The results still need to be confirmed with different patient populations.
Biomechanical evaluation of 3D-printed joint-type orthosis for hallux valgus
Authors: Chen Chen-Sheng , Chang Yu-Sheng , Lin Kuang-Wei , Chien Mu-Jung , Wang Chien-Shun
Published: June 2024

Background:

Orthoses play an important role in the conservative treatment of hallux valgus (HV) with different therapeutic effects. In this study, a new HV orthosis was developed using three-dimensional (3D) printing technology. In addition, its kinematic effect was evaluated using motion analysis.

Methods:

Seventeen participants with an HV angle of >20° were included in the study. The first metatarsophalangeal abduction angle before and after the orthosis was measured statically. Subsequently, dynamic first metatarsophalangeal abduction, dorsiflexion angle and ground reaction force with and without the orthosis were recorded and calculated during walking using a Vicon motion analysis system and force plates. The patients’ comfort scales were determined after the motion analysis.

Results:

The angular corrections of the orthosis in the first metatarsophalangeal abduction were 14.6° and 6.3° under static and dynamic conditions, respectively. Reduced hallux dorsiflexion was observed with the orthosis in the early stance phase. However, no significant changes in ground reaction forces were observed.

Conclusion:

The results of our study confirm the potential of the 3D-printed HV orthosis in the static and dynamic correction of deformities while ensuring patient comfort with minimal impact on hallux kinematics, suggesting the potential of our design for long-term use.
Provision of Behavioral Health Services at Community Health Centers and Hospital Emergency Department Visits
Authors: Carey Kathleen , Cole Megan B.
Published: June 2024

Background:

Numerous US patients seek the hospital emergency department (ED) for behavioral health care. Community Health Centers (CHCs) offer a potential channel for redirecting many to a more patient-centered, lower cost setting.

Objective:

The aim of this study was to identify unique market areas serviced by CHCs and to examine whether CHCs are effective in offsetting behavioral health ED visits.

Research Design:

We identified CHC-year specific service areas using patient origin zip codes. We then estimated random effects models applied to 42 federally qualified CHCs operating in New York State during 2013–2020. The dependent variables were numbers of ED mental health (substance use disorder) visits per capita in a CHC’s service area, drawn from HCUP State Emergency Department Databases. Key explanatory variables measured CHC number of mental health (substance use disorder) visits, number of unique mental health (substance use disorder) patients, and mental health (substance use disorder) intensity, obtained from the HRSA Uniform Data System.

Results:

Controlling for population, we observed small negative effects of CHC behavioral health integration in explaining ED behavioral health utilization. Measures of mental health utilization in CHCs were associated with 1.3%–9.3% fewer mental health emergency department visits per capita in Community Health Centers’ service areas. Measures of substance use disorder utilization in Community Health Centers were associated with 1.3%–3.0% fewer emergency department visits per capita.

Conclusion:

Results suggest that behavioral health integration in CHCs may reduce reliance on hospital EDs, but that policymakers explore more avenues for regional coordination strategies that align services between CHCs and local hospitals.
Highly Stable Beneficiary Attribution in Medicare’s Comprehensive Primary Care Plus Model
Authors: He Fang , Hirsch Ariella , Beadles Chris , Tang Yan , Hagerty Bridget , Irie Sarah
Published: June 2024

Background:

Advanced primary care models are key in moving primary care practices toward greater accountability for the quality and cost of a beneficiary’s care. One critical but often overlooked detail in model design is the beneficiary attribution methodology. Attribution results are key inputs in calculating practice payments. Stable attribution yields predictable practice payments, fostering longer-term investments in advanced primary care.

Objective:

We examine attribution stability for Medicare fee-for-service beneficiaries in Medicare’s Comprehensive Primary Care Plus (CPC+) Model.

Design:

To measure attribution stability, we calculate churn rates, which we define as the percentage of beneficiaries eligible for CPC+ who were not attributed to the same practice in a later period. Using 2017–2021 CPC+ program data and Medicare administrative data, we calculate churn rates for CPC+ overall and for beneficiary subgroups. To assess whether CPC+ attribution was responsive enough to changes in a beneficiary’s practice, we calculate how long before attribution changes following a beneficiary’s long-distance move.

Results:

We find that for every 100 beneficiaries attributed to a CPC+ practice, 88 were still attributed to the same practice a year later (ie, churn rate of 12%), 79 were attributed 2 years later, 74 three years later, and 70 four years later. However, some vulnerable subgroups, such as disabled beneficiaries, had higher churn rates. Our analysis of long-distance movers reveals that only after 5 quarters did attribution change for more than half of these movers.

Conclusions:

Overall, high attribution stability may have encouraged CPC+ practices to make longer-term investments in advanced primary care.
The Medical Costs of Determining Eligibility and Waiting for a Kidney Transplantation
Authors: Xu Kunyao , Dor Avi , Mohanty Suman , Han Jialin , Parvathinathan Gomathy , Braggs-Gresham Jennifer L. , Held Philip J. , Roberts John P. , Vaughan William , Tan Jane C. , Scandling John D. , Chertow Glenn M. , Busque Stephan , Cheng Xingxing S.
Published: June 2024

Background:

Recent efforts to increase access to kidney transplant (KTx) in the United States include increasing referrals to transplant programs, leading to more pretransplant services. Transplant programs reconcile the costs of these services through the Organ Acquisition Cost Center (OACC).

Objective:

The aim of this study was to determine the costs associated with pretransplant services by applying microeconomic methods to OACC costs reported by transplant hospitals.

Research Design, Subjects, and Measures:

For all US adult kidney transplant hospitals from 2013 through 2018 (n=193), we crosslinked the total OACC costs (at the hospital-fiscal year level) to proxy measures of volumes of pretransplant services. We used a multiple-output cost function, regressing total OACC costs against proxy measures for volumes of pretransplant services and adjusting for patient characteristics, to calculate the marginal cost of each pretransplant service.

Results:

Over 1015 adult hospital-years, median OACC costs attributable to the pretransplant services were $5 million. Marginal costs for the pretransplant services were: initial transplant evaluation, $9k per waitlist addition; waitlist management, $2k per patient-year on the waitlist; deceased donor offer management, $1k per offer; living donor evaluation, procurement and follow-up: $26k per living donor. Longer time on dialysis among patients added to the waitlist was associated with higher OACC costs at the transplant hospital.

Conclusions:

To achieve the policy goals of more access to KTx, sufficient funding is needed to support the increase in volume of pretransplant services. Future studies should assess the relative value of each service and explore ways to enhance efficiency.
ANGIOTENSIN II IN THE TREATMENT OF DISTRIBUTIVE SHOCK: A SYSTEMATIC-REVIEW AND META-ANALYSIS
Authors: Xourgia Eleni , Exadaktylos Aristomenis K. , Chalkias Athanasios , Ziaka Mairi
Published: June 2024

Objective: While nonnorepinephrine vasopressors are increasingly used as a rescue therapy in cases of norepinephrine-refractory shock, data on their efficacy are limited. This systematic review and meta-analysis aims to synthesize existing literature on the efficacy of angiotensin II (ATII) in distributive shock. Methods: We preregistered our meta-analysis with PROSPERO (CRD42023456136). We searched PubMed, Scopus, and gray literature for studies presenting outcomes on ATII use in distributive shock. The primary outcome of the meta-analysis was all-cause mortality. We used a random effects model to calculate pooled risk ratio (RR) and 95% confidence intervals (CIs). Results: By incorporating data from 1,555 patients included in 10 studies, we found that however, all-cause mortality was similar among patients receiving ATII and controls (RR = 1.02; 95% CI: 0.89 to 1.16, P = 0.81), the reduction in norepinephrine or norepinephrine-equivalent dose at 3 h after treatment initiation was greater among patients receiving ATII (MD = −0.06; 95% CI: −0.11 to −0.02, P = 0.008), while there were no higher rates of adverse events reported among ATII patients. Conclusions: While ATII did not reduce mortality among distributive shock patients, it allowed for significant adjunctive vasopressor reduction at 3 h without an increase in reported adverse events, deeming it a viable alternative for the increasingly adopted multimodal vasopressor for minimizing catecholamine exposure and its adverse events.
INFLAMMATORY RESPONSES TO POLYMICROBIAL INTRA-ABDOMINAL SEPSIS ARE HIGHLY VARIABLE BUT STRONGLY CORRELATED TO ENTEROBACTERIACEAE OUTGROWTH
Authors: Bongers Kale S. , Chanderraj Rishi , Deng Huiyin , Song Yujing , Newstead Michael W. , Metcalf Joseph D. , Falkowski Nicole R. , Puranik Niyati , Kurabayashi Katsuo , Dickson Robert P. , Singer Benjamin H.
Published: June 2024

Sepsis is a common, heterogeneous, and frequently lethal condition of organ dysfunction and immune dysregulation due to infection. The causes of its heterogeneity, including the contribution of the pathogen, remain unknown. Using cecal slurry, a widely used murine model of intraperitoneal polymicrobial sepsis, as well as 16S ribosomal RNA sequencing and measurement of immune markers, we performed a series of translational analyses to determine whether microbial variation in cecal slurry composition (representing intra-abdominal pathogens) mediated variation in septic response. We found wide variation in cecal slurry community composition that changed markedly over the 24-h course of infection. This variation in cecal slurry bacteria led to large variation in physiologic and inflammatory responses. Severity of inflammatory response was positively correlated with intraperitoneal enrichment with Enterobacteriaceae. Likewise, in a human cohort of patients with intra-abdominal abscesses, Enterobacteriaceae was also associated with increased inflammatory markers. Taken together, these data demonstrate that intra-abdominal Enterobacteriaceae drives inflammation in sepsis both in animal models and human subjects. More broadly, our results demonstrate that pathogen identity is a major driver of the host response in polymicrobial sepsis and should not be overlooked as a major source of phenotypic heterogeneity.
HYDROGEN-RICH SALINE UPREGULATES THE SIRT1/NF-ΚB SIGNALING PATHWAY AND REDUCES VASCULAR ENDOTHELIAL GLYCOCALYX SHEDDING IN SEPSIS-INDUCED ACUTE KIDNEY INJURY
Authors: Lin Liheng , Qiu Deliang , Yang Fei , Xia Yu , Cai Siyuan , Liao Xiaojun , Deng Wanxin , Wu Changxue
Published: June 2024

Sepsis causes dysfunction in different organs, but the pathophysiological mechanisms behind it are similar and mainly involve complex hemodynamic and cellular dysfunction. The importance of microcirculatory dysfunction in sepsis is becoming increasingly evident, in which endothelial dysfunction and glycocalyx degradation play a major role. This study aimed to investigate the effects of hydrogen-rich saline (HRS) on renal microcirculation in septic renal failure, and whether Sirt1 was involved in the renoprotective effects of HRS. Rats model of sepsis was established by cecal ligation and puncture, and septic rats were intraperitoneal injected with HRS (10 mL/kg). We found that in sepsis, the degree of glycocalyx shedding was directly proportional to the severity of sepsis. The seven-day survival rate of rats in the HRS+CLP group (70%) was higher than that of the CLP group (30%). HRS improved acidosis and renal function and reduced the release of inflammatory factors (TNF, IL-1β, and IL-6). The endothelial glycocalyx of capillaries in the HRS+CLP group (115 nm) was observed to be significantly thicker than that in the CLP group (44 nm) and EX527 (67.2 nm) groups by electron microscopy, and fewer glycocalyx metabolites (SDC-1, HS, HA, and MMP9) were found in the blood. Compared with the CLP group, HRS reduced renal apoptosis and upregulated Sirt1 expression, and inhibited the NF-κB/MMP9 signaling pathway. In addition, HRS did not damage immune function in septic rats as well. Generally speaking, our results suggest that HRS can alleviate the inflammatory response, inhibit glycocalyx shedding, improve septic kidney injury, and enhance survival rate.
NOVEL ACTIVE PROTEINS FOR SEPSIS PROGNOSIS REVEALED THROUGH ScRNA-seq AND QUANTITATIVE PROTEOMICS
Authors: Liu Hui , Xiong Wei , Zhong Wu , Hu Yingchun
Published: June 2024

Objective: To uncover critical active proteins influencing sepsis outcomes through multiomics analysis. Methods: This study collected peripheral blood from sepsis patients (NS = 26, SV = 27) and controls (Con = 16). Cellular heterogeneity was assessed using scRNA-seq. Cellular populations were identified through clustering and annotation. Gene set variation analysis was employed to detect pathway alterations in sepsis, while the Viper algorithm estimated protein activity at the single-cell level. Signaling networks were investigated via cell-cell communication analysis. Differentially expressed proteins were identified by DIA proteomics and confirmed through integrated analysis. Prognostic value was evaluated via meta and survival analyses. Results: scRNA-seq of 22,673 features within 34,228 cells identified five cellular clusters and 253 active proteins via Viper, validated by DIA (FC > 2, P < 0.05). Four proteins (SPI1, MEF2A, CBX3, UBTF) with prognostic significance were discovered and mapped onto the cellular landscape. Gene set variation analysis enrichment analysis revealed that the NS group exhibited significant alterations in pathways related to cellular apoptosis and inflammatory responses, while the SV group displayed increased activity in DNA repair and cellular survival pathways. Conclusion: The study’s findings advance the understanding of sepsis pathophysiology by linking differentially active proteins to patient prognosis, paving the way for targeted therapeutic strategies.
Alterations of tau and Camk2 in acute stroke and effects of a multicomponent drug
Authors: Wu Yue , Zhou Rui , Wang Menglan , Xu Jing , Zhang Yi , Wei Junying , Yang Hongjun
Published: June 2024

Background

Stroke is one of the leading causes of death around the world. The sequelae of ischemic stroke cause drastic effects on the quality of life for patients. Sanwujiaowan (SWJW) is a mixture prepared with 5 herbal medicines (Aconiti Lateralis Radix Praeparata, Aconiti Kusnezoffii Radix, Polygoni Multiflori Radix, Aconiti Radix, and Olibanum), with a long history of application in treating the sequelae of stroke.

Objectives

To provide evidence and decipher the mechanism of SWJW in alleviating stroke.

Materials and Methods

In this article, we expanded the indicators of SWJW by an integrated strategy based on signature metabolomics, target proteins, and bioinformatics and probed into the mechanism of SWJW intervention in ischemic stroke in a rat model.

Results

The results indicated that SWJW protected rats from nerve damage during the acute phase of ischemic stroke by regulating tau phosphorylation via the PI3K/Akt pathway.

Conclusions

This study, for the first time, proved that the reduction of phosphorylated tau was harmful for the neural function in the acute phase of ischemic stroke. Meanwhile, the pathological changes of phosphorylated tau proteins were detected in stroke and recalled by SWJW. This finding may provide a new reference for formulating treatment strategies for the acute phase of ischemic stroke.
Comprehensive analysis of Perilla frutescens (L.) Britt. along the value chain in northeast Inner Mongolia
Authors: Chen Yuan , Niu Hui , Fan Lingling , Wen Chunxiu , Wei Xinxin , Zhao Zeyuan , Surenjidiin Seesregdorj , Aruhan  , Li Minhui
Published: June 2024

Objective

To ensure the quality of Perilla frutescens (L.) Britt. and improve the associated benefits for stakeholders, this study analyzed the influences of different circulation channels and stakeholders on the quality, price, and other factors of P. frutescens with consideration to P. frutescens distribution.

Method

We interviewed the local stakeholders and e-commerce platforms in Oroqen Autonomous Banner and Morin Dawa Daur Autonomous Banner regarding the origin, circulation, distribution, and prices of different medicinal parts of P. frutescens. In addition, the maximum entropy model was used to predict the potential distribution of P. frutescens in the study area. According to the Chinese Pharmacopeia (2020 edition), we measured the content of index components in the collected Perillae Folium, Perillae Caulis, and Perillae Fructus samples and evaluated the quality of the samples by quantitative and cluster analyses. Remote sensing was employed to distinguish and calculate the P. frutescens area in highly suitable regions. The autoregressive integrated moving average model was adopted to analyze the Perillae Fructus price in the study area.

Result

The results showed 8 value chains for P. frutescens. The cooperation chain between farmers and enterprises in the study area could maximize the benefits for all stakeholders and guarantee the quality of the medicinal materials. The results of the regionalization analysis showed that the most suitable area for planting P. frutescens was the junction between Oroqen Autonomous Banner and Morin Dawa Daur Autonomous Banner. Chemical results showed that Perillae Fructus and Perillae Caulis samples were unqualified and mostly purchased from e-commerce platforms. We identified 5 land types, among which the cultivated land area was 3247.7501 km2. The price of Perillae Fructus in the study area showed a rising trend, although this trend slowed down.

Conclusion

This study involved various links in the production and circulation of medicinal materials from planting to consumption by consumers, which can help to facilitate the future research on any link. The findings help to guarantee the quality of medicinal materials and benefits of all stakeholders and promote the development of the P. frutescens industry in the study area.
Anti-acute gastric ulcer resistance of Aurantii Fructus Immaturus juice processing Atractylodis Macrocephalae Rhizoma by regulating PTGS2, MAPK1, and KDR targets based on metabolomics and integrated network pharmacology analysis
Authors: Xu Wanai , Wu Jingyu , Yang Danyang , Chen Yuxun , Wu Xiaoying , Wen Rou , Yan Liping , Li Chao , Yu Huan
Published: June 2024

Background

Currently, traditional methods of treating acute gastric ulcer (AGU) have many drawbacks, necessitating an alternative therapy with fewer adverse effects. Atractylodis Macrocephalae Rhizoma (BZ) is known for strengthening the spleen and harmonizing the stomach. BZ processed with Aurantii Fructus Immaturus juice (ZSZBZ), a classic decoction since the Han Dynasty, can enhance the efficacy of BZ. However, the key active components and targets of action of ZSZBZ remain undiscovered.

Aim of the study

This study aimed to investigate the bioactive chemical constituents of ZSZBZ against AGU and their possible mechanisms of action, elucidating the scientific content of ZSZBZ processing.

Materials and methods

Initially, we examined rat stomach histopathology and conducted ELISA for oxidative stress and inflammation. Subsequently, we investigated underlying mechanisms using metabolomics. Further analysis of potent components and key targets in ZSZBZ was conducted through liquid chromatography-mass spectrometry analysis combined with network pharmacology. Finally, key targets were analyzed by Western blot.

Results

ZSZBZ improved gastric histopathology, reversing high alcohol-induced oxidative stress (SOD, CAT) and inflammatory level (TNF-α, IL-6) disorders. This is associated with ZSZBZ’s regulation of amino acid metabolism, energy metabolism, and inflammatory response-related metabolic pathways, along with key targets PTGS2, MAPK1, and KDR. The significant increase in potency of ZSZBZ may be attributed to elevated levels of naringenin, hesperidin, hesperidin, and rhamnoceroside after concoction.

Conclusions

Combining metabolomics and network pharmacology, this study elucidated that ZSZBZ enhanced gastroprotection by modulating amino acid metabolism, antioxidant, and inflammation-related targets and pathways, providing insights into the bioactive compounds and potential mechanisms of herbal concoctions.